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 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.
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 induce activation and aggregation of additional platelets on the injured endothelium. Another receptor is assembled on the platelet surface membrane from glycoproteins IIb and IIIa. Fibrinogen binds to the glycoprotein IIb/IIIa complexes of adjacent platelets, connecting them into aggregates.
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 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 molecular weight kininogen, prekallikrein, and activated factor XI (factor XIa) interact to 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 (the factor VIIa/tissue factor complex also activates factor IX—see Fig. 1: Pathways in blood coagulation. and Table 1: Components of Blood Coagulation Reactions).
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Activation of the intrinsic or extrinsic pathway activates the common pathway, resulting in formation of the fibrin clot. Three steps are involved in common pathway activation:
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.
The prothrombin activator cleaves prothrombin into thrombin and another fragment.
Thrombin induces the generation of fibrin polymers from fibrinogen. Thrombin also activates factor XIII, an enzyme that catalyzes formation of stronger bonds between adjacent fibrin monomers, as well as factor VIII and factor XI.
Ca2+ ions are needed in most thrombin-generating reactions (Ca2+-chelating agents [eg, citrate, ethylenediaminetetraacetic acid] are used in vitro as anticoagulants). Vitamin K–dependent clotting factors (factors II, VII, IX, and X) cannot bind normally to phospholipid surfaces through Ca2+ bridges and function in blood coagulation when the factors are synthesized in the absence of vitamin K.
Although the coagulation pathways 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 molecular weight 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 can be activated both by factor XIa and factor VIIa/tissue factor complexes.
In vivo, initiation of the extrinsic pathway occurs when injury to blood vessels brings blood into contact with 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. Factor IXa, combined with its cofactor, factor VIIIa, on phospholipid membrane surfaces generates additional factor Xa. Factor X activation by both factor VIIa/tissue factor and factor IXa/VIIIa complexes is required for normal hemostasis. This requirement for factors VIII and IX explains why hemophilia type A (deficiency of factor VIII) or type B (deficiency of factor IX) results in bleeding despite an intact extrinsic coagulation pathway initiated by factor VIIa/tissue factor complexes.
Several inhibitory mechanisms prevent activated coagulation reactions from amplifying uncontrollably, causing extensive local thrombosis or disseminated intravascular coagulation. These mechanisms include
Inactivation of coagulation factors:
Plasma protease inhibitors (antithrombin, tissue factor pathway inhibitor, α2-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 free protein S, form a complex that inactivates factors VIIIa and Va by proteolysis. Thrombin, when bound to a receptor on endothelial cells (thrombomodulin), activates protein C. Activated protein C, in combination with free protein S and phospholipid cofactors, proteolyzes and inactivates factors VIIIa and Va.
Fibrin deposition and lysis must be balanced to maintain temporarily and subsequently remove 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, and plasminogen activators cleave plasminogen into plasmin (see Fig. 2: Fibrinolytic pathway.). Plasmin then proteolyzes fibrin into soluble fibrin degradation products that are swept away in the circulation.
There are several plasminogen activators:
Streptokinase, urokinase, and recombinant tPA (alteplase) have all been used therapeutically to induce fibrinolysis in patients with acute thrombotic disorders.
Regulation of fibrinolysis:
Fibrinolysis 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 α2-antiplasmin, which quickly inactivates any free plasmin escaping from clots. Some α2-antiplasmin is also cross-linked to fibrin polymers by the action of factor XIIIa during clotting. This cross-linking 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 July 2012 by Joel L. Moake, MD
Content last modified September 2013