Disseminated intravascular coagulation pathophysiology: Difference between revisions

Jump to navigation Jump to search
No edit summary
No edit summary
 
Line 6: Line 6:
__NOTOC__
__NOTOC__
{{DIC}}
{{DIC}}
{{CMG}}; {{AE}} {{OK}}
{{CMG}}; {{AE}} {{OK}}


Line 12: Line 13:


==Pathophysiology==
==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). 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]].<ref name="pmid10648405">{{cite journal |vauthors=Nieuwland R, Berckmans RJ, McGregor S, Böing AN, Romijn FP, Westendorp RG, Hack CE, Sturk A |title=Cellular origin and procoagulant properties of microparticles in meningococcal sepsis |journal=Blood |volume=95 |issue=3 |pages=930–5 |date=February 2000 |pmid=10648405 |doi= |url=}}</ref><ref name="pmid26776504">{{cite journal |vauthors=Liaw PC, Ito T, Iba T, Thachil J, Zeerleder S |title=DAMP and DIC: The role of extracellular DNA and DNA-binding proteins in the pathogenesis of DIC |journal=Blood Rev. |volume=30 |issue=4 |pages=257–61 |date=July 2016 |pmid=26776504 |doi=10.1016/j.blre.2015.12.004 |url=}}</ref>
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>
* 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>


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>
=== '''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>


[[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>
=== 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.


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. 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>
=== 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]].
* It seems that the formation of both [[thrombin]] and [[plasmin]] are required for the development of [[DIC]].

Latest revision as of 19:47, 4 September 2018

https://https://www.youtube.com/watch?v=Gmh01S0msfY%7C350}}

Disseminated intravascular coagulation Microchapters

Home

Patient Information

Overview

Historical Perspective

Classification

Pathophysiology

Causes

Differentiating Disseminated intravascular coagulation from other Diseases

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications and Prognosis

Diagnosis

Diagnostic Study of Choice

History and Symptoms

Physical Examination

Laboratory Findings

Electrocardiogram

X Ray

Echocardiograph and Ultrasound

CT

MRI

Other Imaging Findings

Other Diagnostic Studies

Treatment

Medical Therapy

Surgery

Prevention

Cost-Effectiveness of Therapy

Future or Investigational Therapies

Case Studies

Case #1

Disseminated intravascular coagulation pathophysiology On the Web

Most recent articles

cited articles

Review articles

CME Programs

Powerpoint slides

Images

American Roentgen Ray Society Images of Disseminated intravascular coagulation pathophysiology

All Images
X-rays
Echo & Ultrasound
CT Images
MRI

Ongoing Trials at Clinical Trials.gov

US National Guidelines Clearinghouse

NICE Guidance

FDA on Disseminated intravascular coagulation pathophysiology

CDC on Disseminated intravascular coagulation pathophysiology

Disseminated intravascular coagulation pathophysiology in the news

Blogs on Disseminated intravascular coagulation pathophysiology

Directions to Hospitals Treating Disseminated intravascular coagulation

Risk calculators and risk factors for Disseminated intravascular coagulation pathophysiology

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.


Template:WS Template:WH