Disseminated intravascular coagulation pathophysiology: Difference between revisions

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General characteristics:
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{{DIC}}


* DIC is a hemorrhagic syndrome originating in the small blood vessels
{{CMG}}; {{AE}} {{OK}}
* DIC is caused by uncontrolled activation of clotting factors and fibrinolytic enzymes
 
* Tissue necrosis and bleeding are results of DIC
==Overview==
DIC is a hemorrhagic syndrome originating in the small blood vessels. DIC is caused by uncontrolled activation of [[clotting factors]] and [[fibrinolytic]] [[enzymes]]. Tissue [[necrosis]] and [[bleeding]] are consequences of DIC. Under [[Homeostasis|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 [[Fibrinolysis|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]], the presence of [[thrombin]] is critical, as it is the central [[proteolytic]] [[enzyme]] of coagulation and is also necessary for the breakdown of clots, or [[fibrinolysis]].
 
==Pathophysiology==
DIC is an acquired syndrome characterized by the intravascular activation of coagulation due to sepsis, trauma, malignancy, liver disease, obstetric disorders, envenomation, vascular anomalies and major transfusion reactions. It can originate from and cause damage to the microvasculature, which may eventually lead to  organ dysfunction. Under [[Homeostasis|homeostatic]] conditions, the body is maintained in a state of [[hematological]] equilibrium of [[coagulation]] and [[fibrinolysis]] termed as [[hemostasis]]. The activation of the [[coagulation]] cascade yields [[thrombin]] that converts [[fibrinogen]] to [[fibrin]]; the stable [[fibrin]] clot being the final product of coagulation cascade. The fibrinolytic system then functions to break down [[fibrinogen]] and fibrin. Activation of the [[Fibrinolysis|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).
 
=== '''DIC as a disease process''' ===
* DIC occurs secondary to a clinical disorder. The clinical spectrum includes sepsis, trauma, malignancy, liver disease, obstetric disorders, envenomation, vascular anomalies and major transfusion reactions.
* Ocurrence of DIC in a patient should always be seen as an indicator of another life-threatening condition and warrants thorough diagnostic evaluation.
 
=== '''Mediators of induction of DIC''' ===
* DIC may be induced by either or both of the following mechanisms:
** As a consequence of systemic inflammatory response, there is activation of cytokine network and thereby coagulation system as in sepsis or polytrauma and/or
** Release of pro-coagulant products into the blood stream such as in malignancies or obstetrical cases.
 
* In [[DIC]], the processes of [[coagulation]] and [[fibrinolysis]] lose control, 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.<ref name="pmid24366358">{{cite journal |vauthors=Martinod K, Wagner DD |title=Thrombosis: tangled up in NETs |journal=Blood |volume=123 |issue=18 |pages=2768–76 |date=May 2014 |pmid=24366358 |pmc=4007606 |doi=10.1182/blood-2013-10-463646 |url=}}</ref> 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]], [[Macrophage|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]]), tumor necrosis factor, and [[endotoxin]]. 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 activation, TF binds with [[coagulation]] factors that then trigger both the intrinsic and the extrinsic pathways of [[coagulation]].<ref name="pmid24423888">{{cite journal |vauthors=Hellum M, Øvstebø R, Brusletto BS, Berg JP, Brandtzaeg P, Henriksson CE |title=Microparticle-associated tissue factor activity correlates with plasma levels of bacterial lipopolysaccharides in meningococcal septic shock |journal=Thromb. Res. |volume=133 |issue=3 |pages=507–14 |date=March 2014 |pmid=24423888 |doi=10.1016/j.thromres.2013.12.031 |url=}}</ref>
 
=== '''Activation of coagulation cascade''' ===
* 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 bed|microvascular]] and [[Macrovascular disease|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="pmid234638">{{cite journal |vauthors=Gordon SG, Franks JJ, Lewis B |title=Cancer procoagulant A: a factor X activating procoagulant from malignant tissue |journal=Thromb. Res. |volume=6 |issue=2 |pages=127–37 |date=February 1975 |pmid=234638 |doi= |url=}}</ref><ref name="pmid23650392">{{cite journal |vauthors=Martinod K, Demers M, Fuchs TA, Wong SL, Brill A, Gallant M, Hu J, Wang Y, Wagner DD |title=Neutrophil histone modification by peptidylarginine deiminase 4 is critical for deep vein thrombosis in mice |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=110 |issue=21 |pages=8674–9 |date=May 2013 |pmid=23650392 |pmc=3666755 |doi=10.1073/pnas.1301059110 |url=}}</ref><ref name="pmid834136">{{cite journal |vauthors=Sack GH, Levin J, Bell WR |title=Trousseau's syndrome and other manifestations of chronic disseminated coagulopathy in patients with neoplasms: clinical, pathophysiologic, and therapeutic features |journal=Medicine (Baltimore) |volume=56 |issue=1 |pages=1–37 |date=January 1977 |pmid=834136 |doi= |url=}}</ref>
 
=== Consumptive coagulopathy and bleeding sequelae ===
* [[Coagulation]] inhibitors are also consumed in this process. Decreased inhibitor levels will permit more [[clotting]] so that a feedback system develops in which increased clotting leads to more [[clotting]]. At the same time, [[thrombocytopenia]] occurs because of the entrapment of [[platelets]]. [[Clotting]] factors are consumed in the development of multiple clots, which contributes to the bleeding seen with [[DIC]].<ref name="pmid9518049">{{cite journal |vauthors=Gordon SG, Mielicki WP |title=Cancer procoagulant: a factor X activator, tumor marker and growth factor from malignant tissue |journal=Blood Coagul. Fibrinolysis |volume=8 |issue=2 |pages=73–86 |date=March 1997 |pmid=9518049 |doi= |url=}}</ref>
* Simultaneously, excess circulating [[thrombin]] assists in the conversion of [[plasminogen]] to [[plasmin]], resulting in [[fibrinolysis]]. The breakdown of clots results in excess amounts of FDPs, which have powerful [[anticoagulant]] properties, contributing to [[hemorrhage]].
* The excess [[plasmin]] also activates the [[complement]] and [[kinin]] systems.<ref name="pmid19855397">{{cite journal |vauthors=Xu J, Zhang X, Pelayo R, Monestier M, Ammollo CT, Semeraro F, Taylor FB, Esmon NL, Lupu F, Esmon CT |title=Extracellular histones are major mediators of death in sepsis |journal=Nat. Med. |volume=15 |issue=11 |pages=1318–21 |date=November 2009 |pmid=19855397 |pmc=2783754 |doi=10.1038/nm.2053 |url=}}</ref>
* Activation of these systems leads to many of the clinical symptoms that patients experiencing [[DIC]] exhibit, 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.
 
=== Summary ===
As a summary:<ref name="pmid7770905">{{cite journal |vauthors=Capon SM, Goldfinger D |title=Acute hemolytic transfusion reaction, a paradigm of the systemic inflammatory response: new insights into pathophysiology and treatment |journal=Transfusion |volume=35 |issue=6 |pages=513–20 |date=June 1995 |pmid=7770905 |doi= |url=}}</ref><ref name="pmid19222477">{{cite journal |vauthors=Levi M, Toh CH, Thachil J, Watson HG |title=Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology |journal=Br. J. Haematol. |volume=145 |issue=1 |pages=24–33 |date=April 2009 |pmid=19222477 |doi=10.1111/j.1365-2141.2009.07600.x |url=}}</ref><ref name="pmid25843168">{{cite journal |vauthors=Kim JE, Lee N, Gu JY, Yoo HJ, Kim HK |title=Circulating levels of DNA-histone complex and dsDNA are independent prognostic factors of disseminated intravascular coagulation |journal=Thromb. Res. |volume=135 |issue=6 |pages=1064–9 |date=June 2015 |pmid=25843168 |doi=10.1016/j.thromres.2015.03.014 |url=}}</ref>
 
* It seems that the formation of both [[thrombin]] and [[plasmin]] are required for the development of [[DIC]].
* A variety of triggering events can result in [[thrombin]] and [[plasmin]] formation, including damage to [[RBCs]], [[platelets]], or the [[endothelium]].
* After the [[coagulation]] system has been activated, the pathophysiology of [[DIC]] is similar in all disorders.
* Circulating [[thrombin]] cleaves fibrinopeptides A and B from [[fibrinogen]] resulting in the formation of [[fibrin]] monomers.
*:* These monomers polymerize into a [[fibrin]] clot, which traps [[platelets]] and results in [[thrombosis]], organ [[ischemia]] and [[thrombocytopenia]].
*:* [[Thrombin]] also induces endothelial cells to release:
*:*:* [[endothelin]], a potent [[vasoconstrictor]], and,
*:*:* E [[selectin]], which binds [[granulocytes]] and [[lymphocytes]], resulting in further [[cytokine]] release as well as release of [[Platelet-activating factor|platelet activating factor]].
* At the same time, [[plasmin]] cleaves the carboxy-terminal end of [[fibrinogen]] into fibrinogen degradation products, and cleaves [[fibrin]] into [[fibrin]] degradation products.
*:* The circulating FDPs (fibrin and fibrinogen) interfere with the polymerization of [[fibrin]] monomers, resulting in further [[hemorrhage]].
*:* Additionally, the [[fibrinogen]] degradation products D and E impair [[platelet]] function, worsening the [[bleeding]].
*:* The [[fibrin]] degradation products and D-dimer induce synthesis of [[IL-1]] and [[IL-6]], which cause further endothelial damage, as well as [[plasminogen]] activator inhibitor type 1 (PAI-1) which inhibits [[fibrinolysis]] resulting in accelerated [[thrombus]] formation.
*:* FDPs also stimulate the release of [[tissue factor]], which accelerates [[thrombosis]] via the extrinsic coagulation pathway.
*:*:* The release of large amounts of [[tissue factor]] (i.e. in obstetrical cases) can also initiate [[DIC]].
*:* Other effects of [[plasmin]] include:
*:*:* biodegredation of factors V, VII, IX and XI --> hemorrhage.
*:*:* complement activation, which results in [[RBC]] lysis --> release of ADP and membrane [[phospholipids]] (procoagulant material).
* As can be seen, the above soup results in a mess of [[Thrombosis in the vena cava|thrombosis]] and [[hemorrhage]].
*[[DIC]] is seen in a wide variety of clinical conditions and is most commonly associated with infection (esp. GN org --> [[endotoxin]]), [[malignancy]] and [[obstetrical]] complications.
 
==References==
{{reflist|2}}
 
[[Category:Hematology]]
[[Category:Cardiology]]
 
 
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[[Category:Hematology]]
[[Category:Cardiology]]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2]

Overview

DIC is a hemorrhagic syndrome originating in the small blood vessels. DIC is caused by uncontrolled activation of clotting factors and fibrinolytic enzymes. Tissue necrosis and bleeding are consequences of DIC. 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, the presence of thrombin is critical, as it is the central proteolytic enzyme of coagulation and is also necessary for the breakdown of clots, or fibrinolysis.

Pathophysiology

DIC is an acquired syndrome characterized by the intravascular activation of coagulation due to sepsis, trauma, malignancy, liver disease, obstetric disorders, envenomation, vascular anomalies and major transfusion reactions. It can originate from and cause damage to the microvasculature, which may eventually lead to organ dysfunction. Under homeostatic conditions, the body is maintained in a state of hematological equilibrium of coagulation and fibrinolysis termed as hemostasis. The activation of the coagulation cascade yields thrombin that converts fibrinogen to fibrin; the stable fibrin clot being the final product of coagulation cascade. 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).

DIC as a disease process

  • DIC occurs secondary to a clinical disorder. The clinical spectrum includes sepsis, trauma, malignancy, liver disease, obstetric disorders, envenomation, vascular anomalies and major transfusion reactions.
  • Ocurrence of DIC in a patient should always be seen as an indicator of another life-threatening condition and warrants thorough diagnostic evaluation.

Mediators of induction of DIC

  • DIC may be induced by either or both of the following mechanisms:
    • As a consequence of systemic inflammatory response, there is activation of cytokine network and thereby coagulation system as in sepsis or polytrauma and/or
    • Release of pro-coagulant products into the blood stream such as in malignancies or obstetrical cases.

Activation of coagulation cascade

Consumptive coagulopathy and bleeding sequelae

Summary

As a summary:[8][9][10]

References

  1. Martinod K, Wagner DD (May 2014). "Thrombosis: tangled up in NETs". Blood. 123 (18): 2768–76. doi:10.1182/blood-2013-10-463646. PMC 4007606. PMID 24366358.
  2. Hellum M, Øvstebø R, Brusletto BS, Berg JP, Brandtzaeg P, Henriksson CE (March 2014). "Microparticle-associated tissue factor activity correlates with plasma levels of bacterial lipopolysaccharides in meningococcal septic shock". Thromb. Res. 133 (3): 507–14. doi:10.1016/j.thromres.2013.12.031. PMID 24423888.
  3. Gordon SG, Franks JJ, Lewis B (February 1975). "Cancer procoagulant A: a factor X activating procoagulant from malignant tissue". Thromb. Res. 6 (2): 127–37. PMID 234638.
  4. Martinod K, Demers M, Fuchs TA, Wong SL, Brill A, Gallant M, Hu J, Wang Y, Wagner DD (May 2013). "Neutrophil histone modification by peptidylarginine deiminase 4 is critical for deep vein thrombosis in mice". Proc. Natl. Acad. Sci. U.S.A. 110 (21): 8674–9. doi:10.1073/pnas.1301059110. PMC 3666755. PMID 23650392.
  5. Sack GH, Levin J, Bell WR (January 1977). "Trousseau's syndrome and other manifestations of chronic disseminated coagulopathy in patients with neoplasms: clinical, pathophysiologic, and therapeutic features". Medicine (Baltimore). 56 (1): 1–37. PMID 834136.
  6. Gordon SG, Mielicki WP (March 1997). "Cancer procoagulant: a factor X activator, tumor marker and growth factor from malignant tissue". Blood Coagul. Fibrinolysis. 8 (2): 73–86. PMID 9518049.
  7. Xu J, Zhang X, Pelayo R, Monestier M, Ammollo CT, Semeraro F, Taylor FB, Esmon NL, Lupu F, Esmon CT (November 2009). "Extracellular histones are major mediators of death in sepsis". Nat. Med. 15 (11): 1318–21. doi:10.1038/nm.2053. PMC 2783754. PMID 19855397.
  8. Capon SM, Goldfinger D (June 1995). "Acute hemolytic transfusion reaction, a paradigm of the systemic inflammatory response: new insights into pathophysiology and treatment". Transfusion. 35 (6): 513–20. PMID 7770905.
  9. Levi M, Toh CH, Thachil J, Watson HG (April 2009). "Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology". Br. J. Haematol. 145 (1): 24–33. doi:10.1111/j.1365-2141.2009.07600.x. PMID 19222477.
  10. Kim JE, Lee N, Gu JY, Yoo HJ, Kim HK (June 2015). "Circulating levels of DNA-histone complex and dsDNA are independent prognostic factors of disseminated intravascular coagulation". Thromb. Res. 135 (6): 1064–9. doi:10.1016/j.thromres.2015.03.014. PMID 25843168.


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