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Zoya Gurm, B.S.
Zaher K. Otrock, M.D., Ph.D.

Last author update: 29 November 2022
Last staff update: 29 November 2022

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PubMed Search: Coagulation physiology

Zoya Gurm, B.S.
Zaher K. Otrock, M.D., Ph.D.
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Cite this page: Gurm Z, Otrock ZK. Physiology. website. Accessed March 28th, 2023.
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:


Intrinsic pathway

Thrombomodulin function

Thrombomodulin protein

Board review style question #1
What are the basic components of hemostasis?

  1. Phospholipids, platelets and coagulation proteins
  2. Tissue factor, platelets and phospholipids
  3. Vascular endothelium, platelets and coagulation proteins
  4. Vascular endothelium, platelets and fibrinogen
  5. Vascular endothelium, tissue factor and platelets
Board review style answer #1
C. Vascular endothelium, platelets and coagulation proteins

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Reference: Coagulation - Physiology
Board review style question #2
Which coagulation factor deficiency has normal PT and aPTT?

  1. Factor II
  2. Factor V
  3. Factor X
  4. Factor XIII
Board review style answer #2
D. Factor XIII

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Reference: Coagulation - Physiology
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