BLEEDING DISORDERS

CAUSED BY VESSELS WALL ABNORMALITIES

RELATED TO REDUCED PLATELET NUMBER: THROMBOCYTOPENIA

·         IDIOPATHIC THROMBOCYTOPENIC PURPURA [IPT]

·         ACUTE IDIOPATHIC THROMBOCYTOPENIC PURPURA

·         DRUG INDUCED THROMBOCYTOPENIA

·         HIV-ASSOCIATED THROMBOCYTOPENIA

THROMBOTIC

·         MICROANGIPATHIES THROMBOTIC

·         THROMBOPENIC

·         PURPURA AND HEMOLYTIC UREMIC SYNDROME

RELATED TO DEFECTIVE PLATELET FUNCTIONS

HEMORRAGIC DIATHESES RELATED TO ABNORMALITIES IN CLOTTING FACTORS

·         DEFICIENCY IN FACTOR VIII- Vvw COMPLEX

·         VON WILLEBRAND DISEASE

·         HEMOPHILIA A [FACTOR VIII DEFICIENCY]

·         HEMOPHILIA B [CHRISTMAS DISEASE, FACTOR IX DEFICIENCY]

DISSEMINATED INTRACASCULAR COAGULATION [DIC].

Bleeding disorders

Description and causes

Presentation

o        family history of bleeding after minor surgical procedures, dental procedures, childbirth, or other trauma

o        Can be an isolated event bleeding episodes

o        medications that can cause a bleeding problem

1.         semisynthetic penicillins,

2.         cephalosporins,

3.         dipyridamole,

4.        thiazides,

5.         alcohol,

6.         quinidine,

7.        chlorpromazine,

8.        sulfonamides,

9.         INH,

10.      rifampin,

11.      methyldopa,

12.      phenytoin,

13.     barbiturates,

14.      warfarin,

15.     heparin,

16.      thrombolytic agents,

17.      NSAIDs

18.      ASA,

19.      diuretics,

20.      allopurinol,

21.     TMP/SMX.

o        capillary bleeding and fragility.

22.     Cushing syndrome

23.      Marfan's syndrome.

24.     senile purpura,"

25.      petechiae secondary to coughing,

26.     sneezing,

27.     Valsalva maneuver, blood pressure measurement, vasculitis ("palpable purpura"), scurvy (vitamin C deficiency), or exogenous steroids.

o        Telangiectasias are suggestive of Osler-Weber-Rendu syndrome.

Differentiation of Platelet Versus Coagulation Defect

.

1.        Platelet defects.

2.        Generally have immediate onset of bleeding after trauma.

3.        Bleeding is predominantly in :

4.        skin,

5.        mucous membranes,

6.        nose,

7.        GI

8.         urinary tracts.

9.        Bleeding may be observed as:

10.      petechiae (<3 mm)

11.      ecchymoses (>3 mm).

12.      Must differentiate from vasculitic "palpable purpura."

13.     Coagulation system defects.

14.     "Deep" bleeding (in the joint spaces, muscles' and retroperitoneal spaces) is common.

15.     Observed on exam as hematomas and hemarthroses

Differentiation of Platelet Versus Coagulation Defect  

Bleeding can be attributable to either platelet problems or coagulation defects.

.Platelet defects.

1.        immediate onset of bleeding after trauma.

2.        Bleeding is predominantly in:

i.    skin,

ii.    mucous membranes,

iii.     nose, GI

iv.     urinary tracts.

1.        Bleeding may be observed as:

·         petechiae (<3 mm)

·          ecchymoses (>3 mm).

·          Must differentiate from vasculitic "palpable purpura."

Coagulation system defects.

 "Deep" bleeding in:

·         the joint spaces,

·         muscles'

·         retroperitoneal spaces.

 Observed on exam as hematomas and hemarthroses.

Von Willebrand's disease.

Defective aggregation.

Defective activation or secretion.

·         Most common hereditary coagulation disorder.

·         Autosomal dominant.

·         Abnormal synthesis of von Willebrand's factor (vWf) causing decreased platelet adhesion and decreased serum levels of factor VIII:C (vWf is carrier for factor VIII:C).

·         Type I is absent vWf; type II is abnormal, nonfunctional vWf.

rare

1.        Ingestion of aspirin or NSAIDs.

2.        High-dose penicillin.

3.        Storage pool defects. Vary rare. The platelet's are activated but secrete "inactive" granules, that is, gray platelet syndrome and dense granule deficiency syndrome.

4.        Can treat these with platelet transfusion

Thrombocytosis

Thrombocytopenia.

Idiopathic thrombocytopenic purpura (ITP).

Disseminated intravascular coagulation (DIC).

Occurs in:

v      myeloproliferative disease

v      polycythemia vera,

v      myeloid metaplasia with myelofibrosis,

v      essential thrombocytosis).

In these states platelets are often poorly functioning with abnormal aggregation leading to a bleeding disorder.

The platelets in those with a reactive thrombocytosis (such as cancer, inflammation) function well.

Causes include:

v      decreased production,

v      increased splenic sequestration,

v      increased platelet destruction.

v      Consider also HELLP syndrome and preeclampsia in pregnant females.

Marrow aplasia.

 Infiltration secondary to malignancy or fibrosis.

 vitamin deficiency.

Diagnose by bone marrow biopsy.

Multiple drugs including :

ethanol,

estrogens,

 thiazides,

 cytotoxic drugs (cytosine arabinoside, daunorubicin, cyclophosphamide, busulfan, methotrexate, 6-mercaptopurine, .).

1.        Infectious causes including

sepsis,

AIDS,

 EBV,

ehrlichiosis,

Colorado tick fever,

Rocky Mountain spotted fever, babesiosis,

malaria, .

2.        Increased sequestration in spleen secondary to portal HTN

secondary to cirrhosis),

myeloproliferative disease.

3.        Immunologic destruction.

After bacterial or viral infections,

 drugs (sulfonamides, quinidine, INH, sedative or hypnotics, chlorpromazine, digoxin, methyldopa, heparin),

idiopathic thrombocytopenic purpura (ITP).

4.        Nonimmunologic destruction

. Vasculitis,

 DIC,

 thrombotic thrombocytopenic purpura (TTP),

 hemolytic uremic syndrome (HUS),  prosthetic heart valves.

Antibodies form against platelets.

Frequently preceded by:

v       URI or other viral infection.

More frequent in:

·                            women,

·                             HIV,

·                            mononucleosis (EBV),

·                           Graves' disease,

·                              hyperthyroidism.

Presents as:

·          petechiae;

·         women may have increased uterine bleeding,

·         other bleeding such as CNS, gums.

Diagnosis.

By bone marrow : increase in megakaryocytes.

 antiplatelet antibodies (90% sensitive but only 25% specific).

·         Occurs as a result of:

v      Complications of obstetrics including:

·         abruptio placentae,

·         saline abortion,

·         retained products of conception,

·         amniotic fluid embolism,

·         eclampsia.

Infection

 especially gram negative with endotoxin release.

Malignancy

especially :

              adenocarcinoma of pancreas

                prostate,

                acute leukemia.

Rarely

head trauma,

 prostatic surgery,

venomous snake bites,

·         Clinically.

Subacute. Thromboembolic events including:

v      DVT

v      , heart valve thrombosis,

v      stroke,

v      extremity infarction,  

Acute.

Serious bleeding complications with depletion of clotting factors.

·         Diagnosis.

·         Elevated PT/INR or elevated PTT,

·         thrombocytopenia,

·         reduced level of fibrinogen,

·         elevated D-dimer,

·          elevated fibrin degradation products (fibrin split products).

·         Will also have evidence of microangiopathic hemolysis including schistocytes, helmet cells,  

Hemophilia A. Deficiency of factor VIII,

Hemophilia B.

Factor XI deficiency.

v      X-linked recessive.

v      Diagnose by factor VIII assay. PT and thrombin clot time are normal.

v      PTT generally elevated but may be normal if >30% activity (mild disease).

v      . Deficiency of factor IX (Christmas disease),

v      X-linked recessive.

v      Diagnose by factor IX assay

v      Autosomal recessive disease occurring primarily in Ashkenazi Jews

Hepatocellular insufficiency

Vitamin K deficiency

Coumarin anticoagulants.

decreased production of vitamin K-dependent factors II, VII, IX, X.

1.        Cholestasis and other GI disease causing impaired absorption of lipid-soluble vitamin K.

2.        Poor dietary intake of vitamin K.

3.        Broad-spectrum antibiotics. Gut bacteria produce vitamin K. Loss of these bacteria from antibiotics can lead to vitamin K deficiency.

Paraproteinemias.

Thrombotic thrombocytopenic purpura.

Hemolytic uremic syndrome.

Henoch-Schönlein purpura.

Miscellaneous.

Cryoglobulinemia, macroglobulinemia,

 myeloma

TTP and hemolytic uremic syndrome may be variants of the same disease.

·         Presents with:

o        thrombocytopenia,

o        microangiopathic

o        hemolytic anemia (schistocytes, helmet cells on smear),

with elevated LDH, fever, renal failure, mental status changes, focal neurologic deficits.

·         Generally occurs in those 10 to 40 years of age with peak about 25 years. May occur in postpartum period.

·         Diagnose by biopsy of vessels, clinical presentation.

·         Mortality 60% to 80%, and most adults die within 10 days of disease onset.

·         Forty percent 10-year recurrence rate if survive initial insult

1.        Usually in:

 infants,

 children,

pregnant or postpartum women.

2.        Presents with thrombocytopenia,

3.         fever,

4.         microangiopathic hemolytic anemia,

5.        hypertension,

6.        acute renal failure with anuria.

7.        Etiology.

8.        In some cases, indicated by a :

diarrheal illness caused by Escherichia coli O157:H7 which produces Shiga toxin (also known as verocytotoxin).

Has been found in pond water, apple cider and uncooked or undercooked hamburger.

Day care is also a risk.

9.        Some cases are related to use of cytotoxic drugs (especially chemotherapeutic agents) drugs or cancer.

10.     5% mortality in children, 60% to 80% in adults.

A generally self-limited IgA vasculitis.

1.        May follow URI or streptococcal infection.

2.        Presents with:

 purpura,

arthralgias,

colicky abdominal pain,

 hematuria (from nephritis).

3.        Aspirin and corticosteroids have been used for joint pain and GI symptoms respectively. Corticosteroids do not change the course of the associated renal disease.

Causes of vascular defects include:

v      SLE,

v      rheumatoid arthritis,

v      Sjögren syndrome, amyloidosis

Antithrombin III (HUMAN)
THROMBATE IIIÆ

Antithrombin III (Human); THROMBATE IIIÆ; Bayer Corp., Pharmaceutical Div.

Supplied: 500 IU & 1000 IU

Clinical Pharmacology Antithrombin III (AT-III)

Antithrombin III is an alpha2-glycoprotein of MW 58000, and is normally present in the human plasma at a concentration of approx. 12.5 mg/dl. It is the major inhibitor of thrombin. Inactivation of thrombin by AT-III occurs by formation of a covalent bond resulting in an inactive 1:1 stoichiometric complex between the two. AT-III is also capable of inactivating other components of the coagulation cascade including factors IXa, Xa, XIa, and XIIa, as well as plasmin. The neutralization rate of serine proteases by AT-III is greately accelerated by the presence of heparin.

AT-III Deficiency

The prevalence of the hereditary deficiency of AT-III is estimated to be one per 2000 to 5000 in the general population. The pattern of inheritance is autosomal dominant. In affected individuals, spontaneous episodes of thrombosis and pulmonary embolism may be associated with AT-III levels of 40%-60% of normal. The episodes usually appear after the age of 20, the risk increasing with age and in association with surgery, pregnancy and delivery. The frequency of thromboembolic events in hereditary AT-III deficiency during pregnancy has been reported to be 70%. Several studies of the beneficial use of (human) AT-III concentrates during pregnancy in women with hereditary deficiency have been reported. Greater than 85% of individuals with hereditary AT-III deficiency have had at least one thrombotic episode by the age of 50 years. 60% of patients show recurrent thrombosis. Clinical signs of pulmonary embolic events occur in 40% of affected individuals.

Indications and Usage

Antithrombin III is indicated for the treatemtn of patients with hereditary AT-III deficiency in connection with surgical or obstetrical procedures or when they suffer from thromboembolism. The diagnosis of AT-III hereditary deficiency should be based on a clear family history of venous thrombosis as well as decreased plasma AT-III levels, and the exclusion of acquired deficiency.
AT-III in plasma may be measured by amidolytic assays, clotting assays, or by immunoassays. The latter does not detect all hereditary AT-III deficiencies.

AT-III levels in neonates of parents with hereditary AT-III deficiency should be measured immediately after birth. (Fatal neonatal thromboembolism, such as arotic thrombi in children of women with hereditary antithrombin III deficiency, has been reported.)

Contraindications: NONE

Dosage and Administration

Functional Activity is stated in International Units (IU), potentcy is calibrated against a WHO antithrombin III reference preparation.
Dosage should be determined on an individual basis based on the pre-therapy plasma AT-III level, in order to increase plasma AT-III levels to the level found in normal plasma (100%). It can be calculated using this formula:

units required (IU) = [(desired - baseline AT-III level in %)][weight in kg] / 1.4

The above formula is based on an espected incremental invivo recovery above baseline levels for AT-III of 1.4% per IU per kg administered. Thus, if a 70 kg individual has a baselin AT-III level of 57%, in order to increase AT-III to 120%, the initial AT-III dose would be [(120-57)] [70] / 1.4 = 3150 IU total.

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