Medical Pharmacology Chapter 39: Drugs that Influence Coagulation

Drugs and Blood Coagulation

• Introduction

  • Abnormal states of hemostasis

    •  Bleeding (impaired hemostasis)

    •  Thrombus formation (stimulated hemostasis)

Blood Coagulation: Mechanisms

• Thrombogenesis: Sequence and Characteristics

  • Normal:

    • Normal vascular endothelial cells:

      • Not thrombogenic (platelet/clotting factors do not adhere)

       

    • "Blood coagulation pathways in vivo."

      Beards G "Blood coagulation pathways in vivo." http://en.wikipedia.org/wiki/File:Coagulation_in_vivo.png

  •  Injury. → thrombogenesis

    1. Immediate response: vasospasm

    2. Platelet adherence to damaged epithelium (binds to collagen) referred to as platelet adhesion. (collagen-platelet membrane glycoprotein Ia receptor interaction)

    3. Platelets binding to each other: platelet aggregation

    4. Platelets form a gelatinous mass (losing individual membranes): viscous metamorphosis. → platelet plug (temporary cessation of bleeding)

    5. Platelet plug -- reinforcement by fibrin

    6. Fibrin reinforcement:

       •  Damaged vessel .→ exposed collagen + platelet content released

         • Platelet degranulation releases aggregating substances:

           •  ADP

           •  TXA₂

           •  5-HT

       •  Local thrombin production:

         • Platelet ADP release (ADP inducer of platelet aggregation)

         • Prostaglandin synthesis (derived from platelet membrane arachidonic acid)

           • Thrombogenesis/vasoconstriction: thromboxane A₂ , TXA₂)

           • Thrombogenesis inhibitor: prostacyclin

  •  White Thrombus:

    • Where: high-pressure arteries

    • Circulating platelet adherence to regions of abnormal epithelium

    • Aggregated-platelet thrombus→ reduced flow

    • Red thrombus forms around white thrombus nidus

  •  Red Thrombus:

    • Forms either secondary to white thrombus or de novo -- low pressure veins

    • Thrombus forms a fibrin network longer tail entraps red cells)

      •  Fibrin tail may detach forming emboli which may travel to pulmonary arteries

  • Summary: platelets

    • Platelet nidus: most significant for arterial thrombus

      •  Concerns: arterial thrombi . → local vessel occlusion/ischemia

    • Fibrin tail (red thrombus):most significant for venous thrombus

      •  Concerns: venous thrombi .→ embolization at distant sites

•   Blood Coagulation-- soluble fibrinogen → insoluble fiber

  • Overview:  blood coagulation

    • Cascade process:

      • Clotting factors zymogen → limited proteolysis→active protease → activates next clotting factor→solid fibrin clot

  • Sequence:

    • Fibrinogen (factor I; soluble fiber precursor) substrate for thrombin (enzyme, factor IIa)→fibrin clot

      •  Thrombin formed from activation of its zymogen, prothrombin (factor II)

      •  Prothrombin (factor II): bound by a calcium to platelet phospholipid (PL); activated factor X (Xa) + activated factor Va converts prothrombin (factor II) → circulating thrombin

    • Possible initiation step:

      • Tissue factor (TF) + factor VII

    • Regulation factors:

      •  Tissue factor pathway inhibitor (TFPI)

      •  Endogenous anticoagulants: protein C, protein S: down-regulation of blood clotting amplification by proteolysis factors Va, VIIIa and IXa.

    • Drug influences:

      •  Oral anticoagulants: inhibits clotting factor synthesis (e.g.: heparin inhibits activity of certain activated factors.)

Classical Blood Coagulation Pathway

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.