Management of Disseminated Intravascular Coagulation

1. Disseminated
Intravascular
Coagulation

2. History
● 1834
○ Dupuy - 1st description of DIC
● 1865
○ Trousseau - tendency to thrombosis, in patients with malignancies
● 1873
○ Naunyn - disseminated thrombosis-IV injection of dissolved red cells
○ Wooldridge - procoagulant involved–substance in stroma of red cells
● 1955
○ Ratnoff – DIC, in women with fetal death or amniotic fluid embolism
● 1961
○ Lasch - concept of consumption coagulopathy
○ McKay - DIC - pathogenic feature of variety of diseases

3. Definition
● Disseminated intravascular coagulation (DIC) - a
clinicopathologic syndrome
○ Widespread intravascular coagulation
exposure / production of procoagulants insufficiently balanced by natural
anticoagulant mechanisms & endogenous fibrinolysis
○ Perturbation of endothelium in microcirculation
stimulated inflammatory cells & release of inflammatory mediators
○ Tissue ischemia - occlusive microthrombi
○ Bleeding
consumption of platelets & coagulation factors; in some cases, excessive
fibrinolytic response

4. Pathogenesis
● Inflammation and Endothelium in DIC
● Role of Cytokines and Tissue Factor
● Amplifying Role of Thrombin & Platelets
● Role of Coagulation Proteases in Upregulating Inflammation
● Role of Fibrinogen and Fibrin
● Role of Natural Anticoagulant Pathways
● Dysregulation of Fibrinolysis
● Role of Oxidative Stress
● Consumption of Hemostatic Factors

5. Endothelial perturbation – sine qua non of DIC

6. Inflammation

Coagulation
•Activated mononuclear
cells & endothelial cells
induce TF expression 
activates platelets &
coagulation system
•Activated coagulation
proteases bind to
protease-activated
receptors (PARs) 
induce pro-inflammatory
stimuli  cytokines that
target endothelial cells &
mononuclear cells

7. Physiologic anticoagulant
mechanisms & their
point of impact in
coagulation system
•In sepsis, these
mechanisms are impaired
(green arrows)
•1. Protein C system -
dysfunctional
•2. TFPI - insufficiency
•3. AT - Low levels &
Glycosaminoglycans -
impaired on perturbed
endothelial cells

9. Consumption of Hemostatic Factors
● Thrombin genesis  fibrin deposition  consumption of platelets,
fibrinogen, factors V & VIII, protein C, AT, & components of fibrinolytic
system
● Decreased synthesis by liver
● Bleeding, thrombosis, or both can result
● Bleeding may be promoted by fibrinolysis - derived FDPs that exhibit
anticoagulant & antiplatelet effects
● Microangiopathic hemolytic anemia  blood cells passing through
vessels partially occluded by thrombi

11. Major causes
•Infectious diseases &
malignant disorders
together account for
approximately 2/3rd
of DIC cases

13. Frequency (%) & Type of
Organ Dysfunction or
Other Clinical
Manifestations in Case
Series of Patients with DIC
Clinical manifestations are
attributable to DIC, the
underlying disease, or both
Bleeding manifestations
common in all series
Considerable variation in
other systemic
involvolvement

15. Bleeding
● Acute DIC - heralded by hemorrhage into skin at multiple
sites
Petechiae, ecchymoses
Oozing - venipunctures, arterial lines, catheters, injured tissues
Mucosal bleeds are also common
Massive bleeding into GIT, lungs, CNS, or orbit may occur
● Chronic DIC - usually exhibit minor skin & mucosal
bleeding

16. Thrombosis and
Thromboembolism
Extensive organ
dysfunction
Microvascular thrombi
Venous and/or arterial
thromboembolism
Organ Manifestation
Skin Purpura, bleeding from injury sites,
hemorrhagic bullae, focal necrosis, acral
gangrene
Cardiovascular Shock, acidosis, myocardial infarction,
cerebro-vascular events
Renal Acute renal insufficiency (acute tubular
necrosis), oliguria, hematuria, renal
cortical necrosis
Liver Hepatic failure, jaundice
Lungs Adult respiratory distress syndrome,
hypoxemia, edema, hemorrhage
GIT Bleeding, mucosal necrosis and
ulceration, intestinal ischemia
CNS Coma, convulsions, focal lesions,
bleeding, Cerebral embolism
Adrenals Adrenal insufficiency (hemorrhagic
necrosis)

17. Thrombotic Microangiopathy
● Pathogenesis of DIC, activation of the coagulation system 
thrombotic microangiopathy
● Different from another thrombotic microangiopathy, TTP-
HUS, results from primary platelet activation due to defect
in VWF cleaving protease (ADAMTS13)
● Different coagulation abnormalities that usually permit
these disorders to be distinguished

18. DIC /TTP
Test DIC TTP
Platelet count Decreased Decreased
Fibrinogen Decreased Normal
FDP Increased Normal
D-dimer Increased Normal
Antithrombin Decreased Normal
Schistocytes Present Present
Plasma clotting
times
Prolonged Normal
Euglobulin lysis
time
Shortened Normal

19. Malignancy associated DIC
● Malignancy - hypercoagulable state - TF expression by circulating tumor cells &
cancer procoagulant (activates factor X directly, independent of TF/VIIa
complex)
● DIC in APML
Release of TF  IL-1 and TNF-α  downregulate endothelial thrombomodulin, 
compromising protein C anticoagulant pathway
Upregulation of Annexin II (plasminogen receptor on surface of malignant
promyelocytes)
May be reversed by inducing cellular differentiation
● Present acutely with hemorrhage in APML, or as migratory thrombophlebitis in
solid tumors (Trousseau's syndrome)

20. Mortality
● Acute DIC - serious complication; high mortality rate, determined
in part by the underlying disease
● Reported mortality rate  40-80% in patients with severe
sepsis, trauma, or burns
● Risk factors for death include increasing age & severity of the
organ dysfunction and hemostatic abnormalities
● It is not clear, if poor outcome reflects effects of DIC or
consequences of systemic inflammatory response
Siegal T, Seligsohn U, Aghai E, Modan M. Clinical and laboratory aspects of disseminated
intravascular coagulation (DIC): a study of 118 cases. Thromb Haemost 1978; 39:122

21. Diagnosis
● Laboratory findings different in acute and chronic DIC
● Evidence of both thrombin generation and increased
fibrinolysis
● The degree of abnormalities may correlate with the severity
of disease
● Other difficulties
DIC in patients with liver disease
D/D DIC from TTP-HUS
Concomitant factor deficiencies/acquired bleeding disorders

22. Acute DIC
● Diagnosis suggested by
History (eg, sepsis, trauma, malignancy),
Clinical presentation, moderate to severe thrombocytopenia
(<100,000/microL)
Microangiopathic changes on peripheral smear

23. Chronic DIC
● Laboratory studies are variable
● Slower rate of consumption of coagulation factors balanced by enhanced
synthesis of these proteins
● Platelet count may be only moderately reduced
● Plasma fibrinogen is often normal or slightly elevated
● Diagnosis largely based upon
○ evidence of microangiopathy on the peripheral blood smear
○ increased levels of FDPs and particularly, D-dimer

24. Coagulation abnormalities in DIC
Parameter
Acute (decompensated)
DIC
Chronic (compensated)
DIC
Platelet count Reduced Variable
Prothrombin time Prolonged Normal
Activated partial
thromboplastin time
Prolonged Normal
Thrombin time Prolonged Normal
Plasma fibrinogen Reduced Normal-elevated
Plasma factor V Reduced Normal
Plasma factor VIII Reduced Normal
Fibrin degradation
products
Elevated Elevated
D-dimer Elevated Elevated

25. Fibrin Degradation Products, D-dimer
● Clinically significant DIC - unlikely if there is no
biochemical evidence of accelerated fibrinolysis
● D-dimer levels reflect degradation of cross linked fibrin
● Most common abnormal parameter
● Methods – Latex Agglutination, ELISA
● Not specific for DIC, multiple other causes
● Quantification of D-Dimer - more specific

27. Causes of elevated D-Dimer levels
Arterial thromboembolic disease
Myocardial infarction
Stroke
Acute limb ischemia
Atrial fibrillation
Intracardiac thrombus
Venous thromboembolic disease
Deep vein thrombosis ,PTE
Disseminated intravascular coagulation
Preeclampsia and eclampsia
Abnormal fibrinolysis; use of
thrombolytic agents
Cardiovascular disease
Severe sepsis/inflammation
Surgery/trauma (eg, tissue ischemia,
necrosis)
Vasoocclusive episode of sickle cell
disease
Severe liver disease (decreased
clearance)
Malignancy
Renal disease
Nephrotic syndrome (eg, renal vein
thrombosis)
Acute renal failure
Chronic renal failure and underlying
cardiovascular disease
Normal pregnancy
Venous malformations

28. PT, aPTT
● Prothrombin time —
Prolongation reflects reduced activity of components of extrinsic &
common pathways
Include factors VII, X, V, and prothrombin, (most frequently
decreased clotting proteins in DIC)
● Activated PTT —
APTT measures intrinsic & common pathways of coagulation
Sensitive to deficiencies of factors XII, XI, IX and VIII

29. Fibrinogen
● Usually low in acute decompensated DIC
● May be elevated as an acute phase reactant in certain
chronic conditions, including pregnancy
● Quantitative assessment of fibrinogen levels must be
considered while keeping the underlying diagnosis in mind
● Normal Values = 1.5-3.0 g/dL

30. Other Investigations
● Specific factor levels –
Factors V & VIII, usually significantly depressed
Prothrombin levels may be normal in some patients, particularly those
with abruptio placentae
Reduced levels of antithrombin , protein C & protein S (Protease
Inhibitors)
● Measurement of soluble fibrin monomers
● Thrombin time – usually prolonged due to hypofibrinogenemia &
presence of FDPs

31. Thrombin-catalyzed conversion of fibrinogen to
fibrin involves release of FPA and FPB.

32. Molecular Markers
● Prothrombin fragment 1 + 2 is an easily performed reliable
marker for FXa generation
● Fibrinopeptide A is a marker of thrombin acting on
fibrinogen
● Thrombin precursor protein

33. Prothrombin
Factor Xa
Fibrinopeptide A
Prothrombin
fragment 1+2
thrombin
Fibrinopeptide A
Fibrinogen

34. Global Tests of Hemostasis
● New point-of-care testing methods -
Thromboelastography (TEG) -
overall picture of ex vivo coagulation
● Theoretical advantage of TEG -
provides idea of platelet function as
well as fibrinolytic activity
● No systematic studies on diagnostic
accuracy of TEG for diagnosis of DIC
IM – REVIEW; Disseminated intravascular coagulation: a review for the internist
Marcel Levi • Tom van der Poll; Intern Emerg Med; DOI 10.1007/s11739-012-0859-9

35. Diagnostic Algorithm for Diagnosis of Overt DIC

36. Number of points on
the ISTH DIC score
and 28-day mortality
in patients with
severe sepsis
Data were derived
from the placebo
group (n = 840) in the
PROWESS trial on the
efficacy of activated
protein C in sepsis

37. Therapy
● Controlled studies difficult to perform - variabilities in DIC triggers, clinical
presentations & grades of severity
● Decisions regarding treatment must be individualized
● Success of management related to
rapid, vigorous measures against underlying disease
support of vital functions
close clinical observation
availability of 24-hour coagulation laboratory services
adequate supply of platelet concentrate, cryoprecipitate, FFP & PRBC for
replacement therapy
Heparin, when indicated, administered by continuous infusion

38. Treatment of Underlying Disorders & Vital Support
● Vigorous treatment of underlying disorder to alleviate/remove
inciting injurious cause
● Sepsis-induced DIC - aggressive use of intravenous antibiotics
and source control (e.g., by surgery or drainage)
● Other examples - cancer surgery or chemotherapy, uterus
evacuation/hysterectomy in abruptio placentae, resection of
aortic aneurysm, & debridement of crushed tissues
● Aggressive supportive care

39. Blood Component Therapy
● Administration of blood components might "add fuel to the fire”
● FFP infusion
○ may cause volume overload & capillary leak exacerbation
○ Increase risk of inducing / worsening pulmonary edema, ARDS & ascites
● Prothrombin complex concentrate (PCC)
○ Partially overcomes obstacle of fluid overload; does not contain factor V
○ May worsen coagulopathy because of traces of activated factors
● Purified coagulation factor concentrates
○ To correct specific deficiencies of coagulation factors

40. Blood Component Therapy
● Platelet transfusion - to prevent bleeding into ischemic or
damaged organs (particularly CNS)
Threshold platelet count that prompt transfusion is patient &
disease specific
Indicated in patients with active bleeding / invasive procedure /
risk of bleeding complications
● Cryoprecipitate used to rapidly raise fibrinogen & factor VIII
levels (fibrinogen level is less than 1 g/L)
Cryoprecipitate - 4-5 times fibrinogen/ml compared to FFP
FFP – fibrinogen sufficient for mild to moderate hypofibrinogemia

41. Heparin Administration & Other Anticoagulants
● Heparin therapy in patients with DIC remains controversial
● Safety of heparin treatment is debatable in DIC patients who are prone
to bleeding
● May be beneficial in some categories of chronic DIC
○ malignancy, purpura fulminans, and aortic aneurysm (prior to
resection)
○ thromboembolic complications in large vessels & pre-surgery in
patients with chronic DIC
● Antithrombin levels must be normal for heparin to be effective

42. Heparin Administration & Other Anticoagulants
● Chronic DIC - metastatic carcinoma or aortic aneurysm
continuous infusion heparin 500-750 U/h (if no response in 24 hrs, escalate dose)
● Acute DIC –
when intensive blood component replacement fails to improve excessive bleeding
when thrombosis threatens to cause irreversible tissue injury (e.g., acute cortical
necrosis of the kidney or digital gangrene)
● Hyperacute DIC - mismatched transfusion, amniotic fluid embolism, septic
abortion, and purpura fulminans
IV bolus 5000-10,000 U heparin, with replacement of blood products
Continuous infusion of 500 - 1000 U/h heparin necessary until underlying disease
responds to treatment

43. Inhibitors of Fibrinolysis
● Patients with DIC should not be treated with antifibrinolytic agents such as -
EACA or tranexamic acid - block fibrinolysis that preserves tissue perfusion
Severe thrombosis may occur
● Different situation in patients with DIC accompanied by primary
fibrino(geno)lysis, as in some cases of
○ APL, heat stroke, amniotic fluid embolism, & carcinoma prostate
● In these conditions, fibrinolytic inhibitors considered (preceded by replacement
of depleted blood components & heparin infusion), provided
(1) Patient is bleeding profusely & has not responded to replacement therapy
(2) Excessive fibrino(geno)lysis, i.e., rapid whole blood clot lysis or a very short euglobulin
lysis time

44. Protein C concentrate
● Patients with homozygous / acquired protein C deficiency (eg, due to
meningococcemia) may develop purpura fulminans
● Such patients may benefit from administration of protein C concentrate
● The administration of FFP as a source of protein C is difficult because of
the short half-life of protein C in plasma
● Anecdotal reports that repeated plasma exchange - helpful in
maintaining normal levels of protein C when PCC is not available

45. Recombinant Factor VIIa
● Used as a "last resort" in some patients with severe DIC
associated haemorrhage due to obstetric or other causes
● Dosing – 90 µg/m² iv every 2 hours until bleeding ceases
● Problems –
Thrombotic complications may occur
Short half life, may need frequent dosing
Cost
Franchini M, Manzato F, Salvagno GL, Lippi G. Potential role of recombinant activated factor VII for the treatment
of severe bleeding associated with disseminated intravascular coagulation: a systematic review. Blood Coagul
Fibrinolysis 2007; 18:589.

46. DIAGNOSIS
TREATMENT

47. Trials Of APC In Sepsis + DIC
PROWESS (2001) ADDRESS (2005) RESOLVE (2007)
ENHANCE
(2009)
PROWESS-
SHOCK (2011)
APROCCHS
(2010)
BENEFIT NO BENEFIT HARM

48. Take Home Message
● DIC - a serious and multifaceted complication of a variety of disease states
● The etiology is related to an imbalance of pro and anticoagulant activity in
response to the underlying pathology
● Both bleeding and thrombosis may be seen
● Thrombotic events especially microthrombosis may contribute to end organ
damage
● Aggressive therapy directed at the underlying state is the cornerstone of
management
● Replacement of deficient pro and anticoagulant factors along with judicious use of
heparin is helpful

49. Dr Harshit Khurana
THANK YOU