View source for Disseminated intravascular coagulation

{{Short description|Medical condition where blood clots block small blood vessels}}
{{cs1 config|name-list-style=vanc}}
{{Infobox medical condition (new)
| name            = Disseminated intravascular coagulation
| synonyms        = Disseminated intravascular coagulopathy, consumptive coagulopathy, defibrination syndrome<ref name=NIH2017/>
| image           = Acute_thrombotic_microangiopathy_-_pas_-_very_high_mag.jpg
| caption         = [[Micrograph]] showing acute [[thrombotic microangiopathy]] due to DIC in a [[kidney biopsy]]. A [[thrombus|clot]] is present in the [[Hilum (anatomy)|hilum]] of the [[Glomerulus (kidney)|glomerulus]] (center of image).
|field= [[Hematology]]
| symptoms        = [[Chest pain]], [[shortness of breath]], leg pain, problems speaking, problems moving part of the body, bleeding<ref name=NIH2017/>
| complications   = [[Organ failure]]<ref name=Mer2016/>
| onset           =
| duration        =
| types           = Acute, chronic<ref name=NIH2017/>
| causes          = [[Sepsis]], [[surgery]], [[major trauma]], [[cancer]], [[complications of pregnancy]], [[snake bites]], [[frostbite]], [[burn]]s<ref name=NIH2017/>
| risks           =
| diagnosis       = [[Blood tests]]<ref name=Mer2016/>
| differential    = [[Thrombotic thrombocytopenic purpura]], [[hemolytic-uremic syndrome]]<ref name=NIH2017/>
| prevention      =
| treatment       = Directed at the underlying condition<ref name=Levi2007/>
| medication      = [[platelet transfusion|Platelets]], [[cryoprecipitate]], [[fresh frozen plasma]], [[heparin]]<ref name=Mer2016/>
| prognosis       = 20–50% risk of death<ref name=Nat2016/>
| frequency       = 1% of people admitted to hospital<ref name=Nat2016/>
| deaths          =
}}
<!-- Definition and symptoms -->
'''Disseminated intravascular coagulation''' ('''DIC''') is a condition in which [[blood clot]]s form throughout the body, blocking [[Microvessel|small blood vessels]].<ref name=NIH2017/> Symptoms may include [[chest pain]], [[shortness of breath]], leg pain, problems speaking, or problems moving parts of the body.<ref name=NIH2017/> As [[clotting factors]] and [[platelet]]s are used up, [[bleeding]] may occur.<ref name=NIH2017>{{cite web|title=Disseminated Intravascular Coagulation {{!}} NHLBI, NIH|url=https://www.nhlbi.nih.gov/health-topics/disseminated-intravascular-coagulation|publisher=www.nhlbi.nih.gov|access-date=20 December 2017|language=en}}</ref> This may include [[hematuria|blood in the urine]], [[GI bleed|blood in the stool]], or bleeding into the skin.<ref name=NIH2017/> Complications may include [[organ failure]].<ref name=Mer2016/>

<!-- Cause and diagnosis -->
Relatively common causes include [[sepsis]], [[surgery]], [[major trauma]], [[cancer]], and [[complications of pregnancy]].<ref name=NIH2017/> Less common causes include [[snake bites]], [[frostbite]], and [[burn]]s.<ref name=NIH2017/> There are two main types: acute (rapid onset) and chronic (slow onset).<ref name=NIH2017/> Diagnosis is typically based on [[blood tests]].<ref name=Mer2016/> Findings may include [[thrombocytopenia|low platelets]], low [[fibrinogen]], high [[International normalized ratio|INR]], or high [[D-dimer]].<ref name=Mer2016>{{cite web|title=Disseminated Intravascular Coagulation (DIC) - Hematology and Oncology|url=https://www.merckmanuals.com/en-ca/professional/hematology-and-oncology/coagulation-disorders/disseminated-intravascular-coagulation-dic|website=Merck Manuals Professional Edition|access-date=20 December 2017|language=en-CA|date=September 2016}}</ref>

<!-- Treatment and epidemiology -->
Treatment is mainly directed towards the underlying condition.<ref name=Mer2016/><ref name=Levi2007>{{cite journal|last=Levi|first=M|s2cid=7158989|title=Disseminated Intravascular Coagulation|journal=Critical Care Medicine|year=2007|volume=35|issue=9|pages=2191–2195|pmid=17855836|doi=10.1097/01.CCM.0000281468.94108.4B}}</ref> Other measures may include giving [[platelet transfusion|platelets]], [[cryoprecipitate]], or [[fresh frozen plasma]].<ref name=Mer2016/> Evidence to support these treatments, however, is poor.<ref name=Mer2016/> [[Heparin]] may be useful in the slowly developing form.<ref name=Mer2016/> About 1% of people admitted to hospital are affected by the condition.<ref name=Nat2016/> In those with sepsis, rates are between 20% and 50%.<ref name=Nat2016/> The risk of death among those affected varies from 20% to 50%.<ref name=Nat2016>{{cite journal|last1=Gando|first1=Satoshi|last2=Levi|first2=Marcel|last3=Toh|first3=Cheng-Hock|s2cid=4059451|title=Disseminated intravascular coagulation|journal=Nature Reviews Disease Primers|date=2 June 2016|volume=2|pages=16037|doi=10.1038/nrdp.2016.37|pmid=27250996}}</ref>

==Signs and symptoms==
In DIC, the underlying cause usually leads to symptoms and signs, and DIC is discovered on laboratory testing. The onset of DIC can be sudden, as in endotoxic shock or [[amniotic fluid embolism]], or it may be insidious and chronic, as in cancer. DIC can lead to multiorgan failure and widespread bleeding.<ref name="isbn0-7216-7335-X">{{cite book|author1=Robbins, Stanley L. |author2=Cotran, Ramzi S. |author3=Kumar, Vinay |author4=Collins, Tucker |title=Robbins' Pathologic Basis of Disease|edition=6|publisher=Saunders|location=Philadelphia|year=1999|isbn=0-7216-7335-X}}</ref>

==Causes==
DIC can occur in the following conditions:<ref name="isbn0-7216-7335-X"/><ref name=david>{{cite book|title=Davidson's Principles and Practice of Medicine|edition=19|year=2002|publisher=Churchill Livingstone|isbn=0-443-07036-9}}</ref><ref name=hoffman>{{cite book|title=Haematology: Basic Principles and Practice|edition=6|year=2012|publisher=Elsevier Saunders|isbn=978-1437729283}}</ref><ref name="isbn0-7020-2458-9">{{cite book|author1=Clark, Michael |author2=Kumar, Parveen J. |title=Clinical Medicine: A Textbook for Medical Students and Doctors|edition=4|publisher=W.B. Saunders|location=Philadelphia|year=1998|isbn=0-7020-2458-9}}</ref>
* [[Cancer]]: solid [[tumor]]s and [[Tumors of the hematopoietic and lymphoid tissues|blood cancers]] (particularly [[acute promyelocytic leukemia]])
* [[Complications of pregnancy]]: [[abruptio placentae]], [[pre-eclampsia]] or [[eclampsia]], [[amniotic fluid embolism]], retained intrauterine [[fetal demise]], [[septic abortion]], [[postpartum hemorrhage]]
* Massive tissue injury:  [[Injury|trauma]], [[burn]], [[hyperthermia]], [[rhabdomyolysis]], surgery
* [[Infection]]: [[sepsis|bacterial]] ([[Gram-negative]] or [[Gram-positive]]), [[viral disease|viral]], [[Mycosis|fungal]], or [[protozoan infection|protozoan]]
* [[Transfusion reaction]]: [[ABO incompatibility]]
* [[Allergic reaction|Allergic]] or [[toxicity|toxic reaction]]: [[snake venom]]
* [[Hemangioma]]: [[Kasabach–Merritt syndrome]]
* [[Aortic aneurysm]]

[[Liver disease]], [[HELLP syndrome]], [[thrombotic thrombocytopenic purpura]], [[hemolytic uremic syndrome]], and [[malignant hypertension]] may mimic DIC but originate via other pathways.<ref>{{cite web |url=https://www.lecturio.com/concepts/disseminated-intravascular-coagulation/| title=Disseminated Intravascular Coagulation|website=The Lecturio Medical Concept Library |access-date= 12 July 2021}}</ref> It is not the same as conditions where the blood vessels leak, such as [[capillary leak syndrome]].<ref>{{cite journal |last1=Siddall |first1=E |last2=Khatri |first2=M |last3=Radhakrishnan |first3=J |title=Capillary leak syndrome: etiologies, pathophysiology, and management |journal=Kidney International |date=2017 |volume=92 |issue=1 |pages=37–46 |doi=10.1016/j.kint.2016.11.029 |pmid=28318633}}</ref>

==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"/>

==Diagnosis==
[[File:Schizocyte_smear_2009-12-22.JPG|thumb|upright=1.3|Blood film showing red blood cell fragments ([[schistocytes]])]]
The diagnosis of DIC is not made on a single laboratory value, but rather the constellation of laboratory markers and a consistent history of an illness known to cause DIC. Laboratory markers consistent with DIC include:<ref name=Levi2007/><ref name="hoffman"/><ref name="Levi19222477">{{cite journal|last=Levi|first=M|author2=Toh, C-H|title=Guidelines for the diagnosis and management of disseminated intravascular coagulation|journal=British Journal of Haematology|year=2009|volume=145|issue=5|pages=24–33|pmid=19222477|doi=10.1111/j.1365-2141.2009.07600.x|display-authors=etal|doi-access=|s2cid=694153}}</ref>
* Characteristic history (this is important because severe liver disease can essentially have the same laboratory findings as DIC)
* Prolongation of the [[prothrombin time]] (PT) and the [[activated partial thromboplastin time]] (aPTT) reflect the underlying consumption and impaired synthesis of the [[Coagulation#The coagulation cascade|coagulation cascade]].
* Fibrinogen level was initially thought to be useful in the diagnosis of DIC but because it is an acute phase reactant, it will be elevated due to the underlying inflammatory condition. Therefore, a normal (or even elevated) level can occur in over 57% of cases. A low level, however, is more consistent with the consumptive process of DIC.
* A rapidly declining platelet count
* High levels of fibrin degradation products, including [[D-dimer]], are found owing to the intense fibrinolytic activity stimulated by the presence of fibrin in the circulation.
* The [[peripheral blood smear]] may show fragmented [[red blood cell]]s (known as [[schistocytes]]) due to [[shear stress]] from [[thrombus|thrombi]]. However, this finding is neither sensitive nor specific for DIC

A diagnostic algorithm has been proposed by the International Society of Thrombosis and Haemostasis. This algorithm appears to be 91% sensitive and 97% specific for the diagnosis of overt DIC. A score of 5 or higher is compatible with DIC and it is recommended that the score is repeated daily, while a score below 5 is suggestive but not affirmative for DIC and it is recommended that it is repeated only occasionally:<ref name="Levi19222477"/><ref name="Taylor11816725">{{cite journal|last=Taylor|first=F|author2=Toh, C-h|s2cid=39696424|title=Towards Definition, Clinical and Laboratory Criteria, and a Scoring System for Disseminated Intravascular Coagulation|journal=Thrombosis and Haemostasis|year=2001|volume=86|issue=5|pages=1327–30|pmid=11816725|display-authors=etal|doi=10.1055/s-0037-1616068}}</ref> It has been recommended that a scoring system be used in the diagnosis and management of DIC in terms of improving outcome.<ref name="Gando22713612">{{cite journal|last=Gando|first=S|title=The Utility of a Diagnostic Scoring System for Disseminated Intravascular Coagulation|journal= [[Critical Care Clinics]] |year=2012|volume=28|issue=3|pages=378–88|pmid=22713612|doi=10.1016/j.ccc.2012.04.004}}</ref>
* Presence of an underlying disorder known to be associated with DIC (no=0, yes=2)
* Global coagulation results
** Platelet count (>&nbsp;100k =&nbsp;0, <&nbsp;100k =&nbsp;1, <&nbsp;50k =&nbsp;2)
** Fibrin degradation products such as D-Dimer (no increase = 0, moderate increase = 2, strong increase = 3)
** Prolonged prothrombin time (<&nbsp;3 sec = 0, >&nbsp;3 sec = 1, >&nbsp;6 sec = 2)
** Fibrinogen level (>&nbsp;1.0g/L =&nbsp;0; <&nbsp;1.0g/L = 1<ref>{{cite journal|doi=10.1111/j.1365-2141.2009.07600.x | pmid=19222477 | volume=145 | issue=1 | title=Guidelines for the diagnosis and management of disseminated intravascular coagulation | journal=British Journal of Haematology | pages=24–33| year=2009 | last1=Levi | first1=M. | last2=Toh | first2=C. H. | last3=Thachil | first3=J. | last4=Watson | first4=H. G. | doi-access= | s2cid=694153 }}</ref>)

==Treatment==
Treatment of DIC is centered on treating the underlying condition. Transfusions of [[platelets]] or [[fresh frozen plasma]] can be considered in cases of significant bleeding, or those with a planned invasive procedure. The target goal of such transfusion depends on the clinical situation. [[Cryoprecipitate]] can be considered in those with a low [[fibrinogen]] level. Treatment of thrombosis with anticoagulants such as heparin is rarely used due to the risk of bleeding.{{citation needed|date=July 2020}}

Recombinant human activated [[protein C]] was previously recommended in those with severe sepsis and DIC, but [[drotrecogin alfa]] has been shown to confer no benefit and was withdrawn from the market in 2011.<ref>{{Cite web|last=Armstrong|first=Drew|date=October 25, 2011|title=Lilly Pulls Xigris Off Markets After Sepsis Drug Fails Study|url=https://www.bloomberg.com/news/articles/2011-10-25/lilly-pulls-xigris-from-markets-after-sepsis-drug-fails-study|access-date=June 26, 2020|website=[[Bloomberg News]]}}</ref>

Recombinant factor VII has been proposed as a "last resort" in those with severe hemorrhage due to obstetric or other causes, but conclusions about its use are still insufficient.<ref name="Franchini">{{cite journal|last=Franchini|first=M |author2=Manzato, F |author3=Salvagno GL|s2cid=37247533 |title=Potential role of recombinant activated factor VII for the treatment of severe bleeding associated with disseminated intravascular coagulation: a systematic review|journal=Blood Coagul Fibrinolysis|year=2007|volume=18|issue=7|pages=589–93|pmid=17890943|doi=10.1097/MBC.0b013e32822d2a3c|display-authors=etal}}</ref>

==Prognosis==
Prognosis varies depending on the underlying disorder, and the extent of the intravascular [[thrombosis]] (clotting).  The prognosis for those with DIC, regardless of cause, is often grim: between 20% and 50% of patients will die.<ref name=Becker />  DIC with [[sepsis]] (infection) has a significantly higher rate of death than DIC associated with trauma.<ref name=Becker>Becker, Joseph U and Charles R Wira. [http://emedicine.medscape.com/article/779097-overview Disseminated intravascular coagulation] {{Webarchive|url=https://web.archive.org/web/20100130095332/http://emedicine.medscape.com/article/779097-overview |date=2010-01-30 }} at [[eMedicine]], 10 September 2009</ref>

==Epidemiology==
DIC is observed in approximately 1% of academic hospital admissions.<ref>{{cite journal|last1=Matsuda|first1=T|title=Clinical aspects of DIC--disseminated intravascular coagulation|journal=Pol J Pharmacol.|date=Jan–Feb 1996|volume=48|issue=1|pages=73–5|pmid=9112631}}</ref> DIC occurs at higher rates in people with bacterial sepsis (83%),<ref>{{cite journal|last1=Smith|first1=OP|title=Use of protein-C concentrate, heparin, and haemodiafiltration in meningococcus-induced purpura fulminans.|journal=Lancet|date=1997|volume=350|issue=9091|pages=1590–1593|doi=10.1016/s0140-6736(97)06356-3|pmid=9393338|s2cid=38614343}}</ref> severe trauma (31%),<ref>{{cite journal|last1=Gando|first1=S|title=Disseminated intravascular coagulation and sustained systemic inflammatory response syndrome predict organ dysfunctions after trauma: application of clinical decision analysis.|journal=Ann Surg|date=1999|volume=229|issue=1|pages=121–127|doi=10.1097/00000658-199901000-00016|pmid=9923809|pmc=1191617}}</ref> and cancer (6.8%).<ref>{{cite journal|last1=Sallah|first1=S|title=Disseminated intravascular coagulation in solid tumors: clinical and pathologic study.|journal=Thromb. Haemost.|date=2001|volume=86|issue=3|pages=828–833|doi=10.1055/s-0037-1616139|pmid=11583315|s2cid=11667422}}</ref>

==References==
{{reflist}}

{{Medical resources
|  DiseasesDB      = 3765
|  ICD10           = {{ICD10|D|65||d|65}}
|  ICD9            = {{ICD9|286.6}}
|  ICDO            =
|  OMIM            =
|  MedlinePlus     = 000573
|  eMedicineSubj   = med
|  eMedicineTopic  = 577
|  eMedicine_mult  = {{eMedicine2|emerg|150}}
|  MeshID          = D004211
|ICD11={{ICD11|3B20}}}}
{{Diseases of the skin and appendages by morphology}}
{{Diseases of megakaryocytes|us=y}}
{{Authority control}}

{{DEFAULTSORT:Disseminated Intravascular Coagulation}}
[[Category:Coagulopathies]]
[[Category:Intensive care medicine]]
[[Category:Medical emergencies]]
[[Category:Oncological emergencies]]
[[Category:Vascular-related cutaneous conditions]]
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