DISSEMINATED

INTRAVASCULAR
COAGULATION
Dr. Abhineet
PG Registrar
Dept of Transfusion Medicine and Immunohematology
HISTORY

 At the beginning of the 1980s, Spero and colleagues correctly proclaimed that DIC is a
sign that “death is coming”.

 Since then, DIC has been recognized as a serious, well-defined and life-threatening
condition, which is elicited by diverse infectious and non-infectious insults.
DEFINITION

 The Scientific and Standardization Committee (SSC) on DIC of the International

Society on Thrombosis and Haemostasis (ISTH) defined DIC as :

 An acquired syndrome characterized by the intravascular activation of coagulation

with a loss of localization arising from different causes.

 It can both originate from and cause damage to the microvasculature, which, if
sufficiently severe, can produce organ dysfunction.
 The core features of DIC are indicative of systemic thrombin generation that is not
restricted to the site of insult and endothelial cell injury, which gives rise to organ
dysfunction

 Combined with these changes, inhibition of fibrinolysis synergistically results in

microvascular thrombosis that — in concert with haemodynamic and metabolic
derangements — contributes to organ dysfunction.
EPIDEMIOLOGY
DIC is a frequent complication of a systemic inflammatory response syndrome (SIRS).

 SIRS can be caused by infectious insults (for ex., sepsis, which is life-threatening
organ dysfunction caused by a dysregulated host response to infection)
 Non-infectious insults for example- trauma.
 Sepsis and trauma are two predominant clinical conditions associated with DIC.
 Other important underlying DIC-associated disorders include:
• Organ destruction (such as severe pancreatitis),
• Malignancy (solid tumours and haematological cancers),
• Obstetrical calamities (such as amniotic fluid embolism, placental abruption, serious
pre-eclampsia and postpartum haemorrhage )
EPIDEMIOLOGY
 The incidence and mortality of DIC vary according to the period, country, place of treatment
(ward or intensive care unit), diagnostic criteria and underlying disorders.

 The differences in mortality between patients who are diagnosed according to the ISTH (a
mortality rate of 46%) and the JAAM scoring system (a mortality rate of 22%) depend on the
differences in the nature of the two diagnostic criteria.

 The ISTH criteria diagnose full-blown DIC, whereas the JAAM criteria diagnose DIC that has
not yet reached the stage of decompensation.

 Rough estimations show an improvement in mortality due to DIC over the past two decades.
COAGULATION PHYSIOLOGY

TF-FVII
TF+FVIIa+FI
X
FX-FV-FII-
FIIa
Anticoagulation
pathway
MECHANISM and PATHOPHYSIOLOGY

 Thrombi (blood clots) are formed as the result of coagulation and comprise fibrin and
activated platelets. .
 Coagulation cascade involves a series of proteolytic reactions in which inactive serine
proteases become activated and, in turn, activate subsequent proteases in the pathway.
 Initiation of activation of blood coagulation occurs through the TF–F VII pathway and
ultimately results in the generation of thrombin.
 Thrombin is the central protease in the activation of coagulation .
 Generation of thrombin is not only crucial for the conversion of fibrinogen into fibrin
but thrombin also augments its own generation by activating various other coagulant
enzymes and cofactors (such as factor VIII, factor IX and factor XI) .

 Thrombin is a potent agonist of platelet aggregation .

 Thrombin-induced cleavage of small fragments from fibrinogen leads to the formation

of fibrin monomers and, successively, polymers.

 To further strengthen the clot crosslinking of fibrin is mediated by thrombin-activated

factor XIII (factor XIIIa).
 Activation of coagulation is regulated by three main anticoagulant
pathways:

1. Antithrombin.

2. The protein C system.

3. Tissue factor pathway inhibitor (TFPI).

Pathogenetic Pathways in DIC
 Innate immunity and coagulation are closely related and regulate each other
when activated by diverse insults.

 Inflammation, haemostasis and immunothrombosis, maintain body homeostasis

and promote recovery from the insults.

 Severe insults perturb these control mechanisms, leading to the systemic

activation of coagulation and the inflammatory cascade, followed by DIC.

 In turn, DIC gives rise to multiple organ dysfunction and affects patient
outcomes
Triggers of coagulation activation in DIC
 Tissue factor - principal initiator of thrombin generation in DIC
Triggers of coagulation activation in DIC

 In sepsis and trauma, DIC is triggered by : systemic inflammatory response, in which

inflammatory cytokines are the most important mediators.

 In patients with cancer the activation of coagulation can initially be triggered by other
routes, such as the expression of procoagulant factors -including tissue factor(TF) or
factor X-activating cysteine protease.

 In obstetrical calamities like placental abruption or amniotic fluid embolism- release of

coagulation-initiating molecules

 Patients with severe trauma or cancer, studies have shown that DIC is triggered by the
TF–F VIIa pathway.
Triggers of coagulation activation in DIC
 ROLE OF PLATELETS:
• Platelets can be activated directly, - by pro-inflammatory mediators such as platelet-
activating factor.
• Expression of TF results in the generation of thrombin, which may further activate platelets.
• The activated platelet membrane then forms a perfect scaffold on which further coagulation
activation occurs.
• Platelets express P-selectin on their surface, which regulates the adhesion of platelets to
leukocytes and the vascular endothelium and also boosts the expression of TF on
mononuclear cells.
• This increased expression is caused by the binding of platelets to mononuclear cells and the
subsequent activation of nuclear factor-κB (NF-κB).
• Endothelium disruption enhances platelet–vessel wall interactions and involves the
substantial release of ultra-large von Willebrand factor (vWF) multimers from the
endothelium .
• Ultra-large vWF multimers are detected in patients with DIC and ADAMTS13 deficiency,
and the association between low levels of ADAMTS13 and the severity of DIC in sepsis is
confirmed.
 Propagation of coagulation activation

 Function of all three physiological anticoagulant pathways is impaired in sepsis

induced activation of coagulation. (Antithrombin, protein C system, TFPI)
 Reduced levels of antithrombin (which forms complexes with and inhibits thrombin
and factor Xa , is one of the most important inhibitors of coagulation ) reduced level of
Antithrombin is a characteristic feature of DIC.
ANTI-THROMBIN:-
 Reductions in the levels of antithrombin are caused by a combination of processes,
including
• Reduced protein synthesis,
• Increased clearance through the formation of protease–antithrombin complexes
• Extravascular loss due to increased vascular permeability
• Degradation by neutrophil elastases.
• Reduced availability of Heparan sulfate – (HS- increases activity of Antithrombin)
Activated Protein C:-

 APC and its cofactor protein S form an additional line of defense against the excessive
activation of coagulation .
 Thrombin forms a complex with the endothelial cell membrane-associated molecule
thrombomodulin, and this complex converts protein C to its active form - APC .
 Thrombin+ thrombomodulin stimulates the activation of the thrombin activatable
fibrinolysis inhibitor (TAFI)- impairs endogenous fibrinolysis and stimulates sustained
fibrin deposition .
 APC proteolytically degrades FVa and FVIIIa, attenuating thrombin generation and
fibrin formation.
 Clinical studies- Decreased levels of protein C and protein S are associated with
reduced survival in sepsis induced DIC
TFPI:-

 Is present at the surface of the vascular endothelium or bound to lipoproteins in the

circulation and inhibits tissue factor - factor VIIa complex.

 Studies show TFPI can block endotoxin-induced coagulation.

 Observations in patients with sepsis have not generated conclusive results regarding the
relevance of this inhibitory system in DIC, as plasma concentrations of TFPI were not
lower in most patients than in normal controls.

 Animal models demonstrate the relevance of TFPI in DIC - deficiency of TFPI

increased the sensitivity of rabbits to DIC induced by tissue factor and administration
of TFPI diminished the detrimental effects of experimental bacteraemia in baboons.
Impaired endogenous fibrinolysis:-
 Plasminogen is the inactive form of plasmin, enzyme - proteolytically degrades fibrin
clots.
 Reaction to inflammatory mediators- sharp increase in plasminogen activators (tissue-
type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA))
due to their release from the endothelium.
 Intensification of plasminogen activation and subsequent plasmin generation is
followed by a persistent increase in the levels of plasminogen activator inhibitor 1
(PAI‑1).
 PAI-1 - results in a sustained impairment of fibrinolysis in sepsis
Inflammation and coagulation in DIC

 Derangement of coagulation and fibrinolysis in DIC is mediated by several cytokines:

Tumour necrosis factor (TNF), IL‑6 and IL‑1 .
 Trials show - complete blockage of sepsis-induced enhancement of TNF did not affect
the activation of coagulation.
 Studies in patients with sepsis who were administered an anti- TNF monoclonal
antibody did not show any effect of this treatment on survival.
 By contrast, the administration of a specific anti-IL‑6 antibody resulted in the complete
inhibition of lipopolysaccharide-induced activation of coagulation in primates.
 IL‑6 rather than TNF is important in mediating the procoagulant response in DIC.
 Direct role of IL-1 in coagulation secondary to sepsis remains unresolved.
 Activated coagulant factors and coagulation inhibitors interact with other coagulation
proteins AND with specific cellular receptors that subsequently turn on signalling
pathways.
 Coagulant proteases affect inflammatory activity by binding to protease-activated
receptors (PARs) which are transmembrane domain, G protein-coupled
receptors(GPCR).
 PARs- act as their own ligand.
 Binding and cleavage by an activated coagulant protease results in the exposure of a
neo-amino terminus that in turn activates the same receptor (and possibly neighbouring
receptors), causing transmembrane signalling .
 Four different PARs: PAR1, PAR3 and PAR4 - Thrombin receptors.
 PAR2 is activated by F Xa, the TF–FVIIa complex and trypsin.
 PAR1 can also act as a receptor for F Xa and the TF-F VIIa complex.
 Role of extracellular DNA and DNA-binding proteins in DIC :
• Histones and high mobility group protein B1 (HMGB1) are released from nucleosomes
of degraded cells and might form a surface on which the assembly of activated
coagulant factor complexes could be greatly facilitated.
• Histones activate platelets and stimulate thrombin generation.
• Activation and binding of neutrophils by DNA components result in the formation of
neutrophil extracellular traps (NETs).
• NET’s trap and kill pathogens by using their contents: histones, DNA and potent
proteases.
• NETs have been found to promote excessive thrombosis by multiple mechanisms:
1. Activation of factor XII,
2. Inactivation of TFPI
3. Provision of a mesh for platelet binding and aggregation.
4. Proteolytic cleavage of physiological anticoagulants by neutrophil elastase- abundant in
NETs
Pathophysiology of organ dysfunction
 DIC is an intermediary condition that causes ‘haemostatic complication’ in background
of underlying disorders.
 DIC is an independent predictor of mortality regardless of the underlying condition.
 Although the DIC process can be triggered and shaped by an underlying disease-
specific process, its pathogenetic effects and systemic dissemination that lead to
multiple organ dysfunction and death are probably governed by somewhat independent
pathophysiological pathways and mediators.
 Acute phase reactants from the liver .
 Mixed pathology, which includes microvascular thrombosis, haemorrhages and oedema
caused by vascular leakage.
Multifaceted consequences of thrombin
generation

 Physiological role of thrombin and the multiple well-orchestrated coagulant,

anticoagulant, profibrinolytic and antifibrinolytic, functions of thrombin in the
coagulation cascade.
 In DIC - loss of opposing effects owing to the excessive generation of thrombin.
 Disrupts the balance.
 Disproportionate consumption of these different components at rates that are difficult to
predict, tend to vary over the course of the illness and may be shaped by the underlying
inciting pathology.
 Disease-specific tailoring of DIC is the loss of the protein C receptors
(thrombomodulin and EPCR) from endothelial surfaces at vulnerable vascular sites, in
the case of DIC in cerebral malaria.
 Cytoadherence of Plasmodium falciparum-infected erythrocytes in microvessels within
the brain.
 Localized cerebral microvascular thrombosis, especially as infected erythrocytes bind
to EPCR, thereby reducing the generation of APC .
 Loss of EPCR can also contribute to compromised vascular endothelial barrier
function, vascular leakage, oedema and microhaemorrhages due to the loss of
cytoprotective signalling through the APC–EPCR–PAR1 pathway.
DIC Phenotypes
Phenotypes of DIC
 Early hyperfibrinolyic (haemorrhagic) phase, which is a response to the surge of
thrombin in the early stages following severe trauma .

 Followed by a procoagulant (thrombotic) phase after 24–48 hours- which is mainly

attributable to the excessive expression of PAI‑1 on the surface of platelets and
activated endothelial cells, as well as to the suppression of protein C anticoagulant
pathway.
 When the vector for hyperfibrinolysis is remarkable and dominant- bleeding is
the primary symptom; this type is called the bleeding type or hyperfibrinolysis
predominance type of DIC.

 Seen in patients with leukemia, such as acute promyelocytic leukemia (APL),

obstetric diseases, or aortic aneurysms.
 When the vector for hypercoagulation is remarkable and dominant- organ
failure is the main symptom; this type of DIC is called the organ failure type,
hypercoagulation predominance type or hypofibrinolysis type of DIC.

 Seen in patients with infection, particularly sepsis.

Mechanisms that disseminate thrombin
generation

 Abnormal and excessive expression of tissue factor on the surfaces of activated cells
and derived microparticles.
 Platelet polyphosphate-dependent activation of F-XI.
 Increased consumption (and reduced production) of anticoagulant factors (protein C
and antithrombin).
 Increased exposure of negatively charged surfaces that dramatically enhance thrombin
generation.
 The newly recognized role of DAMPs in promoting and fuelling thrombin generation
Immunothrombosis and DAMPs

 Clot formation also involves activated neutrophils and monocytes -

‘immunothrombosis’
 Monocyte-derived tissue factor expression is believed to be an important mediator of
immunothrombosis.
 Interactions between neutrophils monocytes and platelets - generate and propagate
thrombosis in vivo.
 Damage associated molecular patterns (DAMPs- Histones and DNA) mediate
immunothrombosis, also causes direct cellular toxicity that contributes to organ injury
and multiple organ dysfunctions.
 Circulating histones directly induce features of thrombosis and DIC in vivo, and
mediate specific organ injuries, such as lung, cardiac, liver, renal, and endothelial
injury.
 Functional consequences of circulating histones include:

• Platelet aggregation and thrombocytopaenia

• Thrombi that are particularly resistant to lysis.
• Vascular leakage and the release of pro-inflammatory cytokines
• Extracellular traps by leukocytes, especially neutrophils.
 Studies show that increased levels of circulating histones are observed in patients with
DIC .
 Histone– DNA complexes (nucleosomes) might be important clinical prognostic
markers and predictors of multiple organ dysfunctions and mortality in patients with
DIC .
Diagnosis, screening and prevention
 DIC can manifest at any point in the spectrum between bleeding and thrombosis.
 Bleeding - ranging from oozing at venipuncture sites to major organ haemorrhage.
 Microvascular thrombosis - organ dysfunction.
 Archetypal expression of organ dysfunction is the skin manifestation of purpura
fulminans- appears bruised owing to bleeding under the surface, but also ischaemic
owing to the reduced blood supply
 Increased in vivo thrombin generation is central to the pathogenesis of DIC:
 assays can detect its generation - the thrombin generation assay
 Detection of increased levels of thrombin–antithrombin complexes
 The activation of the protein C pathway - measuring increased levels of APC and
detecting APC–inhibitor complexes
 Activity on fibrinogen - measuring the levels of fibrinopeptide A or soluble fibrin
monomer.
 Measuring the levels of endogenous anticoagulants (protein C and antithrombin).
 These tests are not readily available , the generation time is longer and are not cost
effective.
 Rapid and practical tests of global coagulation:
 Prothrombin time,
 activated Partial thromboplastin time (aPTT; which is a global measure of the intrinsic
pathway of coagulation)
 Number of platelets in circulation (which can fall as part of DIC consumption)
 Levels of fibrinogen.
 Markers of fibrin formation and its lysis, such as D-dimer.
Management

 Theoretical cornerstone of DIC management is the- specific and vigorous treatment of

the underlying conditions (the insults).
 Controlled DIC- the endothelial regulatory network for coagulation control is
temporarily overridden and DIC will reverse quickly when the predisposing condition
is removed or stopped (such as in cases of transfusion reactions or placental abruption).
 Uncontrolled DIC is characterized by the overriding of the regulatory factors and the
degradation of the endothelial network (which occurs, for instance, in sepsis and
trauma)
 In uncontrolled DIC, in addition to the management of underlying disorders, it is
essential to install supportive treatment aimed at DIC itself.
 Early treatment, before DIC is diagnosed, might deteriorate physiological haemostasis
and immunothrombosis against injuries and pathogens and exacerbate the underlying
conditions.

 Repeated evaluation of the DIC score is required to monitor the DIC status, which
improves the diagnostic accuracy and the ability of the DIC scoring system to predict
clinical outcomes.
 Substitution therapy :
 Transfusion of platelets, fresh frozen plasma (FFP) and coagulant factor concentrates
in patients who are at risk of bleeding or those with bleeding due to consumption
coagulopathy.

 PRC:

 The transfusion of platelets is recommended in DIC patients with active

bleeding and a platelet count of <50 × 109 L−1 or in those with a high risk of
bleeding and a platelet count of <20 × 109 L−1.

Guidance for diagnosis and treatment of disseminated intravascular coagulation from harmonization of the
recommendations from three guidelines H. Wada,J. Thachil,M. Di Nisio,P. Mathew,S. Kurosawa,S. Gando,H.k. Kim
,J.d. Nielsen,
 FFP:
The administration of FFP may be useful in patients with active bleeding with
either prolonged PT/APTT (>1.5 times normal) or decreased fibrinogen
(<1.5 g dL−1). It should be considered in DIC patients requiring an invasive
procedure with similar laboratory abnormalities.

Guidance for diagnosis and treatment of disseminated intravascular coagulation from harmonization of the
recommendations from three guidelines H. Wada,J. Thachil,M. Di Nisio,P. Mathew,S. Kurosawa,S. Gando,H.k. Kim
,J.d. Nielsen,
 Administration of fibrinogen concentrate or cryoprecipitate may be
recommended in actively bleeding patients with persisting severe
hypofibrinogenemia (<1.5 g L−1) .

Guidance for diagnosis and treatment of disseminated intravascular coagulation from harmonization of the
recommendations from three guidelines H. Wada,J. Thachil,M. Di Nisio,P. Mathew,S. Kurosawa,S. Gando,H.k. Kim
,J.d. Nielsen,
 Prothrombin complex concentrate (PCC) :

 Concentrated product composed of three or four vitamin K-dependent coagulant

factors(II, VII, IX and X) and contains no (or a very small amounts) of anticoagulant
proteins, such as protein C, protein S and antithrombin.

 PCC should be used carefully alongside monitoring of the DIC score and the
measurement of antithrombin and/or protein C levels.
 Recombinant human activated factor VII (rhFVIIa ):

 Recent Cochrane review concluded that the use of rhFVIIa to promote haemostasis
does not have proven effectiveness and that it increases the risk of arterial events.
 Anticoagulants :
 The ISTH guidance recommends the use of unfractionated heparin or low-molecular-
weight heparin (LMWH) in DIC with the thrombotic phenotype.
 Prophylaxis of VTE with unfractionated heparin or LMWH is advocated in critically
ill, non-bleeding patients with DIC .
 Anticoagulant factor concentrates :
Wada, H., Matsumoto, T. & Yamashita, Y. Diagnosis and treatment of disseminated intravascular coagulation (DIC)
according to four DIC guidelines. j intensive care 2, 15 (2014). https://doi.org/10.1186/2052-0492-2-1
Acute promyelocytic leukaemia

 Massive plasmin is formed on the assembly of plasminogen and t-PA on cell surface-
associated annexin II.
 Excess plasmin induces haemorrhagic disorder in patients with APL.
 Small double-blind study showed that tranexamic acid (an antifibrinolytic agent that
inhibits plasmin-mediated degradation of fibrin) was effective for the control of
haemorrhage without thromboembolic complications in APL.
 However, after the introduction of all-trans retinoic acid (ATLA) as a front-line therapy
for APL, a recent historical control study showed no potential benefit of the
prophylactic use of tranexamic acid in patients with APL who were treated with ATLA
 Trauma:

 Weibel–Palade bodies are storage granules of endothelial cells.

 Upon traumatic shock-induced hypoperfusion, these bodies release t-PA into the
circulation, which results in systemic fibrinolysis (or fibrinogenolysis) in addition to
DIC-induced secondary fibrinolysis .
 There is immediate t-PA release but the induction and expression of PAI1 (also known
as SERPINE1) mRNA usually takes several hours
 Extreme imbalance between the levels of t-PA and PAI ‑1 are the main cause of
hyperfibrinolysis in patients with DIC during the first few hours after trauma.
 Tranexamic acid can reduce the risk of death in patients with bleeding trauma and
should be given as early as possible because any delay reduces its efficacy and might
be harmful.
Quality of life

 Quality of life of patients who develop DIC is highly dependent on the conditions and
prognoses of the disorders underlying DIC .

 A logistic regression analysis demonstrated that, on the day of diagnosis of severe

sepsis, the complication of DIC was an independent predictor of 28 ‑day and hospital
mortality and that the DIC score could also predict a patient’s prognosis.

 Another study has shown that, on the day of the injury, the complication of DIC was
found to be an independent predictor of death of patients with trauma
 DIC could predict the need for massive transfusions, and DIC scores on admission to
the emergency department were found to be significantly correlated with the
transfusion volume of platelet concentrates, packed red blood cells and FFP.

 These findings clearly indicate that the quality of life of patients with DIC can be aided
by the improvement of both the underlying disease and DIC itself.
SUMMARY
References

 Nature primer - Disseminated intravascular coagulation Satoshi Gando1, Marcel

Levi2 and Cheng-Hock Toh. Published: 02 June 2016
 Guidance for diagnosis and treatment of disseminated intravascular
coagulation from harmonization of the recommendations from three
guidelines H. Wada,J. Thachil,M. Di Nisio,P. Mathew,S. Kurosawa,S. Gando,
H.k. Kim,J.d. Nielsen,
 Google images.
Thank You