Disseminated Intravascular

Coagulation

Galila Zaher
MRCPath 2005
Definition
 “DIC is an acquired syndrome
characterized by the intravascular
activation of coagulation with loss of
localization arising from different causes.
 It can originate from and cause damage
to the microvasculature, which if
sufficiently severe, can produce organ
dysfunction.”
Scientific Subcommittee on DIC of ISTH, July , 2001
 Disseminated Intravascular
Coagulation (DIC)
Is not a disease, but a complication of various disorders
Conditions with activation of coagulation factors
DIC should always be considered in critically ill

 Thrombin generation Secondary fibrinolysis

 Widespread
Platelets Consumption
microvascular thrombosis
coagulation factors and
inhibitors Consumption.

Thrombin generation, fibrinolysis and inhibition

of fibrinolysis  thrombosis and/or bleeding
Symptoms And Sings
 Microvascular clot formation is the primary event in
DIC
 Signs of organ dysfunction determine the clinical
symptoms
 Indistinguishable from SIRS/Sepsis and MODS.
 Microclot formation → Organ failure
 Lung dysfunction
i. Acute pulmonary microembolism syndrome
ii. Late pulmonary microembolism syndrome →
ARDS , Microatelectasis and capillary leakage
 Acute renal failure
i. Oligouria or anuria
ii. Microscopic or macroscopic hematuria
Symptoms And Sings
 Cerebral dysfunction :Confusion & Blurring of
consciousness
 Dermal changes :microthrombosis / bleedings
i. Focal hemorrhagic necroses : face & peripheral
extremities.
ii. Petechiae and/or ecchymoses.
 Additional symptoms can result from
dysfunction of the liver, endocrine glands and
other organs.
Causes Of DIC
 Severe infections
 Trauma
 Organ destruction
 Malignancy
 Obstetric complications
 Vascular abnormalities
 Severe toxic or immunologic
reactions
Septicemia: bacterial, viral or fungal infections
Fractures : polytrauma, neurotrauma, fat
embolism
Severe skin and soft tissue trauma
Severe burns
Major surgical interventions
Pancreatitis
Acute liver necrosis
Heat stroke
Metastatic cancer
Tumor necrosis
Amniotic fluid embolism
Placental abruption
Preeclampsia and eclampsia
Dead fetus syndrome
Giant hemangioma
Hereditary teleangiectasis
Large vascular aneurysms
Snake bites
Transfusion reactions
Transplant reactions
Invasive circulatory supportive devices (i.e.
mechanical heart)
Extracorporal circulation
Factors Accelerating DIC
 Shock  Chronic renal insufficiency
 Acidosis  Chronic hepatic insufficiency
 Hypoxemia  Malnutrition
 Stasis  Impaired anti-coagulation
activity
 Dehydration
 Impaired fibrinolytic activity
 Hyperthermia
 Phagocytic dysfunction
 Laboratory Diagnosis
Analysis Early changes Late changes
Platelets / 
APTT  
Fibrinogen  
D-dimer  
F:II,VII,X  
Protein C  
Anti-thrombin  
TAT complex  
Soluble fibrin  
Diagnostic Algorithm for Overt DIC

 Risk assessment: Does the patient have an underlying

disorder known to be associated with overt DIC? If yes:
proceed; If no: do not use this algorithm.
 Order global coagulation tests (platelet count, PT,
fibrinogen, soluble fibrin monomers or fibrin degradation
products)
 Score global coagulation test results
 Calculate score
 Scoring System For DIC
Risk assessment: YES NO
Underlying disorder known to be associated with DIC Continue Stop
Global coagulation
tests

Platelet count
(> 100 = 0, < 100 = 1, < 50 = 2)

Soluble fibrin/D-dimer
(no increase = 0), ↑ moderate increase: =2, ↑ ↑ strong
increase = 3
Prolongation of PT
(<3 sec = 0; >3 -6 sec =1; >6 sec = 2)
Fibrinogen level
(> 1.0 g/l = 0; < 1.0 g/l = 1)
Calculate score
Calculated Score
 Patient scores is >5: compatible with overt DIC,
(decompensated hemostasis) repeat scoring daily
 Patient scores is <5: suggestive (not affirmative)
for non-overt DIC, repeat next 1-2 days
Taylor, Thromb Haemostas 2001;86:1327-1330
 Algorithm for Diagnostic Sequence for Determining Non-
overt DICK Non-overt DIC

1. Risk assessment:
Does the patient have an underlying disorder known to be associated with DIC? If yes:
proceed
2. General criteria
Platelet count >100 x 109/L = <100 x 109/L Rising = -1 Stable = Falling = Score
0 =1 0 1
PT prolongation <3s >3s Falling = -1 Stable = Rising = 1
0
Soluble fibrin or Normal Raised Falling = -1 Stable = Rising = 1
FDPs 0
3. Specific criteria
Antithrombin Normal = - Low = 1
1
Protein C Normal = - Low = 1
1
TAT complexes Normal = - High = 1
1
4. Calculate score
General Treatment

 Treatment of underlying disorder

 Antibiotic treatment of infections
 Surgical debridement and drainage of infected
foci
 Immobilization of fractures
 Evacuation of uterus in obstetric DIC
Supportive Treatment
 Supportive treatment of MODS
 Shock : fluids, catecholamines
 Hypoxemia : oxygen, mechanical ventilation
 Renal failure : diuretics, renal replacement
therapy
 Severe anemia : blood transfusion
Hemostatic Therapy
 Antithrombotic treatment
 AT concentrate.
 Concurrent treatment with heparin should
be avoided, heparin worsens
thrombocytopenia
 Fresh frozen plasma (FFP) When bleeding;
administer after antithrombin
 Platelets : severe thrombocytopenia + bleeding
 Antifibrinolytic treatment Should be avoided
ATenative
 A quality antithrombin (AT)concentrate
 Loading dose for adult (70 kg) patient 2 x 1500
IU vials
 Follow up treatment based on measured AT
levels
 Free from denatured AT (Hellstern et al, 1995)
 Two specific viral inactivation steps (SD +
pasteurization)
 When treating DIC with AT ,heparin should be
avoided due to high risk of bleeding comlications
Hoffmann et al, 2002
Biologic Markers in Measuring Non-
overt DIC

 AT and TAT complexes (↑ procoagulation)

 E-selection and thrombomodulin (endothelial
perturbation)
 FSPs or D-dimers (fibrinolysis)
 IL-6, TNF-α, IL-Iβ (cytokine and receptor
upregulation)
 Sepsis

Pro-inflammatory
cytokines
IL-6 TNF-α

Inhibition of Depression of
TF- physiological fibrinolysis
activation of anticoagulant due to high
coagulation pathways levels of PAI-1.

Enhanced Impaired
fibrin fibrin
formation removal

Microvascular
thrombosis
Practice Points
 DIC is not a disease entity on itself but is always
associated to an underlying disease.
 There is no single laboratory test with adequate accuracy
to establish the presence or absence of DIC.
 Most laboratory tests for DIC have a relatively high
sensitivity but a low specificity
 A combination of tests may guide the clinician towards a
confirmation or rejection of a diagnosis of DIC, for
example following the recently established guidelines of
the International Society of Thrombosis and Hemostasis.
Inflammation causing loss of homeostasis of the RES/MV organ. Significant injury of the endothelium occurring as a result of candidate injury
states has the potential for causing significant perturbation of the RES/MV organ in an activation sequence, summarized here. The left side
indicates the anatomic site for the on-going acceleration of the inflammatory and hemostatic processes indicated in the flow diagram, an implies a
semblance of the sequence itself. In many, if not most, instances, however, these events are occurring in parallel. Indeed, in the case of
acceleration to overt DIC, these processes are not only occurring in parallel, but in fact are being recapitulated at diffuse and distal anatomic sites
throughout the body. Specific steps of this activation process are discussed in the text. For example, bacterial lipopolysaccharide, vascular injury
(e.g. abruptio placenta), etc. PAI-I plasminogen activator.
 Scoring system for DIC
YES NO
Underlying disorder known to be associated with DIC Continu Stop
e

• Platelet count
- (> 100 = 0, < 100 = 1, < 50 = 2)…………………..
• Soluble fibrin/D-dimer
- (normal = 0), ↑ =2, ↑ ↑ = 3)……………………….
• Prolongation of PT
- (< 3s = 0, 3-6s = 1, > 6 = 2)……………………….
• Fibrinogen
- (> 1g/1 = 0, < 1g/1 = 1)…………………………...
• Calculate score

When the patient scores >5 it is DIC*

If the calculated score is
• >5: compatible with overt DIC, repeat scoring daily
• <5: suggestive (not affirmative) for non-overt DIC, repeat next 1-2
days
*) Overt DIC with a decompensated hemostatic system
Ref: Taylor, FB jr et al. Towards definition, clinical and laboratory
criteria, and a scoring system for disseminated intravascular
coagulation. Thromb Haemostas 2001;86:1327-1330.
 DIC Subcommittee of the
ISTH

Dr Galila Zaher
Consultant Haematologist
MRCPath
 Normal Homeostasis

Homeostasis: cellular (vascular, MMS) and 

chemical elements( coagulation factors).
Homeostasis are activated by inflammation . 

Vascular injury homeostasis is temporarily 

lost.
In extreme injury the RES capacity to 
restore homeostasis is compromised.
Overt DIC is the outcome . 
 Sepsispro-inflammatory cytokines

IL1-B TNF

TF Natural anticoagulant Impaired Fibrinolysis (PAI-1)

Enhance fibrin formation Impaired fibrin removal

Microvascular thrombosis
 Inflammatory cells

IL-B TNF

TF-VIIa TPI

IIIIa TM-IIa

Fibrinogen Fibrin PCAPC

Fibrinolysis Va,VIIIaVi,VIIIi
Clinical conditions associated
with DIC
Sepsis/severe infection . 
Trauma . 
Organ destruction . 
Malignance. 
Obstetrical calamities. 
Vascular abnormalities. 
Server hepatic failure. 
Severe immunologic reactions. 
Recreational drugs 
Transplant rejection 
DIC
An acquired syndrome characterized by:
The intravascular activation of 
coagulation.
Activated platelets (PL) for thrombin 
formation
Consumption of pro-coagulant factors& 
natural anticoagulant.
Widespread fibrin deposition . 
Impaired fibrinolysis (PAI-1). 
Micro vascular occlusion. 
DIC

Pro-inflammatory & pro-hemostatic. 

Non-overt DIC. 
Overt DIC. 
Multiple organ dysfunction . 
Decreased survival potential 
ISTH SSC
 Impaired fibrynolysis
activation of coagulation

Thrombotic obstruction consumption of Coagulation

Hamper blood supply

Serious bleeding

Multiple organ dysfunction

 Non-overt DIC

The injury not localized but self- 

limited no exhaustion of
compensatory mechanisms.
Cellular, hormonal and enzymatic 
responses to the injury are operating
sufficiently.
Haemostatic system is stressed but 
compensated.
Reasons for such a distinction:
Earlier diagnosis. 

Earlier management. 

Assess natural history . 

Management triggering (antibiotics 

,APC )
Assess treatment response (APC). 
DIAGNOSIS OF DIC

No single test with accuracy to 

establish the +/- of DIC.
Most lab tests high sens but low sp. 

Battery of tests . 

Serial testing. 

Inevitable delay. 
Diagnostic scoring criteria for DIC

General criteria:
Platelets count <100. 
PT prolongation >3s. 
FDPs raised. 
Specific criteria:
Anti-thrombin.
Protein C.
TAT complex.
If >5 compatible with overt DIC ,if <5reapet scoring
daily :suggestive of non overt DIC.
BIOLOGIC MARKERS TO MEASURE
NON-OVERT DIC

Platelet activation. 

Endothelial cell perturbation, E-selectin 

&TM
Pro-coagulant activation/inhibition AT & 
TAT
Initiation of fibrinolysis FDPs & D-dimers. 

Cytokine and receptor: IL-I IL-6, TNF- 

.
APC (T-TM). 
The gold standard

Single. .i

Sensitive . .ii

Specific. .iii

Simple. .iv

Rapid for non-overt DIC. .v

Transmittance Waveform (TW)
Charting optical changes in light 
transmittance over the duration of clot
formation.
The waveform shows an abrupt and rapid 
decrease in light transmission after the
initiation of Ca2+.
The normal TW is a sigmoid shaped. 
Classify and quantify specific factor 
deficiencies, presence of heparin .

( Downey et al).
Transmittance Waveform in DIC

Atypical TW APTT; biphasic waveform (BPW) 

Gradual decrease in light transmission after the 
addition of Ca2+.
Early, before conventional biochemical markers 
.
Serially determined of the BPW predict 
outcome .
Downey concluded that the BTW provides, a 
simple, rapid and robust measurement,
appropriate clinical interventions.
APTT BPW

Not influenced by analytical variables:

Time from venepuncture 
Freeze-thawing . 
Platelet count . 
APTT reagent . 
Not associated with medication or 
plasma expanders.
BPW & DIC

Diagnosis . 

The BTW preceded other 

laboratory tests (18 h).
Monitor progression from non-overt 
to overt DIC.
Monitoring the early response to 
therapy .
Transmittance Waveform in Non-overt DIC

Assessing prognosis: MR 44% Vs 26%.. 

Sensitivity 97.6% 

Specificity 98%. Only detected in DIC. 

PPV 74% . 

Direct relationship between the 

steepness & severity of haemostatic
dysfunction, and clinical progression.
The BTW

Gradual decrease in light transmission after the 

addition of Ca2+.
BTW is due to the rapid formation of a 
precipitate and change in turbidity in re-
calcified plasma.
The precipitate contained (VLDL) plus (CRP). 
The Ca2+-dependent formation of a complex 
between CRP and VLDL accounts for the BTW.
New Modalities In DIC

APC concentrate . 

Heparin. 

Anti-thrombin concentrates . 

TFPI. 

rNAPc2. 

rIL-10 . 
APC concentrate

Endotoxemia(T-TM). 
Depression of PC system . 
Enhance the pro-coagulant state. 
In sepsis reduce MR . 
24 g/kg/h for 96 h. 
The first intervention shown to be 
effective in reducing mortality in
sepsis.
Anti-thrombin concentrates

AT markedly reduced in sepsis. •

Consumption, degradation , and impaired •

synthesis.
Low levels in sepsis increased •
mortality.
II/III clinical studies . •

Doses  supra-physiological plasma levels •

No significant reduction in MR in sepsis. •

 rNAPc2: 
Inhibitor of the ternary complex
(TF- VIIa and activated factor X).
Derived from nematode •
anticoagulant proteins.
rIL-10 : abrogate the endotoxin- 
induced affects on coagulation
 Heparin: 
Experimental studies : partly inhibit the 
activation of coagulation in sepsis and other
causes of DIC.
Outcome events never been demonstrated in 
controlled clinical trials.
rTFPI : 
Block endotoxin-induced thrombin generation •
with promising results.
Sepsis : modestly reduced, or even increased, •
concentrations of TFPI.
Concluding remarks
No single test with accuracy to establish the 
+/- of DIC.
Diagnostic scoring criteria for . 
Downey concluded that the BTW provides, 
a simple, rapid and robust measurement,
appropriate clinical interventions.
Not influenced by analytical variables: 
APC conc The first intervention shown to 
be effective in reducing mortality in
sepsis.
Thanks
 Sepsis( lipopolysaccharide)

Direct endothelial injury Mononuclear cells

IL1β ,TNF& E-selection

Activation of coagulation
FDPs depend on fibrin generation 
and clearance.
High predictive value of PAI-1 
multi-organ failure .
A high level of soluble fibrin is an 
early indicator.
D-dimer an indicator of fibrin 
formation.