Editing Coagulation

{{Short description|Process of formation of blood clots}}
{{About|blood clotting}}
{{Use dmy dates|date=July 2019}}
{{Infobox body process
|name              = Coagulation
|image  = File:Coagulation in vivo.png|right|thumb|
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|caption           = Blood coagulation pathways ''in vivo'' showing the central role played by [[thrombin]]
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'''Coagulation''', also known as '''clotting''', is the process by which [[blood]] changes from a [[liquid]] to a [[gel]], forming a [[thrombus|blood clot]]. It results in [[hemostasis]], the cessation of blood loss from a damaged vessel, followed by repair. The process of coagulation involves [[Platelet-activating factor|activation]], [[Cell adhesion|adhesion]] and aggregation of [[platelet]]s, as well as deposition and maturation of [[fibrin]].

Coagulation begins almost instantly after an injury to the [[endothelium]] that lines a [[blood vessel]]. Exposure of blood to the subendothelial space initiates two processes: changes in platelets, and the exposure of subendothelial [[Tissue factor|platelet tissue factor]] to [[coagulation factor VII]], which ultimately leads to cross-linked [[fibrin]] formation. Platelets immediately form a plug at the site of injury; this is called ''primary hemostasis. Secondary hemostasis'' occurs simultaneously: additional coagulation factors beyond factor VII ([[#Coagulation factors|listed below]]) respond in a cascade to form fibrin strands, which strengthen the [[platelet plug]].<ref name="Furie">{{Cite journal |last=Furie |first=Barbara C. |last2=Furie |first2=Bruce |date=December 2005 |title=Thrombus formation in vivo |journal=The Journal of Clinical Investigation |volume=115 |issue=12 |pages=3355–62 |doi=10.1172/JCI26987 |pmc=1297262 |pmid=16322780}}</ref>

Coagulation is highly [[Conserved sequence|conserved]] throughout biology. In all [[mammal]]s, coagulation involves both cellular components (platelets) and [[protein]]aceous components (coagulation or clotting factors).<ref name="Michelson2006">{{Cite book |title=Platelets |date=2007 |isbn=978-0-12-369367-9 |doi=10.1016/B978-0-12-369367-9.X5760-7}}{{pn|date=September 2024}}</ref><ref name="medline2024">{{Cite web |title=Coagulation Factor Tests |url=https://medlineplus.gov/lab-tests/coagulation-factor-tests/ |access-date=27 April 2024 |website=MedlinePlus Medical Test |language=en}}</ref> The pathway in humans has been the most extensively researched and is the best understood.<ref>{{Cite book |last=Schmaier |first=Alvin H. |title=Concise guide to hematology |last2=Lazarus |first2=Hillard M. |publisher=Wiley-Blackwell |year=2011 |isbn=978-1-4051-9666-6 |location=Chichester, West Sussex, UK |page=91 |oclc=779160978}}</ref> Disorders of coagulation can result in problems with [[Bleeding|hemorrhage]], [[Bruise|bruising]], or [[thrombosis]].<ref name="isbn1-4051-8460-4">{{Cite book |last=Lillicrap |first=D. |url=https://archive.org/details/practicalhemosta00keyn |title=Practical Hemostasis and Thrombosis |last2=Key |first2=Nigel |last3=Makris |first3=Michael |last4=Denise |first4=O'Shaughnessy |publisher=Wiley-Blackwell |year=2009 |isbn=978-1-4051-8460-1 |pages=1–5 |url-access=limited}}</ref>

==List of coagulation factors==
There are 13 traditional clotting factors, as named below,<ref name="Openstax Anatomy & Physiology attribution">{{CC-notice|cc=by4|url=https://openstax.org/books/anatomy-and-physiology/pages/18-5-hemostasis}} {{Cite book |last=Betts |first=J Gordon |title=Anatomy & Physiology |last2=Desaix |first2=Peter |last3=Johnson |first3=Eddie |last4=Johnson |first4=Jody E |last5=Korol |first5=Oksana |last6=Kruse |first6=Dean |last7=Poe |first7=Brandon |last8=Wise |first8=James |last9=Womble |first9=Mark D |date=2023 |publisher=OpenStax CNX |isbn=978-1-947172-04-3 |location=Houston |chapter=§18.5 Homeostasis |chapter-url=https://openstax.org/books/anatomy-and-physiology/pages/18-5-hemostasis |last10=Young |first10=Kelly A}}</ref> and other substances necessary for coagulation:

{| class="wikitable"
|+ Coagulation factors and related substances
|-
! Number/Name !! Synonym(s) !! Function !! Associated genetic disorders !! Type of molecule !! Source !! Pathway(s)
|-
| Factor I || [[Fibrinogen]] || Forms fibrin threads in blood clots || {{blist|[[Congenital afibrinogenemia]]|[[Familial renal amyloidosis]]}} || [[Plasma protein]] || Liver || Common pathway; converted into fibrin
|-
| Factor II* || [[Prothrombin]] || Its active form (IIa) activates [[platelet]]s, factors I, V, VII, VIII, XI, XIII, [[protein C]] || {{blist|[[Thrombophilia]]|[[Prothrombin thrombophilia]] (Prothrombin G20210A)<ref name="GHR2018">{{Cite web |title=Prothrombin thrombophilia |url=https://medlineplus.gov/genetics/condition/prothrombin-thrombophilia/ |url-status=live |archive-url=https://web.archive.org/web/20230912225514/https://medlineplus.gov/genetics/condition/prothrombin-thrombophilia/ |archive-date=12 September 2023 |access-date=2023-09-11 |website=MedlinePlus}}</ref>}}
| Plasma protein || Liver || Common pathway; converted into thrombin
|-
| Factor III|| {{blist|[[Tissue factor]] |tissue thromboplastin}} || Co-factor of factor VIIa, which was formerly known as factor III || || Lipoprotein mixture || Damaged cells and platelets || Extrinsic
|-
| Factor IV || {{blist|Calcium|Calcium ions|Ca<sup>2+</sup> ions}} || Required for coagulation factors to bind to phospholipids, which were formerly known as factor IV || || Inorganic ions in plasma || Diet, platelets, bone matrix || Entire process of coagulation
|-
| [[Factor V]] || {{blist|Proaccelerin|labile factor|Ac-globulin}} || Co-factor of factor X with which it forms the [[prothrombinase]] complex || [[Activated protein C resistance]] || Plasma protein || Liver, platelets || Extrinsic and intrinsic
|-
| Factor VI || {{blist|''Unassigned'' –<br>old name of factor Va<br>(activated form of factor V)|accelerin (formerly)}} || N/A || N/A || N/A ||
|-
| [[Factor VII]]* || {{blist|Proconvertin|Serum Prothrombin Conversion Accelerator (SPCA)|Stable factor}} || Activates factors IX, X; increases rate of catalytic conversion of prothrombin into thrombin || Congenital [[factor VII deficiency]] || Plasma protein || Liver || Extrinsic
|-
| [[Factor VIII]] || {{blist|Antihemophilic factor A|Antihemophilic factor (AHF)|Antihemophilic globulin (AHG)}} || Co-factor of factor IX with which it forms the [[tenase]] complex || [[Hemophilia A]] || Plasma protein factor || Platelets and endothelial cells || Intrinsic
|-
| [[Factor IX]]* || {{blist|Antihemophilic factor B|Christmas factor|plasma thromboplastin component (PTC)}} || Activates factor X, forms [[tenase]] complex with factor VIII || [[Hemophilia B]] || Plasma protein || Liver || Intrinsic
|-
| [[Factor X]]* || {{blist|Stuart-Prower factor|Stuart factor}} || Activates factor II, forms [[prothrombinase]] complex with factor V || Congenital Factor X deficiency || Protein || Liver || Extrinsic and intrinsic
|-
| [[Factor XI]] || {{blist|Plasma thromboplastin antecedent (PTA)|Antihemophilic factor C}} || Activates factor IX || [[Hemophilia C]] || Plasma protein || Liver || Intrinsic
|-
| [[Factor XII]] || Hageman factor || Activates XI, VII, prekallikrein and plasminogen || {{nobr|[[Hereditary angioedema]] type III}} || Plasma protein || Liver || Intrinsic; initiates clotting in vitro; also activates plasmin
|-
| [[Factor XIII]] || Fibrin-stabilizing factor || Crosslinks fibrin threads || Congenital factor XIIIa/b deficiency || Plasma protein || Liver, platelets || Common pathway; stabilizes fibrin; slows down fibrinolysis
|-
| [[Vitamin K]] || Clotting vitamin || Essential factor to the hepatic [[gamma-glutamyl carboxylase]] that adds a [[carboxyl]] group to [[glutamic acid]] residues on factors II, VII, IX and X, as well as [[Protein S]], [[Protein C]] and [[Protein Z]]<ref name="Vitamin K">{{Cite book |last=Waller |first=Derek G. |title=Medical Pharmacology and Therapeutics |last2=Sampson |first2=Anthony P. |date=2018 |isbn=978-0-7020-7167-6 |pages=175–90 |chapter=Haemostasis |doi=10.1016/B978-0-7020-7167-6.00011-7}}</ref> || [[Vitamin K deficiency]] || Phytyl-substituted naphthoquinone derivative || [[Gut microbiota]]<br>(e.g. [[Escherichia coli|E. coli]]<ref>{{Cite journal |last=Blount |first=Zachary D. |date=2015-03-25 |title=The unexhausted potential of E. coli |journal=eLife |volume=4 |page=e05826 |doi=10.7554/eLife.05826 |pmc=4373459 |pmid=25807083 |doi-access=free}}</ref>),<br>dietary sources || Extrinsic<ref>{{Cite web |title=Coagulation Cascade: What Is It, Steps, and More {{!}} Osmosis |url=https://www.osmosis.org/answers/coagulation-cascade#:~:text=The%20extrinsic%20pathway%20begins%20when,vitamin%20K%20to%20be%20activated. |url-status=live |archive-url=https://web.archive.org/web/20230908085238/https://www.osmosis.org/answers/coagulation-cascade#:~:text=The%20extrinsic%20pathway%20begins%20when,vitamin%20K%20to%20be%20activated. |archive-date=2023-09-08 |access-date=2023-09-08 |website=www.osmosis.org}}</ref>
|-
| [[von Willebrand factor]] || || Binds to VIII, mediates platelet adhesion || [[von Willebrand disease]] || Blood glycoprotein || Blood vessels' [[endothelia]],<br> bone marrow<ref>{{Cite web |title=VWF gene: MedlinePlus Genetics |url=https://medlineplus.gov/genetics/gene/vwf/#:~:text=Von%20Willebrand%20factor%20is%20made,by%20an%20enzyme%20called%20ADAMTS13. |url-status=live |archive-url=https://web.archive.org/web/20230511200104/https://medlineplus.gov/genetics/gene/vwf/#:~:text=Von%20Willebrand%20factor%20is%20made,by%20an%20enzyme%20called%20ADAMTS13. |archive-date=11 May 2023 |access-date=2023-09-08 |website=medlineplus.gov}}</ref> ||
|-
| [[Prekallikrein]] || Fletcher factor || Activates XII and prekallikrein; cleaves HMWK || Prekallikrein/Fletcher factor deficiency
|-
| [[Kallikrein]] || || Activates plasminogen ||
|-
| [[High-molecular-weight kininogen]] || {{blist|Fitzgerald factor|HMWK}} || Supports reciprocal activation of factors XII, XI, and prekallikrein || [[Kininogen deficiency]]
|-
| [[Fibronectin]] || || Mediates cell adhesion || [[Glomerulopathy]] with fibronectin deposits
|-
| [[Antithrombin]] III || || Inhibits factors IIa, Xa, IXa, XIa, and XIIa || [[Antithrombin III deficiency]]
|-
| [[Heparin cofactor II]] || || Inhibits factor IIa, cofactor for heparin and [[dermatan sulfate]] ("minor antithrombin") || Heparin cofactor II deficiency
|-
| [[Protein C]] || || Inactivates factors Va and VIIIa || [[Protein C deficiency]]
|-
| [[Protein S]] || || Cofactor for activated protein C (APC, inactive when bound to C4b-binding protein || [[Protein S deficiency]]
|-
| [[Protein Z]] || || Mediates thrombin adhesion to phospholipids and stimulates degradation of factor X by ZPI || [[Protein Z deficiency]]
|-
| [[Protein Z-related protease inhibitor]] || ZPI || Degrades factors X (in presence of protein Z) and XI (independently ||
|-
| [[Plasminogen]] || || Converts to plasmin, lyses fibrin and other proteins || Plasminogen deficiency type I (ligneous conjunctivitis)
|-
| [[alpha 2-antiplasmin|α<sub>2</sub>-Antiplasmin]] || || Inhibits plasmin || Antiplasmin deficiency
|-
| [[alpha-2-Macroglobulin|α<sub>2</sub>-Macroglobulin]] || || Inhibits plasmin, kallikrein, and thrombin ||
|-
| [[Tissue plasminogen activator]] || t-PA or TPA || Activates plasminogen || {{blist|Familial [[hyperfibrinolysis]]|[[Thrombophilia]]}}
|-
| [[Urokinase]] || || Activates plasminogen || [[Quebec platelet disorder]]
|-
| [[Plasminogen activator inhibitor-1]] || PAI-1 || Inactivates tPA and urokinase (endothelial PAI || Plasminogen activator inhibitor-1 deficiency
|-
| [[Plasminogen activator inhibitor-2]] || PAI-2 || Inactivates tPA and urokinase || Plasminogen activator inhibitor-1 deficiency
|-
| [[Cancer procoagulant]] || || Pathological activator of [[factor X]]; linked to thrombosis in various [[cancer]]s<ref>{{Cite journal |last=Gordon |first=S. G. |last2=Mielicki |first2=W. P. |date=March 1997 |title=Cancer procoagulant: a factor X activator, tumor marker and growth factor from malignant tissue |journal=Blood Coagulation & Fibrinolysis |volume=8 |issue=2 |pages=73–86 |doi=10.1097/00001721-199703000-00001 |issn=0957-5235 |pmid=9518049}}</ref>||
|-
! colspan=7 | <nowiki>*</nowiki> Vitamin K is required for biosynthesis of these clotting factors<ref name="Vitamin K" />
|}

==Physiology==
[[File:VWF-GP1ba.png|thumb|300px|right|The interaction of vWF and GP1b alpha. The GP1b receptor on the surface of platelets allows the platelet to bind to vWF, which is exposed upon damage to vasculature. The vWF A1 domain (yellow) interacts with the extracellular domain of GP1ba (blue).]]
Physiology of blood coagulation is based on [[hemostasis]], the normal bodily process that stops bleeding. Coagulation is a part of an integrated series of haemostatic reactions, involving plasma, platelet, and vascular components.<ref>{{Cite journal |last=Bloom |first=A. L. |date=1990 |title=Physiology of blood coagulation |journal=Haemostasis |volume=20 |issue=Suppl 1 |pages=14–29 |doi=10.1159/000216159 |issn=0301-0147 |pmid=2083865}}</ref>

Hemostasis consists of four main stages:
* [[Vasoconstriction]] (vasospasm or vascular spasm): Here, this refers to contraction of smooth muscles in the [[tunica media]] layer of [[endothelium]] (blood vessel wall).
* Activation of platelets and [[platelet plug]] formation:
** Platelet activation: [[Platelet activator]]s, such as [[platelet activating factor]] and [[thromboxane A2]],<ref>{{Cite book |last=Abeles |first=Aryeh M. |title=Rheumatology |last2=Pillinger |first2=Michael H. |last3=Abramson |first3=Steven B. |date=2015 |isbn=978-0-323-09138-1 |pages=169–82 |chapter=Inflammation and its mediators |doi=10.1016/B978-0-323-09138-1.00023-1}}</ref> activate platelets in the bloodstream, leading to attachment of platelets' membrane receptors (e.g. [[glycoprotein IIb/IIIa]]<ref>{{Cite journal |last=Charo |first=I.F. |last2=Bekeart |first2=L.S. |last3=Phillips |first3=D.R. |date=July 1987 |title=Platelet glycoprotein IIb-IIIa-like proteins mediate endothelial cell attachment to adhesive proteins and the extracellular matrix. |journal=Journal of Biological Chemistry |volume=262 |issue=21 |pages=9935–38 |doi=10.1016/S0021-9258(18)61053-1 |pmid=2440865 |doi-access=free}}</ref>) to [[extracellular matrix]]<ref>{{Cite journal |last=Watson |first=Steve |date=April 2009 |title=Platelet Activation by Extracellular Matrix Proteins in Haemostasis and Thrombosis |journal=Current Pharmaceutical Design |volume=15 |issue=12 |pages=1358–72 |doi=10.2174/138161209787846702 |pmid=19355974}}</ref> proteins (e.g. von Willebrand factor<ref>{{Cite journal |last=Wagner |first=D. D. |last2=Urban-Pickering |first2=M. |last3=Marder |first3=V. J. |date=January 1984 |title=Von Willebrand protein binds to extracellular matrices independently of collagen |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=81 |issue=2 |pages=471–75 |bibcode=1984PNAS...81..471W |doi=10.1073/pnas.81.2.471 |issn=0027-8424 |pmc=344699 |pmid=6320190 |doi-access=free}}</ref>) on cell membranes of damaged endothelial cells and exposed [[collagen]] at the site of injury.<ref>{{Cite journal |last=Vermylen |first=Jos |last2=Verstraete |first2=Marc |last3=Fuster |first3=Valentin |date=1986-12-01 |title=Role of platelet activation and fibrin formation in thrombogenesis |journal=Journal of the American College of Cardiology |series=Symposium on Thrombosis and Antithrombotic Therapy – 1986 |volume=8 |issue=6, Supplement 2 |pages=2B–9B |doi=10.1016/S0735-1097(86)80002-X |issn=0735-1097 |pmid=3537069 |s2cid=23789418 |doi-access=free}}</ref>
** Platelet plug formation: The adhered platelets aggregate and form a temporary plug to stop bleeding. This process is often called "primary hemostasis".<ref>{{Cite book |last=Blanchette |first=V. S. |url=https://books.google.com/books?id=EQ3zDQAAQBAJ |title=SickKids Handbook of Pediatric Thrombosis and Hemostasis |last2=Brandão |first2=L. R. |last3=Breakey |first3=V. R. |last4=Revel-Vilk |first4=S. |year=2016 |publisher=Karger Medical and Scientific Publishers |isbn=978-3-318-03026-6 |chapter=Primary and secondary hemostasis, regulators of coagulation, and fibrinolysis: Understanding the basics |chapter-url=https://books.google.com/books?id=EQ3zDQAAQBAJ&dq=Primary+and+secondary+hemostasis&pg=PR28}}</ref>
* [[Coagulation cascade]]: It is a series of enzymatic reactions that lead to the formation of a stable blood clot. The endothelial cells release substances like tissue factor, which triggers the extrinsic pathway of the coagulation cascade. This is called as "secondary hemostasis".<ref>{{Cite web |title=Coagulation Cascade: What Is It, Steps, and More |url=https://www.osmosis.org/answers/coagulation-cascade#:~:text=The%20coagulation%20cascade%2C%20or%20secondary,ultimately%20produces%20a%20blood%20clot. |url-status=live |archive-url=https://web.archive.org/web/20230908085238/https://www.osmosis.org/answers/coagulation-cascade#:~:text=The%20coagulation%20cascade%2C%20or%20secondary,ultimately%20produces%20a%20blood%20clot. |archive-date=8 September 2023 |access-date=2023-10-15 |website=www.osmosis.org}}</ref>
* [[Fibrin clot]] formation: Near the end of the extrinsic pathway, after [[thrombin]] completes conversion of fibrinogen into fibrin,<ref name="Weisel2017">{{Cite book |last=Weisel |first=John W. |title=Fibrous Proteins: Structures and Mechanisms |last2=Litvinov |first2=Rustem I. |date=2017 |isbn=978-3-319-49672-6 |series=Subcellular Biochemistry |volume=82 |pages=405–56 |chapter=Fibrin Formation, Structure and Properties |doi=10.1007/978-3-319-49674-0_13 |issn=0306-0225 |pmc=5536120 |pmid=28101869}}</ref> [[factor XIIIa]] (plasma transglutaminase;<ref name="Weisel2017" /> activated form of fibrin-stabilizing factor) promotes fibrin cross-linking, and subsequent stabilization of fibrin, leading to the formation of a fibrin clot (final blood clot), which temporarily seals the wound to allow [[wound healing]] until its inner part is dissolved by [[fibrinolytic enzyme]]s, while the clot's outer part is shed off.

After the fibrin clot is formed, [[clot retraction]] occurs and then [[clot resolution]] starts, and these two process are together called "tertiary hemostasis". Activated platelets contract their internal actin and myosin fibrils in their cytoskeleton, which leads to shrinkage of the clot volume. [[Plasminogen activator]]s, such as [[tissue plasminogen activator]] (t-PA), activate [[plasminogen]] into plasmin, which promotes lysis of the fibrin clot; this restores the flow of blood in the damaged/obstructed blood vessels.<ref>{{Cite book |last=LaPelusa |first=Andrew |title=StatPearls |last2=Dave |first2=Heeransh D. |date=2024 |publisher=StatPearls Publishing |chapter=Physiology, Hemostasis |pmid=31424847 |chapter-url=http://www.ncbi.nlm.nih.gov/books/NBK545263/}}</ref>

===Vasoconstriction===
{{main|Vasoconstriction}}
When there is an injury to a blood vessel, the endothelial cells can release various vasoconstrictor substances, such as endothelin<ref>{{Cite journal |last=Loscalzo |first=J. |date=1995 |title=Endothelial injury, vasoconstriction, and its prevention |journal=Texas Heart Institute Journal |volume=22 |issue=2 |pages=180–84 |pmc=325239 |pmid=7647603}}</ref> and thromboxane,<ref>{{Cite journal |last=Yau |first=Jonathan W. |last2=Teoh |first2=Hwee |last3=Verma |first3=Subodh |date=2015-10-19 |title=Endothelial cell control of thrombosis |journal=BMC Cardiovascular Disorders |volume=15 |page=130 |doi=10.1186/s12872-015-0124-z |issn=1471-2261 |pmc=4617895 |pmid=26481314 |doi-access=free}}</ref> to induce the constriction of the smooth muscles in the vessel wall. This helps reduce blood flow to the site of injury and limits bleeding.

===Platelet activation and platelet plug formation===
When the endothelium is damaged, the normally isolated underlying collagen is exposed to circulating platelets, which bind directly to collagen with collagen-specific [[glycoprotein Ia/IIa]] surface receptors. This adhesion is strengthened further by [[von Willebrand factor]] (vWF), which is released from the endothelium and from platelets; vWF forms additional links between the platelets' [[glycoprotein Ib/IX/V]] and A1 domain. This localization of platelets to the extracellular matrix promotes collagen interaction with platelet [[glycoprotein VI]]. Binding of collagen to [[glycoprotein VI]] triggers a signaling cascade that results in activation of platelet integrins. Activated integrins mediate tight binding of platelets to the extracellular matrix. This process adheres platelets to the site of injury.<ref name="PracticalH1">{{Cite book |last=Nigel Key |url=https://archive.org/details/practicalhemosta00keyn |title=Practical Hemostasis and Thrombosis |last2=Michael Makris |publisher=Wiley-Blackwell |year=2009 |isbn=978-1-4051-8460-1 |page=2 |display-authors=etal |url-access=limited}}</ref>

Activated platelets release the contents of stored granules into the blood plasma. The granules include [[Adenosine diphosphate|ADP]], [[serotonin]], [[platelet-activating factor]] (PAF), [[von Willebrand factor|vWF]], [[platelet factor 4]], and [[Thromboxane A2|thromboxane A<sub>2</sub>]] (TXA<sub>2</sub>), which, in turn, activate additional platelets. The granules' contents activate a [[G protein-coupled receptor|G<sub>q</sub>-linked protein receptor]] cascade, resulting in increased calcium concentration in the platelets' cytosol. The calcium activates [[protein kinase C]], which, in turn, activates [[Phospholipase A2|phospholipase A<sub>2</sub>]] (PLA<sub>2</sub>). PLA<sub>2</sub> then modifies the [[integrin]] membrane [[glycoprotein IIb/IIIa]], increasing its affinity to bind [[fibrinogen]]. The activated platelets change shape from spherical to stellate, and the [[fibrinogen]] cross-links with [[glycoprotein IIb/IIIa]] aid in aggregation of adjacent platelets, forming a platelet plug and thereby completing primary hemostasis).<ref name="Pallister1b">{{Cite book |last=Watson |first=M. S. |title=Haematology |last2=Pallister |first2=C. J. |publisher=Scion Publishing |year=2010 |isbn=978-1-904842-39-2 |edition=2nd |pages=334–36 |oclc=1023165019}}</ref>

===Coagulation cascade===
{{Anchor|The coagulation cascade}}
[[File:Classical blood coagulation pathway.png|right|thumb|350px|The classical blood coagulation pathway<ref name="Pallister1">{{Cite book |title=Haematology |vauthors=Pallister CJ, Watson MS |publisher=Scion Publishing |year=2010 |isbn=978-1-904842-39-2 |pages=336–47}}</ref>]]

[[File:Rapaport Coagulation Cascade.svg|thumb|Modern coagulation pathway. Hand-drawn composite from similar drawings presented by Professor Dzung Le, MD, PhD, at UCSD Clinical Chemistry conferences on 14 and 21 October 2014. Original schema from Introduction to Hematology by Samuel I. Rapaport. 2nd ed.; Lippencott: 1987. Dr Le added the factor XI portion based on a paper from about year 2000. Dr. Le's similar drawings presented the development of this cascade over 6 frames, like a comic.]]
The coagulation cascade of secondary hemostasis has two initial pathways which lead to ''[[fibrin]]'' formation. These are the ''contact activation pathway'' (also known as the intrinsic pathway), and the ''tissue factor pathway'' (also known as the extrinsic pathway), which both lead to the same fundamental reactions that produce fibrin. It was previously thought that the two pathways of coagulation cascade were of equal importance, but it is now known that the primary pathway for the initiation of blood coagulation is the ''tissue factor'' (extrinsic) pathway. The pathways are a series of reactions, in which a [[zymogen]] (inactive enzyme precursor) of a [[serine protease]] and its [[glycoprotein]] co-factor are activated to become active components that then catalyze the next reaction in the cascade, ultimately resulting in cross-linked fibrin. Coagulation factors are generally indicated by [[Roman numeral]]s, with a lowercase ''a'' appended to indicate an active form.<ref name="Pallister1" />

The coagulation factors are generally [[enzyme]]s called [[serine protease]]s, which act by cleaving downstream proteins. The exceptions are tissue factor, FV, FVIII, FXIII.<ref>{{Cite web |title=Coagulation Factor |url=https://www.clotbase.bicnirrh.res.in/flow_ln.php |url-status=live |archive-url=https://web.archive.org/web/20161211075403/https://www.clotbase.bicnirrh.res.in/flow_ln.php |archive-date=11 December 2016 |access-date=20 May 2018 |website=Clotbase.bicnirrh.res.in}}</ref> Tissue factor, FV and FVIII are glycoproteins, and Factor XIII is a [[transglutaminase]].<ref name="Pallister1" /> The coagulation factors circulate as inactive [[zymogens]].
The coagulation cascade is therefore classically divided into three pathways. The ''tissue factor'' and ''contact activation'' pathways both activate the "final common pathway" of factor X, thrombin and fibrin.<ref name="Hoffbrand2">{{Cite book |last=Hoffbrand |first=A. V. |title=Essential Haematology |last2=Pettit |first2=J. E |last3=Moss |first3=P. A. H. |date=2002 |publisher=Blackwell Science |isbn=978-0-632-05153-3 |edition=4th |location=London |pages=241–43 |oclc=898998816}}</ref>

====Tissue factor pathway (extrinsic)====
{{Anchor|Extrinsic pathway}}
The main role of the [[tissue factor]] (TF) pathway is to generate a "thrombin burst", a process by which [[thrombin]], the most important constituent of the coagulation cascade in terms of its feedback activation roles, is released very rapidly. FVIIa circulates in a higher amount than any other activated coagulation factor. The process includes the following steps:<ref name="Pallister1" />

# Following damage to the blood vessel, FVII leaves the circulation and comes into contact with tissue factor expressed on tissue-factor-bearing cells ([[stromal cell|stroma]]l fibroblasts and leukocytes), forming an activated complex (TF-FVIIa).
# TF-FVIIa activates FIX and FX.
# FVII is itself activated by thrombin, FXIa, FXII, and FXa.
# The activation of FX (to form FXa) by TF-FVIIa is almost immediately inhibited by [[tissue factor pathway inhibitor]] (TFPI).
# FXa and its co-factor FVa form the [[prothrombinase]] complex, which activates [[prothrombin]] to thrombin.
# Thrombin then activates other components of the coagulation cascade, including FV and FVIII (which forms a complex with FIX), and activates and releases FVIII from being bound to vWF.
# FVIIIa is the co-factor of FIXa, and together they form the "[[tenase]]" complex, which activates FX; and so the cycle continues. ("Tenase" is a contraction of "ten" and the suffix "-ase" used for enzymes.)

====Contact activation pathway (intrinsic)====
{{Anchor|Intrinsic pathway}}
The [[contact activation system|contact activation pathway]] begins with formation of the primary complex on [[collagen]] by [[high-molecular-weight kininogen]] (HMWK), [[prekallikrein]], and [[Hageman factor|FXII (Hageman factor)]]. [[Prekallikrein]] is converted to [[kallikrein]] and FXII becomes FXIIa. FXIIa converts FXI into FXIa. Factor XIa activates FIX, which with its co-factor FVIIIa form the [[tenase]] complex, which activates FX to FXa. The minor role that the contact activation pathway has in initiating blood clot formation (or more specifically, physiological [[hemostasis]]) can be illustrated by the fact that individuals with severe deficiencies of FXII, HMWK, and [[prekallikrein]] do not have a bleeding disorder. Instead, contact activation system seems to be more involved in inflammation,<ref name="Pallister1" /> and innate immunity.<ref name="Long2016">{{Cite journal |vauthors=Long AT, Kenne E, Jung R, Fuchs TA, Renné T |date=March 2016 |title=Contact system revisited: an interface between inflammation, coagulation, and innate immunity |journal=Journal of Thrombosis and Haemostasis |volume=14 |issue=3 |pages=427–37 |doi=10.1111/jth.13235 |pmid=26707513 |doi-access=free}}</ref> Interference with the pathway may confer protection against thrombosis without a significant bleeding risk.<ref name=Long2016/>

Inhibition of factor XII and PK interferes with innate immunity in animal models.<ref name=Long2016/> More promising is [[Factor XI#Inhibition|inhibition of factor XI]], which in early clinical trials have shown the expected effect.<ref>{{Cite journal |vauthors=Ruff CT, Patel SM, Giugliano RP, Morrow DA, Hug B, Kuder JF, Goodrich EL, Chen SA, Goodman SG, Joung B, Kiss RG, Spinar J, Wojakowski W, Weitz JI, Murphy SA, Wiviott SD, Parkar S, Bloomfield D, Sabatine MS |date=January 2025 |title=Abelacimab versus Rivaroxaban in Patients with Atrial Fibrillation |journal=The New England Journal of Medicine |volume=392 |issue=4 |pages=361–71 |doi=10.1056/NEJMoa2406674 |pmid=39842011}}</ref>

====Final common pathway====
{{Anchor|Common pathway}}
The division of coagulation in two pathways is arbitrary, originating from laboratory tests in which clotting times were measured either after the clotting was initiated by glass, the intrinsic pathway; or clotting was initiated by thromboplastin (a mix of tissue factor and phospholipids), the extrinsic pathway.<ref name="troisi">{{Cite journal |vauthors=Troisi R, Balasco N, Autiero I, Sica F, Vitagliano L |date=August 2023 |title=New insight into the traditional model of the coagulation cascade and its regulation: illustrated review of a three-dimensional view |journal=Research and Practice in Thrombosis and Haemostasis |volume=7 |issue=6 |page=102160 |doi=10.1016/j.rpth.2023.102160 |pmc=10506138 |pmid=37727847}}</ref>

Further, the final common pathway scheme implies that prothrombin is converted to thrombin only when acted upon by the intrinsic or extrinsic pathways, which is an oversimplification. In fact, thrombin is generated by activated platelets at the initiation of the platelet plug, which in turn promotes more platelet activation.<ref>{{Cite journal |vauthors=Hoffman M |date=September 2003 |title=A cell-based model of coagulation and the role of factor VIIa |journal=Blood Rev |volume=17 |issue=Suppl 1 |pages=S1–5 |doi=10.1016/s0268-960x(03)90000-2 |pmid=14697207}}</ref>

Thrombin functions not only to convert [[fibrinogen]] to fibrin, it also activates Factors VIII and V and their inhibitor [[protein C]] (in the presence of [[thrombomodulin]]). By activating Factor XIII, [[covalent bond]]s are formed that crosslink the fibrin polymers that form from activated monomers.<ref name="Pallister1" /> This stabilizes the fibrin network.<ref>{{Cite journal |vauthors=Moroi M, Induruwa I, Farndale RW, Jung SM |date=March 2022 |title=Factor XIII is a newly identified binding partner for platelet collagen receptor GPVI-dimer-An interaction that may modulate fibrin crosslinking |journal=Res Pract Thromb Haemost |volume=6 |issue=3 |page=e12697 |doi=10.1002/rth2.12697 |pmc=9035508 |pmid=35494504}}</ref>

The coagulation cascade is maintained in a prothrombotic state by the continued activation of FVIII and FIX to form the [[tenase]] complex until it is down-regulated by the anticoagulant pathways.<ref name="Pallister1" />

====Cell-based scheme of coagulation====
A newer model of coagulation mechanism explains the intricate combination of cellular and biochemical events that occur during the coagulation process ''[[in vivo]]''. Along with the procoagulant and anticoagulant plasma proteins, normal physiologic coagulation requires the presence of two cell types for formation of coagulation complexes: cells that express tissue factor (usually extravascular) and platelets.<ref>{{Cite journal |vauthors=Hoffman MM, Monroe DM |date=September 2005 |title=Rethinking the coagulation cascade |journal=Curr Hematol Rep |volume=4 |issue=5 |pages=391–96 |pmid=16131441}}</ref>

The coagulation process occurs in two phases. First is the initiation phase, which occurs in tissue-factor-expressing cells. This is followed by the propagation phase, which occurs on activated [[platelet]]s. The initiation phase, mediated by the tissue factor exposure, proceeds via the classic extrinsic pathway and contributes to about 5% of thrombin production. The amplified production of thrombin occurs via the classic intrinsic pathway in the propagation phase; about 95% of thrombin generated will be during this second phase.<ref name="Hoffman-2003">{{Cite journal |last=Hoffman |first=M. |date=August 2003 |title=Remodeling the blood coagulation cascade |journal=Journal of Thrombosis and Thrombolysis |volume=16 |issue=1–2 |pages=17–20 |doi=10.1023/B:THRO.0000014588.95061.28 |pmid=14760207 |s2cid=19974377}}</ref>

===Fibrinolysis===
{{Main|Fibrinolysis}}
Eventually, blood clots are reorganized and resorbed by a process termed ''[[fibrinolysis]]''. The main enzyme responsible for this process is [[plasmin]], which is regulated by [[plasmin activator]]s and [[plasmin inhibitor]]s.<ref name="Hoffbrand" />

===Role in immune system===
The coagulation system overlaps with the [[immune system]]. Coagulation can physically trap invading microbes in blood clots. Also, some products of the coagulation system can contribute to the [[innate immune system]] by their ability to increase vascular permeability and act as [[chemotactic agent]]s for [[phagocytic cell]]s. In addition, some of the products of the coagulation system are directly [[antimicrobial]]. For example, [[beta-lysine]], an amino acid produced by platelets during coagulation, can cause [[lysis]] of many [[Gram-positive bacteria]] by acting as a cationic detergent.<ref name="Mayer">{{Cite book |last=Mayer |first=Gene |title=Immunology |date=2011 |publisher=University of South Carolina |series=Immunology Section of Microbiology and Immunology On-line |chapter=Ch. 1. Innate (non-specific) immunity |chapter-url=https://pathmicro.med.sc.edu/ghaffar/innate.htm |archive-url=https://web.archive.org/web/20141021042930/https://pathmicro.med.sc.edu/ghaffar/innate.htm |archive-date=21 October 2014}}</ref> Many [[acute-phase protein]]s of [[inflammation]] are involved in the coagulation system. In addition, pathogenic bacteria may secrete agents that alter the coagulation system, e.g. [[coagulase]] and [[streptokinase]].<ref>{{Cite journal |vauthors=Peetermans M, Vanassche T, Liesenborghs L, Lijnen RH, Verhamme P |date=November 2016 |title=Bacterial pathogens activate plasminogen to breach tissue barriers and escape from innate immunity |journal=Crit Rev Microbiol |volume=42 |issue=6 |pages=866–82 |doi=10.3109/1040841X.2015.1080214 |pmid=26485450}}</ref>

Immunohemostasis is the integration of immune activation into adaptive clot formation.  Immunothrombosis is the pathological result of crosstalk between immunity, inflammation, and coagulation.  Mediators of this process include [[damage-associated molecular pattern]]s and [[pathogen-associated molecular pattern]]s, which are recognized by [[toll-like receptor]]s, triggering procoagulant and proinflammatory responses such as formation of [[neutrophil extracellular traps]].<ref name=Yong23/>

===Cofactors===
Various substances are required for the proper functioning of the coagulation cascade:

====Calcium and phospholipids====
[[Calcium]] and [[phospholipid]]s (constituents of [[platelet]] membrane) are required for the [[tenase]] and prothrombinase complexes to function.<ref>{{Cite journal |last=Palta |first=A. |last2=Palta |first2=S. |last3=Saroa |first3=R. |date=2014 |title=Overview of the coagulation system |journal=Indian Journal of Anaesthesia |volume=58 |issue=5 |pages=515–23 |doi=10.4103/0019-5049.144643 |issn=0019-5049 |pmc=4260295 |pmid=25535411 |doi-access=free}}</ref> Calcium mediates the binding of the complexes via the terminal gamma-carboxy residues on Factor Xa and Factor IXa to the phospholipid surfaces expressed by platelets, as well as procoagulant microparticles or [[microvesicles]] shed from them.<ref>{{Cite journal |last=Signorelli |first=Salvatore Santo |last2=Oliveri Conti |first2=Gea |last3=Fiore |first3=Maria |last4=Cangiano |first4=Federica |last5=Zuccarello |first5=Pietro |last6=Gaudio |first6=Agostino |last7=Ferrante |first7=Margherita |date=2020-11-26 |title=Platelet-Derived Microparticles (MPs) and Thrombin Generation Velocity in Deep Vein Thrombosis (DVT): Results of a Case–Control Study |journal=Vascular Health and Risk Management |volume=16 |pages=489–95 |doi=10.2147/VHRM.S236286 |issn=1176-6344 |pmc=7705281 |pmid=33273818 |doi-access=free}}</ref> Calcium is also required at other points in the coagulation cascade. Calcium ions play a major role in the regulation of coagulation cascade that is paramount in the maintenance of hemostasis. Other than platelet activation, calcium ions are responsible for complete activation of several coagulation factors, including coagulation Factor XIII.<ref>{{Cite journal |last=Singh |first=S. |last2=Dodt |first2=J |last3=Volkers |first3=P. |last4=Hethershaw |first4=E. |last5=Philippou |first5=H. |last6=Ivaskevicius |first6=V. |last7=Imhof |first7=D. |last8=Oldenburg |first8=J. |last9=Biswas |first9=A. |date=5 August 2019 |title=Structure functional insights into calcium binding during the activation of coagulation factor XIII A |journal=Scientific Reports |volume=9 |issue=1 |page=11324 |bibcode=2019NatSR...911324S |doi=10.1038/s41598-019-47815-z |issn=2045-2322 |pmc=6683118 |pmid=31383913}}</ref>

====Vitamin K====
[[Vitamin K]] is an essential factor to the hepatic [[gamma-glutamyl carboxylase]] that adds a [[carboxyl]] group to [[glutamic acid]] residues on factors II, VII, IX and X, as well as [[Protein S]], [[Protein C]] and [[Protein Z]]. In adding the gamma-carboxyl group to glutamate residues on the immature clotting factors, Vitamin K is itself oxidized. Another enzyme, ''[[Vitamin K epoxide reductase]]'' (VKORC), reduces vitamin K back to its active form. Vitamin K epoxide reductase is pharmacologically important as a target of anticoagulant drugs [[warfarin]] and related [[coumarin]]s such as [[acenocoumarol]], [[phenprocoumon]], and [[dicumarol]]. These drugs create a deficiency of reduced vitamin K by blocking VKORC, thereby inhibiting maturation of clotting factors. Vitamin K deficiency from other causes (e.g., in [[malabsorption]]) or impaired vitamin K metabolism in disease (e.g., in [[liver failure]]) lead to the formation of PIVKAs (proteins formed in vitamin K absence), which are partially or totally non-gamma carboxylated, affecting the coagulation factors' ability to bind to phospholipid.<ref name="Paulus">{{Cite journal |last=Paulus |first=MC |last2=Drent |first2=M |last3=Kouw |first3=IWK |last4=Balvers |first4=MGJ |last5=Bast |first5=A |last6=van Zanten |first6=ARH |date=1 July 2024 |title=Vitamin K: a potential missing link in critical illness-a scoping review. |journal=Critical Care |volume=28 |issue=1 |page=212 |doi=10.1186/s13054-024-05001-2 |pmc=11218309 |pmid=38956732 |doi-access=free}}</ref>

===Regulators===
[[File:Coagulation full.svg|400px|thumb|right|Coagulation with arrows for negative and positive feedback.]]
Several mechanisms keep platelet activation and the coagulation cascade in check.<ref name="Dicks24">{{Cite journal |last=Dicks |first=AB |last2=Moussallem |first2=E |last3=Stanbro |first3=M |last4=Walls |first4=J |last5=Gandhi |first5=S |last6=Gray |first6=BH |date=9 January 2024 |title=A Comprehensive Review of Risk Factors and Thrombophilia Evaluation in Venous Thromboembolism. |journal=Journal of Clinical Medicine |volume=13 |issue=2 |page=362 |doi=10.3390/jcm13020362 |pmc=10816375 |pmid=38256496 |doi-access=free}}</ref> Abnormalities can lead to an increased tendency toward thrombosis:

====Protein C and Protein S====
[[Protein C]] is a major physiological anticoagulant. It is a vitamin K-dependent [[Serine protease|serine protease enzyme]] that is activated by thrombin into activated protein C (APC). Protein C is activated in a sequence that starts with Protein C and thrombin binding to a cell surface protein [[thrombomodulin]]. Thrombomodulin binds these proteins in such a way that it activates Protein C. The activated form, along with [[protein S]] and a phospholipid as cofactors, degrades FVa and FVIIIa. Quantitative or qualitative deficiency of either (protein C or protein S) may lead to [[thrombophilia]] (a tendency to develop thrombosis). Impaired action of Protein C (activated Protein C resistance), for example by [[Factor V Leiden|having the "Leiden" variant of Factor V]] or high levels of FVIII, also may lead to a thrombotic tendency.<ref name=Dicks24/>

====Antithrombin====
[[Antithrombin]] is a [[serine protease inhibitor]] ([[serpin]]) that degrades the serine proteases: thrombin, FIXa, FXa, FXIa, and FXIIa. It is constantly active, but its adhesion to these factors is increased by the presence of [[heparan sulfate]] (a [[glycosaminoglycan]]) or the administration of [[heparin]]s (different heparinoids increase affinity to FXa, thrombin, or both). Quantitative or qualitative deficiency of antithrombin (inborn or acquired, e.g., in [[proteinuria]]) leads to thrombophilia.<ref name=Dicks24/>

====Tissue factor pathway inhibitor (TFPI)====
[[Tissue factor pathway inhibitor]] (TFPI) limits the action of tissue factor (TF). It also inhibits excessive TF-mediated activation of FVII and FX.<ref>{{Cite journal |vauthors=Maroney SA, Mast AE |date=June 2015 |title=New insights into the biology of tissue factor pathway inhibitor |journal=J Thromb Haemost |volume=13 |issue=Suppl 1 |pages=S200–07 |doi=10.1111/jth.12897 |pmc=4604745 |pmid=26149025}}</ref>

====Plasmin====
[[Plasmin]] is generated by proteolytic cleavage of plasminogen, a plasma protein synthesized in the liver. This cleavage is catalyzed by [[tissue plasminogen activator]] (t-PA), which is synthesized and secreted by endothelium. Plasmin proteolytically cleaves fibrin into fibrin degradation products that inhibit excessive fibrin formation.{{citation needed|date=June 2022}}

====Prostacyclin====
[[Prostacyclin]] (PGI<sub>2</sub>) is released by endothelium and activates platelet G<sub>s</sub> protein-linked receptors. This, in turn, activates [[adenylyl cyclase]], which synthesizes cAMP. cAMP inhibits platelet activation by decreasing cytosolic levels of calcium and, by doing so, inhibits the release of granules that would lead to activation of additional platelets and the coagulation cascade.<ref name="Hoffbrand">{{Cite book |last=Hoffbrand |first=A.V. |title=Essential haematology |publisher=Blackwell Science |year=2002 |isbn=978-0-632-05153-3 |location=Oxford |pages=243–45}}</ref>

== Medical assessment ==
Numerous medical tests are used to assess the function of the coagulation system:<ref name="medline2024" /><ref name="Lillicrap">{{Cite book |last=David Lillicrap |url=https://archive.org/details/practicalhemosta00keyn |title=Practical Hemostasis and Thrombosis |last2=Nigel Key |last3=Michael Makris |last4=Denise O'Shaughnessy |publisher=Wiley-Blackwell |year=2009 |isbn=978-1-4051-8460-1 |pages=[https://archive.org/details/practicalhemosta00keyn/page/n22 7]–16 |url-access=limited}}</ref>
* Common: [[Partial thromboplastin time|aPTT]], [[prothrombin time|PT]] (also used to determine [[International normalized ratio|INR]]), [[fibrinogen]] testing (often by the ''Clauss fibrinogen assay''),<ref name="Stang">{{Cite book |last=Stang |first=LJ |title=Haemostasis |last2=Mitchell |first2=LG |date=2013 |isbn=978-1-62703-338-1 |series=Methods in Molecular Biology |volume=992 |pages=181–92 |chapter=Fibrinogen |doi=10.1007/978-1-62703-339-8_14 |pmid=23546714}}</ref> [[platelet]] count, platelet function testing (often by [[PFA-100]]), [[thrombodynamics test]].
* Other: [[Thrombin clotting time|TCT]], [[bleeding time]], [[mixing test]] (whether an abnormality corrects if the patient's plasma is mixed with normal plasma), coagulation factor assays, [[antiphospholipid antibody|antiphospholipid antibodies]], [[D-dimer]], genetic tests (e.g. [[factor V Leiden]], [[prothrombin]] mutation G20210A), [[dilute Russell's viper venom time]] (dRVVT), miscellaneous platelet function tests, [[thromboelastography]] (TEG or Sonoclot), [[euglobulin lysis time]] (ELT).

The contact activation (intrinsic) pathway is initiated by activation of the [[contact activation system]], and can be measured by the [[partial thromboplastin time|activated partial thromboplastin]] time (aPTT) test.<ref>{{Cite journal |vauthors=Rasmussen KL, Philips M, Tripodi A, Goetze JP |date=June 2020 |title=Unexpected, isolated activated partial thromboplastin time prolongation: A practical mini-review |journal=Eur J Haematol |volume=104 |issue=6 |pages=519–25 |doi=10.1111/ejh.13394 |pmid=32049377}}</ref>

The tissue factor (extrinsic) pathway is initiated by release of [[tissue factor]] (a specific cellular lipoprotein), and can be measured by the [[prothrombin time]] (PT) test.<ref name="medline">{{Cite web |title=Prothrombin Time Test and INR (PT/INR): MedlinePlus Medical Test |url=https://medlineplus.gov/lab-tests/prothrombin-time-test-and-inr-ptinr/#:~:text=A%20prothrombin%20time%20(PT)%20test,as%20clotting%20(coagulation)%20factors. |access-date=28 April 2024 |website=medlineplus.gov |language=en}}</ref> PT results are often reported as ratio ([[International normalized ratio|INR]] value) to monitor dosing of oral anticoagulants such as [[warfarin]].<ref>{{Cite journal |vauthors=Dorgalaleh A, Favaloro EJ, Bahraini M, Rad F |date=February 2021 |title=Standardization of Prothrombin Time/International Normalized Ratio (PT/INR) |journal=Int J Lab Hematol |volume=43 |issue=1 |pages=21–28 |doi=10.1111/ijlh.13349 |pmid=32979036}}</ref>

The quantitative and qualitative screening of fibrinogen is measured by the [[thrombin clotting time]] (TCT). Measurement of the exact amount of fibrinogen present in the blood is generally done using the ''Clauss fibrinogen assay''.<ref name="Stang" /> Many analysers are capable of measuring a "derived fibrinogen" level from the graph of the Prothrombin time clot.

If a coagulation factor is part of the contact activation or tissue factor pathway, a deficiency of that factor will affect only one of the tests: Thus [[hemophilia A]], a deficiency of factor VIII, which is part of the contact activation pathway, results in an abnormally prolonged aPTT test but a normal PT test. Deficiencies of common pathway factors prothrombin, fibrinogen, FX, and FV will prolong both aPTT and PT. If an abnormal PT or aPTT is present, additional testing will occur to determine which (if any) factor is present as aberrant concentrations.

Deficiencies of fibrinogen (quantitative or qualitative) will prolong PT, aPTT, thrombin time, and [[reptilase time]].

==Role in disease==
Coagulation defects may cause hemorrhage or thrombosis, and occasionally both, depending on the nature of the defect.<ref name="isbn1-4051-8050-1">{{Cite book |last=Hughes-Jones |first=N. C. |title=Haematology |last2=Wickramasinghe |first2=S. N. |last3=Hatton |first3=Chris |date=2008 |publisher=Wiley-Blackwell Publishers |isbn=978-1-4051-8050-4 |edition=8th |pages=[https://archive.org/details/lecturenoteshaem0000unse/page/145 145]–66 |oclc=1058077604}}</ref>

[[File:Gp1brec3.png|thumb|160px|right|The GP1b-IX receptor complex. This protein receptor complex is found on the surface of platelets, and in conjunction with [[GP5 (gene)|GPV]] allows for platelets to adhere to the site of injury. Mutations in the genes associated with the glycoprotein Ib-IX-V complex are characteristic of [[Bernard–Soulier syndrome]].]]

===Platelet disorders===
Platelet disorders are either congenital or acquired. Examples of congenital platelet disorders are [[Glanzmann's thrombasthenia]], [[Bernard–Soulier syndrome]] (abnormal [[Glycoprotein Ib-IX-V Receptor Complex|glycoprotein Ib-IX-V complex]]), [[gray platelet syndrome]] (deficient [[alpha granules]]), and [[delta storage pool deficiency]] (deficient [[dense granules]]). Most are rare. They predispose to hemorrhage. [[Von Willebrand disease]] is due to deficiency or abnormal function of [[von Willebrand factor]], and leads to a similar bleeding pattern; its milder forms are relatively common.{{Citation needed|date=November 2021}}

Decreased platelet numbers (thrombocytopenia) is due to insufficient production (e.g., [[myelodysplastic syndrome]] or other bone marrow disorders), destruction by the immune system ([[immune thrombocytopenic purpura]]), or consumption (e.g., [[thrombotic thrombocytopenic purpura]], [[hemolytic-uremic syndrome]], [[paroxysmal nocturnal hemoglobinuria]], [[disseminated intravascular coagulation]], [[heparin-induced thrombocytopenia]]).<ref>{{Cite web |title=Disseminated Intravascular Coagulation |url=https://www.lecturio.com/concepts/disseminated-intravascular-coagulation/ |url-status=live |archive-url=https://web.archive.org/web/20210712111249/https://www.lecturio.com/concepts/disseminated-intravascular-coagulation/ |archive-date=12 July 2021 |access-date=12 July 2021 |website=The Lecturio Medical Concept Library}}</ref> An increase in platelet count is called [[thrombocytosis]], which may lead to formation of [[Thrombosis|thromboembolisms]]; however, thrombocytosis may be associated with increased risk of either thrombosis or hemorrhage in patients with [[myeloproliferative neoplasm]].<ref>{{Cite journal |vauthors=Andreescu M, Andreescu B |date=March 2024 |title=A Review About the Assessment of the Bleeding and Thrombosis Risk for Patients With Myeloproliferative Neoplasms Scheduled for Surgery |journal=Cureus |volume=16 |issue=3 |page=e56008 |doi=10.7759/cureus.56008 |pmc=11007487 |pmid=38606222 |doi-access=free}}</ref>

===Coagulation factor disorders===
The best-known coagulation factor disorders are the [[hemophilia]]s. The three main forms are [[hemophilia A]] (factor VIII deficiency), [[hemophilia B]] (factor IX deficiency or "Christmas disease") and [[hemophilia C]] (factor XI deficiency, mild bleeding tendency).<ref>{{Cite journal |vauthors=Demoy M, Labrousse J, Grand F, Moyrand S, Tuffigo M, Lamarche S, Macchi L |date=June 2024 |title=[Factor XI deficiency: actuality and review of the literature] |journal=Ann Biol Clin (Paris) |language=French |volume=82 |issue=2 |pages=225–36 |doi=10.1684/abc.2024.1884 |pmid=38702892}}</ref>

[[Von Willebrand disease]] (which behaves more like a platelet disorder except in severe cases), is the most common hereditary bleeding disorder and is characterized as being inherited autosomal recessive or dominant. In this disease, there is a defect in von Willebrand factor (vWF), which mediates the binding of glycoprotein Ib (GPIb) to collagen. This binding helps mediate the activation of platelets and formation of primary hemostasis.{{medical citation needed|date=August 2020}}

In acute or chronic [[liver failure]], there is insufficient production of coagulation factors, possibly increasing risk of bleeding during surgery.<ref>{{Cite journal |display-authors=6 |vauthors=Huber J, Stanworth SJ, Doree C, Fortin PM, Trivella M, Brunskill SJ, Hopewell S, Wilkinson KL, Estcourt LJ |date=November 2019 |editor-last=Cochrane Haematology Group |title=Prophylactic plasma transfusion for patients without inherited bleeding disorders or anticoagulant use undergoing non-cardiac surgery or invasive procedures |journal=The Cochrane Database of Systematic Reviews |volume=2019 |issue=11 |page=CD012745 |doi=10.1002/14651858.CD012745.pub2 |pmc=6993082 |pmid=31778223}}</ref>

[[Thrombosis]] is the pathological development of blood clots. These clots may break free and become mobile, forming an [[Embolism|embolus]] or grow to such a size that occludes the vessel in which it developed. An [[embolism]] is said to occur when the [[thrombus]] (blood clot) becomes a mobile embolus and migrates to another part of the body, interfering with blood circulation and hence impairing organ function downstream of the occlusion. This causes [[ischemia]] and often leads to ischemic [[necrosis]] of tissue. Most cases of [[venous thrombosis]] are due to acquired states (older age, surgery, cancer, immobility).  Unprovoked venous thrombosis may be related to inherited [[thrombophilia]]s (e.g., [[factor V Leiden]], antithrombin deficiency, and various other genetic deficiencies or variants), particularly in younger patients with family history of thrombosis; however, thrombotic events are more likely when acquired risk factors are superimposed on the inherited state.<ref>{{Cite journal |vauthors=Middeldorp S, Nieuwlaat R, Baumann Kreuziger L, Coppens M, Houghton D, James AH, Lang E, Moll S, Myers T, Bhatt M, Chai-Adisaksopha C, Colunga-Lozano LE, Karam SG, Zhang Y, Wiercioch W, Schünemann HJ, Iorio A |date=November 2023 |title=American Society of Hematology 2023 guidelines for management of venous thromboembolism: thrombophilia testing |journal=Blood Adv |volume=7 |issue=22 |pages=7101–38 |doi=10.1182/bloodadvances.2023010177 |pmc=10709681 |pmid=37195076}}</ref>

==Pharmacology==

===Procoagulants===
{{Anchor|Procoagulants}}
The use of [[Adsorption|adsorbent]] chemicals, such as [[zeolite]]s, and other [[hemostatic agent]]s are also used for sealing severe injuries quickly (such as in traumatic bleeding secondary to gunshot wounds). Thrombin and fibrin [[glue]] are used surgically to treat bleeding and to thrombose aneurysms. [[Hemostatic Powder Spray TC-325]] is used to treated gastrointestinal bleeding.{{citation needed|date=May 2023}}

[[Desmopressin]] is used to improve platelet function by activating [[arginine vasopressin receptor 1A]].<ref>{{Cite journal |last=Kaufmann |first=J.E. |last2=Vischer |first2=U.M. |date=April 2003 |title=Cellular mechanisms of the hemostatic effects of desmopressin (DDAVP) |journal=Journal of Thrombosis and Haemostasis |volume=1 |issue=4 |pages=682–89 |doi=10.1046/j.1538-7836.2003.00190.x |pmid=12871401}}</ref>

Coagulation factor concentrates are used to treat [[hemophilia]], to reverse the effects of anticoagulants, and to treat bleeding in people with impaired coagulation factor synthesis or increased consumption. [[Prothrombin complex concentrate]], [[cryoprecipitate]] and [[fresh frozen plasma]] are commonly used coagulation factor products. [[Factor VII|Recombinant activated human factor VII]] is sometimes used in the treatment of major bleeding.

[[Tranexamic acid]] and [[aminocaproic acid]] inhibit fibrinolysis and lead to a ''de facto'' reduced bleeding rate. Before its withdrawal, [[aprotinin]] was used in some forms of major surgery to decrease bleeding risk and the need for blood products.

[[File:FXa-rivaroxaban.png|thumb|300px|right|[[Rivaroxaban]] drug bound to the [[coagulation factor Xa]]. The drug prevents this protein from activating the coagulation pathway by inhibiting its [[enzyme|enzymatic activity]].]]

===Anticoagulants===
{{Main|Antiplatelet drug|Anticoagulant}}

Anticoagulants and anti-platelet agents (together "antithrombotics") are amongst the most commonly used medications. [[Antiplatelet drug|Anti-platelet agents]] include [[aspirin]], [[dipyridamole]], [[ticlopidine]], [[clopidogrel]], [[ticagrelor]] and [[prasugrel]]; the parenteral [[glycoprotein IIb/IIIa inhibitors]] are used during [[angioplasty]]. Of the anticoagulants, [[warfarin]] (and related [[coumarin]]s) and [[heparin]] are the most commonly used. Warfarin affects the vitamin K-dependent clotting factors (II, VII, IX, X) and protein C and protein S, whereas heparin and related compounds increase the action of antithrombin on thrombin and factor Xa. A newer class of drugs, the [[direct thrombin inhibitor]]s, is under development; some members are already in clinical use (such as [[lepirudin]], [[argatroban]], [[bivalirudin]] and [[dabigatran]]). Also in clinical use are other small molecular compounds that interfere directly with the enzymatic action of particular coagulation factors (the [[Anticoagulant#Directly acting oral anticoagulants|directly acting oral anticoagulants]]: [[dabigatran]], [[rivaroxaban]], [[apixaban]], and [[edoxaban]]).<ref name="pmid22345595">{{Cite journal |vauthors=Soff GA |date=March 2012 |title=A new generation of oral direct anticoagulants |journal=Arteriosclerosis, Thrombosis, and Vascular Biology |volume=32 |issue=3 |pages=569–74 |doi=10.1161/ATVBAHA.111.242834 |pmid=22345595 |doi-access=free}}</ref>

==History==

===Initial discoveries===
Theories on the coagulation of blood have existed since antiquity. Physiologist [[Johannes Peter Müller|Johannes Müller]] (1801–1858) described fibrin, the substance of a [[thrombus]]. Its soluble precursor, [[fibrinogen]], was thus named by [[Rudolf Virchow]] (1821–1902), and isolated chemically by [[Prosper Sylvain Denis]] (1799–1863). [[Alexander Schmidt (physiologist)|Alexander Schmidt]] suggested that the conversion from fibrinogen to fibrin is the result of an [[enzyme|enzymatic]] process, and labeled the hypothetical enzyme "[[thrombin]]" and its precursor "[[prothrombin]]".<ref>{{Cite journal |last=Schmidt A |year=1872 |title=Neue Untersuchungen über die Faserstoffgerinnung |journal=Pflügers Archiv für die gesamte Physiologie |volume=6 |pages=413–538 |doi=10.1007/BF01612263 |s2cid=37273997}}</ref><ref>Schmidt A. Zur Blutlehre. Leipzig: Vogel, 1892.</ref> [[Nicolas Maurice Arthus|Arthus]] discovered in 1890 that calcium was essential in coagulation.<ref>{{Cite journal |vauthors=Arthus M, Pagès C |year=1890 |title=Nouvelle theorie chimique de la coagulation du sang |journal=Arch Physiol Norm Pathol |volume=5 |pages=739–46}}</ref><ref name="Shapiro">{{Cite journal |vauthors=Shapiro SS |date=October 2003 |title=Treating thrombosis in the 21st century |journal=The New England Journal of Medicine |volume=349 |issue=18 |pages=1762–64 |doi=10.1056/NEJMe038152 |pmid=14585945}}</ref> [[Platelet]]s were identified in 1865, and their function was elucidated by [[Giulio Bizzozero]] in 1882.<ref name="Brewer">{{Cite journal |vauthors=Brewer DB |date=May 2006 |title=Max Schultze (1865), G. Bizzozero (1882) and the discovery of the platelet |journal=British Journal of Haematology |volume=133 |issue=3 |pages=251–58 |doi=10.1111/j.1365-2141.2006.06036.x |pmid=16643426 |doi-access=free}}</ref>

The theory that thrombin is generated by the presence of [[tissue factor]] was consolidated by [[Paul Morawitz]] in 1905.<ref>{{Cite journal |last=Morawitz P |year=1905 |title=Die Chemie der Blutgerinnung |journal=Ergebn Physiol |volume=4 |pages=307–422 |doi=10.1007/BF02321003 |s2cid=84003009}}</ref> At this stage, it was known that ''thrombokinase/thromboplastin'' (factor III) is released by damaged tissues, reacting with ''prothrombin'' (II), which, together with [[calcium in biology|calcium]] (IV), forms ''thrombin'', which converts fibrinogen into ''fibrin'' (I).<ref name="Giangrande">{{Cite journal |vauthors=Giangrande PL |date=June 2003 |title=Six characters in search of an author: the history of the nomenclature of coagulation factors |journal=British Journal of Haematology |volume=121 |issue=5 |pages=703–12 |doi=10.1046/j.1365-2141.2003.04333.x |pmid=12780784 |s2cid=22694905}}</ref>

===Coagulation factors===
The remainder of the biochemical factors in the process of coagulation were largely discovered in the 20th century.{{citation needed|date=September 2022}}

A first clue as to the actual complexity of the system of coagulation was the discovery of ''proaccelerin'' (initially and later called Factor V) by {{ill|Paul Owren|no}} (1905–1990) in 1947. He also postulated its function to be the generation of accelerin (Factor VI), which later turned out to be the activated form of V (or Va); hence, VI is not now in active use.<ref name=Giangrande/>

Factor VII (also known as ''serum prothrombin conversion accelerator'' or ''proconvertin'', precipitated by barium sulfate) was discovered in a young female patient in 1949 and 1951 by different groups.

[[Factor VIII]] turned out to be deficient in the clinically recognized but etiologically elusive [[haemophilia A|hemophilia A]]; it was identified in the 1950s and is alternatively called ''antihemophilic globulin'' due to its capability to correct hemophilia A.<ref name=Giangrande/>

Factor IX was discovered in 1952 in a young patient with [[haemophilia B|hemophilia B]] named [[Stephen Christmas]] (1947–1993). His deficiency was described by Dr. Rosemary Biggs and Professor [[R.G. MacFarlane]] in Oxford, UK. The factor is, hence, called Christmas Factor. Christmas lived in Canada and campaigned for blood transfusion safety until succumbing to transfusion-related [[AIDS]] at age 46. An alternative name for the factor is ''plasma thromboplastin component'', given by an independent group in California.<ref name=Giangrande/>

Hageman factor, now known as factor XII, was identified in 1955 in an asymptomatic patient with a prolonged bleeding time named of John Hageman. Factor X, or Stuart-Prower factor, followed, in 1956. This protein was identified in a Ms. Audrey Prower of London, who had a lifelong bleeding tendency. In 1957, an American group identified the same factor in a Mr. Rufus Stuart. Factors XI and XIII were identified in 1953 and 1961, respectively.<ref name=Giangrande/>

The view that the coagulation process is a "cascade" or "waterfall" was enunciated almost simultaneously by MacFarlane<ref name="pmid14167839">{{Cite journal |vauthors=Macfarlane RG |date=May 1964 |title=An enzyme cascade in the blood clotting mechanism, and its function as a biochemical amplifier |journal=Nature |volume=202 |issue=4931 |pages=498–99 |bibcode=1964Natur.202..498M |doi=10.1038/202498a0 |pmid=14167839 |s2cid=4214940}}</ref> in the UK and by Davie and Ratnoff<ref name="pmid14173416">{{Cite journal |vauthors=Davie EW, Ratnoff OD |date=September 1964 |title=Waterfall sequence for intrinsic blood clotting |journal=Science |volume=145 |issue=3638 |pages=1310–12 |bibcode=1964Sci...145.1310D |doi=10.1126/science.145.3638.1310 |pmid=14173416 |s2cid=34111840}}</ref> in the US, respectively.

===Nomenclature===
The usage of [[Roman numeral]]s rather than eponyms or systematic names was agreed upon during annual conferences (starting in 1955) of hemostasis experts. In 1962, consensus was achieved on the numbering of factors I–XII.<ref>{{Cite journal |vauthors=Wright IS |date=February 1962 |title=The nomenclature of blood clotting factors |journal=Canadian Medical Association Journal |volume=86 |issue=8 |pages=373–74 |pmc=1848865 |pmid=14008442}}</ref> This committee evolved into the present-day International Committee on Thrombosis and Hemostasis (ICTH). Assignment of numerals ceased in 1963 after the naming of Factor XIII. The names Fletcher Factor and Fitzgerald Factor were given to further coagulation-related proteins, namely [[prekallikrein]] and [[high-molecular-weight kininogen]], respectively.<ref name=Giangrande/>

Factor VI{{Citation needed|date=December 2018}} is unassigned, as accelerin was found to be activated Factor V.

==Other species==
All mammals have an extremely closely related blood coagulation process, using a combined cellular and serine protease process.{{citation needed|date=October 2012}} It is possible for any mammalian coagulation factor to "cleave" its equivalent target in any other mammal.{{citation needed|date=October 2012}} The only non-mammalian animal known to use serine proteases for blood coagulation is the [[horseshoe crab]].<ref name="pmid15170505">{{Cite journal |vauthors=Osaki T, Kawabata S |date=June 2004 |title=Structure and function of coagulogen, a clottable protein in horseshoe crabs |journal=Cellular and Molecular Life Sciences |volume=61 |issue=11 |pages=1257–65 |doi=10.1007/s00018-004-3396-5 |pmc=11138774 |pmid=15170505 |s2cid=24537601}}</ref> Exemplifying the close links between coagulation and inflammation, the horseshoe crab has a primitive response to injury, carried out by cells known as amoebocytes (or [[Hemocyte (invertebrate immune system cell)|hemocytes]]) which serve both hemostatic and immune functions.<ref name="Yong23">{{Cite journal |last=Yong |first=J |last2=Toh |first2=CH |date=21 December 2023 |title=Rethinking coagulation: from enzymatic cascade and cell-based reactions to a convergent model involving innate immune activation. |journal=Blood |volume=142 |issue=25 |pages=2133–45 |doi=10.1182/blood.2023021166 |pmid=37890148 |doi-access=free}}</ref><ref name="Iwanaga">{{Cite journal |last=Iwanaga |first=S |date=May 2007 |title=Biochemical principle of Limulus test for detecting bacterial endotoxins. |journal=Proceedings of the Japan Academy. Series B, Physical and Biological Sciences |volume=83 |issue=4 |pages=110–19 |bibcode=2007PJAB...83..110I |doi=10.2183/pjab.83.110 |pmc=3756735 |pmid=24019589}}</ref>

== See also ==
{{Portal|Medicine}}
* [[Agglutination (biology)]]
* [[Antihemorrhagic]]
* [[Post-vaccination embolic and thrombotic events]]

== References ==
{{Reflist}}

== Further reading ==
* {{Cite journal |last=Hoffman |first=Maureane |last2=Monroe |first2=Dougald |date=2001 |title=A Cell-based Model of Hemostasis |journal=Thrombosis and Haemostasis |volume=85 |issue=6 |pages=958–65 |doi=10.1055/s-0037-1615947 |pmid=11434702}}
* {{Cite journal |vauthors=Hoffman M, Monroe DM |date=February 2007 |title=Coagulation 2006: a modern view of hemostasis |journal=Hematology/Oncology Clinics of North America |volume=21 |issue=1 |pages=1–11 |doi=10.1016/j.hoc.2006.11.004 |pmid=17258114}}

== External links ==
* {{Commons category-inline|Coagulation}}

{{Coagulation}}
{{Coagulation physiology}}
{{Authority control}}

[[Category:Coagulation system]]
[[Category:Blood]]