Page 1974 - Williams Hematology ( PDFDrive )

1949

CHAPTER 114 clot is extended beyond its beneficial size, when a clot occurs inappropri-

CONTROL OF COAGULATION ately at sites of vascular disease, or when a clot embolizes to other sites in
the circulatory bed. For normal hemostasis, both procoagulant and anticoag-
REACTIONS ulant factors must interact with the vascular components and cell surfaces,
including the vessel wall (Chap. 115) and platelets (Chap. 112). Moreover, the
action of the fibrinolytic system must be integrated with coagulation reactions
for timely formation and dissolution of blood clots (Chap. 135). This chapter
Laurent O. Mosnier and John H. Griffin on control of coagulation highlights the major physiologic mechanisms for
downregulation of blood coagulation reactions and the plasma proteins that
inhibit blood coagulation, with an emphasis on those mechanisms whose
SUMMARY defects are clinically significant based on insights gleaned from consideration
of the hereditary thrombophilias (Chap. 130). Chapter 113 provides a complete
The blood coagulation system, like a powerful idling engine, is always active description of blood coagulation factors and hemostatic pathways.
and generating thrombin at very low levels, poised for explosive thrombin
generation. Positive feedback activation of factors V, VII, VIII, and XI imparts
special threshold properties to blood coagulation, making the coagulant
response nonlinearly responsive to stimuli. Overt blood coagulation represents BLOOD COAGULATION PATHWAYS
a threshold system with apparent all-or-none responses to various levels of
stimuli, and an ensemble of opposing reactions determines the ultimate AND THE PROTEIN C PATHWAYS
upregulation and downregulation of thrombin generation both locally and Although decades have elapsed since the elaboration of the cascade
systemically. Cellular and humoral anticoagulant mechanisms synergize with model for blood coagulation (see Chap. 113, Fig. 113–27), the basic
1,2
plasma coagulation inhibitors to prevent massive thrombin generation in the outline of sequential conversions of protease zymogens to active ser-
absence of a substantial procoagulant stimulus. This chapter highlights mech- ine proteases is still useful, albeit with important modifications (see
anisms that inhibit blood coagulation, with an emphasis on defects of plasma Chap. 113, Fig. 113–28), to represent blood coagulation reactions. The
proteins that cause hereditary thrombophilias. Major thrombophilic defects major conceptual advances for procoagulant pathways in the past two
involve the anticoagulant protein C pathway, comprising multiple cofactors decades emphasize both positive and negative feedback reactions affect-
or effectors that additionally include thrombomodulin, endothelial protein C ing thrombin generation as depicted in Fig. 114–1.
receptor, protein S, high-density lipoprotein, and factor V. Activated protein C In positive feedback reactions, procoagulant thrombin activates
3–5
exerts multiple protective homeostatic actions, including proteolytic inactiva- platelets and factors V, VIII, and XI (Chap. 113). Small amounts of
tion of factors Va and VIIIa, as well as direct cell-signaling activities involving thrombin can be generated by trace amounts of tissue factor via the
extrinsic pathway. Subsequently, thrombin can activate factors XI, VIII,
protease activated receptors 1 and 3, endothelial cell protein C receptor, inte- and V, thereby stimulating each of the steps in the intrinsic pathway,
grin CD11b/CD18, and apolipoprotein E receptor 2. The factor V Leiden variant thereby amplifying thrombin generation (see Fig. 114–1).
causes hereditary activated protein C resistance by impairing the ability of the In negative feedback reactions, anticoagulant activated protein
protein C pathway to inhibit coagulation because it cannot properly cleave C (APC) that is generated on endothelial cell surfaces (Fig. 114–2)
6–8
factor Va Leiden. Plasma protease inhibitors are also key to block coagulation. downregulates coagulation (see Figs. 114–1 and 114–3). Furthermore,
Antithrombin inhibits thrombin and factors Xa, IXa, XIa, and XIIa, in reactions APC can exert direct cytoprotective effects on cells via reactions that
stimulated by physiologic heparan sulfate or pharmacologic heparins. Tissue involve certain receptors, including endothelial cell protein C recep-
factor pathway inhibitor neutralizes the extrinsic coagulation pathway factors tor (EPCR) and protease-activated receptor-1 (PAR-1) (Fig. 114–4),
VIIa and Xa. Other plasma protease inhibitors can also neutralize various coag- PAR-3, integrin CD11b/CD18, and possibly apolipoprotein E receptor 2
7,8
ulation proteases. (apoER2). APC’s cytoprotective effects include antiinflammatory and
Control of coagulation reactions is essential for normal hemostasis. As part antiapoptotic activities, as well as alterations of gene-expression profiles
of the tangled web of host defense systems that respond to vascular injury, the and stabilization of endothelial barriers (see “Activated Protein C Activ-
ities” below). Because inflammation, apoptosis, and vascular barrier
blood coagulation factors (Chap. 113) act in concert with the endothelium and breakdown contribute significantly to reactions that promote thrombin
blood cells, especially platelets, to generate a protective fibrin-platelet clot, generation, such direct cytoprotective effects of APC on cells indirectly
forming a hemostatic plug. Pathologic thrombosis occurs when the protective downregulate thrombin generation. 7,8
For APC generation by the protein C cellular pathway, binding
of thrombin to thrombomodulin converts the bound thrombin from
a procoagulant enzyme to an anticoagulant enzyme that converts the
protein C zymogen to an anticoagulant serine protease, APC (see Figs.
Acronyms and Abbreviations: APC, activated protein C; apoER2, apolipoprotein E 114–1 and 114–2). This surface-dependent reaction is enhanced by the
receptor 2; CD11b/CD18, Mac-1; EPCR, endothelial cell protein C receptor; GLA, γ-car- EPCR that binds protein C. 6,9,10 With the aid of its nonenzymatic cofac-
boxyglutamic acid; GPI, glycosylphosphatidylinositol; HDL, high-density lipoprotein; tor, protein S, as well as other potential lipid and protein cofactors, APC
NMDA, N-methyl-d-aspartate; PAR-1, protease-activated receptor-1; serpin, serine inactivates factors Va and VIIIa by highly selective proteolysis, yielding
protease inhibitor; SHBG, sex hormone–binding globulin; TFPI, tissue factor pathway inactive (i) cofactors, that is, factors V and VIII (see Fig. 114–3 and
i
i
inhibitor; TNF, tumor necrosis factor; ZPI, protein Z–dependent protease inhibitor. Chap. 113, Figs. 113–11 and 113–13). Protein S also can directly inhibit
factors VIIIa, Xa, and Va. 11–13 Thus, APC and protein S inhibit multiple
steps in the intrinsic coagulation pathway.

Kaushansky_chapter 114_p1949-1966.indd 1949 9/18/15 10:05 AM