• Information
  1. Summary of Agents
  2. Aminocaproic Acid
  3. Tranexamic Acid
  4. Aprotinin
  5. Recombinanat Activated Factor VII
  6. Desmopressin
  7. Factor VIII
  8. Factor IX

A. Summary of Agents

1. Aminocaproic Acid
2. Tranexamic Acid
3. Aprotonin
4. Desmopressin
5. Factor VIII
6. Factor IX

B. Aminocaproic Acid

1. Binds reversibly to plasminogen, blocks activity
2. Antifibrinolytic activity
3. Utility similar to tranexamic acid (see below)
4. Typical dosage: 50-60mg/kg q 4 hours; consider 150mg/kg loading dose
5. Probably as effective as aprotonin and appears to be safer [1]

C. Tranexamic Acid

1. 4-aminomethyl)cyclohexanecarboxylic acid
2. Binds reversibly to plasminogen, blocks activity
3. Antifibrinolytic activity
4. Reduces need for red blood cell (RBC), platelet, fresh-frozen plasma transfusion
5. Treatment Utility
   1. Primary Menorrhagia: 10-15mg/kg q8 hours until arrest of bleeding
   2. Bleeding in Urinary Tract: 10-15mg/kg q8 hours then switch to oral 20mg/kg q8
   3. Includes post-prostatectomy bleeding
   4. Oral Bleeding
   5. May have utility in symptomatic thrombocytopenia
   6. Cardiac Surgery - may have limited efficacy
   7. Treatment is continued until bleeding stops
6. Probably as effective as aprotonin and appears to be safer [1]

D. Aprotinin (Trasylol®)

1. Polypeptide MW 6512 from bovine lung
2. Anti-inflammatory, anti-fibrinolytic, and platelet-sparing effects
   1. Inhibits the proteases trypsin, chymotrypsin, plasmin, and kallikrein
   2. Blocks plasmin activity and kallikrein catalyzed formation of activated Factor XII
   3. Therefore, blocks initiation of coagulation, as well as clot dissolution
   4. Dose required for kalikrein inhibition is ~4X higher than that for plasmin inhibition
3. Indications
   1. Cardiac surgery - no longer recommended as increased overall mortality [3,12]
   2. Orthotopic liver transplantation - clearly reduces blood loss and transfusions [4]
   3. Pharmacologic reduction of blood loss with aprotonin or lysine analogues reduces mortality, need for transfusion, and rethoracotomy in heart surgery patients [5]
4. Administered as intravenous bolus followed by continuous infusion
   1. Cardiac surgery dose is 2 million units bolus, then 500,000 units IV drip via infusion
   2. Dose is similar in liver transplant
5. Some risk of hypersensitivity reactions
6. Risk Factors in CABG [3]
   1. Aprotinin associated with 2X risk of renal failure, 1.5X risk of MI or CHF, 1.8X risk of stroke or encephalopathy in CABG patients [7]
   2. Early mortality risk increased 1.3-1.8X versus lysine analogs after CABG [9,10,12]
   3. Overall 1.5X increased mortality at 5 years versus lysine analogs in CABG [3]
   4. Appears to be safe with respect to kidney function for on-pump cardiac surgery [8]
   5. Combined aprotinin and ACE inhibitors for off-pump cardiac surgery associated with significantly increased risk (1.8X) of post-operative renal dysfunction [8]
   6. In general, aprotonin use in CABG is not appropriate except in unusual circumstances

E. Recombinanat Activated Factor VII (rFVIIa, NovoSeven®) [6]

1. Labelled for treatment of bleeding episodes in hemophilia patients with inhibitors
2. rFVIIa is inactive until it reaches site of injury and binds tissue factor and activated platelets
   1. On binding tissue factor, Factor X is activated to Factor Xa
   2. Factor Xa generates small amounts of thrombin
   3. Small amounts of thrombin activate platelets further
3. Has been used very successfully to stop bleeding from trauma or surgery
4. Reduced growth of hematoma in acute intracerebral hemorrhage but did not improve clinical and did increase arterial thromboembolic events [11]
5. Generally safe but some increased risk of arterial (~55%) or venous (~45%) thromboses
6. Dosing
   1. Hemophilia: 90 µg/kg
   2. Serious bleeding or trauma: up to 200µg/kg initially, then 90-120 µg/kg
   3. Prostate cancer surgery: 20-40µg/kg single pre-operative injection
   4. No benefit shown with 100-120µg/kg in liver transplant patients
   5. May beneficial in bleeding esophageal varices in patients with Child Class B or C cirrhosis

F. Desmopressin

1. 1-D-amino-8-D-arginine vasopressin
2. Long acting analog of vasopressin (antidiuretic hormone, ADH)
3. Temporarily increases release of Factor VIII and von Willebrand factor from endothelial cells
4. Dose is 0.3µg/kg IV or 300µg for adults or 150µg for children intranasally
5. Utility
   1. Treatment of choice for Type 1 vWF disease
   2. Also clearly effective in mild hemophilia A
   3. May be effective in some patients with uremia (who have increased bleeding times)
   4. Shortens or normalizes bleeding times in these patients
   5. Not effective for reducing bleeding in most patients with cirrhosis
   6. May be used for anti-platelet drug induced bleeding (aspirin, clopidogrel,ticlopidine)

G. Factor VIII

1. For treatment of patients with hemophilia A
2. All patients previously untreated
3. Essentially no side effects, no treatment failures of recombinant protein
4. ~20% of hemophilia A patients develop inhibitors (anti-FVIII antibodies)
   1. These antibodies may cross react with porcine FVIII
   2. The antibody titers may decrease between factor infusions
   3. May require desensitization (tolerance) or immunosuppressive therapy
   4. Plasmapheresis may be required in emergent situations
5. Various factor preparations are available for bypassing anti-Factor VIII Abs
   1. Porcine Factor VIII
   2. Inhibitor Bypass activities - usually patients cross reactive inhibitors (FIBA)
   3. Activated Factor IX (F IXa) or activated Factor VII (F VIIa)
   4. None of these activities are as effective as Factor VIII itself

H. Factor IX

1. Replacement therapy for patients with severe hemophilia B
2. Recombinant Factor IX is now available

References

1. Mannucci PM and Levi M. 2007. NEJM. 356(22):2301
2. Mannucci PM. 1998. NEJM. 339(4):245
3. Mangano DT, Miao Y, Vuylsteke A, et al. 2007. JAMA. 297(5):471
4. Porte RJ, Molenaar IQ, Begliomini B, et al. 2000. Lancet. 355(9212):1303
5. Levi M, Cromheecke ME, de Jonge E, et al. 1999. 354(9194):1940
6. NovoSeven for Non-Hemophilia Hemostasis. 2004. Med Let. 46(1181):33
7. Mangano DT, Tudor IC, Dietzel C. 2006. NEJM. 354(4):353
8. Mouton R, Finch D, Davies I, et al. 2008. Lancet. 371(9611):475
9. Schneeweiss S, Seeger JD, Landon J, Walker AM. 2008. NEJM. 358(8):771
10. Shaw AD, Stafford-Smith M, White WD, et al. 2008. NEJM. 358(8):784
11. Mayer SA, Brun NC, Begtrup K, et al. 2008. NEJM. 358(20):2127
12. Fergusson DA, H©bert PC, Mazer CD, et al. 2008. NEJM. 358(22):2319