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Overview of Coagulation and Fibrinolysis

Overview of Coagulation and Fibrinolysis

Hemostasis, or the cessation of bleeding, occurs within the intravascular compartment lined with endothelium. Normal hemostasis and thrombosis involves a number of factors. These factors include platelets, granulocytes, and monocytes as well as the coagulation (clot forming), the fibrinolytic (clot lysing) and anticoagulant (regulating) protein systems. Each of the three protein systems balances the activities of the other. In addition, the integrity of the vessel wall endothelium is contributory. In recent years there has been a great evolution in our understanding of the physiologic hemostatic system ( Fig. 38-1 ). For decades the hemostatic system has been referred to as the ‘coagulation cascade’ based upon the waterfall hypothesis of Ratnoff & Davies and MacFarland who published, almost simultaneously, a sequence of proteolytic reactions starting with factor XII (Hageman factor) activation and ending with formed thrombin proteolyzing fibrinogen to form a clot ( Ratnoff, 1964 ; MacFarland, 1964 ). However, at the onset, this hypothesis for physiologic hemostasis was untenable. At the time of publication of these hypotheses, it was known that factor XII deficiency was not associated with bleeding ( Ratnoff, 1955 ). Thus the physiologic basis for this system to be activated by factor XII was questioned. Further, by the mid-1970s the cofactors for factor XII activation, prekallikrein and high-molecular-weight kininogen, were identified, and deficiencies of these proteins were not associated with a bleeding state ( Weuppers, 1972 ; Colman, 1975 ; Saito, 1975 ). Other mechanisms for physiologic hemostasis were sought. In 1977, Osterud and Rappaport recognized that factor VIIa is able to activate factor IX to factor IXa ( Osterud, 1977 ). Later, Broze and colleagues recognized that the kinetics of tissue factor pathway inhibitor (TFPI) were such that under physiologic circumstances the factor VIIa–tissue factor complex cannot directly activate factor X but has to go through factor IX activation ( Broze, 2003 ). These latter two studies indicate the important role of the factor VIIa–tissue factor pathway for physiologic hemostasis. A key remaining question was how does factor XI, whose deficiency is associated with bleeding, become activated under physiologic circumstances? In 1991, Gailiani and Broze found that formed thrombin can activate factor XI, resulting in amplification of the coagulation system under stress ( Gailiani, 1991 ). Presently, physiologic hemostasis is believed to be an interacting system of activation and amplification of several zymogens that become serine proteases. The initiator of physiologic hemostasis is factor VIIa when bound to its cofactor tissue factor. Regulation of expression of tissue factor provides a major modulation of physiologic hemostasis. Thrombin in turn amplifies the process by activating factor XI, leading to additional factor IX activation. The fibrinolytic system's role is to lyse clot formed by thrombin. The anticoagulation system's role is to regulate all the enzymes of the coagulation and fibrinolytic systems so that there is no inappropriate excess of clotting or bleeding.

 

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Figure 38-1  Schematic diagram of physiologic hemostasis. Note that the ‘contact phase’ factors comprising factor XII, HK (high molecular weight kininogen) and PK (prekallikrein) are shown grayed; although factor XI can be activated by this route under artificial in vitro conditions such as in the PTT test (see Fig. 38-8 ), this pathway is not believed to contribute to normal physiologic hemostasis. Similarly, whereas Tissue factor/VIIa can directly activate X to Xa in the in vitro PT test under conditions which supra-physiological concentrations of Tissue factor are employed, this reaction is shown as grayed because it does not contribute significantly to clot formation under normal in vivo physiological conditions. Normal clotting in vivo accordingly is initiated when sufficient Tissue factor/VIIa becomes available to activate factor IX to IXa. Subsequently, IXa in the presence of VIIIa activates X to Xa, which in turn activates prothrombin to thrombin in the presence of Va. Thrombin not only then proceeds to clot fibrinogen and to activate platelets (see Fig. 38-2 ), but additionally exerts critically important positive feedback by activating factors VIII and V. Thrombin has further been shown capable of activating factor XI, thereby providing an additional pathway for the activation of factor IX. PL (phosopholipid present on the surface membranes of platelets in vivo) and Ca++ (calcium ions) contribute to reactions as indicated.

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It is important for the pathologist to understand the physiologic basis of hemostasis. However, the clinical laboratory assays used to examine the coagulation system are based upon the original coagulation cascade hypothesis. Although these tests do not represent physiologic hemostasis, they are still very useful for diagnosis of potential bleeding disorders. Thus the pathologist needs to understand the distinction between physiologic coagulation, fibrinolysis, and anticoagulation and the tests that we use to measure these systems. This chapter endeavors to clarify this distinction for the reader. In the first part of this chapter, the details of physiologic coagulation, fibrinolysis, and the regulation of coagulation will be presented. In the second part of this chapter, a description of the assays performed to measure bleeding disorders will be presented, together with a discussion of the limitations of these assays for characterizing physiologic hemostasis. In the third part of this chapter, an overview of congenital bleeding disorders will be presented. Last, this chapter will present the acquired bleeding disorders, the most common forms of bleeding states one actually encounters.

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