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Chapter 059. Bleeding and Thrombosis (Part 1)

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10.10.2023

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Harrisons Internal Medicine Chapter 59. Bleeding and ThrombosisBleeding and Thrombosis: Introduction The human hemostatic system provides a natural balance between procoagulant and anticoagulant forces. The procoagulant forces include platelet adhesion and aggregation and fibrin clot formation; anticoagulant forces include the natural inhibitors of coagulation and fibrinolysis.Under normal circumstances, hemostasis is regulated to promote blood flow; however, it is also prepared to clot blood rapidly to arrest blood flow and prevent exsanguination.After bleeding is successfully halted, the system remodels the damaged vessel to restore normal blood flow. The major components of the hemostatic system, which function in concert, are...
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Chapter 059. Bleeding and Thrombosis (Part 1) Chapter 059. Bleeding and Thrombosis (Part 1) Harrisons Internal Medicine > Chapter 59. Bleeding and Thrombosis Bleeding and Thrombosis: Introduction The human hemostatic system provides a natural balance betweenprocoagulant and anticoagulant forces. The procoagulant forces include plateletadhesion and aggregation and fibrin clot formation; anticoagulant forces includethe natural inhibitors of coagulation and fibrinolysis. Under normal circumstances, hemostasis is regulated to promote bloodflow; however, it is also prepared to clot blood rapidly to arrest blood flow andprevent exsanguination. After bleeding is successfully halted, the system remodels the damagedvessel to restore normal blood flow. The major components of the hemostaticsystem, which function in concert, are (1) platelets and other formed elements ofblood, such as monocytes and red cells; (2) plasma proteins (the coagulation andfibrinolytic factors and inhibitors); and (3) the vessel wall itself. Steps of Normal Hemostasis Platelet Plug Formation On vascular injury, platelets adhere to the site of injury, usually thedenuded vascular intimal surface. Platelet adhesion is mediated primarily by vonWillebrand factor (vWF), a large multimeric protein present in both plasma and inthe extracellular matrix of the subendothelial vessel wall, which serves as theprimary molecular glue, providing sufficient strength to withstand the highlevels of shear stress that would tend to detach them with the flow of blood.Platelet adhesion is also facilitated by direct binding to subendothelial collagenthrough specific platelet membrane collagen receptors. Platelet adhesion results in subsequent platelet activation and aggregation.This process is enhanced and amplified by humoral mediators in plasma (e.g.,epinephrine, thrombin); mediators released from activated platelets (e.g.,adenosine diphosphate, serotonin); and vessel wall extracellular matrixconstituents that come in contact with adherent platelets (e.g., collagen, vWF). Activated platelets undergo the release reaction, during which they secretecontents that further promote aggregation and inhibit the naturally anticoagulantendothelial cell factors. During platelet aggregation (platelet-platelet interaction), additionalplatelets are recruited from the circulation to the site of vascular injury, leading tothe formation of an occlusive platelet thrombus. The platelet plug is anchored andstabilized by the developing fibrin mesh. The platelet glycoprotein (Gp) IIb/IIIa (α IIbβ3) complex is the mostabundant receptor on the platelet surface. Platelet activation converts the normallyinactive GpIIb/IIIa receptor into an active receptor, enabling binding to fibrinogenand vWF. Because the surface of each platelet has about 50,000 GpIIb/IIIa fibrinogenbinding sites, numerous activated platelets recruited to the site of vascular injurycan rapidly form an occlusive aggregate by means of a dense network ofintercellular fibrinogen bridges. Since this receptor is the key mediator of plateletaggregation, it has become an effective target for antiplatelet therapy. Fibrin Clot Formation Plasma coagulation proteins (clotting factors) normally circulate in plasmain their inactive forms. The sequence of coagulation protein reactions thatculminate in the formation of fibrin was originally described as a waterfall or acascade. Two pathways of blood coagulation have been described in the past: theso-called extrinsic, or tissue factor, pathway and the so-called intrinsic, or contactactivation, pathway. We now know that coagulation is normally initiated throughtissue factor (TF) exposure and activation through the classic extrinsic pathway,but with critically important amplification through elements of the classic intrinsicpathway, as illustrated in Fig. 59-1. These reactions take place on phospholipidsurfaces, usually the activated platelet surface. Coagulation testing in thelaboratory can reflect other influences due to the artificial nature of the in vitrosystems used (see below). Figure 59-1

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