Regulatory mechanisms counterbalance the tendency of clots to form. Hemostatic abnormalities can lead to excessive bleeding or thrombosis .
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 and table Components of Blood Coagulation Reactions ).
The coagulation factors are produced in the liver with the exception of factor VIII , which is synthesized in liver sinusoidal cells and endothelial cells outside the liver. Tissue factor expression is normally restricted to perivascular cells so that extrinsic pathway activation only occurs in the event of vessel wall injury.
Pathways in Blood Coagulation
Components of Blood Coagulation ReactionsComponents of Blood Coagulation Reactions
Factor Number or Name
A precursor of fibrin monomers (and polymers)
The precursor of thrombin
Thrombin converts fibrinogen to fibrin; activates soluble factors V, VIII, XI, and XIII; and binds to thrombomodulin to activate protein C
Is vitamin K–dependent
Is activated to factor Va, a cofactor for the enzyme factor Xa in the factor Xa /factor Va/phospholipid complex, which cleaves prothrombin to thrombin
Is present in alpha granules in platelets
Factor Va inactivated by activated protein C in complex with free protein S
Binds to tissue factor and is then activated to form the enzymatic component of the factor VIIa /tissue factor complex, which activates factor X and, possibly, factor IX
Is vitamin K–dependent
Is activated to factor VIIIa , a cofactor for the enzyme factor IXa in the factor IXa/factor VIIIa/phospholipid complex, which activates factor X
Is a large cofactor protein (as is factor V)
Is secreted bound to von Willebrand factor multimers from the Weibel-Palade bodies of endothelial cells (factor VIII also circulates with von Willebrand factor )
As factor VIIIa, is inactivated by activated protein C in complex with free protein S (as is factor Va)
Is activated to factor IXa, the enzyme of the factor IXa/factor VIIIa/phospholipid complex, which activates factor X
Is vitamin K–dependent
Is activated to factor Xa , the enzyme of the factor Xa /factor Va/phospholipid complex, which cleaves prothrombin to thrombin
Is vitamin K–dependent
Plasma thromboplastin antecedent
Is activated to factor XIa, which may activate factor IX
Participates in a reciprocal reaction in which it is activated to kallikrein by factor XIIa
As kallikrein, catalyzes further activation of factor XII to factor XIIa
Circulates as a biomolecular complex with high molecular weight kininogen
High molecular weight kininogen
Circulates as a bimolecular complex with prekallikrein
When activated to factor XIIa by surface contact, kallikrein, or other factors, it activates prekallikrein and factor XI, triggering the intrinsic coagulation pathway in vitro
Fibrin stabilizing factor
When activated by thrombin , catalyzes formation of peptide bonds between adjacent fibrin monomers to strengthen and stabilize fibrin clots
Is activated by thrombin bound to surface membrane-bound thrombomodulin (CD141); then proteolyzes and inhibits (in the presence of free protein S and phospholipid) the cofactor activity of factor VIIIa and factor Va
Is vitamin K–dependent
Circulates in plasma as free protein S and as protein S bound to C4b-binding protein of the complement system
Functions in its free form as a cofactor for activated protein C
Is vitamin K–dependent
Cell surface factors
Is a protein that is present in the membranes of certain tissue cells, including perivascular fibroblasts, endothelial cells, boundary epithelial cells (eg, epithelial cells of the skin, amnion, and gastrointestinal and genitourinary tracts), glial cells of the nervous system, monocytes, macrophages, and some tumor cells
It is exposed to flowing blood during injury or inflammation, binds factor VIIa , and initiates the extrinsic coagulation pathway
Acidic phospholipid (primarily phosphatidyl serine) present on the surface of activated platelets, endothelial cells, and other tissue cells
Is a component of the factor IXa/VIIIa/phospholipid complex which activates factor X and of the factor Xa /factor Va/phospholipid complex which activates prothrombin
Is an endothelial cell surface binding site for thrombin which, when bound to thrombomodulin, activates protein C
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 and protein S.
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 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 . These mechanisms include
Plasma protease inhibitors (antithrombin, tissue factor pathway inhibitor, alpha 2-macroglobulin, and heparin cofactor II) inactivate coagulation enzymes. Antithrombin inhibits thrombin , factor Xa , factor XIa, and factor IXa.
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 [CD141]), activates protein C. Activated protein C, in combination with free protein S and an endothelial cell protein C receptor, proteolyzes and inactivates factors VIIIa and Va.
In addition to normally present inactivators, there are a number of anticoagulant medications that potentiate the inactivation of coagulation factors (see figure Anticoagulants and Their Sites of Action ).
Heparin enhances antithrombin activity. Unfractionated heparin (UFH) and low molecular weight heparins (LMWH) enhance activity of antithrombin to inactivate factors IIa ( thrombin
heparin structure, enhances antithrombin inactivation of factor Xa but not factor IIa ( thrombin ).
Parenteral direct thrombin
The direct oral anticoagulants include the thrombin factor Xa atrial fibrillation , deep venous thrombosis (DVT), and pulmonary embolism (PE).
Anticoagulants and Their Sites of Action