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Hemostasis, the arrest of bleeding from an injured blood vessel, requires the combined activity of vascular, platelet, and plasma factors. Regulatory mechanisms counterbalance the tendency of clots to form. Hemostatic abnormalities can lead to excessive bleeding or thrombosis.
Vascular
Factors
Vascular factors reduce blood loss from trauma through local vasoconstriction (an immediate reaction to injury) and compression of injured vessels by extravasation of blood into surrounding tissues. Vessel wall injury triggers the attachment and activation of platelets and production of fibrin; platelets and fibrin combine to form a clot.
Platelet
Factors
Various mechanisms, including endothelial cell nitric oxide and prostacyclin, promote blood fluidity by preventing platelet stasis and dilating intact blood vessels. These mediators are no longer produced when the vascular endothelium is disrupted. Under these conditions, platelets adhere to the damaged intima and form aggregates. Initial platelet adhesion is to von Willebrand's factor (VWF), previously secreted by endothelial cells into the subendothelium. VWF binds to receptors on the platelet surface membrane (glycoprotein Ib/IX). Platelets anchored to the vessel wall undergo activation. During activation, platelets release mediators from storage granules, including adenosine diphosphate (ADP). Other biochemical changes resulting from activation include hydrolysis of membrane phospholipids, inhibition of adenylate cyclase, mobilization of intracellular Ca, and phosphorylation of intracellular proteins. Arachidonic acid is converted to thromboxane A2; this reaction requires cyclooxygenase and is inhibited irreversibly by aspirin and reversibly by many NSAIDs. ADP, thromboxane A2, and other mediators draw additional platelets to the injured endothelium (platelet aggregation) and activate them. Another receptor is assembled on the platelet surface membrane from glycoproteins IIb and IIIa. Fibrinogen binds to the glycoprotein IIa-IIIb complexes of adjacent platelets, connecting them.
Platelets provide surfaces for the assembly and activation of coagulation complexes and the generation of thrombin. Thrombin converts fibrinogen to fibrin; fibrin strands bind aggregated platelets to help secure the platelet-fibrin hemostatic plug.
Plasma
Factors
Plasma coagulation factors interact to produce thrombin, which converts fibrinogen to fibrin. Radiating from and anchoring the hemostatic plug, fibrin strengthens the clot.
In the intrinsic pathway, factor XII, high mol wt kininogen, prekallikrein, and activated factor XI (factor XIa) produce factor IXa from factor IX. Factor IXa then combines with factor VIIIa and procoagulant phospholipid (present on the surface of activated platelets and tissue cells) to form a complex that activates factor X. In the extrinsic pathway, factor VIIa and tissue factor directly activate factor X (see
Fig. 1: Hemostasis: Pathways in blood coagulation. and
Table 1: Hemostasis: Components of Blood Coagulation Reactions  ).
Activation of the intrinsic or extrinsic pathway activates the common pathway, resulting in formation of the fibrin clot. Three steps are involved: (1) A prothrombin activator is produced on the surface of activated platelets and tissue cells. The activator is a complex of an enzyme, factor Xa, and 2 cofactors, factor Va and procoagulant phospholipid. (2) The prothrombin activator cleaves prothrombin into thrombin and another fragment. (3) Thrombin induces the generation of fibrin polymers from fibrinogen. Thrombin also activates factor XIII, an enzyme that catalyzes formation of stronger bonds between fibrin molecules, as well as factor VIII and factor XI.
Ca ions are needed in most thrombin-generating reactions (Ca-chelating agents [eg, citrate, ethylenediaminetetraacetic acid] are used in vitro as anticoagulants). Vitamin K–dependent clotting factors (factors II, VII, IX, and X) normally cannot bind to phospholipid surfaces through Ca bridges or function in blood coagulation when synthesized in the absence of vitamin K.
Although the coagulation pathways described above are helpful in understanding mechanisms and laboratory evaluation of coagulation disorders, in vivo coagulation is predominantly via the extrinsic pathway. People with hereditary deficiencies of factor XII, high mol wt kininogen, or prekallikrein have no bleeding abnormality. People with hereditary factor XI deficiency have a mild to moderate bleeding disorder. In vivo, factor XI (an intrinsic pathway factor) is activated when a small amount of thrombin is generated. Factor IX (an intrinsic factor) is activated by the extrinsic pathway.
In vivo initiation of the extrinsic pathway occurs directly when injury to blood vessels brings blood into contact with the tissue factor on membranes of cells within and around the vessel walls. This contact with tissue factor generates factor VIIa/tissue factor complexes that activate factor X and factor IX (an intrinsic factor). Factor IXa, combined with its cofactor, factor VIIIa, on phospholipid membrane surfaces generates additional factor Xa. Factor X activation by both routes is required for normal hemostasis. This requirement for factors VIII and IX explains why hemophilia (deficiency of either factor VIII or factor IX) results in bleeding despite an intact extrinsic coagulation pathway.
Regulatory
Mechanisms
Several inhibitory mechanisms prevent activated coagulation reactions from amplifying uncontrollably, causing extensive local thrombosis or disseminated intravascular coagulation. These mechanisms include inactivation of procoagulant enzymes, fibrinolysis, and clearance of activated clotting factors, especially by the liver.
Inactivation of coagulation
factors:
Plasma protease inhibitors (antithrombin, tissue factor pathway inhibitor, α
2-macroglobulin, heparin cofactor II) inactivate coagulation enzymes. Antithrombin inhibits thrombin, factor Xa, factor XIa, and factor IXa. Heparin enhances antithrombin activity.
Two vitamin K–dependent proteins, protein C and protein S, form a complex that inactivates factors VIIIa and Va by proteolysis. Thrombin, when bound to a receptor on endothelial cells called thrombomodulin, activates protein C. Activated protein C combines with protein S and phospholipid as cofactors to proteolyze factors VIIIa and Va.
Fibrinolysis:
Fibrin deposition and lysis must be balanced to maintain and remold the hemostatic seal during repair of an injured vessel wall. The fibrinolytic system dissolves fibrin by means of plasmin, a proteolytic enzyme. Fibrinolysis is activated by plasminogen activators released from vascular endothelial cells. Plasminogen activators and plasminogen from plasma bind to fibrin. Plasminogen activators catalyze cleavage of plasminogen, creating plasmin (see
Fig. 2: Hemostasis: Fibrinolytic pathway.). Plasmin produces soluble fibrin degradation products that are swept into the circulation.
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Fig. 2
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Fibrinolytic pathway.
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Fibrin deposition and fibrinolysis must be balanced during repair of an injured blood vessel wall. Injured vascular endothelial cells release plasminogen activators (tissue plasminogen activator, urokinase), activating fibrinolysis. Plasminogen activators catalyze cleavage of plasminogen, creating plasmin, which dissolves clots. Fibrinolysis is controlled by plasminogen activator inhibitors (PAls; eg, PAl-1) and plasmin inhibitors (eg, α
2-antiplasmin).
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Plasminogen activators are categorized into several types. Tissue plasminogen activator (tPA), from endothelial cells, is a poor activator when free in solution but an efficient activator when bound to fibrin in proximity to plasminogen. A second type, urokinase, exists in single-chain and double-chain forms with different functional properties. Single-chain urokinase cannot activate free plasminogen but, like tPA, can readily activate plasminogen bound to fibrin. A trace concentration of plasmin cleaves single-chain to double-chain urokinase, which activates plasminogen in solution as well as plasminogen bound to fibrin. Epithelial cells that line excretory passages (eg, renal tubules, mammary ducts) secrete urokinase, which is the physiologic activator of fibrinolysis in these channels. Streptokinase , a bacterial product not normally found in the body, is another potent plasminogen activator. Streptokinase , urokinase, and recombinant tPA ( alteplase ) have all been used therapeutically to induce fibrinolysis in patients with acute thrombotic disorders.
Regulation of
fibrinolysis:
Fibrinolysis itself is regulated by plasminogen activator inhibitors (PAIs) and plasmin inhibitors that slow fibrinolysis. PAI-1, the most important PAI, inactivates tPA and urokinase and is released from vascular endothelial cells and activated platelets. The primary plasmin inhibitor is α
2-antiplasmin, which quickly inactivates free plasmin escaping from clots. Some α
2-antiplasmin is also cross-linked by factor XIIIa to fibrin during clotting; it may prevent excessive plasmin activity within clots. tPA and urokinase are rapidly cleared by the liver, which is another mechanism of preventing excessive fibrinolysis.
Last full review/revision November 2005
Content last modified November 2005
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