TOC |  STAT | Heme

BLEEDING DISORDERS

Diagnosis:
History of bleeding easily spontaneously or after trauma, family history, deficient or defective Factor VIII:C coagulant activity level; bleeding time is normal (not prolonged as in von Willebrand's disease)

I. Platelet disorders

• A. Thrombocytopenia (decreased platelet count)
• B. Platelet dysfunction (prolonged bleeding time): congenital, thrombocytosis, drugs: aspirin, persantin, etc.

Platelet Function Screen (Dade Behring PFA-100)

• Collagen/Epinephrine
• Collagen/ADP (only if Collagen/Epinephrine results abnormal)

Platelet Aggregation Studies

• Full panel (ADP, collagen, epinephrine, ristocetin)
• Ristocetin-induced platelet aggregation panel
• Arachidonic acid (only if aggregation with epinephrine is abnormal)

II. Coagulation factor disorders
A. Prolonged Prothrombin Time (PT) extrinsic system
     (VII, X, V, Prothrombin, fibrinogen, XIII)

1. Liver failure: II, VII, IX, X, V, I
2. Vit. K deficiency or Couomadin Rx: II, VII, IX, X
3. Disseminated intravascular coagulation (DIC)
4. Coagulation factor anticoagulant: Lupus anticoagulant. It is an antibody that causes markedly prolonged PTT. The pt usually does not have hemorrhagic disorder, but quite prone to the development of thromboembolism (venous > arterial thromboses). Anti cardiolipin antibodies are frequently associated with the lupus anticoagulant, & the venous & cerebral thrombosis is strongly correlated with its titer.
5. Fibrinolytic states, t PA, streptokinase, urokinase, liver & prostate Ca

B. Prolonged activated Partial Thromboplastin Time (PTT) intrinsic system
    (XII, XI, X, IX, VIII, V, Prothrombin, fibrinogen)

1. HEMOPHILIA A (see record) - factor VIII deficiency
   A rare hereditary hemorrhagic disorder affecting 1:10,000 males
2. HEMOPHILIA B (see record) - factor IX deficiency (Christmas disease)
   A sex linked disorder that is clinically indistinguishable from hemophilia A.
3. Von Willebrand Disease : prolonged bleeding time, low vW protein/VIII complex
4. Heparin Rx: inactivation of thrombin, also IX, X, XI, XII via antithrombin III
5. DIC: consumption of coagulation factors

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III. Vascular defects (non thrombocytopenic purpura)

• A. Senile purpura
• B. Cushing's syndrome
• C. Drugs: steroid, aspirin, penicillin, sulfa, etc.
• D. SCHONLEIN HENOCH PURPURA (see record) (allergic or anaphylatoid vasculitis)
• E. Infectious purpura: meningococcemia, virus, septicemia, SBE
• F. Hereditary hemorrhagic telangiectasia
• G. Scurvy (vit. C deficiency)
• H. Dysproteinemia: macroglobulinemia, cryoglobulinemia, myeloma
• I.  Misc: fat embolism

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Hemostatic Drugs  
Ref:  NEJM 7/23/1998;339:245  Pier Mannuccio Mannucci

Desmopressin / DDAVP (1-deamino-8D-arginine vasopressin)
can increase the plasma concentrations of factor VIII (as in Hemophilia A), & the von Willebrand factor (as in von Willebrand's disease) for a short time.

Indications:  It is the Rx of choice for pts with mild hemophilia A or type I von Willebrand's disease who have spontaneous bleeding or who are scheduled to undergo surgery.  
It has also been used in uremic patients with prolonged bleeding time.  (Conjugated estrogens are an alternative to DDAVP for uremic pts with bleeding problems.)
It might be used as a prophylactic Rx for cirrhosis pts who need invasive diagnostic procedures and have a prolonged bleeding time, although they might have high plasma concentrations of factor VIII & vWF.

The usual dose:  0.3 ug/kg IV or subc or intranasal dose of 300 ug in adults & 150 ug in children.
Plasma concentrations of factor VIII & von Willebrand factor will be 2-4x higher with Rx, reaching a peak 30-60 min after IV, 60-90 min after subc or intranasal administration.  These doses can be repeated prn at intervals of 12-24 hours, but tachyphylaxis may occur after 3-4 doses.

Type I von Willebrand's diseases & mild hemohpilia patients will respond to DDAVP Rx.  
Type II von Willebrand's disease with dysfunctional von Willebrand factor or Type III von Willebrand's disease with severe vWF deficiency will usually not normalize the bleeding time with Rx.

Side Effects of DDAVP:
Common side effects include mild facial flushing & headache.  It can cause water retention & hyponatremia.  Arterial thrombosis has occurred in a few pts.

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Anti-fibrinolytic Amino Acids

• Aminocaproic acid (6-aminohexanoic acid)
  - 50-60 mg/kg IV or PO q4h.
• Tranexamic acid (4-aminomethylcyclohexanecarboxylic acid)  
  - 10-15 mg/kg q 8 hrs IV, followed by 20 mg/kg q8h PO until bleeding stops.
  Mouthwash containing tranexamic acid 1 g q6h are effective for the prevention of oral bleeding in hemophilic pts & in pts who require dental extraction while receiving long term oral anticoagulant Rx.
  - 10x more potent than aminocaproic acid & has a longer half-life.

Both drugs bind reversibly to plasminogen & thereby block the binding of plasminogen to fibrin & its activation & transformation to plasmin.  Both are effective even when bleeding is not associated with lab. signs of excessive fibrinolysis.  

Indications:  

• may be used if needed in excessive mentrual bleeding, peptic ulcer bleeding, urinary tract bleeding post prostatectomy.
• are useful for the control of bleeding after dental extractions in hemophilic pts.
• may reduce blood loss during cardiac surgery, liver transplant surgery, or joint replacement surgery.  aminocfaproic acid 150 mg/kg IV bolus before the operation, followed by an infusion of 15 mg/kg/hour during the operation, and for tranexamif acid 10 mg/kg IV before the operation, followed by 1 mg/kgh/h during the operation.

Side Effects:
Sx are dose-dependent & usually involve the GI tract, such as N&V, abd. pain, & diarrhea.  The main risk is thrombotic complications.

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Aprotinin - Antiproteolytic agent

It inhibits the action of several serine proteases, such as trypsin, chymotrypsin, plasmin, & tissue & plasma kallikrein, through the formation of reversible enzyme-inhibitor complexes.  Hence, it inhibits the initiation of both coagulation & fibrinolysis induced by the contact of blood with a foreign surface.  It does not affect platelet function.  It is inactive when given orally.

It reduced blood loss during cardiac surgery, IV  2 million KIU before surgery & a continuous infusion of 0.5 million KIU during surgery.  It also reduced blood loss in liver transplantation surgery.

Side Effects:
hypersensitivity reaction, particularly after repeated exposure.  Most reactions occurred when it was administered a second time within 6 months after the first exposure.  It can also cause venous & arterial thrombosis.  There is a concern with the possibility of transmitting the agent responsible for bovine spongiform encephalopathy  (Crazy cow disease)  & new variant Creutzfeldt-Jacob disease.

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Conjugated Estrogens
shorten prolonged bleeding times & reduce or stop bleeding in pts with uremia.

Dosage:  a single daily infusion of 0.6 mg/kg, repeated for 4-5 days, shortened the bleeding time by about 50 % for at least 2 weeks.  A daily oral dose of 50 mg shortened the bleeding time after an average of 7 days of Rx.

2008