Editing Coagulation (section)

==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>