Editing Disseminated intravascular coagulation (section)

==Pathophysiology==
[[Image:Coagulation full.svg|thumb|400px|The coagulation cascade of secondary hemostasis.]]
Under homeostatic conditions, the body is maintained in a finely tuned balance of coagulation and [[fibrinolysis]]. The activation of the coagulation cascade yields [[thrombin]] that converts [[fibrinogen]] to [[fibrin]]; the stable fibrin clot being the final product of [[hemostasis]]. The fibrinolytic system then functions to break down fibrinogen and fibrin. Activation of the fibrinolytic system generates [[plasmin]] (in the presence of thrombin), which is responsible for the lysis of fibrin clots. The breakdown of fibrinogen and fibrin results in polypeptides called [[fibrin degradation products]] (FDPs) or fibrin split products (FSPs). In a state of homeostasis between clot formation and clot dissolution, the presence of plasmin is critical, as it is the central proteolytic enzyme of coagulation and is necessary for the breakdown of fibrin clots, or fibrinolysis.<ref>{{cite journal |last1=Lijnen |first1=HR |last2=Collen |first2=D |title=Mechanisms of physiological fibrinolysis |journal=Baillières Clinical Hematology |date=1995 |volume=8 |issue=2 |pages=277–290 |doi=10.1016/s0950-3536(05)80268-9 |pmid=7549063}}</ref>

In DIC, the processes of coagulation and fibrinolysis are dysregulated, and the result is widespread clotting with resultant bleeding. Regardless of the triggering event of DIC, once initiated, the pathophysiology of DIC is similar in all conditions. One critical mediator of DIC is the release of a transmembrane glycoprotein called [[tissue factor]] (TF). TF is present on the surface of many cell types (including endothelial cells, macrophages, and monocytes) and is not normally in contact with the general circulation, but is exposed to the circulation after vascular damage. For example, TF is released in response to exposure to cytokines (particularly [[interleukin 1]]), [[Tumor necrosis factor-alpha|tumor necrosis factor]], and [[endotoxin]].<ref name=Robbins>Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; & Mitchell, Richard N. (2007). ''Robbins Basic Pathology'' (8th ed.). Saunders Elsevier. pp. 469-471 {{ISBN|978-1-4160-2973-1}}</ref> This plays a major role in the development of DIC in septic conditions. TF is also abundant in tissues of the lungs, brain, and placenta. This helps to explain why DIC readily develops in patients with extensive trauma. Upon exposure to blood and platelets, TF binds with activated factor VIIa (normally present in trace amounts in the blood), forming the extrinsic tenase complex. This complex further activates factor IX and X to IXa and Xa, respectively, leading to the common coagulation pathway and the subsequent formation of thrombin and fibrin.<ref name="hoffman"/>

The release of endotoxin is the mechanism by which [[Gram-negative]] [[sepsis]] provokes DIC. In [[acute promyelocytic leukemia]], treatment causes the destruction of leukemic granulocyte precursors, resulting in the release of large amounts of proteolytic enzymes from their storage granules, causing microvascular damage. Other malignancies may enhance the expression of various oncogenes that result in the release of TF and [[plasminogen activator inhibitor-1]] (PAI-1), which prevents fibrinolysis.<ref name="pmid17108099">{{cite journal |vauthors=Rak J, Yu JL, Luyendyk J, Mackman N |title=Oncogenes, trousseau syndrome, and cancer-related changes in the coagulome of mice and humans |journal=Cancer Res. |volume=66 |issue=22 |pages=10643–6 |year=2006 |pmid=17108099 |doi=10.1158/0008-5472.CAN-06-2350 |url=http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=17108099|doi-access= |url-access=subscription }}</ref>

Excess circulating thrombin results from the excess activation of the coagulation cascade. The excess thrombin cleaves fibrinogen, which ultimately leaves behind multiple fibrin clots in the circulation. These excess clots trap platelets to become larger clots, which leads to microvascular and macrovascular thrombosis. This lodging of clots in the microcirculation, in the large vessels, and in the organs is what leads to the ischemia, impaired organ perfusion, and end-organ damage that occurs with DIC.<ref name="auto1">{{cite web |url=https://www.nhlbi.nih.gov/health-topics/disseminated-intravascular-coagulation| title=Disseminated Intravascular Coagulation
|website=National Heart, Lung And Blood Institute |access-date= 12 July 2021}}</ref><ref name="auto">{{cite web |url=https://emedicine.medscape.com/article/199627-overview| title=Disseminated Intravascular Coagulation (DIC)
|website=Medscape |access-date= 12 July 2021}}</ref>

Coagulation inhibitors are also consumed in this process. Decreased inhibitor levels will permit more clotting so that a [[positive feedback]] loop develops in which increased clotting leads to more clotting. At the same time, thrombocytopenia occurs and this has been attributed to the entrapment and consumption of platelets. Clotting factors are consumed in the development of multiple clots, which contributes to the bleeding seen with DIC.<ref name="auto1"/><ref name="auto"/>

Simultaneously, excess circulating thrombin assists in the conversion of plasminogen to plasmin, resulting in fibrinolysis. The breakdown of clots results in an excess of FDPs, which have powerful anticoagulant properties, contributing to hemorrhage. The excess plasmin also activates the complement and kinin systems. Activation of these systems leads to many of the clinical symptoms that patients experiencing DIC exhibits, such as shock, hypotension, and increased vascular permeability. The acute form of DIC is considered an extreme expression of the intravascular coagulation process with a complete breakdown of the normal homeostatic boundaries. DIC is associated with a poor prognosis and a high mortality rate.<ref name="auto1"/><ref name="auto"/>

There has been a recent challenge however to the basic assumptions and interpretations of the pathophysiology of DIC.  A study of sepsis and DIC in animal models has shown that a highly expressed receptor on the surface of hepatocytes, termed the [[Ashwell-Morell receptor]], is responsible for thrombocytopenia in bacteremia and sepsis due to ''[[Streptococcus pneumoniae]]'' (SPN) and possibly other pathogens. The [[thrombocytopenia]] observed in SPN sepsis was not due to increased consumption of coagulation factors such as platelets, but instead was the result of this receptor's activity, enabling hepatocytes to ingest and rapidly clear platelets from circulation.<ref>{{cite journal|last=Grewal|first=PK|author2=Uchiyama, S |author3=Ditto, D |author4=Varki, N |author5=Le, DT |author6=Nizet, V |author7= Marth, JD |title=The Ashwell receptor mitigates the lethal coagulopathy of sepsis.|journal=Nature Medicine|date=June 2008|volume=14|issue=6|pages=648–55|pmid=18488037|doi=10.1038/nm1760 |pmc=2853759}}</ref> By removing prothrombotic components before they participate in the coagulopathy of DIC, the Ashwell-Morell receptor lessens the severity of DIC, reducing thrombosis and tissue necrosis, and promoting survival. The hemorrhage observed in DIC and among some tissues lacking this receptor may therefore be secondary to increased thrombosis with loss of the mechanical vascular barrier.<ref name="auto1"/><ref name="auto"/>

Activation of the [[Coagulation#Contact activation pathway (intrinsic)|intrinsic]] and [[Coagulation#Tissue factor pathway (extrinsic)|extrinsic coagulation pathways]] causes excess thrombus formation in the blood vessels. Consumption of coagulation factors due to extensive coagulation in turn causes bleeding.<ref name="auto1"/><ref name="auto"/>