Overview of Hemostasis

Vascular factors reduce blood loss due to 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 the generation of fibrin polymers from fibrinogen; platelets and fibrin combine to form a clot.

Various mechanisms, including endothelial cell nitric oxide and prostacyclin, promote blood fluidity by preventing platelet aggregation 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 long strings of von Willebrand factor (VWF) that have been previously secreted by, and anchored to, stimulated endothelial cells. 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 of aggregation, including adenosine diphosphate (ADP) from storage granules.

Other biochemical changes resulting from activation include

Arachidonic acid is converted to thromboxane A2; this reaction requires platelet cyclooxygenase and is inhibited irreversibly by aspirin and reversibly by many NSAIDs (nonsteroidal anti-inflammatory drugs).

ADP, thromboxane A2, and other mediators induce activation and aggregation of additional platelets on the injured endothelium. Platelet receptors for ADP include the P2Y12 receptor, which sends signals to suppress adenylate cyclase, decreases cyclic adenosine monophosphate (cAMP) levels, and promotes activation of the glycoprotein IIb/IIIa receptor (assembled on the activated 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 into fibrin monomers, and the fibrin monomers polymerize into fibrin polymers that bind aggregated platelets into platelet-fibrin hemostatic plugs.

Coagulation factors interact on platelet and endothelial cell surfaces to produce thrombin, which converts fibrinogen to fibrin. By 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, endothelial cells, and tissue cells) to form a complex that activates factor X.

In the extrinsic pathway, factor VIIa and tissue factor (TF) directly activate factor X (and, perhaps, also factor IX—see figure Pathways in blood coagulation Pathways in Blood Coagulation and table Components of Blood Coagulation Reactions Components of Blood Coagulation Reactions ).

Many (or most) coagulation proteins are produced in vascular endothelial cells, including the endothelial cells lining liver sinusoids. Some coagulation proteins may also be produced by other cell types (eg, tissue factor by fibroblasts).

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:

Calcium ions are required in most thrombin-generating reactions and, therefore, calcium-chelating agents (eg, citrate, ethylenediaminetetraacetic acid) are used in vitro as anticoagulants. Vitamin K–dependent clotting factors (factors II, VII, IX, and X) normally bind to phospholipid surfaces through calcium bridges to function in blood coagulation. Coagulation reactions cannot occur properly in the absence of vitamin K. Vitamin K-dependent coagulation regulatory proteins include protein C, protein S, and protein Z.

Although the coagulation pathways are helpful in understanding mechanisms and laboratory evaluation of coagulation disorders, in vivo coagulation does not include factor XII, prekallikrein, or high molecular weight kininogen. People with hereditary deficiencies of these factors have no bleeding abnormality. People with hereditary factor XI deficiency may have a mild to moderate bleeding disorder. In vitro, soluble factor XI can be activated by thrombin. There is, however, no consistent relationship between plasma factor XI levels and the likelihood or extent of bleeding. Soluble factor IX can be activated in vitro 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 possibly factor IX). Factor IXa, combined with its cofactor, factor VIIIa, on phospholipid membrane surfaces also generates factor Xa. Factor X activation by factor IXa/VIIIa complexes is required for normal hemostasis. This requirement for factors VIII and IX explains why hemophilia Hemophilia Hemophilias are common hereditary bleeding disorders caused by deficiencies of either clotting factor VIII or IX. The extent of factor deficiency determines the probability and severity of bleeding... read more type A (deficiency of factor VIII) or type B (deficiency of factor IX) results in bleeding. Factor X activation by factor VIIa/tissue factor complexes in the extrinsic coagulation pathway does not generate sufficient thrombin (and fibrin) to prevent bleeding in patients with severe hemophilia A or B.

Several inhibitory mechanisms prevent activated coagulation reactions from amplifying uncontrollably, causing extensive local thrombosis or disseminated intravascular coagulation Disseminated Intravascular Coagulation (DIC) Disseminated intravascular coagulation (DIC) involves abnormal, excessive generation of thrombin and fibrin in the circulating blood. During the process, increased platelet aggregation and coagulation... read more . These mechanisms include