Porth's Essentials of Pathophysiology, 4e

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Hematopoietic Function

U N I T 3

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The Coagulation Cascade The coagulation cascade is the third component of the hemostasis. It is a stepwise process resulting in the con- version of the soluble plasma protein fibrinogen into insoluble fibrin strands. The fibrin strands create a meshwork that cements platelets and other blood com- ponents together to form the clot. The coagulation process results from the activation of what have traditionally been designated the intrinsic and the extrinsic pathways 1,3 (Fig. 12-3). The intrinsic pathway, which is a relatively slow process, begins in the circulation with the activation of factor XII (Hageman factor). The extrinsic pathway, which is a much faster process, begins with trauma to the blood vessel or sur- rounding tissues and the release of an adhesive lipopro- tein called tissue factor (also known as thromboplastin or factor III) from the subendothelial cells. In the presence of calcium, factors V and VII form a complex that, in turn, activates factor X. The terminal steps in both path- ways are the same: the activation of factor X and the con- version of prothrombin (II) to thrombin (IIa). Thrombin then acts as the enzyme to convert fibrinogen (I) to fibrin (Ia), the material that stabilizes a clot. The intrinsic sys- tem is activated as blood comes in contact with collagen in the injured vessel wall; the extrinsic system is activated when blood is exposed to tissue extracts. However, this classification is largely artificial since both systems are needed for normal hemostasis, and many interrelations exist between them. 8 Moreover, each system is activated when blood leaks out of the vascular system.

Clinical laboratories assess the function of the two limbs of the coagulation pathway through two standard assays: the prothrombin time (PT) and the partial throm- boplastin time (PTT). The PT assesses the function of the extrinsic pathway (factors VII, X, V, II, and fibrinogen), while the PTT assesses the function of the intrinsic path- way (factors XII, XI, IX, VII, X, V, II, and fibrinogen). 3 Once initiated, the coagulation cascade must be restricted to the local site of vascular injury to prevent clotting from occurring in the entire vascular system. Several natural anticoagulants function to control clot- ting—antithrombin III, proteins C and S, and tissue factor pathway inhibitor. 4 Antithrombin III inhibits the activity of thrombin (IIa) and factors IXa, Xa, XIa, and XIIa (see Fig. 12-3). It is activated by binding to hepa- rin-like molecules on endothelial cells. Proteins C and S are two vitamin K–dependent plasma proteins that inac- tivate the cofactors Va and VIIIa. Tissue factor pathway inhibitor is a protein secreted by the endothelium that inactivates factor Xa and tissue factor VIIa complexes. The anticoagulant drugs warfarin and heparin are used to prevent thromboembolic disorders, such as deep vein thrombosis and pulmonary embolism. 6 Warfarin acts by decreasing prothrombin and other procoagula- tion factors. It alters vitamin K in a manner that reduces its ability to participate in the synthesis of the vitamin K–dependent coagulation factors in the liver. Warfarin is readily absorbed after oral administration. Its maximum effect takes 36 to 72 hours because of the varying half- lives of different clotting factors that remain in the circu- lation. Heparin is naturally formed and released in small

Intrinsic system (blood or vessel injury)

XII

XIIa

XI

XIa

Extrinsic system (tissue factor)

IXa Ca ++

IX

VIIa

VII

VIII

Ca ++

Thrombin

VIIIa

Xa Ca ++

X

X

FIGURE 12-3. The intrinsic and extrinsic coagulation pathways. The terminal steps in both pathways is the same. Calcium, factor X, and platelet phospholipids combine to form prothrombin activator, which then converts prothrombin (II) to thrombin (IIa).This interaction causes conversion of fibrinogen (I) into the fibrin (Ia) strands that create the insoluble blood clot.

Prothrombin

Thrombin

Ca ++

Fibrinogen

Fibrin (monomer)

Fibrin (polymer)