Editing Coagulation (section)

===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>