Coagulation
General
Physiology
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Last staff update: 29 November 2022
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PubMed Search: Coagulation physiology
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Cite this page: Gurm Z, Otrock ZK. Physiology. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/coagulationphysiology.html. Accessed April 2nd, 2025.
Definition / general
- Hemostasis is a highly complex process of clot formation in response to blood vessel injury (Indian J Anaesth 2014;58:515)
- Disorders in the hemostatic pathway can lead to either hypercoagulability (in which excessive clot formation occurs) or bleeding disorders (in which clot formation does not adequately stop bleeding)
Essential features
- Hemostasis can be categorized into 3 stages (Curr Med Chem 2004;11:2245):
- Primary hemostasis is the formation of a weak platelet plug at the site of vascular injury
- Secondary hemostasis is the formation of a fibrin plug by coagulation factors; coagulation factor activation occurs via the intrinsic and extrinsic pathways, which merge to form the common pathway
- Tertiary hemostasis describes the anticoagulation and fibrinolytic balance to promote healing and prevent excessive clotting
- The 3 major constituents of the hemostatic system are platelets, coagulation proteins and endothelium (Cardiovasc Diagn Ther 2018;8:568)
Primary hemostasis
- During injury to vascular endothelium, the first response to prevent blood loss is vasoconstriction which activates endothelial cells (Ann Med 2012;44:405)
- Formation of the platelet plug in primary hemostasis is primarily orchestrated by interactions between the endothelium, von Willebrand factor (vWF) and platelets (Arterioscler Thromb Vasc Biol 2020;40:1441)
- Activated endothelial cells secrete vWF, which recruits platelets to the site of injury and results in a sequence of platelet adhesion, activation and aggregation (Int J Biochem Cell Biol 2021;131:105900, Hematol Oncol Clin North Am 2021;35:1069)
- Platelet adhesion occurs when vWF, bound to exposed subendothelial collagen, interacts with glycoprotein Ib / IX / V on platelets (Arterioscler Thromb Vasc Biol 2008;28:403)
- vWF is a plasma glycoprotein, stored in alpha granules secreted by platelets and Weibel-Palade bodies in the endothelium (Blood 2015;125:2019)
- Platelet activation results in changes in platelet and membrane morphology and secretion of microparticles from intracellular granules
- Upon activation, platelet cytoplasm and cytoskeleton rearrange to increase surface area and enable adherence to endothelium (Thromb Haemost 2002;88:186)
- Platelet aggregation is mediated by glycoprotein IIb / IIIa (GpIIb / IIIa) on the platelet surface
- During platelet activation, GpIIb / IIIa undergoes a conformational change into the active form; activated GpIIb / IIIa has high affinity for ligand binding and promotes platelet aggregation into the initial platelet plug (Blood 2007;109:5087)
Secondary hemostasis
- In secondary hemostasis, the fibrin plug is formed by the activated coagulation factors (Ann Med 2012;44:405)
- Fibrinogen is cleaved into fibrin by factor II (thrombin) at the end of the common pathway (Arterioscler Thromb Vasc Biol 2011;31:494)
- Insoluble fibrin is crosslinked by factor XIII, which strengthens the fibrin plug
- Coagulation factors are synthesized in the liver, except factor VIII and vWF (Blood Coagul Fibrinolysis 2000;11:S69)
- Coagulation proteins circulate as inactive zymogens; factors must undergo enzymatic cleavage to function (Hemodial Int 2006;10:S2)
- Factors II, VII, IX and X and protein C and S are synthesized in a vitamin K dependent manner; vitamin K epoxide reductase is a key enzyme in the vitamin K cycle (Vitam Horm 2008;78:23)
- Warfarin is an inhibitor of vitamin K epoxide reductase and suppresses the synthesis of active factors II, VII, IX and X and protein C and S
- Protein C and S are anticoagulant proteins that degrade factor Va and VIIIa (Adv Clin Exp Med 2013;22:459)
- The model of secondary hemostasis is comprised of 2 separate pathways, the intrinsic and extrinsic pathway, that merge to form a common pathway; in vivo, it appears that these pathways may not be so distinctly separated
Intrinsic pathway
- Intrinsic pathway is comprised of factors VIII, IX, XI, XII, prekallikrein and high molecular weight kininogen (Indian J Anaesth 2014;58:515)
- The pathway is initiated when factor XII (Hageman factor) is activated by exposure to negatively charged molecules such as inorganic polyphosphate released by platelets (Cell 2009;139:1143)
- Factor XIIa initiates a chain of activation involving factor XI, IX, VIII and ultimately factor X, initiating the common pathway with the activation of thrombin (factor II) (Arterioscler Thromb Vasc Biol 2019;39:331)
- Factor XIIa additionally converts prekallikrein to kallikrein; the functions of kallikrein include converting prorenin to renin, kininogen to bradykinin and further activating factor XII (J Clin Invest 2002;109:1007)
- The function of the intrinsic and common pathways of coagulation is measured with activated partial thromboplastin time (aPTT); aPTT measures the time it takes plasma to form a clot when exposed to factor XII activator (Methods Mol Biol 2013;992:111)
- Prolonged aPTT can be indicative of a factor deficiency, such as hemophilia or an inhibitor to the intrinsic or common pathway; an aPTT mixing study is used to differentiate between these causes (Eur J Haematol 2020;104:519)
Extrinsic pathway
- Extrinsic pathway is comprised of tissue factor and factor VII (Indian J Anaesth 2014;58:515)
- Tissue factor (TF) is a glycosylated protein expressed on subendothelial tissues; TF is activated in response to vascular wall damage (Curr Pharm Des 2015;21:1152)
- Activated TF binds to and activates factor VII
- Factor VIIa converts factor X into factor Xa, initiating the common pathway
- Clinically, the extrinsic and common coagulation pathways are assessed by prothrombin time (PT); PT is a measurement of the time it takes for clot formation when plasma is exposed to tissue factor (StatPearls: Prothrombin Time [Accessed 15 June 2022])
Common pathway
- Both the intrinsic and extrinsic pathways of coagulation lead to the activation of factor X
- Common pathway involves fibrinogen (factor I), factors II, V and X
- Prothrombinase complex is formed by factor Xa, factor V and calcium; this complex converts prothrombin (factor II) to thrombin (factor IIa) (Indian J Anaesth 2014;58:515)
- Thrombin converts fibrinogen to fibrin, further activates factors V and VIII and cleaves factor XIII (Blood 2005;106:2605)
- Factor XIII further stabilizes the clot by covalently crosslinking fibrin (Blood 2005;106:2605)
- Antithrombin is a protease inhibitor that inhibits activated coagulation factors, primarily thrombin and Xa (J Thromb Haemost 2020;18:3142)
Tertiary hemostasis
- Tertiary hemostasis is the process of fibrinolysis (clot dissolution), in which fibrin is cleaved to prevent excessive clotting
- Tissue type plasminogen activator (tPA) is produced by endothelial cells to mediate clot breakdown; urokinase type plasminogen activator (uPA) also functions in fibrinolysis (Front Immunol 2019;10:1348)
- In the presence of fibrin, tPA and uPA cleave plasminogen to plasmin (J Thromb Haemost 2007;5:804)
- Plasmin is a serine protease that degrades fibrin clot to soluble fibrin and fibrinogen degradation products (Int J Mol Sci 2021;22:2758)
- D dimer is a soluble fibrin degradation product that is used as an important clinical marker for coagulation and fibrinolysis (Am J Hematol 2019;94:833)
- Fibrinolysis inhibitors, such as antiplasmin (which binds and inactivates fibrin) and plasminogen activator inhibitor 1 (PAI1; inhibitor of uPA / tPA), prevent excessive fibrinolysis (FEBS J 2005;272:4852, Transfus Apher Sci 2019;58:572)
Diagrams / tables
Contributed by Zaher K. Otrock, M.D.
Summary of secondary hemostasis
Images hosted on other servers:
Coagulation
Intrinsic pathway
Thrombomodulin function
Thrombomodulin protein
Board review style question #1
What are the basic components of hemostasis?
- Phospholipids, platelets and coagulation proteins
- Tissue factor, platelets and phospholipids
- Vascular endothelium, platelets and coagulation proteins
- Vascular endothelium, platelets and fibrinogen
- Vascular endothelium, tissue factor and platelets
Board review style question #2
Which coagulation factor deficiency has normal PT and aPTT?
- Factor II
- Factor V
- Factor X
- Factor XIII
Board review style answer #2
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