Disseminated intravascular coagulation (DIC)

The college has shown some interest in this condition, but usually, it appears as the answer to a data interpretation question ("What's wrong with these coags?"). Examples include:

Apart from these, DIC comes up frequently in the past papers as an important complication to mention (eg. in the discussion of amniotic fluid embolism,  etc etc). Only once have the candidates been asked the fairly relevant question, "how will you manage this situation?" Thankfully, there's plenty of literature, accessible with minimal effort. A basic Google Scholar search for "dissminated intravascular coagulation" will yield a dozen review articles, all titled "Disseminated intravascular coagulation", spanning maybe forty years. The 2016 paper by Boral et al was the main basis for this chapter

Definition and diagnostic criteria for DIC

This condition has a solid definition, forged from the fires of Mount Doom by the International Society
on Thrombosis and Haemostasis in 2001:

DIC is “...an acquired syndrome characterized by intravascular activation of coagulation with loss of localization arising from different causes that can originate from and cause damage to the microvasculature, which if sufficiently severe, can produce organ dysfunction”

These are the defining features of "overt" DIC. Obviously by the time you have "coagulation with loss of localization" you're already in a pretty bad shape, which is why the same body has proposed a slightly adjusted definition to assist in the making of an earlier diagnosis. They (Iba et al, 2017) framed this adjusted definition in terms of altered parameters, which were all slightly less severe than the original 2001 diagnostic criteria. In this fashion, we have ended up here:

Item Score         Range Range
Platelets 2 <50 <100
  1 50-100 100-150                 
D-dimer 2 Strong increase -
  1 Moderate increase          -
INR 2 ≥6 >1.4
  1 3-6 1.2-1.4
Fibrinogen 1 <1g/L -
SOFA score 2 - ≥2
  1 - 1
Total score cut-off:   ≥5 ≥4

To simplify this complex system, SIC is a DIC which still hasn't had time to waste all your clotting factors, but which is already associated with the dysfunction of one or more organ systems, because it is associated with sepsis and that's the new definition of sepsis

Fibrin degradation products seem to be a valuable adjunct for the laboratory diagnosis of DIC.

In essence, a D-dimer is a small protein breakdown product, consising of two crosslinked D-fragments of fibrin. A longer explanation, with pictures and extensive bibliography, is also available. The presence of an elevated D-dimer confirms that somewhere fibrin is being degraded. 

Pathophysiology of DIC

If one day the CICM exam candidates are asked, "outline the pathophysiology of DIC in under the minutes", they will have difficulties, unless they've rehearsed this at least once before. Obviously they all know the underlying processes, but to put everything together into a neat structure under pressure and in a short period of time would be challenging for anybody. To prepare them for these end times, here is a pre-digested blurb, describing the pathophysiology of DIC:

  • Activation of coagulation by inflammation
    • Proinflammatory cytokines are secreted by immune cells
    • Tissue factor (a potent procoagulant) is expressed on macrophages and monocytes
    • Due to inflammation, endothelial dysfunction exposes more of the procoagulant surfaces behind the endothelium
    • Exposed phosphatidylserine on the surface of damaged cells is also procoagulant 
    • All of these processes are systemic, and lead to the depletion of clotting factors by their consumption
  • Inactivation of anticoagulant systems
    • Depletion of the endothelial glycocalyx disrupts its normal anticoagulant activity (it's usually full of heparin-like molecules and antithrombin)
    • Circulating antithrombin is rapidly depleted
    • Trombomodulin and protein C anticoagulant systems are also vulnerable to depletion
    • Thus, as the result of consumption of clotting factors, all the anticoagulant factors are also consumed
  • Inactivation of fibrinolysis (this is mainly seen in septic DIC)
    • Vascular endothelial cells usually secrete plasminogen activator inhibitor-1
    • Endothelial dysfunction leads to increased circulating soluble plasminogen activator inhibitor-1
    • This prevents fibrinolysis; the result is a failure to degrade microvascular thrombi, which persist and therefore cause organ dysfunction
  • Platelet aggregation 
    • Because of the widespread activation of the coagulation cascade there is also widespread platelet activation
  • Organ system dysfunction
    • Disseminated activation of platelets and clotting factors leads to the formation of numerous microthrombi
    • Because of the inactivated fibrinolytic system, these tend to lodge in the microcirculation and remain there, decreasing regional blood flow 
    • At the same time, blood flow to other regions increases because of uncontrolled vasodilation
    • This results in microvascular shunting

Causes of DIC

The causes of DIC are numerous. Here is a good list of causes, reproduced with zero modification from Papageorgeou et al (2018):

Clinical Conditions Triggering DIC Causes of DIC
Sepsis or severe infection Potentially any microorganism but particularly gram-negative bacteria
Viral infections (ie, viral hemorrhagic fever)
Rickettsia infection
Trauma Severe tissue injury
Head injury
Fat embolism
Heat stroke of shock
Organ destruction Pancreatitis, severe inflammation, tissue necrosis
Malignancy Solid tumors (pancreatic, stomach, colorectal cancer, mucin secreting adenocarcinoma)
Hematological malignancies (acute promyelocytic leukemia especially)
Obstetrical calamities Placental abruption
Placenta previa
Amniotic fluid embolism
Intrauterine death
HELLP syndrome
Vascular abnormalities Aortic aneurysm
Giant hemangiomas (Kasabach-Merritt syndrome)
Liver disease Cirrhosis
Acute hepatic necrosis
Severe toxic or immunological reactions Graft-versus-host disease
Transplant reaction
Snake bites (such as from those belonging to the genus Echis)
Severe transfusion reactions (incompatible blood transfusion reactions)

Causes of peripartum DIC

In the context of pregnancy and PPH one can narrow down one's list of possibile aetiologies.

Still, there is quite a large number of potential peripartum causes for DIC:

  • Abruptio placentae
  • Placenta accreta
  • Amniotic fluid embolism
  • Retained dead fetus
  • Abortion induced with hypertonic fluids (saline or urea)
  • Intrauterine sepsis
  • Incompatible blood transfusion

An excellent review article lists these, and others, and delves deep into their pathophysiology and management.

Management of DIC

  • "Treat the cause" is the main strategy. For example, with intrauterine sepsis such as that presented in Question 24.2 from the second paper of 2021, early source control by means of a dilation and curettage would probably shorten the duration and decrease the severity of the illness.
  • Avoid exogenous clotting factors. This is a non-controversial management recommendation, which is nonetheless probably wrong. Observe:
    •  A lot of these patient will ooze and bleed, as they will likely have either lines, or surgical wounds, traumatic injuries, or various other sources of blood loss. It would be tempting to give these coagulopathic people clotting factors to replace what they have lost.
    • The conventional teaching is that this sort of factor replacement would be an error. The procoagulant process which caused all of their platelets to aggregate is still ongoing. If you feed more clotting factors into the mill, all this will do is produce more microthrombi, and contribute to the worsening of the organ system dysfunction. 
    • This theory has never been proven experimentally. In the sense that, there is neither clinical bedside evidence that factor replacement during DIC does any harm, nor laboratory evidence that there is an increase of microcirculatory thromboemboli. 
    • As the result, though most resources acknowledge this theory, they also caution to add that serious bleeding should still be treated with clotting factor replacement, and if the patient is at significant risk of bleeding, one might even consider giving enough fibrinogen and platelets to prevent spontaneous bleeding.
  • Theoretical strategies and those which look promising but which have not yet met with widespread approval include the following:


Boral, Benjamin M., Dennis J. Williams, and Leonard I. Boral. "Disseminated intravascular coagulation." American journal of clinical pathology 146.6 (2016): 670-680.

Slofstra, Sjoukje, Arnold Spek, and Hugo ten Cate. "Disseminated intravascular coagulation." The Hematology Journal 4.1 (2013): 295-302.

Levi, Marcel, and Hugo Ten Cate. "Disseminated intravascular coagulation."New England Journal of Medicine 341.8 (1999): 586-592.

Letsky, Elizabeth A. "Disseminated intravascular coagulation." Best Practice & Research Clinical Obstetrics & Gynaecology 15.4 (2001): 623-644.

Carr, J. Meehan, M. McKinney, and J. McDonagh. "Diagnosis of disseminated intravascular coagulation. Role of D-dimer." American journal of clinical pathology 91.3 (1989): 280-287.

Adam, Soheir S., Nigel S. Key, and Charles S. Greenberg. "D-dimer antigen: current concepts and future prospects." Blood 113.13 (2009): 2878-2887.

Iba, Toshiaki, Marcel Levi, and Jerrold H. Levy. "Sepsis-induced coagulopathy and disseminated intravascular coagulation." Seminars in thrombosis and hemostasis. Vol. 46. No. 01. Thieme Medical Publishers, 2020.

Taylor Jr, Fletcher B., et al. "Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation." Thrombosis and haemostasis 86.11 (2001): 1327-1330.

Iba, Toshiaki, et al. "New criteria for sepsis-induced coagulopathy (SIC) following the revised sepsis definition: a retrospective analysis of a nationwide survey." BMJ open 7.9 (2017): e017046.

Papageorgiou, Chrysoula, et al. "Disseminated intravascular coagulation: an update on pathogenesis, diagnosis, and therapeutic strategies." Clinical and Applied Thrombosis/Hemostasis 24.9_suppl (2018): 8S-28S.

Levi, Marcel, and Marie Scully. "How I treat disseminated intravascular coagulation." Blood, The Journal of the American Society of Hematology 131.8 (2018): 845-854.

Gando, Satoshi, et al. "A randomized, controlled, multicenter trial of the effects of antithrombin on disseminated intravascular coagulation in patients with sepsis." Critical care 17.6 (2013): 1-10.

Aoki, Nobuo, et al. "A comparative double-blind randomized trial of activated protein C and unfractionated heparin in the treatment of disseminated intravascular coagulation." International journal of hematology 75.5 (2002): 540-547.

Saito, H., et al. "Efficacy and safety of recombinant human soluble thrombomodulin (ART‐123) in disseminated intravascular coagulation: results of a phase III, randomized, double‐blind clinical trial." Journal of Thrombosis and Haemostasis 5.1 (2007): 31-41.

Abraham, Edward, et al. "Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial." Jama 290.2 (2003): 238-247.

Jaimes, Fabián, et al. "Unfractioned heparin for treatment of sepsis: A randomized clinical trial (The HETRASE Study)." Critical care medicine 37.4 (2009): 1185-1196.