Usmle review
Danil
hammoudi.md
Sinoe
medical association
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Plasma
cells are the end-effector cells of the B-lymphocyte lineage that produce and
secrete antigen specific antibodies. |
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Plasma
cells originate from antigen specific B cells after a number of activation, proliferation,
and differentiation steps. |
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Malignant Plasma Cells |
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However,
when plasma cells become malignant due to a variety of causes multiple
myeloma is the result. To
the left is an immunohistochemistry stain of a bone marrow biopsy. The |
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The normal
plasma cell is a long-lived, mononuclear cell that does not divide. ·
Plasma cells develop from an earlier precursor,
the slowly proliferating plasmoblasts. ·
These cells migrate to the bone marrow from lymph
nodes after stimulation by antigen and helper T cells. ·
Plasma cells produce most of the IgG and IgA in the
serum, at a production rate of 1
ng per cell per day. ·
After several weeks to months, apotosis
(programmed cell death) of normal plasma cells occurs in the bone marrow. ·
In contrast to
normal plasma cells, myeloma cells have the appearance of immature plasmoblasts. ·
Myeloma cells do not differentiate completely
and are slow to proliferate. ·
Their failure to differentiate is believed
to be the result of chromosomal translocations, deregulation, or mutation of
particular cancer genes. ·
Although the
exact etiology of MM is unknown, current evidence supports a "two-hit"
hypothesis ·
The two-hit hypothesis suggests that, 1. first, a cancer-stimulating event causes a
subclinical monogammopathy; 2. then a second event leads to the development of MM. ·
Exposure to
these combined oncogenic events leads to the expression of the cancerous
potential within the plasma cell. ·
As a result,
myeloma cells show continuous growth and prolonged survival. ·
The survival
of these myeloma cells is further enhanced by the presence of interleukin-6. ·
Myeloma cells contain receptors for interleukin-6, and
when interleukin-6 binds to this receptor, it promotes tumor growth and
prolongs cellular survival. ·
The combination of growth and prolonged
survival lead to the clinical features of multiple myeloma |
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Plasma
cell proliferation may occur in several anatomical sites as witnessed by the
existence of multiple plasma cell-rich areas:
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Malignant Plasma
Cells |
When plasma cells become malignant,
the disease multiple myeloma is diagnosed, a neoplasm characterized by the accumulation
of monoclonal plasma cells which show 3 features:
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The
normal cell counts are listed here demonstrating normal blood cell
composition. However,
with multiple myeloma, all these blood cell counts become significantly
reduced, leading to anemia, neutropenia, and thrombocytopenia. |
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multiple myeloma
1.
bone pain,
2.
hypercalcemia,
3.
and spinal
cord compression.
1.
hyperviscosity,
2.
amyloidosis,
3.
and renal failure
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most common primary malignant neoplasm
of bone
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50-70y; M:F 2:1
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symptoms: vague bone pain of
progressive severity, fever, anemic sxs
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complications: pathologic fractures
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solitary plasmacytoma: solitary osseous
focus of MM (uncommon)
x-ray findings:
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loss of bone density - from diffuse
marrow involvement
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"punched out" lesions - esp.
skull, long bones
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diffuse bone destruction - esp. pelvis, sacrum
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invasion of soft tissues - often
paraspinal, extrapleural mass
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osteosclerosis - very rare
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metastatic calcifications -
particularly kidneys, occ. lungs
NB: does not involve pedicles of
spine
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The malignant cell of myeloma is believed to originate at a stage of B
lymphocyte ontogeny in a cell more primitive than the end stage mature plasma
cells which make up the bulk of the tumour. ·
Unique immunoglobulin gene
rearrangements can be demonstrated in the malignant plasma cells of most
individuals and these rearrangements are stable throughout the course of the
disease. ·
Immunoglobulin gene
rearrangement studies demonstrate that the process of somatic hypermutation
has already occurred in the malignant clone, thus indicating that the cell of
origin is at the stage of pre-plasma cell or memory B cell in lymphocyte
differentiation. ·
Such mutations in the
immunoglobulin gene, by uniquely identifying the gene sequences of the
idiotype, have allowed the development of sensitive assays for minimal
residual disease based on the highly specific sequences of the complementary
determining regions (CDRs) of the immunoglobulin gene as well as the
development of in situ hybridisation staining of individual malignant cells
to determine more accurately blood contamination and tissue distribution. ·
Although previously thought to have been infrequent, recent studies
have demonstrated the existence of chromosomal abnormalities in almost all
patients with myeloma ·
Abnormalities frequently involve
the immunoglobulin heavy chain gene locus on the long arm of chromosome 14, often with translocations to a number
of different non-immunoglobulin genes containing partner chromosomes. ·
The site of translocation on
chromosome 14 is different, however, from the sites of translocations seen in
other B cell malignancies. ·
In myeloma, the translocation
involves the immunoglobulin switch regions which regulate heavy chain class
switching to either the alpha, gamma, or epsilon chains. ·
The non-immunoglobulin partners include chromosomes such as 11q, 4q,
6p and 16q, and newly identified oncogenes have been shown to be present at
some of these breakpoints. ·
Such genes include cyclin D, fibroblastic
growth factor, and interferon regulatory factor IV. ·
Interestingly, these
cytogenetic changes are also present in patients with monoclonal gammopathy
of uncertain significance (MGUS), suggesting that they are fundamental to the
disease process but that additional events are required to develop fully the
malignant phenotype. ·
Another frequent and
significant chromosome abnormality is the
loss of chromosome 13, which has proven to be a significantly adverse
prognostic indicator in patients with myeloma. ·
Various other genetic abnormalities have been observed in patients
with myeloma. ·
These include
ras mutations, retinoblastoma gene loss, p53 mutations and cyclin D inhibitor
abnormalities. ·
Such abnormalities are more often observed in patients with advanced
disease and thus may be a reflection of increasing genetic instability as the
malignancy progresses ·
The Role of Human Herpes Virus 8 (HHV8) Infected Stroma in Myeloma ·
Studies on the bone marrow stromal cells of myeloma patients have
identified a key role for these cells which secrete cytokines crucial to the
growth of the malignant clone, as well as an involvement in a variety of
mechanisms which lead to the prevention of apoptosis in malignant plasma
cells. ·
For instance, Interleukin 6 (IL-6) produced by bone marrow stromal
cells has been demonstrated both to enhance growth and prevent apoptosis of
malignant plasma cells. ·
HHV8 is a newly identified herpes virus which was first described in
cases of HIV associated Kaposi's sarcoma. ·
It has also been identified in two
other B cell disorders, primary effusion lymphoma and multi-centric
Castleman's disease. ·
In these cases the virus is
localised to the malignant cells. ·
By contrast, some groups have
recently documented HHV8 sequences in the genome of the stroma cells of
patients with myeloma but not in the stromal cells of other lymphoid
malignancies. ·
HHV8 has been reported in both bone marrow biopsies and peripheral
blood, and although different sequences have been determined among different
patients, the same sequence has always been found in one particular patient
at different sites. ·
These and other workers on HHV8 have found, for instance, a viral
homologue for the IL-6 gene, thus raising the possibility that virally
infected stromal cells could potentiate the malignancy ·
By contrast, European and other US-based studies have not always
identified the virus, raising the question of whether this agent is truly
aetiological or, perhaps, a reflection of HHV incidence in various population
groups. · Thus any possible role for this virus in the development of myeloma at this stage remains unclear and any potential studies to assess the possible utility of antiviral therapies have not yet been initiated. |
· The presenting symptom of multiple myeloma is usually pain. The patient may have a normocytic, normochromic anemia secondary to marrow failure and an increased ESR.
·
Hypercalcemia may
cause confusion, weakness and lethargy. Other symptoms may include cachexia,
spinal cord compression and renal insufficiency.
· Bacterial infections are common because of a lack of normal immunoglobulin production.
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Monoclonal immunoglobulin is found on serum
electrophoresis. Light chain subunits of immunoglobulin are called BenceJones
proteins and are present in urine.
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The radiological
appearance of multiple myeloma is characterized by irregular lytic defects of
different sizes. These lytic areas are often described as "punched
out" and have no periosteal reaction.
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Erosion begins intramedullarly and
progresses through the cortex.
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MRI is useful for delineating spinal lesions.
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Bone scan can fail to have increased uptake in
25% of patients suggesting a plain film skeletal survey should always be done.l
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On gross
examination, the marrow space has been replaced by a diffuse gelatinous red
brown tissue. Tumor nodules of approximately 1 cm in size may be present.
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Microscopically, multiple
myeloma is composed of sheets of plasma cells. The degree of cytologic atypia
of these cells has no prognostic value.
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The osteolytic lesions are caused by increased
osteoclastic resorption that is stimulated by cytokines released by-the plasma
cells.
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Treatment of
multiple myeloma consists of palliative chemotherapy or bone marrow transplant.
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Only patients
with complete remission of their disease experience any bony healing.
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Bisphosphonates
are used to inhibit resorption of bone and subsequent hypercalcemia.
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Untreated, a
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The cause of death is usually infection or a
hemorrhage.
· A hallmark of the diagnosis of MM is the demonstration of monoclonal kappa or lambda light chain on serum or urine electrophoresis.
· An elevated IgG component is the most frequent abnormality found (53%), followed by elevated IgA (25%) and elevated IgD (1%).
· About 20% of those with MM also have an M-spike on electrophoresis due to the monoclonal light chains (Bence Jones protein).
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Urine protein electrophoresis is the most
efficient test to detect these monoclonal light chains (Bence Jones
proteinuria).
· Less than 1% of MM patients present with no monoclonal proteins detected, thus resulting in what is termed the "nonsecretory" form of the disease.
· In these cases, immunofluorescent staining of plasma cells is necessary to identify the monoclonal light chains.
· Definitive diagnosis is made by bone marrow aspiration/biopsy confirming plasma cell proliferation.
· A plasma cell content of 15 to 20% is necessary for definitive diagnosis (normal is less than 5%).
· In addition to the nonsecretory form of MM, some patients have a monoclonal gammopathy of undetermined significance.
· These patients have elevated serum monoclonal IgG or IgA without evidence of MM.
· Monoclonal gammopathy is relatively common, occurring in about 0.15% of the general population.
· Long-term follow-up of these patients is critical given that overt MM can develop in 16% of these patients.
· Continued surveillance using radiography and protein electrophoresis is necessary.
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Risk Factors
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Age:Perhaps the most significant risk factor for multiple myeloma is age, the median age at diagnosis being 72 years. |
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Multiple myeloma is rare in people under 40, with a progressive increase in incidence with age. To the right is a logged graph that shows the dramatic increase in incidence from age 40 to >80. |
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In a study detecting MGUS with M-protein serum levels, the incidence increases 20-fold when comparing patients aged 30-49 and patients aged 70-89. |
Race:
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Genetics:
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A large study was done on white & black males to determine whether there was an association of human leukocyte antigens of class I and Class II with the disease:
A study was done using 43 families to determine the genetic association among those with either MGUS or multiple myeloma:
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Smoking:Studies have shown that the risk of developing myeloma is 3-fold greater in subjects who have ever smoked than in those who had never smoked. |
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Occupation:Studies have also shown a positive association between the following specific occupations/industries and myeloma:
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No Longer Considered Risk Factors:
Radiation Exposure:Although studies done on Hiroshima/Nagasaki radiation exposure survivors between 1950 and 1976 showed a positive association with multiple myeloma, reanalysis of the data using updated methods (Dosimetry System) shows no such association with the disease nor frequency of a monoclonal gammopathy. |
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Socioeconomic Status:A case-control study at Duke failed to demonstrate any association of myeloma with family income, education, occupation, dwelling size or an index of crowding in the home. |
Symptoms
The symptoms of multiple myeloma most commonly include one or more of the
following:
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bone pain and skeletal fractures,
including compression fractures of the spine, which can cause severe pain and
neurologic symptoms
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infections,
especially bacterial infections of the respiratory and urinary tracts
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generalized symptoms
including fatigue, weight loss, and general malaise, which can relate to anemia
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hypercalcemia,
which can cause nausea, vomiting, altered mental states, depression, headache,
and in severe cases, coma
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loss of kidney function,
which can cause fatigue, a buildup of fluid in the lower limbs, and excessive
thirst
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hyperviscosity
(a thickening of the blood caused by excessive protein) can cause bruising,
rash, nosebleeds, vision loss, headache, dizziness, and peripheral neuropathy
(numbness, tingling, burning pain in the extremities)
In
about one third of patients, multiple myeloma is detected before symptoms
appear, through routine blood tests that pick up elevated levels of
immunoglobulin proteins
The symptoms of MM vary from person
to person, and will depend on the extent and stage of the disease. The symptoms
are caused by the malignant plasma cells and the myeloma paraproteins they
produce.
Symptoms involve three major body
systems; the skeletal system, the renal system and the bone marrow.
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The
Skeletal System
The most common symptom associated
with MM is bone pain.
Bone pain is experienced by
approximately 70% of myeloma sufferers.
Pain is frequently felt in the
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lower
back,
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ribs
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spine,
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and is caused by myeloma cells eroding the bones causing them to fracture
easily.
On x-ray imaging, the areas of myeloma
activity can be seen as "punched out" lesions on the bone surface
Bone erosion may lead to hyper-calcemia
(high blood calcium levels). People suffering from hyper-calcemia may
experience symptoms of confusion, nausea, tiredness, constipation, thirst, increased urine
output, and dehydration.
·
The
Renal System
Kidney problems occur in
approximately 50% of patients with MM at some stage of their illness.
Kidney function may be affected for
a number of reasons.
Firstly, the myeloma proteins circulating in
the blood can be deposited in the kidneys and cause obstruction and
inflammation.
(Those abnormal proteins
excreted in the urine is called Bence-Jones protein.)
Secondly, calcium from the eroded
bones may be deposited in the kidneys causing obstruction and inflammation.
Kidney failure can result if these
causes of kidney function are left untreated, especially if dehydration should
develop.
Other aggravating factors may
include urinary tract infection and high blood urate level that MM patients are also
prone to develop.
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The
Bone Marrow
Plasma cells are predominantly found
within the bone marrow, which is the location of blood cell production. When
the plasma cell becomes malignant it gradually takes over of the bone marrow,
preventing it from producing normal blood cells. As such, myeloma sufferers may
experience
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anemia,
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thrombocytopenia
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leukopenia.
Another complication of multiple
myeloma is hyper-viscosity.
This condition occurs in
approximately 5% of individuals with myeloma.
It refers to the presence of high
concentrations of myeloma paraprotein in
the blood.
These paraproteins increase the ‘viscosity’ or
thickness of the blood, potentially impairing blood circulation.
The viscous blood flow may provoke a heart attack or stroke.
Similarly impeded circulation to small blood
vessels in the eyes may cause visual disturbances or blindness.
Restricted blood circulation to the vessels of
organs or limbs may lead to pain and tissue necrosis.
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1. bone pain, 2. pathologic fractures, 3. weakness, anemia, 4. infection (often resulting from pneumococcal infection), 5. hypercalcemia, 6. spinal cord compression, 7. or renal failure. Physicians
increasingly are identifying asymptomatic patients through routine blood
screening. Typically, a large gap between the total
protein and the albumin observed on an automated chemistry panel suggests a
problem (ie, protein minus albumin equals globulin).
Physical:
Causes:
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HOW IS MYELOMA DIAGNOSED
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The initial
approach to the patient is to establish the diagnosis by:
1. Detection of
an M-protein in the serum or urine.
2. Detection of
more than 10% plasma cells on a bone marrow examination.
3. Detection of
lytic bone lesions or generalized osteoporosis in skeletal x-rays.
4. Presence of
soft tissue plasmacytomas.
Other important tests which help to evaluate patients include:
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b2 microglobulin
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C-reactive
protein
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blood count
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calcium level
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kidney function
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type of abnormal myeloma protein [bence
jones protein type]
Bence
Jones protein: a portion of the abnormal myeloma
protein referred to as the "light chains
monoclonal (M) protein:
the protein made by myeloma cells
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A
critical diagnostic criteria, however, is the characteristic abnormal plasma
cell pathology. It is no longer adequate to assume that the demonstration of
lytic bone lesions plus a paraprotein is sufficient for the diagnosis.
Morphological confirmation can usually be easily sought from bone marrow
aspiration or from fine needle aspiration of a skeletal lesion or plasmacytoma.
The main differential diagnoses are
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MGUS,
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smouldering myeloma,
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systemic amyloidosis,
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lymphoma
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metastatic carcinoma.
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Newer
radiological investigations, such as magnetic resonance imaging (MRI) of the
spine, have proven to be extremely useful, especially for the accurate
demonstration of neurological complications.
·
In
the future, whole body MRI may become the radiological investigation of choice
for all myeloma patients.
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An application of particular importance may be
the accurate separation of solitary plasmacytoma from disseminated multiple
myeloma.
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Several
additional investigations are of importance in predicting the prognosis and
guiding treatment decisions in individual patients.
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These
include
1.
the bone marrow plasma
cell labelling index (PCLI)
2.
and blood levels of
beta-2-microglobulin ("ß2M),
3.
C-reactive protein,
4.
thymidine kinase
5.
lactic acid dehydrogenase.
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Of these, the ß2M and PCLI
are the most powerful predictive assays.
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The
differentiation of smouldering myeloma from active (treatment-requiring)
myeloma is not always easy.
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The decision to instigate specific therapy, as
opposed to observation, is based on a number of criteria.
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Of the laboratory investigations, the PCLI is
particularly useful.
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Using dual colour fluorescent
techniques, this assay measures the percentage of plasma cells (bearing the
light chain of the malignant clone) in S phase of the cell cycle (detected by
propidium iodine or bromodeoxyuridine).
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Recent
adaptation to the flow cytometer has dramatically reduced the
labour-intensiveness of this test and thus widened its application.
· A strongly elevated labelling index suggests that the patient has active disease, while a low labelling index is a sine qua non of smouldering myeloma or MGUS.
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ß2M
largely reflects renal function and is in itself an important prognostic
indicator for myeloma.
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In combination with the PCLI, it provides the
most accurate prognostic information, not only in patients who are treated with
conventional chemotherapy, but also in patients who are submitted to high dose
therapy and transplantation protocols.
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For
instance, a patient under 60 years of age, who presents with a low ß2M and a
low labelling index, has a median survival of over six years when treated with
conventional chemotherapy alone.
· The application of information from prognostic marker studies is obviously of great relevance when considering the use of high dose therapy protocols and especially allogeneic transplantation.
Following this a number of tests
will be ordered.
Chest X-rays are likely to be taken
if a chest infection is suspected.
Blood, phlegm, urine and stool
cultures may also be collected to identify the site of infection, especially if
fever is present. ECG (electrocardiograph) and GBPS (gated blood pool scan) may
be required to assess your heart function.
The diagnosis of multiple myeloma
requires examination of the bone marrow.
This procedure is called a bone
marrow biopsy, and is performed under intravenous sedation and local
anaesthesia. Examination of the bone marrow will show an excessive numbers of
plasma cells with an associated reduction in the normal cells.
A bone
marrow biopsy is an outpatient procedure performed under local
anaesthesia and sedation. Using a special disposable needle and syringe, the
doctor will withdraw a small amount of marrow blood from the hip bone (or
uncommonly the breast bone), along with a tiny core of bone marrow tissue.
The procedure takes around twenty
minutes to complete and involves minimal discomfort.
It is only after these tests are
performed that an accurate diagnosis can be made.
The most appropriate therapy can
then be recommended taking into account the findings of these test results,
current symptoms, age and health history.
The
following diseases can be associated with secretion of a monoclonal protein
(M-Component) in the blood:
·
monoclonal gammopathy of undetermined
significance (MGUS)
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multiple myeloma
·
Waldenstrom's macroglobulinemia
·
malignant lymphoma or primary systemic
amyloidosis
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MGUS |
Smoldering Multiple
Myeloma |
Overt
Multiple Myeloma |
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Fibroblasts
and macrophages in bone marrow stroma release interleukin-6 (IL-6) IL-6
has the following characteristics: ·
helps normal plasma cells grow ·
excess production of IL-6
by dendritic cells is an important factor in developent of plasma cell tumors
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clinical studies have revealed
that excess IL-6 productive may result from infection with Kaposi's
sarcoma-associated herpes virus |
Macrophage |
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Chromosomal
abnormalities: Chromosomal
studies involving over 1400 patients have been done since 1959, with 1/3 of MM
patients having clonal chromosomal abnormalities. 500
cases were reported including 166 with extensively presented karyotypes. |
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Aneuploidy
is a common finding with multiple myeloma: ·
hyperdiploidy mostly involves
chromosomes 3,5,7,9,11,19, and 21 ·
hypodiploidy commonly affects
chromosomes 13,8, and x ·
A common specific abnormality
among patients is the t(11;14)(q114;q32)
translocation involving the bci-1 oncogene. Deletion
of chromosome 13 is not uncommon and carries a poor prognosis. |
Imaging Studies:
Procedures:
Histologic Findings: In patients with myeloma, plasma
cells proliferate within the bone marrow, typically in sheets. Plasma cells
are 2-3 times larger than typical lymphocytes; they have eccentric nuclei
that are smooth (round or oval) in contour with clumped chromatin and have a
perinuclear halo or pale zone. The cytoplasm is basophilic. Many descriptions
of myeloma cells describe characteristic, but not diagnostic, cytoplasmic
inclusions, which include Mott cells, Russell bodies, grape cells, and morula
cells. Bone marrow examination reveals plasma cell infiltration, often in
sheets or clumps. This infiltration is different from the lymphoplasmacytic
infiltration observed in patients with Waldenström macroglobulinemia. Staging: Staging is a cumulative evaluation
of all of the diagnostic information garnered and is a useful tool for
stratifying the severity of patients' disease. The staging system for myeloma
is somewhat complex, but it is well correlated with outcome.
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·
Plasma cells are a subset of B cells, which
are the producers of humoral immunity factors termed antibodies. Antibody
molecules are composed of two polypeptide chains: a light chain and a heavy
chain. ·
Cleavage results in the production of
Fab and Fc fragments; the Fab fragment is termed the Bence-Jones protein and
is found in the urine of patients with myeloma. ·
An individual plasma cell can produce
antibody molecules of only a single immunoglobulin to combine with a single
antigen. ·
As such, a plasma cell is termed
monoclonal. ·
Most infections produce a polyclonal
response, since multiple antigens are present on a single bacillus or virus
and activate multiple plasma cells. ·
Electrophoresis during infections
demonstrates an increase in multiple types of proteins as a result of the
multiple humoral and cellular products produced to combat the invading
organism. ·
However, if malignant transformation
occurs in a single plasma cell, its clones produce only a single type of
immunoglobulin, and electrophoresis demonstrates a monoclonal peak
corresponding to this particular immunoglobulin. ·
Infection,
as well as collagen vascular disorders, rheumatoid arthritis, and ulcerative
colitis, also can produce diffuse hypergammaglobulinemia. ·
Waldenström
macroglobulinemia, leukemia, lymphoma, and myeloma produce monoclonal peaks. ·
If a monoclonal protein elevation is
discovered in a patient and additional tests often do not reveal an
underlying etiology, the condition is termed monoclonal gammopathy of
undetermined significance. ·
Most of these patients do not progress
to multiple myeloma but must be followed up regularly to evaluate for an
increase in monoclonal protein levels or the development of lytic bone
lesions. ·
The cause of multiple myeloma is
unknown. ·
Current theories involve chronic
antigenic stimulation of a plasma cell, which results in transformation and
the development of myeloma. ·
However, once a plasma cell is
transformed, it is known to produce innumerable clones, which spread
hematogenously to other myelogenous areas. ·
Once there, these neoplastic cells form
sheets that replace the normal bone marrow. ·
In addition, the myeloma cells produce osteoclast-stimulating factor, a
cytokine that results in bone destruction. ·
The plasma cell activating factor
interleukin 6 is found within bone marrow, resulting in plasma cell
proliferation. ·
The osteoblastic response in myeloma
tends to be suppressed, resulting in the severe demineralization and bone
destruction characteristic of the disease. ·
Secondary hypercalcemia is present |
Durie and Salmon proposed the initial clinical
staging system for multiple myeloma in 1975. Measured myeloma cell mass was
correlated with 5 clinical features as follows:
Using these 5 features, a 3-stage system was
proposed that divided patients into low, intermediate, and high myeloma cell
burden.
Amyloid deposition due to the light chains is a
frequent complication of multiple myeloma.
•The lytic lesion is believed to be due to activation of osteoclasts by
cytokines liberated by the plasma cells. These cytokines include IL-1 and
TGF-beta.
•IL6 may be produced primarily by stromal cells, activated by the plasma
cells.
•IL6 levels are used to measure progress of the tumor.,
In constructing this staging system,
researchers found that stage I patients had a median survival of 191 months,
stage II patients survived from 11-54 months, and stage III patients survived
from 5-34 months.
In the
Race: No racial predilection exists.
•Note the "punched out" circular, hemorrhagic lesions (some
indicated by arrows).
•These are the tumor deposits in the bones of the skull.
•Some of the typical, mature adipocytes of bone marrow are seen in this
field.
•Most of the other cells in this image however, resemble each other.
•A typical cell can be seen at the tip of the black pointer.
•It is a large cell, with a nucleus that is placed at one end of the
cell.
•The cytoplasm is abundant and stains blue (ie. basophilic).
•A paler relatively understained area is seen near the nucleus.
•These features typify a plasma cell.
•Careful examination of this field reveals that most of the cells in
this field resemble that cell.
•Malignant myeloma is a tumor of plasma cells that arises usually in the
bone marrow.
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Bone marrow aspiration and biopsy reveals increased numbers of plasma cells (classically >30%, but may be only 10-30%), often forming clusters or sheets of cells replacing normal marrow elements. This results in anemia, leukopenia, and thrombocytopenia.
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The plasma cells seen in the marrow can be mature - with classic PC features or immature - with prominent nucleoli. Binucleate and multinucleate PCs can be seen. Masses of immunoglobulin may form intracytoplasmic globules or Russell bodies.
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Myeloma cells may also contain crystalline inclusions of immunoglobulin (below left). Cells containing multiple immunoglobulin globules are known as Mott cells (below right).
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The excessive production of an abnormal immunoglobulin is the second major characteristic of myeloma. The
abnormal Ig is most often IgG (50%) and sometimes IgA (25%), but rarely
(<1%) IgM,IgD, or IgE. Production of excess light chain is frequent and is excreted in the urine as Bence Jones proteins. About 20-25% of cases produce only light chains which are often detectable only in the urine. Fewer than 5% of myelomas are nonsecretory. I mmunoglobulin filled cytoplasm may invaginate into the nucleus creating the appearance of an intranuclearinclusion (a Dutcher body).
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Excess Ig in the peripheral blood may result in Rouleaux formation in which immunoglobulin coated RBCs cling together (resembling overlapping pennies). The ESR may be increased secondary to
hyperviscosity. Hyperviscosity is most common with IgM, but can be seen with polymerization of IgA and IgG3. M-proteins can interfere with clotting factors and fibrin polymerization, and can block aggregation by coating platelets. |
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In approximately 75% of patients excess immunoglobulin light chain precipitates in renal tubules forming dense tubular casts and leads to tubular cell atrophy and destruction in a condition known as "myeloma kidney". Although we think of Ig as being in plasma, remember that the majority of Ig is extravascular.
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In about10% of myeloma patients a waxy substance known as amyloid is deposited in vessel walls and extravascular tissues secondary to excess light chain (usually l) production. Amyloid stains lightly eosinophilic with H&E, red-orange with Congo Red, and is birefringent when polarized.
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The EM appearance of amyloid is that of a mass of nonbranching linear fibrils of indeterminant length, 7-10 nm dia. Accumulation of amyloid primarily in glomeruli, but also in vessels and interstium is a major cause of renal failure and death. Heart failure is 2' to amyloid deposition in the conduction system. GI tract infiltration can cause macroglossia, hemorrhage, malabsorption, diarrhea, and obstruction. Vascular damage results in amyloid purpura of the face (eyelids & periorbital tissue), neck and chest. Soft tissue accumulation may lead to the carpal tunnel syndrome. |
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The major
diagnostic criteria for myeloma (any two are needed for the diagnosis) include: - bone marrow plasmacytosis of > 30% of all marrow cells or
masses of infiltrating plasma cells - extraosseous plasmacytoma - monoclonal gammopathy ( IgG > 35 g/L and IgA > 20 g/L ) - urinary light chain excretion of > 1g / 24 hours Minor criteria (one or more of which
together with one major criteria are needed for the diagnosis) include - marrow plasmacytosis of < 30% - lytic bone lesions - evidence of a monoclonal protein but lessor amounts than above - hypoglobulinemia of normal proteins |
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The prognosis for myeloma is highly variable, but left untreated, most patients survive only 6-18 months. Survival correlates with the extent of disease at diagnosis.
Median survival is approximately 6.5 years for stage I myeloma; 5 years for stage II myeloma, and 2 years for stage III myeloma. |
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b2 macroglobulin is another prognostic factor that is predictive of prognosis: levels greater than 6mg corresponding to stage II or III disease. The
presence of amyloid, an IgA M-protein, or CD10 + myeloma cells are poor
prognositic factors. During the early stages of myeloma, especially in asymptomatic patients, the doubling time is long and growth slow, thus initially one may forego treatment. Classic myeloma requires treatment for pain, hypercalcemia, renal failure or anemia. Although no curative therapy exists, a number of theraputic modalities are available. While surgery and radiotherapy play a role in treatment of spinal cord compression and pathologic fractures, chemotherapy is the primary basis of therapy. Standard chemotherapy is remains prednisone and L-phenylalanine mustard (Alkeran) or melphalan. Supportive therapy for dealing with hypercalcemia, infection, and hyperviscosity is essential to good patient care. Death is most often secondary to infection or renal failure. |
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·
Multiple myeloma is a diffuse disease of
the bone marrow. Almost 90% of patients with myeloma have osseous
involvement. Although any bone can be affected, 4 distinct radiographic
patterns of involvement are seen, including (1) normal bone mineralization
without a discrete lytic lesion, (2) diffuse demineralization and no lytic
lesion, (3) a single lesion (plasmacytoma), and (4) widespread lytic lesions.
·
The predominant sites of involvement are
within the axial skeleton and include the vertebral column, ribs, skull,
pelvis, and femora. Most patients have either a number of lytic foci or
diffuse demineralization at diagnosis. Fewer than 10% of patients with
multiple myeloma are diagnosed with only a plasmacytoma found on radiography.
Interestingly, extraosseous myeloma deposits occasionally are found, most
commonly in the lungs, nasopharynx, or paranasal sinuses. ·
Clinical Details: The underlying pathology
of multiple myeloma is expansion of a single line of plasma cells that
replace normal bone marrow and produce monoclonal immunoglobulins. As a
result, in more than 80% of patients, the disease manifests with bone
destruction and pain. Since bone loss occurs mostly in the axial skeleton,
patients with myeloma are at risk for compression fractures of the spine and
pathologic fractures of the major weight-bearing bones of the body. ·
The classic presentation is low back
pain in an older man, with resultant discovery of demineralization or a
myelomatous deposit. The classic presentation has dropped to a frequency of
37% from a high of almost 70% in the 1960s, which may be related to increased
surveillance for other diseases and the incidental discovery of myeloma or
may be a result of increased awareness of the nonclassic manifestations of
the disease. ·
Patients with myeloma develop disorders
relating to replacement of myelogenous marrow by plasma cells. In particular,
anemia is a primary manifestation of the disease (>90% of patients).
Patients also may develop frequent unexplained infections resulting from an
inability to mount an immune response by normal plasma cells (decreased in
number by the favored production of malignant myeloma cells). Generalized
weakness resulting from anemia is a frequent finding, as are the neurologic
symptoms believed to be related to disruption in calcium homeostasis. More
than 40% of patients with myeloma develop weight loss related to their
disease. Finally, as many as 13% of myeloma patients have bleeding disorders,
mostly related to low platelet production. ·
The diagnostic laboratory finding in
myeloma is monoclonal hypergammaglobulinemia. IgG myeloma is the most common,
followed by IgA myeloma. As a result of bone destruction, hypercalcemia is a
common manifestation and can be difficult to manage. Other laboratory
abnormalities include hyperuricemia (resulting from elevated cell turnover),
elevated sedimentation rate, and increased levels of alkaline phosphatase. ·
Renal disorders are a common
manifestation of multiple myeloma. Myeloma cells produce large numbers of
proteins. Fragmentation of some of these immunoglobulins produces a special
protein (ie, Bence-Jones protein) that was elucidated in the original
description of the disease. This protein, as well as others produced by the
malignant plasma cells, may be deposited in the kidney tubules. The
proteinemia in myeloma often exceeds the resorptive ability of the kidney,
resulting in proteinuria, and in particular, spillage of Bence-Jones protein.
In addition, amyloidosis is a frequent finding (8-15%) in patients with
myeloma and further contributes to parenchymal dysfunction. Calculi often are
found because of elevated uric acid and calcium levels. All of these factors
eventually can result in renal failure and death. The unequivocal diagnosis of myeloma is made when the following 3
criteria are satisfied:
Note that as many as 37% of cases currently are discovered in
asymptomatic patients. Most commonly, examination of the blood for an
unrelated reason reveals an elevated protein level and leads to the eventual
diagnosis of myeloma. These patients may not always meet all 3 diagnostic
criteria. Other laboratory studies have been proposed to provide an
unequivocal diagnosis of myeloma, including the use of special stains and the
detection of nuclear abnormalities. Beta-2 microglobulin has been shown to be
the peripheral marker most associated with activity and progression of
disease. Preferred Examination: The preferred initial radiographic examination for both the
staging and diagnosis of myeloma remains the skeletal survey. Patients
suspected of having multiple myeloma based on bone marrow aspirate or
hypergammaglobulinemia should undergo a radiographic skeletal survey.
Conventionally, the survey has consisted of a lateral radiograph of the
skull, anteroposterior and lateral views of the spine, and anteroposterior
views of the pelvis, ribs, femora, and humeri. Inclusion of these bones is
important for both staging and diagnosis. The finding of more than one lytic lesion in a patient with
myeloma indicates stage III disease. Focused examinations of newly painful
bones are of value in assessing for impending pathologic fracture. Limitations of
Techniques: The skeletal survey has limitations.
Most importantly, a large number of patients diagnosed with asymptomatic
myeloma may have radiographically occult myeloma deposits. At least 30%
cortical bone loss is required to visualize a destructive process, such as
myeloma, with radiographs. In addition, myeloma is a disease of older
patients. Myeloma can present with diffuse demineralization, which may be
indistinguishable from the pattern found in patients with osteoporosis. MRI has been suggested as an additional imaging examination in
patients with myeloma. MRI has the advantage of rapidity and sensitivity for
the presence of disease; however, specificity is limited. Recent papers have
suggested that an MRI examination of the spine may be of value in staging patients
with myeloma, since radiographically occult lesions may be found that can
change therapeutic intervention |
Diseases associated with an M-protein included in this presentation are:
1. Asymptomatic plasma cell neoplasia with minimal evidence of disease aside from the presence of an M-protein (monoclonal gammopathy of undetermined significance, or MGUS).1
2. Symptomatic plasma cell neoplasia
a. primarily
affecting bones
i. multiple
myeloma (94%)
ii. solitary
plasmacytoma (3%)
b.
extramedullary plasmacytoma (3%)
These usually occur in the nasopharynx,
tonsils, or paranasal
sinuses.2
3. Macroglobulinemia. Patients often have lymphadenopathy and
hepatosplenomegaly; less than 5% have lytic bone lesions.
a. asymptomatic
b. symptomatic
Monoclonal (M) "spikes" usually occur in either the b or g regions.
An individual plasma cell produces only one type of light chain, either k or l light chain, but never both.
In plasma cell disorders a clone of cells produces a single light chain type, either k or l .
In plasma cell disorders a clone of cells produces a single light chain type, either k or l . If the clone is large enough, sufficient immunoglobulin is produced to be visible as a "spike" on gel electrophoresis, identifying a monoclonal population of cells.
Nearly all malignant cell populations are monoclonal, where as nearly all reactive populations are polyclonal.
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In a reactive state, antigen is presented to multiple lymphocytes each of which will make a slightly different antibody. Some lymphocytes/plasma cells will make k light chains and some will make l light chains. Even among all the l producing cells, most individual cells each make a slightly different antibody, producing increased amounts of heterogeneous immunoglobulins, or a (polyclonal gammopathy). |
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The key favorable prognosticators for the
durations of complete remission, event-free survival, and overall survival:
Autologous transplantation is
considered feasible and safe in patients > 65 years.
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Systemic Therapy Options in Myeloma |
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Idiotypic myeloma cells can be found in the blood of myeloma patients in
all stages of the disease.1,2
For this reason, when treatment is indicated, systemic chemotherapy must be
considered for all patients with symptomatic plasma cell neoplasms. Patients
with monoclonal gammopathy of undetermined significance (MGUS) or
asymptomatic, smoldering myeloma do not require immediate treatment, but must
be followed carefully for signs of disease progression. Patients with an M-protein in the serum and/or urine are evaluated as follows: 1. Measure and follow the serum M-protein by serum electrophoresis. The M-protein can also be followed by specific nephelometry immunoglobulin assays, however, these assays always overestimate the M-protein because normal immunoglobulins are included in the result. For this reason, baseline and follow-up measurements of the M-protein should be done by the same method.3 2. Measure and follow the amount of M-protein light chains excreted in the urine per 24 hours. First, measure the total amount of protein excreted per 24 hours and multiply this value by the percentage of urine protein that is M-protein, as determined by electrophoresis of concentrated urine protein. 3. Identify the heavy- and light-chain of the M-protein by immunofixation. 4. Measure the hemoglobin, leukocyte, platelet, and differential counts. 5. Determine the percentage of marrow plasma cells. More than one site may need to be sampled because marrow plasma cell distribution tends to be spotty. 6. Take needle aspirates of a solitary lytic bone lesion, extramedullary tumor(s), or enlarged lymph node(s) to determine whether these are plasmacytomas. 7. Evaluate renal function with serum creatinine and a creatinine clearance. Electrophoresis of concentrated urine protein is very helpful in differentiating glomerular lesions from tubular lesions. Glomerular lesions, such as those resulting from glomerular deposits of amyloid or light chain deposition disease, result in the non-selective leakage of all serum proteins into the urine; the electrophoresis pattern of this urine resembles the serum pattern. In most myeloma patients the glomeruli function normally, allowing only the small molecular weight proteins, such as albumin and light chains, to filter into the urine. In the tubules the concentration of protein increases as water is reabsorbed. This leads to precipitation of proteins and the formation of tubular casts, which may injure the tubular cells. With tubular lesions, the typical electrophoresis pattern shows a small albumin peak and a larger light chain peak in the globulin region; this tubular pattern is the usual pattern found in myeloma patients. 8. Measure serum levels of calcium, alkaline phosphatase, lactic dehydrogenase, and, when indicated by clinical symptoms, cryoglobulins and serum viscosity. 9. Obtain radiographs of the skull, ribs, vertebrae, pelvis, shoulder girdle, and long bones. 10. Perform magnetic resonance imaging (MRI) if a paraspinal mass is detected, or if symptoms suggest spinal cord or nerve root compression. 11. If amyloidosis is suspected, do a needle aspiration of subcutaneous abdominal fat and stain the bone marrow biopsy for amyloid as the easiest and safest way to confirm the diagnosis.4 12. Measure serum albumin and beta-2 microglobulin as useful, independent prognostic factors.5,6 13. The marrow plasma cell labeling index, the serum soluble IL-6 receptor, and the number of circulating myeloma cells are under evaluation as prognostic factors.7 These initial studies should be compared with subsequent values at a later time, when it is necessary to decide whether the disease is stable or progressive, responding to treatment or getting worse. The major challenge is to separate the stable asymptomatic group of patients, who do not require treatment, from patients with progressive, symptomatic myeloma who should be treated immediately. Patients with MGUS have an M-protein in the serum and/or urine and fewer than 10% plasma cells in the marrow, but no other signs or symptoms of disease. Those with smoldering myeloma have similar characteristics, but may have more than 10% marrow plasma cells. Since 1% of MGUS patients will progress per year to develop myeloma (most commonly), amyloidosis, a lymphoma, or chronic lymphocytic leukemia, these patients must be followed carefully.8 Treatment is delayed until the disease progresses to the stage that symptoms or signs appear. Patients with MGUS or smoldering myeloma do not respond more frequently, achieve longer remissions or improved survival if chemotherapy is started early, while they are still asymptomatic, as opposed to waiting for progression before treatment is initiated.9 Treatment options for patients with symptomatic myeloma range from relatively simple conventional chemotherapy to high-dose chemotherapy and peripheral stem cell or allogeneic bone marrow transplantation. Treatment choice is determined largely by the age and general health of the patient and should be finely attuned to the preferences of patients and their families. |
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Conventional chemotherapy treatment options
Chemotherapy prolongs the survival of patients with symptomatic myeloma
to a median of 40 to 46 months for patients with stage I disease, 35 to 40
months for patients with stage II disease, and 24 to 30 months for patients
with stage III disease. A well-tolerated chemotherapy regimen producing consistent results is melphalan
and prednisone (MP Other regimens appear to produce similar survival outcomes. They are: 1. VAD: vincristine + doxorubicin + dexamethasone 2. High-dose dexamethasone 3. Cyclophosphamide + prednisone 4. VBMCP (the M2 protocol): vincristine + carmustine + melphalan + cyclophosphamide + prednisone 5. VMCP/VBAP: vincristine + melphalan + cyclophosphamide + prednisone alternating with vincristine + carmustine + doxorubicin + prednisone ·
A randomized,
double-blind study of patients with stage III myeloma showed that monthly
intravenous pamidronate significantly reduces pathologic fractures, bone
pain, spinal cord compression, and the need for bone irradiation (there were
38% skeletal-related events in the treated group versus 51% in the placebo
group after 21 months of therapy, p=.015).[Level of evidence: 1iDii] In
addition, survival was increased (median survival was 21 months versus 14 months)
in the patients receiving pamidronate and second line or greater
chemotherapy. ·
There is no
strong evidence that any alkylating agent is superior to another. All
standard doses and schedules produce equivalent results. However, the
absorption and metabolism of some alkylating agents require special
attention. Melphalan is absorbed erratically from the gastrointestinal tract,
and food interferes with this absorption. For this reason, melphalan should
be administered on an empty stomach, e.g., 1 hour before breakfast. (Food
does not interfere with the absorption of prednisone, which is often given
with breakfast.) The clearance of melphalan from the blood stream is delayed
in patients with renal failure, leading to increased toxic effects; the
initial dose of melphalan should be reduced in patients with a serum
creatinine greater than 2.0 milligrams per deciliter. Cumulative
hematologic toxic effects tends to develop with repeated courses of
melphalan. If slow hematologic recovery prevents repeating a course of
melphalan at 6 to 7 week intervals, consideration should be given to
switching to cyclophosphamide, which allows more rapid marrow recovery. ·
Because
melphalan is absorbed so erratically, the dose should be increased until mild
hematologic toxic effects, or a response, is observed. In patients with
normal renal function, the usual starting dose is 0.25 milligrams per
kilogram per day for 4 days, repeated at 4 to 6 weeks. If no hematologic
toxic effects or response is observed, the dose should be increased by 2 to 4
milligrams per day for 4 days, and blood counts should be repeated weekly.
The dose of melphalan is increased in subsequent courses until mild
leukopenia or thrombocytopenia is observed, with recovery in 4 to 6 weeks. ·
Cyclophosphamide,
in contrast to melphalan, is absorbed well, and clearance from the blood
stream does not influence its toxic effects. Also, the dose of
cyclophosphamide does not have to be reduced in patients with renal
insufficiency. Cyclophosphamide is less toxic to thrombopoiesis than
melphalan, and may be preferred in the treatment of thrombocytopenic
patients. ·
Combinations
of alkylating agents and prednisone, given simultaneously or alternately,
have not proven to be superior to therapy with MP. [Level of evidence: 1iiA]
A meta-analysis of studies comparing melphalan plus prednisone with drug
combinations concluded that both forms of treatment were equally effective.[Level of evidence: 1iiA] Patients who relapsed after
initial therapy with cyclophosphamide and prednisone had no difference in
overall survival (median 17 months) when randomized to VBMCP or VAD. ·
Myeloma
patients who respond to treatment show a progressive fall in the M-protein
until a plateau is reached; subsequent treatment with conventional doses does
not result in any further improvement. This has led investigators to question
how long treatment should be continued. Three clinical trials considered the
role of maintenance therapy; all found no improvement in survival. In a
single study,27
it was observed that maintenance therapy with MP prolonged the initial
remission duration (31 months) compared to no maintenance treatment (23
months). There was no effect on overall survival, however, because the
majority of patients who relapsed in the no maintenance arm responded again
to MP, while those on maintenance MP did not respond to further treatment.
Most therapists recommend continuing induction therapy for at least 12
months. The Canadian group suggests that induction chemotherapy be continued
as long as the M-protein continues to fall; therapy can be discontinued after
the M-protein reaches a plateau that remains stable for 4 months. ·
Maintenance
interferon alfa therapy has been reported in several studies to prolong
initial remission duration. While the impact of interferon maintenance on
disease-free and overall survival has significantly varied among trials, a
meta-analysis of 1543 patients treated on 12 trials randomizing between
interferon maintenance and observation indicated that interferon maintenance
was associated with improved relapse-free survival (27% versus 19% at 3
years, p<0.00001) and overall survival (12% odds reduction, p=0.04).32
In this population, toxic effects may be substantial and must be balanced
against the potential benefits in response duration. ·
Lytic lesions
of the spine should be irradiated if they are associated with an
extramedullary (paraspinal) plasmacytoma, if there is painful destruction of
a vertebral body, or if there is computed tomography or MRI evidence of
spinal cord compression. ·
Back pain
caused by osteoporosis and small compression fractures of the vertebrae
responds best to chemotherapy. Extensive radiation of the spine or long bones
for diffuse osteoporosis may lead to prolonged suppression of hemopoiesis,
and is rarely indicated. · Bisphosphonates are useful for slowing or reversing the osteopenia that is so common in myeloma patients. |
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High-dose chemotherapy options for symptomatic myeloma
The failure of conventional chemotherapy to cure the disease has
led investigators to test the effectiveness of much higher doses of drugs
such as melphalan. The development of techniques for harvesting hemopoietic
stem cells, from marrow aspirates or the peripheral blood of the patient, and
infusing these cells to promote hemopoietic recovery, made it possible for
investigators to test very large doses of melphalan. From the experience with
thousands of patients treated in this way, it is possible to draw a few
conclusions: 1. The risk of early death due to treatment-related toxic effects have been reduced to less than 5%.35
Patients can now be treated as outpatients. 2. High-dose therapy should be reserved for myeloma patients who are still responsive to chemotherapy. Patients with refractory myeloma rarely achieve a complete response to high-dose treatment, and responses are usually brief.36 3. Extensive prior chemotherapy, especially with alkylating agents, compromises marrow hemapoieses and may make the harvesting of adequate numbers of hemopoietic stem cells impossible. 4. After autologous bone marrow transplantation, 84 patients were randomized to receive maintenance interferon or no treatment. [Level of evidence: 1iiA] The interferon group had longer progression-free survival (46 months versus 27 months, p<0.025) and overall survival (75% versus 50%, p<0.01). These results have not been confirmed after peripheral stem cell transplantation. 5. Newly diagnosed patients with progressive disease should be considered candidates for clinical trials of new approaches to treatment. 6. Younger patients in good health tolerate high-dose therapy better than patients with poor performance status.35 The Intergroupe Francais du Myelome randomized 200 previously untreated myeloma patients under 65 years of age to treatment with conventional chemotherapy (alternating courses of VMCP/VBAP) versus high-dose therapy (140 milligrams melphalan per meter squared and total body irradiation, 8 Gy delivered in 4 fractions over 4 days with no lung shielding, followed by autologous bone marrow rescue). Survival and disease-free survival were significantly improved in the high-dose arm (the estimated 5-year survival was 52% versus 12%; the estimated 5-year event-free survival was 28% versus 10%). [Level of evidence: 1iiA] Relapses, however, continue to occur at a constant rate, so that at 5 years, only 28% of those receiving high-dose therapy, and 10% of those on conventional chemotherapy have not relapsed. Event-free survival is significantly better for the high-dose group (p=0.01), but there is no sign of a slowing in the relapse rate, or a plateau, to suggest that any of these patients have been cured. While these data suggest that myeloablative therapy with autologous transplant may prolong survival for patients with multiple myeloma, the finding requires confirmation by the current ongoing intergroup study comparing standard therapy to high-dose options.38 In a prospective randomized trial, 193 patients with multiple myeloma received autologous peripheral stem cell transplantation after high-dose chemotherapy with or without CD34 selection. Although CD34 selection reduced myeloma cell contamination in the stem cell collections, there was no difference in disease-free or overall survival. [Level of evidence: 1iiA] Improvement in survival following high-dose therapy with autologous stem cell support was also suggested by a Scandinavian study in which all symptomatic newly diagnosed patients with multiple myeloma were registered.41 Patients received induction therapy with VAD, followed by stem cell collection following cyclophosphamide and granulocyte-colony stimulating factor (G-CSF). High-dose therapy consisted of melphalan, 200 milligrams per meter squared, with stem cell and G-CSF support. Patients subsequently received maintenance interferon. The outcome of these patients was compared to that of historic controls who met eligibility criteria for the high-dose therapy trial. Survival appeared superior for the intensively-treated group (risk ratio for the control group 1.62, confidence interval 1.22-2.15, p=0.001). The use of historic controls and lack of complete data on pretreatment beta-2-microglobulin levels may have biased the results in favor of the intensive therapy cohort. [Level of evidence: 3iiiA] Another approach to high-dose therapy has been the use of 2 sequential
episodes of high-dose therapy with stem cell support (so-called
"tandem" transplants). In a retrospective analysis of 1000 patients
treated at the In a registry of 162 patients who underwent allogeneic matched
sibling-donor transplants, the actuarial overall survival rate was 28% at 7
years. [Level of evidence: 3iiiA] Favorable prognostic features included low
tumor burden, responsive disease before transplant, and application of
transplantation after first-line therapy. Many patients are not young enough
or healthy enough to undergo these intensive approaches. A definite
graft-versus-myeloma effect has been demonstrated, including regression of myeloma
relapses following the infusion of donor lymphocytes. Allogeneic marrow transplants are too risky to be considered by most patients, but the possibility of a potent, and possibly curative graft-versus-myeloma reaction makes this procedure attractive. Further research is required to make allogeneic transplants less dangerous, and also, perhaps, to find methods for initiating an autoimmune response to the myeloma cells. |
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· Lymphoplasmacytic lymphoma is usually associated with a monoclonal serum paraprotein of immunoglobulin M type (Waldenstrom's macroglobulinemia).
· Most patients have bone marrow, lymph node, and splenic involvement, and some patients may develop hyperviscosity syndrome. Other lymphomas may also be associated with serum paraproteins.
· The management of lymphoplasmacytic lymphoma is similar to that of other low-grade lymphomas, especially diffuse small lymphocytic lymphoma/chronic lymphocytic leukemia
· If the viscosity relative to water is greater than 4, the patient may have manifestations of hyperviscosity. Plasmapheresis is useful for temporary, acute symptoms (such as retinopathy, congestive heart failure, and central nervous system dysfunction), but should be combined with chemotherapy for prolonged control of the disease.
· Symptomatic patients with a serum viscosity of 4 or less are usually started directly on chemotherapy.
· Therapy may be required to correct hemolytic anemia in patients with chronic cold agglutinin disease; chlorambucil, with or without prednisone, is the mainstay.
· Occasionally, a heated room is required for patients whose cold agglutinins become activated by even minor chilling.
· Asymptomatic patients can be monitored for evidence of disease progression without immediate need for chemotherapy.
· The nucleoside analogues 2-chlorodeoxyadenosine and fludarabine have shown significant activity for previously untreated patients with lymphoplasmacytic lymphoma.
· Single-agent alkylators and combination chemotherapy are also active regimens
· Interferon alfa also shows activity in this disease, in contrast to poor responses in patients with multiple myeloma.
· Myeloablative therapy with autologous hematopoietic stem cell support is under evaluation.
· Rituximab, the anti-CD20 monoclonal antibody, is active in 30% of previously treated patients.
Patients with monoclonal gammopathy of undetermined significance (MGUS) have an M-protein in the serum without symptoms or findings of multiple myeloma, macroglobulinemia, amyloidosis, or lymphoma and with fewer than 10% plasma cells in the bone marrow.1,2 Multiple myeloma, other plasma cell dyscrasia, or lymphoma will develop in 5% of patients by 5 years, 15% by 10 years, and 30% by 15 years. Unfortunately, patients who will eventually develop plasma cell malignancy or lymphoma cannot be identified on the basis of level of M-protein, peripheral blood count, type of monoclonal immunoglobulin, percentage of plasma cells in the bone marrow, or levels of normal immunoglobulins. Therefore, all patients with MGUS must be kept under observation to detect increases in M-protein levels and development of one of the above malignancies.
· There are two main types of refractory myeloma patients: primary refractory patients who never achieve a response and progress while still on induction chemotherapy; and secondary refractory patients who do respond to induction chemotherapy, but do not respond to treatment after relapse.
· The primary group may respond to high-dose chemotherapy and autologous stem cell rescue.
· Of the patients who do not achieve a response to induction chemotherapy, a subgroup of about 10% have stable disease and enjoy a survival prognosis that is as good as that for responding patients.
· When the stable nature of the disease becomes established, these patients can discontinue therapy until the myeloma begins to progress again. Others with primary refractory myeloma and progressive disease require a change in therapy; the choices have been reviewed.
· A preliminary report on thalidomide suggests anti-tumor activity with minimal hematologic toxic effects.6 Further clinical trials are underway.
· For patients who respond to their initial therapy, the myeloma growth rate, as measured by the M-protein doubling time, increases progressively with each subsequent relapse and remission durations become shorter and shorter. Marrow function becomes increasingly compromised as patients develop pancytopenia and enter a refractory phase; occasionally the myeloma cells dedifferentiate and extramedullary plasmacytomas develop. The myeloma cells may still be sensitive to chemotherapy, but the regrowth rate during relapse is so rapid that progressive improvement is not observed. At this stage of the disease, high-dose glucocorticoids may be the best approach.7,8 High-dose chemotherapy with growth factor support is being evaluated in these refractory situations.9 Less myelosuppressive regimens can also be used as second- or third-line therapy
Immunosecretory Disorders: Other PCD
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"Nonsecretory" myeloma in which immunoglobulin is not synthesized (true nonsecretory) or secreted but not excreted, is rare (<5%). Cases have been reported in which there is production of J chain but no heavy or light chain. Clinical, hematologic, and radiologic findings are similar to those of standard myeloma. Some have reported fewer problems with infection and less renal damage (no increase in circulating monoclonal immunoglobulin) but survival appears no better than the average myeloma patient.
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Immunosecretory Disorders: MGUS |
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Plasma cell leukemia (plasma cells >2.0x109/L) can be either a primary or a terminal finding in myeloma. Treatment is with aggressive chemotherapy.
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· Monoclonal gammopathy of unknown significance (MGUS) is an asymptomatic disorder in which a monoclonal immunoglobulin is secreted by a fairly stable clone of plasma cells. MGUS is sometimes referred to as dysproteinemia without associated disease. The incidence of MGUS increases with age (1% at age 50 years; 5% at age 70 years; 10% at age 80 years). Approximately 10% of patients with MGUS will develop myeloma within 5 years. Almost 20% will develop a malignant PCD (myeloma, WM, amyloidosis, and ML) within 10 years. · The M protein of MGUS is < 30 g/L, usually IgG, but occassionally IgA or IgM, and without a Bence-Jones protein. · Bone marrow biopsy and aspirate show a mild increase in plasma cells, but no mass lesion. |
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Immunosecretory Disorders: Waldenstrom's
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· Waldenstrom's macroglobulinemia (WM) or primary macroglobulinemia (7% of monoclonal gammopathies) is a malignant proliferation of plasmacytoid lymphocytes corresponding to activated B lymphocytes. · The lymphocytes, plasmacytoid lymphocytes, and plasma cells diffusely infiltrate the bone marrow, lymph nodes, spleen, and liver (but not forming tumor masses, nor lytic lesions as does myeloma). WM is associated with ML, small lymphocytic type. "Flame" cells and Dutcher bodies are more likely to be encountered in WM than in other plasma cell disorders. Mast cells, · while accompaning many lymphoproliferative disorders are especially numerous and characteristic of Waldenstrom's. · The malignant cells secrete a monoclonal IgM protein which causes a macroglobulinemia. The large size of the IgM complexes or paraproteins · increases blood viscosity. Hyperviscosity results in neurologic, visual, and bleeding complications. Cryoglobulins can be seen in WM giving rise to Raynaud's phenomemon. · Waldenstrom's is a slowly progressive disorder, with survival of 2-5 years and longer, that most commonly presents in the sixth and seventh decades. Vague symptoms of weakness, weight loss and a mild bleeding tendency, often many years before diagnosis, are usually the first evidence of disease. Later lymphadenopathy and hepatosplenomegaly become prominent. In general, the clinical course is similar to that of chronic lymphocytic leukemia. · Although not curable, chemotherapy (alkalating agents ie. melphahan) can stay the disease. Plasmapheresis is also useful to quickly remove IgM from the plasma, lowering viscosity and improving blood flow. |
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Immunosecretory Disorders: Cryoglobulins
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· Cryoglobulinemia results from abnormal proteins that precipitate at reduced temperatures. It is associated with PCDs and chronic inflammation. Cryoglobulins can be 1) monoclonal immunoglobulins (Type I) as in myeloma or Waldenstrom's, 2) monoclonal proteins (usually IgM k) complexed to IgG (Type II), or 3) polyclonal immune complexes with no monoclonal component (Type III). Types II and III are associated with connective tissue and autoimmune disorders. Through the formation of protein gels at reduced body temperatures, precipitated cryoglobulins can occlude small vessels giving rise to Raynaud's phenomemon, vascular purpura (cold urticaria) and arthralgia. · Therapy is based on the treatment of the underlying disease and/or plasmapheresis and, of course, avoidance of cold. · Note that cold agglutinins which are RBC antibodies are different from cyroglobulins. |
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Immunosecretory Disorders: Heavy Chain Disease
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· Heavy chain disease (HCD) is a group of very rare PCDs producing excessive amounts of a monoclonal heavy chain, but no light chain. Monoclonal production of each of the major immunoglobulin heavy chain classes results in a different clinical presentation. · Alpha chain disease, also known as Mediterranean lymphoma is the most common of the HCDs. It is most often seen in young adults from the Mediterranean area. The lamina propria of the intestinal mucosa and abdominal lymph nodes are infiltrated by lymphocytes, plasmacytoid lymphocytes, and plasma cells producing a chain proteins. The lymphoid infiltrate of the lamina propria of the intestinal mucosa results in villous atrophy, malabsorption, steatorrhea, diarrhea, and hypocalcemia. An abdominal mass of lymphoid tissue is often present. Serum a chains must be demonstrated for the diagnosis. · Presenting symptoms are most often abdominal pain, diarrhea, and malabsorption. In time a HCD may progress to a large cell B - immunoblastic lymphoma. Survival is variable from a few months to several years. · Gamma chain disease (g HCD) most commonly presents as lymphadenopathy, hepatosplenomegaly, anemia and fever. Although reported as most common in elderly patients g HCD can occur in patients < 20 years of age. No lytic bone lesions are present but plasmacytoid lymphocytes, plasma cells, eosinophils and histiocytes diffusely infiltrate the marrow and lymph nodes. · As many as one third of g HCD patients have an associated autoimmune disease including AIHA, Sjogren's syndrome, rheumatoid arthritis, SLE, thyroiditis, etc. · As with a HCD, survival in g HCD varies greatly from months to years. Death is most often secondary to infection. · Mu chain disease (m HCD) is the least common form of HCD. It is often associated with chronic lymphocytic leukemia (CLL) or with a disease similar to CLL in which there are large numbers of circulating lymphocytes. Marrow plasma cells are characteristically vacuolated. Hepatosplenomegaly is common as a presenting symptom, but without accompaning lymphadenopathy. Excess m chains are present in the peripheral blood and k light chains sometimes found in the urine. · Chemotherapy is similar to that used for CLL. · Chronic lymphocytic leukemia is occassionally (<10% of CLL) accompanied by a monoclonal protein (<2% of monoclonal gammopathies). |
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Immunosecretory Disorders: Amyloidosis
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Amyloidosis is a syndrome in which proteins with a b pleated sheet secondary structure accumulate in tissues. Amyloid stains lightly eosinophilic with H&E, metachromatic with crystal violet. The b pleated sheet structure causes a green birefringence when Congo red stained material is polarized. Amyloid fibrils containing a part of the variable region of the light chain are labeled AL. Amyloid fibrils containing amyloid A, a protein derived from an acute phase reactant are called protein AA.
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Primary amyloidosis ( Amyloid infiltrates cause organ damage resulting in failure as in the nephrotic renal syndrome. Heart failure can be seen secondary to amyloid deposition in the cardiac conduction system. GI tract infiltration can cause macroglossia, hemorrhage, malabsorption, diarrhea, and obstruction. Vascular damage results in amyloid purpura of the face (eyelids & periorbital tissue), neck and chest. Soft tissue accumulation may lead to the carpal tunnel syndrome and to shoulder "pads" virtually diagnostic of amyloidosis. Classifications of Amyloidosis
Amyloidosis Related to Monoclonal Ig Light Chains. AL
amyloid is derived from monoclonal Ig light chains, usually of lambda type,
produced by abnormal clones of Ig-secreting plasma cells (B cells) AL type of
amyloidosis may be primary or may occur secondary to multiple myeloma or some
other monoclonal gammopathy (immunocyte dyscrasia). It is the most common
type of amyloidosis seen in the The Noteworthy, the majority of patients who develop Amyloidosis Associated with Inflammatory or Infectious
Diseases. The amyloid deposits in this form of amyloidosis have a systemic
distribution and contain AA (amyloid-associated) fibrils which are related to
the nonimmunoglobulin AA protein and its serum protein precursor (SAA), an
acute phase reactant synthesized by hepatic cells. Also called reactive or
secondary amyloidosis, this form of amyloidosis occurs mainly as a
complication of long standing inflammatory diseases, most frequently
rheumatoid arthritis (Å 5-10% of rheumatoid patients) and also
dermatomyositis, scleroderma, regional enteritis, and ulcerative colitis. Prior to the antibiotic era, chronic tissue-destructive
infectious diseases, such as tuberculosis, chronic osteomyelitis, and
bronchiectasis, were the most common antecedants of secondary amyloidosis.
Now, amyloidosis often develops as a complication of skin and lung abscesses
occurring in subcutaneous heroin abusers. Reactive-type amyloidosis may also occur in association
with cancer, such as Hodgkin's disease and renal cell carcinoma. Other Amyloids and Disease Associations.
Endocrine-related. Localized
amyloid deposits are associated with hormones produced by certain endocrine
tumors and endocrine glands, such as medullary carcinoma of the thyroid gland
(procalcitonin), islet cell tumors of the pancreas, and the islets of
Langerhans (islet associated polypeptide, IAPP) in patients with type II
diabetes mellitus. Age-related. Amyloid deposits of
transthyretin occur in the heart of elderly patients with senile cardiac
amyloidosis. Beta amyloid protein is deposited in the cerebral blood vessels
and plaques of patients with senile cerebral amyloidosis and Alzheimer's
disease. Formation and deposition of AL and AA amyloid. |
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Immunosecretory Disorders: Summary
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In summary, plasma cell disorders are malignant proliferations of B lymphocyte origin. Although the terminally differentiated cell is the cell we observe, immunologic and molecular genetic studies indicate that the disorders arise in genetic events at an early stage in B cell development. The infiltrating cells are lymphocytes, plasmacytoid lymphocytes, and plasma cells producing monoclonal immunoglobulin proteins. The effects of both the mass of cells and the excess immunoglobulin protein determine the nature of the individual diseases. Thus the disease course can range from an asymptomatic disease to a rapidly progressive fatal illnesses. Despite advances in chemotherapy the plasma cell disorders remain incurable. Immunoglobulins
(Ig) are antibodies. There are five major classes of antibodies: IgG, IgM,
IgA, IgD, and IgE. • IgG is the most abundant of the
classes of immunoglobulins. It is the antibody for viruses, bacteria, and
antitoxins. It is found in most tissues and plasma. • IgM is the first antibody present in
an immune response. • IgA is an early antibody for bacteria
and viruses. It is found in saliva, tears, and all other mucous secreations. • IgD activity is unknown. • IgE is present in the respiratory
secretions. It is an antibody for parasitic diseases, Hodgkin's disease , hay fever, atopic dermatitis , and allergic
asthma ). All
antibodies are made by B-lymphocytes (B-cells). Any disease that harms the
development or function of B-cells will cause a decrease in the amount of
antibodies produced. Since antibodies are essential in fighting infectious
diseases, people with immunoglobulin deficiency syndromes become ill more
often. However, the cellular immune system is still functional, so these
patients are more prone to infection caused by organisms usually controlled
by antibodies. Most of these invading germs (microbes) make capsules, a
mechanism used to confuse the immune system. In a healthy body, antibodies
can bind to the capsule and overcome the bacteria's defenses. The bacteria
that make capsules include the streptococci, meningococci, and Haemophilus
influenzae. These organisms cause such diseases as otitis, sinusitis , pneumonia , meningitis , osteomyelitis , septic arthritis, and sepsis
. Patients with
immunoglobulin deficiencies are also prone to some viral infections,
including echovirus, enterovirus, and hepatitis B . They may also have a bad reaction
to the attenuated version of the polio virus vaccine. There are
two types of immunodeficiency diseases: primary and secondary. Secondary
disorders occur in normally healthy bodies that are suffering from an
underlying disease. Once the disease is treated, the immunodeficiency is
reversed. Immunoglobulin deficiency syndromes are primary immunodeficiency
diseases, occurring because of defective B-cells or antibodies. They account
for 50% of all primary immunodeficiencies, and they are, therefore, the most
prevalent type of immunodeficiency disorders. • X-linked agammaglobulinemia is an
inherited disease. The defect is on the X chromosome and, consequently, this
disease is seen more frequently in males than females. The defect results in
a failure of B-cells to mature. Mature B-cells are capable of making
antibodies and developing "memory," a feature in which the B-cell
will rapidly recognize and respond to an infectious agent the next time it is
encountered. All classes of antibodies are decreased in agammaglobulinemia. • Selective IgA deficiency is an inherited
disease, resulting from a failure of B-cells to switch from making IgM, the
early antibody, to IgA. Although the B-cell numbers are normal, and the
B-cells are otherwise normal (they can still make all other classes of
antibodies), the amount of IgA produced is limited. This results in more
infections of mucosal surfaces, such as the nose, throat, lungs, and
intestine. • Transient hypogammaglobulinemia of infancy
is a temporary disease of unknown cause. It is believed to be caused by a
defect in the development of T-helper cells (cells that recognize foreign
antigens and activate T- and B-cells in an immune response). As the child
ages, the number and condition of T-helper cells improves and this situation
corrects itself. Hypogammaglobulinemia is characterized by low levels of
gammaglobulin (antibodies) in the blood. During the disease period, patients
have decreased levels of IgG and IgA antibodies. In lab tests, the antibodies
that are present do not react well with infectious bacteria. • Common variable immunodeficiency is a
defect in both B cells and T-lymphocytes. It results in a near complete lack
of antibodies in the blood. • Ig heavy chain deletions is a
genetic disease in which part of the antibody molecule isn't produced. It
results in the loss of several antibody classes and subclasses including most
IgG antibodies and all IgA and IgE antibodies. The disease occurs because
part of the gene for the heavy chain has been lost. • Selective IgG subclass deficiencies is a
group of genetic diseases in which some of the subclasses of IgG are not
made. There are four subclasses in the IgG class of antibodies. As the B-cell
matures, it can switch from one subclass to another. In these diseases there
is a defect in the maturation of the B-cells that results in a lack of
switching. • IgG deficiency with hyper-IgM is a
disease that results when the B-cell fails to switch from making IgM to IgG.
This produces an increase in the amount of IgM antibodies present and a
decrease in the amount of IgGaantibodies. This disease is the result of a
genetic mutation. Immunoglobulin
deficiencies are the result of congenital defects affecting the development
and function of B lymphocytes (B-cells). There are two main points in the
development of B-cells when defects can occur. First, B-cells can fail to
develop into antibody-producing cells. X-linked agammablobulinemia is an
example of this disease. Secondly, B-cells can fail to make a particular type
of antibody or fail to switch classes during maturation. Initially, when
B-cells start making antibodies for the first time, they make IgM. As they
mature and develop memory, they switch to one of the other four classes of
antibodies. Failures in switching or failure to make a subclass of antibody
leads to immunoglobulin deficiency diseases. Another mechanism which results
in decreased antibody production is a defect in T-helper cells. Generally,
defects in T-helper cells are listed as severe combined immunodeficiencies. Symptoms
are persistent and frequent infections, diarrhea , failure to thrive , and malabsorption (of
nutrients). An
immunodeficiency disease is suspected when children become ill frequently,
especially from the same organisms. The profile of organisms that cause
infection in patients with immunoglobulin deficiency syndrome is unique and
is preliminary evidence for this disease. Laboratory tests are performed to
verify the diagnosis. Antibodies can be found in the blood. Blood is
collected and analyzed for the content and types of antibodies present.
Depending on the type of immunoglobulin deficiency the laboratory tests will
show a decrease or absence of antibodies or specific antibody subclasses.
Immunodeficiency
diseases can not be cured. Patients are treated with antibiotics and immune serum. Immune serum is
a source of antibodies. Antibiotics are useful for fighting bacteria
infections. There are some drugs that are effective against fungi, but very
few drugs that are effective against viral diseases. Bone marrow transplantation can, in most cases, completely correct the immunodefiency.
Patients
with immunoglobulin defiency syndromes must practice impecable health
maintenance and care, paying particular attention to optimal dental care, in
order to stay in good health. • Antibody Another term for immunoglobulin. A protein molecule that
specifically recognizes and attaches to infectious agents. • T-helper cell A type of cell that recognizes foreign antigens and
activates T- and B-cells in an immune response. Some questions: |
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The arrow points to: A. Albumin B. a 1 globulin C. a 2 globulin D.b globulin E. monoclonal
protein
A : |
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A 78-year-old black man, a retired chemistry professor, comes to you because of lumbosacral vertebral pain. There is no hepatomegaly. Cardiac exam is normal and there is no evidence of arthritis. His Hct, MCV, WBC and differential are normal. Liver enzymes are normal, but total serum protein is mildly elevated. The serum Ca is normal. You find no protein in his urine. A marrow aspirate&biopsy showed 6% plasma cells (normal=0-5%). A roetgenographic survey was negative. His serum protein electrophoresis is shown at right. What is the most likely diagnosis based on the history and laboratory findings? A. Waldenstrom's macroglobulinemia B. Amyloidosis C. Myeloma D. Monoclonal Gammopathy of Unknown Significance E. Heavy Chain Disease
Right , this is a monoclonal gammopathy of unknown significance
(MGUS) in which there is no underlying cause, despite marrow plasmacytosis
and an M protein. MGUS is seen in 5% of people >70yrs of age.
Approximately 10% of MGUS patients develop myeloma within 5 years and almost
20% will develop a malignant PCD (myeloma,WM,
amyloidosis, and ML) within 10 years. Bone
marrow biopsy and aspirate show a mild increase in plasma cells, but no mass
lesion as would be seen in myeloma. The lack of significant lymphadenopathy,
organomegaly, and renal disease argues against myeloma, Waldenstroms, heavy
chain disease, and amyloidosis. Other studies might include
immunoelectrophoresis and immunofixation electrophoresis. |
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A 72-year-old black woman, a retired school teacher, who you see for hypertension and mild arthritis, complains of mid-back and hip pain for 4-5 months. Two days ago she fractured her arm trying to lift her 15 month old grandson. Her Hct is 0.30; the WBC 3.8 x109/L with a normal differential. Serum Ca is elevated at > 12 mg/dL.Urine protein is 3+ positive. Her serum protein electrophoresis is shown at right. Physical examination shows no hepatosplenomegaly, nor lymphadenopathy. What is the most likely primary diagnosis based on the history and laboratory findings? A. Waldenstrom's macroglobulinemia B. Amyloidosis C. Myeloma D. Monoclonal Gammopathy of Unknown Significance E. Heavy Chain Disease What additional studies are needed to confirm your differential diagnosis? A: Right myeloma is more than twice a common in black
individuals as in whites. The complaints of mid-back and hip pain and the
pathologic fracture are typical of the bone lesions of myeloma. Her anemia
and mildly decreased WBC suggest a process involving the marrow. The spillage
of protein in the urine is seen in all but a small number of cases of myeloma
and corresponds in amount to the mass of the lesion. Her serum protein
electrophoresis shows the appearance of a monoclonal band in the g region.
This requires further identification by immunoelectrophoresis. The
bone lesions typical of myeloma are not seen in Waldenstroms
macroglobulinemia. There
is no lymphadenopathy as is common with heavy chain disease. While
amlyoidosis might be part of myeloma, its presentation as primary disease
unassociated with myeloma is generally more subtle than that described in
this case and is without evidence of preceeding disease or bone lesions.
Finally, this monoclonal gammopathy is clearly of clinical significance, not
MGUS. Other
studies should include a bone survey, serum & urine protein
electrophoresis, immunoelectrophoresis, immunofixation electrophoresis, and
serum creatinine.</ For
more on immunoelectrophoresis and immunofixation, return to the question and
proceed to the next question |
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Immunosecretory Disorders: Myeloma
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Immunoelectrophoresis (IEP)is important to confirm and define an apparent monoclonal band seen on SPEP.
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Immunoelectrophoresis (IEP) of a second case in which a monoclonal band was seen on SPEP.
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Immunosecretory Disorders
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Immunofixation electrophoresis (M-fix) is useful for confirmation and specific identification of monoclonal bands. Antibodies against immunoglobulins, in this case IgG, k, and l, are used to identify the protein bands in the serum protein electrophoresis (SPEP) as an IgG l monoclonal band. |
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A 24-year-old woman, recently returned from graduate religious studies in A. Waldenstrom's macroglobulinemia B. Amlyoidosis C. Myeloma D. Monoclonal Gammopathy of Unknown Significance E. Heavy Chain Disease A; Primary amyloidosis is associated with plasma cell
dyscrasias and idiopathic causes. Amyloid
infiltrates cause organ damage resulting in failure. In this case she
developed a nephrotic syndrome. Analgesic nephritis resulting from papillary
necrosis is secondary to the ingestion of large amounts of (2-3 kg of
phenacetin in a 2-3 yr period). Heart failure can be seen secondary to
amyloid deposition in the cardiac conduction system. Soft tissue accumulation
leads to the carpal tunnel syndrome, as evidenced by the tenderness and soft
tissue swelling of both wrists and some numbness/sensation loss in her hands.
A thorough GI exam is indicated as GI tract infiltration can cause macroglossia, hemorrhage, malabsorption, diarrhea, and obstruction. Rectal biopsy is a common means of obtaining tissue evidence of amyloidosis. |
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Immunosecretory Disorders
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A 57 yr-old woman presents with headache & dizziness; numbness & blanching of her fingers. The IEP is at right. The PB smear shows 4+ rouleaux. You find enlarged axillary & inguinal lymph nodes & splenomegaly. X-rays show no lytic bone lesions.
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The immunofixation of this patient is shown at right. Does this confirm your interpretation of the IEP? Based on the history and these results which of the following is the best diagnosis? A. Waldenstrom's macroglobulinemia B. Amlyoidosis C. Myeloma D. Monoclonal Gammopathy of Unknown Significance E. Heavy Chain Disease
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Multiple myeloma is generally characterized by all of the following EXCEPT: A. Monoclonal
gammopathy B. Rouleaux
formation C. Anemia D. Splenomegaly E. Hypercalcemia Common signs and (symptoms) of myeloma include
anemia; lytic bone lesions (bone pain & pathologic fractures);
hypercalcemia (mental status delta, renal calculi, bone pain & abdominal
cramping); increased serum Ig [rouleaux, hyperviscosity syndrome, Raynauds
phenomenon (severe intermittent pallor of digits), bleeding, confusion] and
renal failure. Decreased production of normal Igs produces a high risk of
bacterial infection (especially pneumococcal infection. Splenomegaly
and lymphadenopathy |
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In multiple myeloma the immunoglobulin most commonly elevated is: A. IgA B. IgG C. IgM D. IgD E. IgE In myeloma the abnormal immunoglobulin is most
often IgG (50%) and sometimes IgA (25%), but rarely (<1%) IgM,IgD, or IgE. |
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Multiple myeloma is often associated with: A. Decreased ESR (erythrocyte sedimentation rate) B. Excretion of both kappa & lambda light chains in the urine C. Osteoblastic skeletal lesions D. Renal excretory impairment E. Hyperalbuminemia You would expect to see an increased ESR
(erythrocyte sedimentation rate) due to the increased serum immunoglobulin. The
immunoglobulin is monoclonal and therefore urine spillage of protein would be
monoclonal - kappa or lambda, but not both! The
bone lesions of myeloma are osteolytic. Hypoglobulinemia
is a feature of myeloma, not hyperalbuminemia. Renal
failure resulting in excretory impairment is caused by damage to the renal
tubules from filtered light chains. |
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Which feature is more characteristic of Waldenstrom's macroglobulinemia than multiple myeloma? A. Discrete lytic bone lesions B. Bence-Jones protein in the urine C. Rapid clinical course D. Spleen and lymph node enlargement E. IgA M-spike Discrete lytic bone lesions and Bence-Jones
proteins in the urine are features associated with myeloma, not
Waldenstroms macroglobulinemia. Waldenstroms
is a slowly progressive disorder, with survival of 2-5 years and
longer. Splenomegaly
and lymphadenopathy are features of HCD and Waldenstroms
macroglobulinemia. The
malignant cells of Waldenstroms macroglobulinemia secrete a monoclonal IgM
protein which causes a macroglobulinemia. |
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Hyperviscosity is a complication of which of the following diseases: A. Waldenstrom's macroglobulinemia B. Sickle cell anemia C. IgA Myeloma D. Polycythemia vera E. All of the above Hyperviscosity, caused by either increased cellular
elements or increased serum protein levels, is a feature of all the diseases
listed. Hyperviscosity
is seen with ·
Waldenstroms macroglobulinemia ·
and IgA myeloma because of the increased serum
protein levels; ·
with
polycythemia vera because of the increased numbers of RBCs, ·
and in
sickle cell anemia because of the nondeformability of the sickled
erythrocytes.
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All of the following are complications associated with multiple myeloma EXCEPT: A. Pathologic fractures B. Increased susceptibility to infections D. Hypergammaglobulinemia E. Cryoglobulinemia |
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Characteristic features of various heavy chain diseases include all of the following EXCEPT: A. Increased levels of IgG kappa or lambda light chains B. Association with AIHA, Sjogren's syndrome, SLE, etc. C. Anemia, fever, lymphadenopathy, splenomegaly D. abdominal mass; malabsorption; diarrhea E. Mediterranean lymphoma Heavy chain disease is characterized by increased
amounts of a specific heavy chain -with no light chains. Gamma
HCD is associated with autoimmune diseases including AIHA, Sjogrens syndrome,
rheumatoid arthritis, SLE, thyroiditis, etc. alpha HCD is characterized by a GI
lymphoma known as Mediterranean lymphoma and is associated with an abdominal
mass; malabsorption; diarrhea. Anemia,
fever, lymphadenopathy, splenomegaly are common findings with the HCDs.
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All of the following features of B cell gene rearrangements are true EXCEPT: A. Two attempts at k rearrange ment must take place before an attempt at l rearrangement can take place B. The Cm gene is physically closest to the JH region on chromosome 14 C. A heavy chain class switch allows identical VH/DH/JH antigen specificity to be expressed with different constant regions D. Rearrangement E. The gene for k light chains is located on chromosome 2 and has a single constant region Rearrangement preceeds transcription which preceeds
translation. The statements A.) Two attempts at kappa rearrange ment must take
place before an attempt at lambda rearrangement can take place, and B.) The Cmu gene is physically closest to the JH
region on chromosome 14, and C.) A heavy chain class switch allows identical
VH/DH/JH antigen specificity to be expressed with different constant regions,
and E.) The gene for kappa light chains is located on
chromosome 2 and has a single constant region are all true.
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All of the following are true EXCEPT: A. Maternal IgG can cross the placenta B. Waldenstrom's macroglobulinemia is associated with mature B lymphocytes that have not yet undergone a heavy chain class switch C. IgA is a major immunoglobulin in GI tract and respiratory secretions D. The Fab portion of IgG is important in the activation of complement E. a2-macroglobulin
is a protease inhibitor |
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Enzyme
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Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency is the most common enzyme deficiency known to cause hemolysis. G-6-PD reduces NADP (nicotinamide-adenine-dinucleotide phosphate) to NADPH. NADPH reduces oxidized glutathione (GSSH) to its reduced form GSH. GSH prevents oxidation of RBC membranes and hemoglobin. |
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More than 200 million people, mainly The deficiency is sex-linked (M>F), but with varying degrees of deficiency - mild in blacks and severe in Mediterranean populations. Blacks often have an episodic variant in which oxidant compounds such as antimalarials, sulfonamides, or infections cause hemolysis. In Mediterranean populations G-6-PD deficiency may result in a chronic hemolysis. Women heterozygotes (half the normal amount of RBC) G6PD show increased resistance to P falciparum. |
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G6PD deficiency is usually asymptomatic. During times of oxidant stress the PBS usually shows spherocytes, schistocytes, and "bite" cells and "blister" cells where denatured hemoglobin (Heinz bodies) were removed in the spleen. G6PD enzyme assays reveal relatively high levels in reticulocytes and young erythrocytes, declining in older RBCs. In hemolysis it is the older cells which destroyed. Because of this hemolysis is usually self-limited. |
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Pyruvate kinase deficiency an autosomal recessive disorder causing polychromasia, anisocytosis, poikilocytosis with burr cells and acanthocytes, and NRBCs. Reduced ATP formation causes RBC membrane rigidity, resulting in hemolysis. Symptoms are usually mild as increased 2,3-DPG causes a right shift of the 02-dissociation curve. Persons homozygote for PK deficiency show severe anemia and are usually discovered in childhood. Splenomegaly, cholelithiasis and jaundice are frequent. |
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Methemoglobin is hemoglobin that has been oxidized from the ferrous (Fe++) to the ferric (Fe+++) state, thus unable to bind oxygen. The NADH- methemoglobin reductase enzyme reduces methemoglobin to hemoglobin. Methemoglobinemia results from either inadequate enzyme activity or too much methemoglobin production. Hereditary autosomal recessive deficiency of NADH-methemoglobin reductase presents with cyanosis because methemoglobin cannot carry oxygen. The cyanosis is usually mild, but if severe can be treated with IV methylene blue, activating NADH- methemoglobin reductase. |
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Methemoglobin production may exceed the capacity of the normal NADH- methemoglobin reductase pathway. This can be acquired due to drug or toxic oxidation of hemoglobin (analine dyes, anesthetics-benzocaine; prilocaine, naphthalene, nitrates, nitrites, nitroglycerin, paraquat, phenazopyridine, sulfamethoxazole, trimethadione, etc.). Certain single amino acid substitutions within a hemoglobin globin chain can cause the iron to stabilize in the ferric state. |
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Related is the carboxyhemoglobin that results from carbon monoxide binding to hemoglobin. Hemoglobin binds CO more tightly than oxygen by a factor of 200. The tissues are deprived of oxygen. |
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An inherited M hemoglobin with the amino acid substitution in the b-globin chain would not cause cyanosis until approximately 6 months of age when beta chain production becomes dominant. Prior to 6 months gamma-globin chain production dominates. If the amino acid substitution had been in the alpha chain, the cyanosis would have been present from birth. |
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Of the drug related immune hemolytic anemias which result in an intravascular hemolysis?
A. the hapten formation mechanism
B. the immune complex mechanism
C. the autoimmune mechanism
D. both the immune complex and autoimmune mechanisms
E. both the hapten and immune complex mechanisms
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Only in the immune complex type does intravascular hemolysis occur. In the immune complex type an IgM antibody forms against a drug. This IgM antibody causes formation of circulating immune complexes which activate complement. The complement then binds to RBCs and lyses them within the vascular space. |
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Heparin-induced thrombocytopenia, the most important thrombocytopenia resulting from drug-related antibodies, occurs in up to 5% of patients receiving bovine heparin and in 1% of those receiving porcine heparin. Rarely, patients with heparin-induced thrombocytopenia develop life-threatening arterial thromboses (eg, thromboembolic occlusion of limb arteries, strokes, acute MI).
The thrombocytopenia results from the binding of heparin-antibody complexes to Fc receptors on the platelet surface membrane.
Platelet factor 4, a cationic and strongly heparin-binding protein secreted from platelet alpha granules, may localize heparin on platelet and endothelial cell surfaces.
In addition, platelet factor 4-heparin complexes are the principal antigens.
Platelet clumps can form, causing vessel obstruction.
Heparin should be stopped in any patient who becomes thrombocytopenic. Because clinical trials have demonstrated that 5 days of heparin therapy are sufficient to treat venous thrombosis and because most patients begin oral anticoagulants simultaneously with heparin, heparin can usually be stopped safely. Laboratory assays do not aid these clinical decisions.
A 53-year-old woman presented to the emergency department with petechiae and purpura of the lower legs and blood blisters on the oral mucosa. She reported that her physician had placed her on quinidine for leg cramps about three weeks earlier.
The complete blood count was normal except for a platelet count of 5,000/mm3 (normal, 150,000 to 450,000/mm3). A diagnosis of quinidine-induced thrombocytopenia was made on clinical grounds.
Nonimmune thrombocytopenia is the most common cause of drug-induced thrombocytopenia in hospitalized patients and is typically seen on cancer wards, particularly among leukemia patients. It is invariably associated with bone marrow suppression and characteristically originates as a dose-dependent and quite predictable side effect of treatment with chemotherapeutic agents. Depending on the agent used, the platelet count can fall to very low levels. These patients are usually treated with platelet transfusion. Since none of these episodes is unexpected, with proper treatment the thrombocytopenia is seldom lethal.
Immune thrombocytopenia, as illustrated by this case, can be defined as unexpected--also known as idiosyncratic--thrombocytopenia associated with the administration of a drug. Thrombocytopenia usually begins within days or weeks after drug therapy is started. Occasionally, it happens after long exposure; the thrombocytopenia develops rapidly, and often is so severe that the patient seeks medical attention. Given sufficiently sensitive assays, immune mechanisms for the thrombocytopenia usually can be demonstrated. Typically, the platelet destruction is IgG-mediated; occasionally, it can be mediated by IgM or complement.
A number of drugs seem to have a strong association with immune thrombocytopenia. Although quinine and quinidine cause many such cases, the risk per dose is extremely low, given the fact that quinine is present in tonic water; if quinine were a common allergen, we would see literally tens of thousands of patients with this problem every year.
Other drugs that can cause immune thrombocytopenia include a number of antibiotics, especially the sulfonamides (combination sulfonamides such as trimethoprim-sulfamethoxazole are frequently implicated); the H2 antagonists such as cimetidine; and various other agents, including furosemide. It is important to note that virtually every drug, including commonly used drugs such as acetamin-ophen, have been associated with immune thrombocytopenia.
Case 1 Treatment
Quinidine was withdrawn. The patient was given high-dose IV IgG, 1 g/kg over six to eight hours, repeated on the next day. The platelet count returned to normal over the next four days.
In asymptomatic patients with drug-induced immune thrombocytopenia, the drug should be withdrawn and a structurally different drug should be substituted if the patient's condition requires treatment. For example, in a patient whose thrombocytopenia developed in response to a sulfonamide, therapy might be switched to a cephalosporin, depending on the sensitivity of the infecting organism.
Petechiae in drug-induced thrombocytopenia typically occur on the dependent regions of the body. These patients require intervention.
So-called wet purpura is defined as blood blisters inside the mouth, typically at the bite margins. Patients will describe purple bumps that they can feel with their tongue. Some of those can be the size of a grape; others are smaller. These patients are at risk for major and possibly life-threatening hemorrhage. For that reason, this is the one group of patients who should be admitted to the hospital and given urgent treatment. Complete recovery can be expected provided that the drug is stopped and patients are supported until the thrombocytopenia resolves.
While I rely heavily on symptoms (or lack thereof) to guide the treatment of drug-induced thrombocytopenia, management decisions can also be based on platelet counts. Clinical signs correlate well with the platelet count, so that the end result is usually the same.
Most patients with platelet counts that exceed 20,000/ mm3 are asymptomatic, unless they have taken an antiplatelet agent such as aspirin or alcohol. I have also seen asymptomatic patients with platelet counts as low as 15,000/mm3; such patients apparently have highly functional platelets. Even with counts that low, I will frequently treat only by stopping the drug if the patient is asymptomatic.
Petechiae and purpura are often seen with platelet counts of 10,000 to 20,000/mm3. I usually treat those cases, although there is some latitude in that regard. A platelet count of under 10,000/mm3 means the patient must have intervention. In my experience, platelet counts of 1,000 to 2,000/mm3 are invariably accompanied by major wet purpura. These patients are at great risk for hemorrhage.
The treatment for all patients is the same. First, the drug is stopped. The next step is to consider blockade of the reticuloendothelial system, using high-dose intravenous IgG at a dose of 1 g/kg, over six to eight hours, repeated on the next day. Alternatively, intravenous Rho(D) immune globulin can be given, provided that the patient is Rh-positive. The typical adult dose is 2 to 2.5 mg administered over 30 minutes. Both IV IgG and anti-Rh-D usually raise the platelet count within a few days. The advantages of anti-Rh-D over high-dose IV IgG are that the former is easier to administer, and patients sometimes tolerate it better; for example, it does not cause headaches, as IV IgG often does.
Anti-Rh-D is an antibody against the Rh group on red blood cells--the agent is used to prevent Rh sensitization in Rh-negative mothers with an Rh-positive fetus. An intramuscular preparation is customarily used in those patients; for thrombocytopenia, we use anti-Rh-D that has been modified so that it can be administered intravenously.
The strategy for the use of anti-Rh-D in thrombocytopenia is to give it in a dose high enough that the D sites on red cells are sensitized by the antibody, but not at such a high dose that the cells are completely covered with the antibody. The phagocytic cells that have been destroying platelets then go after the red blood cells because there are so many more of them compared with the platelets. This sets up a so-called reticuloendothelial competitive state, or blockade.
Rarely, we encounter patients who have such severe drug-induced thrombocytopenia that we consider them to have a major risk of fatal hemorrhage. We will tranfuse those patients with random-donor platelets. Although the transfused platelets will not have a normal survival time, they may attract enough of the offending drug to allow the patient's own platelet count to rise.
If a laboratory is sufficiently sophisticated, it is often possible to
demonstrate which drug caused the thrombocytopenia, using a sensitive
diagnostic test to measure drug-dependent binding of antibody to platelets.
That test is performed only in a few centers in the
Once patients have experienced an episode of drug-induced thrombocytopenia, they should never take that drug again, since the thrombocytopenia tends to recur with every subsequent exposure. I recommend that these patients wear a medical alert bracelet to indicate their allergy.
Case 2 Presentation
Gold injections were immediately discontinued. Treatment with high-dose IV IgG raised the platelet count to safe levels, but within two weeks the count began to fall again. She was then given prednisone, 30 mg every other day. After two months, the platelet count had risen to normal levels, and tapering of the prednisone was begun. As the corticosteroid was tapered, however, the platelet count fell again. Three months after the onset of thrombocytopenia, she underwent splenectomy. Afterwards, the platelet count returned to normal levels. Genetic testing showed that the patient's HLA haplotype is B8/DR3.
Gold-induced thrombocytopenia may be the only drug-induced immune thrombocytopenia in which a true and persisting autoantibody develops. There is some debate about this, however, because when gold is used as an injectable therapy for rheumatoid arthritis, it can have an extremely long half-life. Therefore, it is possible that gold leaches from the bones and into the circulation, where it causes persistent thrombocytopenia. Nevertheless, serologic tests in patients with gold-induced thrombocytopenia strongly suggest that these patients have a true autoimmune disorder.
Another interesting aspect of gold-induced thrombocytopenia is that there appears to be a genetic predisposition to the syndrome. Up to 80% of patients carry a specific HLA DR haplotype, B8/DR3. Although B8 and DR3 are closely linked, it is likely that the DR3 alloantigen is the one responsible for the immunogenicity of gold. Why the immune reaction occurs remains unknown.
Unlike patients with other drug-induced thrombocytopenias, however, many of those with gold-induced thrombocytopenia will have a relapse after the IV IgG wears off, which typically occurs in two to four weeks. When that happens, either additional IgG can be given or corticosteroids can be used.
Repeat doses of IgG have limited usefulness. In the average adult, a full treatment with high-dose IgG provides 180 g, which typically doubles the serum IgG concentration. If treatments are given too frequently, that protein load can cause hyperviscosity and heart failure. Equally important, the use of IV IgG in immune thrombocytopenia is associated with a fairly dramatic tachyphylaxis. The initial treatment provides a major boost in the platelet count, the next treatment a smaller one; with each successive treatment, the effectiveness gradually becomes modest. If treatments are withheld for a time, however, the patient will respond to IgG again.
If I have used corticosteroids and the patient continues to have thrombocytopenia after the steroids are tapered, I would move to a splenectomy in these patients. As with idiopathic thrombocytopenia, splenectomy is effective in 60% to 75% of cases.
If the patient does not respond to splenectomy, the physician would be obligated to try other treatments that are used in immune thrombocytopenia, many of which are difficult to administer and may not always be successful. There are also anecdotal reports suggesting that the removal of gold with chelating agents such as desferoxamine can shorten the thrombocytopenia, but that would not be typical therapy.
Case 3 Presentation
A 52-year-old man underwent coronary artery bypass surgery. During surgery, he was treated with full-dose heparin, 30,000 units. Over the next week, he was treated with 5,000 units twice a day.
On day 7 of the patient's hospitalization, a platelet count of 60,000/mm3 was noted, and his right leg became cold and pale. Heparin-induced thrombocytopenia was suspected. Heparin was discontinued. A thrombus was removed by Fogarty catheter from the right superficial femoral artery. Despite the embolectomy, the patient's leg was irreversibly ischemic. He subsequently required a below-knee amputation.
Second, unlike other thrombocytopenic disorders of this type, heparin-induced thrombocytopenia is associated with only a moderate decrease in platelets: Counts typically range from a low of about 50,000/mm3 to a high of about 100,000/mm3. Because of that, cases may go unsuspected and undiagnosed.
Third, heparin-induced thrombocytopenia is the one drug-induced thrombocytopenia that is associated not only with bleeding but also with thrombotic complications. Indeed, the thrombotic complications cause virtually all of the morbidity and mortality in this syndrome.
Finally, there is the issue of litigation. The legal concept of res ipsa loquitur (the thing speaks for itself) is central to these cases, which often involve multimillion-dollar claims for damages: Juries see a plaintiff who entered the hospital with healthy limbs and left an amputee, and it seems self-evident to them that someone must be at fault. Unfortunately, this catastrophic reaction to heparin is unpredictable and often unpreventable.
We have known about heparin-induced thrombocytopenia for more than 30 years, but only in the past five years have we had a thorough understanding of its pathophysiology and its diagnosis. Even more recently have we gained some insight into the treatment of this disorder, although there is still debate on that subject.
Heparin-induced thrombocytopenia is defined as a fall in the platelet count of at least 50%, accompanied by a positive serologic test for the responsible antibody. Onset typically occurs five or more days after the initiation of heparin therapy, with peak onset around seven to 10 days. Rarely, thrombocytopenia begins after two weeks; occasionally (especially if the patient has received heparin in the previous month or two), it can occur as early as first or second day after heparin exposure.
In most patients, the platelet count fall is so mild that they remain asymptomatic. Bleeding is rare. When thrombosis occurs, however--which may not be until several weeks later, perhaps after the discontinuation of heparin--the patient becomes immediately symptomatic. It is then that the diagnosis is often made.
Studies of heparin-induced thrombocytopenia have documented that the incidence is related to several factors. One is the type of heparin used. Bovine heparin carries the greatest risk, possibly as high as 10%; porcine heparin carries a risk of 2% to 4%.
The incidence of heparin-induced thrombocytopenia is also dose-dependent. The frequency is highest in patients who receive full-dose heparin, which is defined as 20,000 to 40,000 units per day. It is lower with low or intermediate doses, defined as 5,000 units two or three times a day; and it is far lower for very-low-dose heparin, which is the amount used to maintain the patency of arterial catheters. The new low-molecular-weight heparins also carry very little risk of heparin-induced thrombocytopenia--probably under 1%. Nevertheless, heparin-induced thrombocytopenia has been identified for every single heparin preparation currently used, by any route and at any dose.
Finally, for unknown reasons, the risk of thrombocytopenia and thrombosis is related to the clinical situation. The risk is lowest on general medical units; quite high on orthopedic surgery units; and highest in patients undergoing cardiopulmonary bypass surgery.
The risk of the thrombocytopenia has been well defined in a number of prospective studies. The risk of thrombotic complications is only now being studied; they appear to be related to the clinical situation itself. In certain patient populations, heparin-induced thrombocytopenia occurs without the clotting complications, whereas in others, both occur. Several recent studies have shown that venous clotting complications outnumber arterial thrombi by three to one. The venous complications consist of deep-vein thrombosis and pulmonary embolism; the arterial complications include peripheral arterial thrombosis and thrombosis of the heart or brain. In addition, skin necrosis is increasingly described as a complication of heparin-induced thrombocytopenia.
Heparin-Induced Thrombocytopenia: Pathophysiology
In the past few years, scientists have identified the target antigen in heparin-induced thrombocytopenia as a complex of heparin and a small platelet alpha-granular component called platelet factor 4 (PF-4). Each heparin molecule bundles two or four PF-4 molecules together, and this complex then binds to the platelet membrane, through a process that remains uncertain. It appears that heparin itself is not immunogenic; rather, the immunogenicity arises from the conformational change in the PF-4 caused by heparin (Figure 1). Patients at risk form an antibody--typically IgG--to the heparin/PF-4 complex. Fortunately, thrombocytopenia develops in only a small proportion of the patients who form such antibodies.
The antibody binds to the heparin/PF-4 complex through its Fab region; its Fc region then binds to the platelet by occupying the platelet Fc receptor, which is of the FCR gamma-2 family (there are approximately 1,000 to 2,000 of these receptors on each platelet). Once this receptor has been occupied, the platelet becomes intensively reactive and will release platelet-derived microparticles into the circulation.
The platelet-derived microparticles, which are procoagulant, appear to be the stimulus responsible for thrombus formation. They pass through the circulation and probably home in on sites of vessel damage, where they activate the coagulation cascade. It is likely that endothelial cells are also the target of the IgG and heparin/PF-4 immune complexes.
Heparin-Induced Thrombocytopenia: Diagnosis
The diagnosis is made on clinical grounds. Physicians should be particularly alert to the possibility of heparin-induced thrombocytopenia when the platelet count falls after five to 10 days of heparin therapy.
The diagnosis can be confirmed in either of two ways. Probably the most sensitive and specific test is the serotonin release assay. This measures platelet activation as indicated by serotonin release from normal platelets in the presence of the patient's serum plus heparin at two concentrations. The assay takes several days to complete, so it is not useful for immediate patient management. The other technique is a recently described ELISA assay that measures the binding of patient IgG to a complex of heparin and PF-4 on microtiter wells. There is some debate as to which test is better. Although there is good agreement of results with the two tests, each may detect the disorder in a few cases that are missed by the other method.
Heparin-Induced Thrombocytopenia: Treatment
The treatment of heparin-induced thrombocytopenia is complex and multipronged. First, one should try to stop the heparin as soon as possible--although that does not necessarily mean that it is stopped the minute the diagnosis is made.
Second, if the patient has had an arterial or venous thrombus, it is appropriate to provide supportive treatment. For example, a patient who has had a myocardial infarction (MI) should be treated according to an MI protocol. For large arterial thrombi, treatment might include physically removing the thrombus from the occluded artery, or using fibrinolytic agents to try to dissolve clots.
The biggest problem is that we now know that the disorder itself can be a prothrombotic state, so we need to try to control ongoing thrombosis. One treatment that should not be used in acute heparin-induced thrombocytopenia is warfarin. The reason is that while warfarin reduces circulating concentrations of vitamin K-dependent clotting factors II, VII, IX, and X, it also reduces those of protein C and protein S, which are natural anticoagulants. Because protein C has a short half-life, it is reduced faster than the prothrombotic proteins, which means that clotting will worsen in some patients.
Unfortunately, heparin-induced thrombocytopenia develops in some patients when treatment is changed from heparin to warfarin in preparation for longer-term anticoagulation, and the diagnosis is not made until after they have already begun to receive warfarin. If they are stable (more than three days) on warfarin, I would continue the drug. Otherwise, I would adminster fresh-frozen plasma to restore protein C levels and provide natural anticoagulation, in addition to providing the standard anticoagulant treatments used for heparin-induced thrombocytopenia.
Three specific anticoagulant treatments are now being tested in
The second treatment category comprises thrombin-specific inhibitors. These include argatroban and hirudin or hirudin analogs. In theory, thrombin-specific inhibitors may be the ideal agents for this disorder.
Ancrod, a drug that has been used in
In addition to those primary treatments, there are a number of supportive treatments that have anecdotal descriptions of efficacy. These include high-dose IgG to try to disrupt the immune complex on the platelet; plasma exchange, which we have used in a number of our patients to try to remove the procoagulant substance; and anticoagulants and antiplatelet drugs, most of which seem to be second-line therapies when compared with the other treatments.
Finally, as with other drug-induced thrombocytopenias, no patient with heparin-induced thrombocytopenia should ever again be exposed to heparin, and I recommend that these patients wear a medical alert bracelet.
Case Commentary
I believe that it is worthwhile to expand on some of the points Kelton makes in his overview of drug-induced thrombocytopenia--namely, the indications for treatment of thrombocytopenia, the medicolegal challenges of heparin therapy in a litigious era, and the role of low-molecular-weight heparin in current therapy.
In general, the risk of bleeding from thrombocytopenia does correlate roughly with clinical signs. Because of the increased venous pressure in the lower extremities caused by dependency--and the resulting challenge to platelet competency--petechiae on the legs are the earliest manifestation of thrombocytopenia. Purpura from minimal trauma occurs next. Once hemorrhage occurs on moist internal membranes such as the mouth or conjunctiva, the risk of serious hemorrhage increases. The presence of those findings, regardless of the severity of the thrombocytopenia, warrants therapy. Kelton indicates that even without the development of "wet" purpura, he tends to intervene when platelet counts are in the range of 10,000 to 20,000/mm3. This is in contrast to current guidelines for treatment of thrombocytopenia resulting from cancer chemo- therapy, which suggest that intervention in the absence of clinical hemorrhagic findings is necessary only when the platelet count is less than 10,000/mm3. The difference in perceived risk may relate to the antigen/antibody coating on platelets interfering with platelet function and adding to hemostatic impairment. When evaluating the bleeding risk in a patient with thrombocytopenia, one must also consider whether the platelet count is continuing to fall, is stable, or is rising; the potential for rapid recovery; and the length of time in which stable thrombocytopenia (at any level) has been present without producing signs or symptoms.
The fact that heparin so frequently causes mild thrombocytopenia and yet is rarely associated with serious arterial or venous thrombosis carries a risk for tort actions against the treating physician if major adverse events ensue. That risk raises the question of what management guidelines should be. For example, should all patients on heparin routinely have platelet count determinations? If so, how often should they be done, and for how long? Kelton notes that although the development of heparin-induced thrombocytopenia usually occurs seven to 10 days after the start of therapy, it can occur as early as the first day (in previously treated patients) or as late as two to three weeks later. If platelet counts fall at all, should heparin be discontinued? Most hematologists would be concerned about a decrease in platelet count below 100,000/mm3 and would then discontinue heparin. Nevertheless, heparin-induced major vascular occlusion has occurred when platelet counts were greater than 100,000/mm3. A major fall in the platelet count--for example, to half of the pretreatment level--would be a matter of some concern, but what should be done if the count falls modestly from a preheparin level of 200,000/mm3 to 145,000/mm3? How can one be sure that an observed minor fall in the count will not become, perhaps two days later, a major decrease in platelets associated with thrombosis?
We do not have clear-cut answers to those questions; I do not believe that firm guidelines have been drawn, either from a medical or a medicolegal perspective. I do believe that prudence dictates that patients on heparin therapy should have a baseline platelet count for subsequent comparison and that platelet counts should be repeated periodically, although the optimal intervals for repeat determinations and the appropriate response to moderate decreases in platelet levels remain unclear.
The potential for heparin-induced thrombocytopenia argues for starting warfarin concomitantly with heparin, when practical, so that oral anticoagulation can be established sooner. Usually that will permit the heparin to be withdrawn early, prior to the time when most heparin-induced thrombocytopenia becomes manifest.
Low-molecular-weight heparin has a number of advantages. Unlike standard heparin, it can be given in fixed doses; in addition, administration is easier, frequent monitoring of anticoagulant effects is unnecessary, and the incidence of drug-induced thrombocytopenia is substantially lower. Moreover, randomized studies are providing increasing evidence that low-molecular-weight heparin works just as well as standard heparin in both prophylaxis and treatment of phlebothrombotic disease. The increased cost of low-molecular-weight heparin needs to be balanced against the decreased expenses associated with administration, obviation of anticoagulant monitoring, and decreased risk of managing the potentially catastrophic complications of heparin-induced thrombocytopenia. There is much to recommend low-molecular-weight heparin as the preferred formulation for phlebothrombotic disease.
Human Diseases Associated with
Immune Complexes
DIFFUSE CONNECTIVE TISSUE DISEASES (CTDs)
Autoimmune Diseases:
Other:
GLOMERULONEPHRITIS (GN)
INFECTIOUS DISEASES
Revised Criteria for the Classification of Systemic Lupus
Erythematosus
|
|
|
|
Criterion: |
Definition: |
|
1. Malar rash |
Fixed erythema, flat or raised,
over the malar eminences, tending to spare the nasolabial folds |
|
2. Discoid rash |
Erythematous raised patches with
adherent keratotic scaling and follicular plugging; atrophic scarring may
occur in older lesions |
|
3. Photosensitivity |
Skin rash as a result of unusual
reaction to sunlight, by patient history or physician observation |
|
4. Oral ulcers |
Oral or nasopharyngeal
ulceration, usually painless, observed by a physician |
|
5. Arthritis |
Nonerosive arthritis involving
two or more peripheral joints, characterized by tenderness, swelling, or
effusion |
|
6. Serositis |
|
|
7. Renal disorder |
|
|
8. Neurologic disorder |
|
|
9. Hematologic disorder |
|
|
10. Immunologic disorder |
|
|
11. Antinuclear antibody |
An abnormal titer of antinuclear
antibody by immunofluorescence or an equivalent assay at any point in time
and in the absence of drugs known to be associated with "drug-induced
lupus" syndrome |
|
|
|
Connective Tissue Diseases Associated with Antinuclear
Antibodies
Some Diseases (Other than CTDs) Associated with Antinuclear
Antibodies
Other Autoimmune Diseases
Infectious diseases
Miscellaneous
ANA Fluorescence Patterns and CTD Association
|
Nuclear Fluorescence Pattern |
Disease Association |
Nature of Reactive Antigen |
|
|
|
|
|
Rim (peripheral) |
SLE |
dsDNA |
|
Homogeneous (diffuse) |
Drug-induced LE, SLE |
Histones, deoxyribonucleopr. |
|
Speckled |
SLE, Sjogren's, MCTD,
scleroderma |
Nonhistone proteins, nuclear
RNPs, etc. |
|
Nucleolar |
Scleroderma |
Nucleolar RNPs |
|
|
||
Special Antibody Assays in the Connective Tissue Diseases
|
|
|||
|
anti-ds DNA |
SLE |
anti-La |
Sjogren's, SLE |
|
anti-Sm |
SLE |
anti-Scl 70 |
Scleroderma |
|
anti-histone |
Drug induced LE, SLE |
anti-nucleolar |
Scleroderma |
|
anti-U1 RNP |
MCTD, SLE |
anti-centromere |
CREST* |
|
anti-Ro |
SLE, Sjogren's |
anti-Jo-1 |
Polymyositis |
|
|
|||
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*Acronym for syndrome of
scleroderma with calcinosis (C), Raynaud's phenomenon (paroxysmal blanching
and numbness of fingers) (R), esophageal dysmotility (E), sclerodactyly (S),
and telangiectasia (T). |
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