Medical Pharmacology Chapter 39: Drugs that Influence Coagulation

Pharmacological Management of Thrombosis

• Venous Thrombosis

  • Most common genetic risk factor: activated protein C resistance

    • Frequency: 20% of patients diagnosed with their first deep venous thrombosis

    • Relative risk: 8X-- heterozygotes; 80X in homozygotes

  • Acquired Disease:

    • Increased thromboembolism risk: associated with arrhythmia

      • Long-term proven efficacy of oral anticoagulants in management of chronic atrial fibrillation

    • Increased thromboembolism risk: associated with prolonged bed rest (deep venous thrombosis/embolism)

  • Antithrombotic Management:

    • Prevention: Goal -- reduce incident/mortality rate from pulmonary embolism

    • Heparin:   prevention of venous thrombosis

      • Intermittent administration (effective prophylaxis) -- subcutaneous

    • Oral Anticoagulants:

      • Generally limited use due to bleeding risk/laboratory prothrombin time monitoring

      • Effective prophylaxis for patients with:

        • Atrial fibrillation

        • Prosthetic heart valves

    • Early postoperative ambulation-- reducing venous stasis

      • Also effective: external pneumatic leg compression

    • Enoxaparin  (Lovenox)-- approved for prophylaxis only in hip replacement patients.

  • Venous Thrombosis -- established

    • Heparin & warfarin -- maximal dosages; similar treatment for pulmonary embolism

    • Small thrombi -- calf veins -- often managed without anticoagulants

    • In patients with recurring thrombi and a positive family history:

      •  Evaluate for protein C or protein S deficiency

      •  Antithrombin III concentrate: maybe helpful in deficient patients

      •  Heparin resistance (associate with antithrombin III deficiency) -- overcome with concentrate

    •  Note:  since warfarin crosses the placental barrier, venous thromboembolic disease in pregnant women: subcutaneous heparin with mandatory monitoring of anticoagulant effect.

• Arterial Thrombosis

  • Platelet-inhibiting agents:

    • Examples

      • Aspirin

      • Ticlopidine (Ticlid)

  • Clinical Uses:  platelet-inhibiting agents

    • Management of unstable angina, transient ischemic attacks, strokes, acute myocardial infarction

    • In myocardial infarction and angina, platelets inhibiting drugs used in combination with:

      •  β-blockers

      • Calcium channel blockers

      • Fibrolytic agents

 Drugs Used in Bleeding Disorders

• Vitamin K

  • Required for biological activity of:

    • Prothrombin

    • Factors VII, IX, X

  • Fat-soluble, available from diet & synthesized by human intestinal bacteria

  • Two natural forms:

    •  Vitamin K₁

      • Phytonadione, from food

    •  Vitamin K₂

      • Menaquinone, found in human tissue, bacterial synthesis

  • Vitamins K₁ and K₂-- require bile salts for absorption from intestinal tract

  • Clinical Issues:vitamin K

    • Vitamin K₁:

      • Given to all newborns; preventative of hemorrhagic due to  vitamin K deficiency (common in premature infants)

      • Deficiency:

        • Hospitalized patients (ICU) due to:

          • Poor diet

          • Parenteral nutrition

          • Recent surgery

          • Multiple antibiotic treatment

          • Uremia

Plasma Fractions:  Bleeding due to factor deficiencies

• Overview:  factors

  • Coagulation defects: primarily --

    • Factor VIII deficiency:  classic hemophilia (hemophilia A)

    • Factor IX deficiency:  Christmas disease, hemophilia B)

    • Concentrated plasma fractions: available to manage hemophilia A & B

  • Factor VIII:-- 2 preparations

    • Cryoprecipitate:  plasma protein fraction; derived from whole blood

      •  Hemophilia (factor VIII)

      •  von Willebrand's disease

      •  Source of fibrinogen (occasionally)

      •  Must match Rh status, i.e. RH-negative women should receive only RH-negative cryoprecipitate

    • Lyophilized factor VIII concentrates:

      • Derived from plasma pools (cryoprecipitate from individual donors, probably safer)

      • Reduced danger of viral disease (hepatitis B, hepatitis C, HIV) transmission by:

        • Pasteurization

        • Ultraviolet radiation

    • Desmopressin acetate (arginine vasopressin)

      • Increases factor VIII activity in patients with mild hemophilia or von Willebrand's disease.

      • Clinically used before minor surgery (e.g.,dental)

  • Factor IX:

    • Freeze-dried plasma concentrates containing:

      • Prothrombin, factor IX, factor X, factor VII

      • Coagulation factors may be activated in manufacturing (heparin may be added to inhibit these factors)

  • Fibrinogen:

    • Forms: plasma, factor VIII cryoprecipitate, lyophilized factor VIII concentrates.

Fibrolytic Inhibitors:  aminocaproic acid

• Aminocaproic acid (Amicar)

  • Aminocaproic Acid

  • Competitive inhibitor of plasminogen activation

  • Rranexamic acid -- aminocaproic acid analog; similar activity

  • Clinical Uses:aminocaproic acid

    • Therapy for bleeding following fibrolytic treatment

    • Adjunctive therapy in hemophilia

    • Prophylaxis: re-bleeding from intracranial aneurysms

  •  Adverse Effects:aminocaproic acid

    • Intravascular thrombosis secondary to plasminogen activator inhibition

    • Hypotension

    • Myopathy

    • Gastrointestinal disturbances

Serine Protease Inhibitors: Aprotinin

• Aprotinin

  • Serine protease inhibitor

  • Inhibits plasmin-streptokinase complex in patients receiving this thrombolytic treatment

  • Significant reduction in bleeding in certain surgeries:

    • Currently approved for patients undergoing coronary artery bypass grafting in which there is a high-risk for excessive blood loss

Primary Reference: O'Reilly, R.A. Drugs Used in Disorders of Coagulation, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 916-940

Handlin, R.I. Bleeding and Thrombosis, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 339-344.