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:

• Question 7 from the first paper of 2022
• Question 24.2 from the second paper of 2021
• Question 13.1 from the second paper of 2013
• Question 29.1 from the second paper of 2012
• Question 6.1 from the second paper of 2008

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:

		DIC	SIC
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)
	Malaria
	Rickettsia infection
Trauma	Severe tissue injury
	Head injury
	Burns
	Fat embolism
	Surgery
	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
	Eclampsia
	HELLP syndrome
Vascular abnormalities	Aortic aneurysm
	Giant hemangiomas (Kasabach-Merritt syndrome)
	Vasculitis
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:
  • Antithrombin-III concentrate (Gando et al, 2013)
  • Activated protein C (Aoki et al, 2002)
  • Thrombomodulin (Saito et al, 2007)
  • Tissue factor pathway inhibitor, also known as tifacogin (Abraham et al, 2003)
  • Heparin, in slowly developing DIC (Jaimes et al, 2009)