Hemostasis and Thrombosis PDF

Hemostasis and Thrombosis  Normal hemostasis comprises a series of regulated processes that maintain blood in a fluid, clot-free state in normal vessels while rapidly forming a localized hemostatic plug at the site of vascular injury.  The pathologic counterpart of hemostasis is thromb...

Hemostasis and Thrombosis  Normal hemostasis comprises a series of regulated processes that maintain blood in a fluid, clot-free state in normal vessels while rapidly forming a localized hemostatic plug at the site of vascular injury.  The pathologic counterpart of hemostasis is thrombosis, the formation of blood clot (thrombus) within intact vessels.  Both hemostasis and thrombosis involve three elements: vascular wall Platelets coagulation cascade.  Normal Hemostasis After initial injury a brief period of arteriolar vasoconstriction occurs allowing platelets to adhere and be activated. Activation of platelets results in a dramatic shape change (from small rounded disks to flat plates with markedly increased surface area) & release of secretory granules.  Within minutes the secreted products have recruited additional platelets (aggregation) to form a hemostatic plug; this is the process of primary hemostasis.  Tissue factor is also exposed at the site of injury. It acts in conjunction with factor VII to activate the coagulation cascade, eventually culminating in thrombin 'generation which cleaves circulating fibrinogen into insoluble fibrin, Creating a fibrin meshwork deposition.  Thrombin also induces further platelet recruitment and granule release. This secondary hemostasis sequence lasts ‘longer than the initial platelet plug. Fibrin and platelet aggregates form a solid permanent plug to prevent any additional hemorrhage.  Endothelial Cells and Coagulation Intact, normal endothelial cells help to maintain blood flow by inhibiting the activation of platelets and coagulation factors.  Endothelial cells stimulated by injury or inflammatory cytokines up regulate expression of procoagulant factors (e.g., tissue factor) that promote clotting, and down regulate expression of anticoagulant factors.  Loss of endothelial integrity exposes subendothelial vWF and basement membrane collagen, stimulating platelet adhesion, platelet activation, and clot formation.  Platelet Adhesion, Activation, and Aggregation Endothelial injury exposes the underlying basement membrane ECM; platelets adhere to the ECM primarily through binding of platelet GpIb receptors to vWF.  Adhesion leads to platelet activation, an event associated with: Secretion of platelet granule contents, including calcium (a cofactor for several coagulation proteins) and ADP (a mediator of further platelet activation) Dramatic changes in shape and membrane composition Activation of GpIIb/IIIa receptors.  The GpIIb/IIIa receptors on activated platelets form bridging crosslinks with fibrinogen, leading to platelet aggregation. Concomitant activation of thrombin promotes fibrin deposition, cementing the platelet plug in place.  Thrombosis There are three primary influences on thrombus formation (Virchow's triad): 1. Endothelial injury, 2. Stasis or turbulence of blood flow. 3. Blood hypercoagulability.  Endothelial injury Endothelial injury is an important cause of thrombosis, particularly in the heart and the arteries, where high flow rates might otherwise impede clotting by preventing platelet adhesion or diluting coagulation factors Ex. thrombosis occur in the cardiac chambers after myocardial infarction and over ulcerated plaques in atherosclerotic arteries  Physical loss of endothelium exposes subendothelial ECM (leading to platelet adhesion), releases tissue factor, and reduces local production of PGI2 and plasminogen activators. Endothelial dysfunction occur in hypertension ,bacterial products, radiation injury, and hypercholesterolemia, and toxins absorbed from cigarette smoke. Alterations in Normal Blood Flow Turbulence contributes to thrombosis by causing endothelial injury or dysfunction, as well as by forming local stasis Stasis is a major contributor to the development of venous thrombi.  Normal blood flow is laminar, so that platelets flow centrally in the vessel lumen, separated from the endothelium by a slower moving clear zone of plasma.  Hypercoagulability It is defined as any alteration of the coagulation pathways that predisposes to thrombosis, and it can be divided into primary (genetic) and secondary (acquired)disorders  Primary (inherited) hypercoagulable.states Ex, mutations in the prothrombin gene which are the most common Causes of secondary hypercoagulable states Cardiac failure &trauma in both stasis or vascular injury may be most important. Oral contraceptive use and the hyperestrogenic state of pregnancy, probably related to increased hepatic synthesis of coagulation factors and reduced synthesis of antithrombin III.  Advance age due to increasing platelet aggregation. Smoking and obesity promote hypercoagulability by unknown mechanisms.  Morphology Thrombi can develop anywhere in the cardiovascular system (e.g., in cardiac chambers, on valves," or in arteries, veins, or capillaries). The size and shape of a thrombus depend on the site of origin and the cause.  Arterial or cardiac thrombi typically begin at sites of endothelial injury or turbulence; venous thrombi characteristically occur at sites of stasis.  Thrombi are focally attached to the underlying vascular surface; arterial thrombi tend to grow in a retrograde direction from the point of attachment, while venous thrombi extend in the direction of blood flow (thus both tend to propagate toward the heart).  The propagating portion of a thrombus tends to be poorly attached and therefore prone to fragmentation, generating an embolus.  Thrombi can have grossly (and microscopically) laminations called lines of Zahn; these represent pale platelet and fibrin layers alternating with darker red cell–rich layers. Significant …they are only found in thrombi that form in flowing blood; and therefore usually distinguish antemortem thrombosis from the bland non laminated clots that form in the postmortem state.  Post Mortem Clotting of blood: Blood separates: - upper plasma layer - translucent, like chicken fat - lower red blood cell layer - very red and resembles red current jelly Difference between post/ante mortem clotting: - Post mortem: no damage to inner surface of vessel and clot can be easily removed - Ante mortem: firmly attached to underlying vascular endothelium, has a white interior and is layered  Fate of the Thrombus Propagation. Thrombi accumulate additional platelets and fibrin, eventually causing vessel obstruction.  Embolization. Thrombi dislodge or fragment and are transported elsewhere in the vasculature.  Dissolution. Thrombi are removed by fibrinolytic activity. Organization and recanalization. Thrombi induce inflammation and fibrosis (organization). These can eventually recanalize (re-establishing some degree of flow), or they can be incorporated into a thickened vessel wall.