Disseminated Intravascular Coagulation

Galila Zaher

MRCPath 2005

DefinitionDefinition

“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 Disseminated Intravascular Coagulation (DIC)Coagulation (DIC)

Is not a disease, but a complication of various disordersConditions with activation of coagulation factorsDIC should always be considered in critically ill

Thrombin generation

Widespread microvascular thrombosis

Secondary fibrinolysis

Platelets Consumption coagulation factors and inhibitors Consumption.

Thrombin generation, fibrinolysis and inhibition of fibrinolysis thrombosis and/or bleeding

Symptoms And SingsSymptoms 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 syndromeii. Late pulmonary microembolism syndrome →

ARDS , Microatelectasis and capillary leakage Acute renal failure i. Oligouria or anuriaii. Microscopic or macroscopic hematuria

Symptoms And SingsSymptoms 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 DICCauses 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 traumaSevere burnsMajor surgical interventionsPancreatitisAcute liver necrosisHeat strokeMetastatic cancerTumor necrosisAmniotic fluid embolismPlacental abruptionPreeclampsia and eclampsiaDead fetus syndromeGiant hemangiomaHereditary teleangiectasisLarge vascular aneurysmsSnake bitesTransfusion reactionsTransplant reactionsInvasive circulatory supportive devices (i.e.

mechanical heart)Extracorporal circulation

Factors Accelerating DICFactors Accelerating DIC

Shock

Acidosis

Hypoxemia

Stasis

Dehydration

Hyperthermia

Chronic renal insufficiency

Chronic hepatic insufficiency

Malnutrition

Impaired anti-coagulation activity

Impaired fibrinolytic activity

Phagocytic dysfunction

Laboratory DiagnosisLaboratory 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 DICDiagnostic 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 DICScoring System For DIC

Risk assessment: Underlying disorder known to be associated with DIC

YESContinueGlobal coagulation tests

NOStop

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 ScoreCalculated 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 = 0

<100 x 109/L =1

Rising = -1 Stable = 0

Falling = 1

Score

PT prolongation < 3 s > 3 s Falling = -1 Stable = 0

Rising = 1

Soluble fibrin or FDPs

Normal Raised Falling = -1 Stable = 0

Rising = 1

3. Specific criteria

Antithrombin Normal = -1

Low = 1

Protein C Normal = -1

Low = 1

TAT complexes Normal = -1

High = 1

4. Calculate score

General TreatmentGeneral 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 TreatmentSupportive Treatment

Supportive treatment of MODS

Shock : fluids, catecholamines

Hypoxemia : oxygen, mechanical ventilation

Renal failure : diuretics, renal replacement therapy

Severe anemia : blood transfusion

Hemostatic TherapyHemostatic 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

ATenativeATenative

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

TF-activation of coagulation

TNF-α

Inhibition of physiological anticoagulant pathways

Depression of fibrinolysis due to high levels of PAI-1.

Enhanced fibrin

formation

Impaired fibrin

removal

Microvascular thrombosis

Practice PointsPractice 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

Underlying disorder known to be associated with DICYESContinue

NOStop

• 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.

Sepsispro-inflammatory cytokines

IL1-B TNF

TF

Enhance fibrin formation

Natural anticoagulant Impaired Fibrinolysis (PAI-1)

Microvascular thrombosis

Impaired fibrin removal

Inflammatory cells

IIIIa

IL-B TNF

Fibrinogen Fibrin

TF-VIIa

Fibrinolysis

TPI

TM-IIa

PCAPC

Va,VIIIaVi,VIIIi

Clinical conditions associated with DIC

Sepsis/severe infection. Trauma. Organ destruction. Malignance.Obstetrical calamities. Vascular abnormalities.Server hepatic failure.Severe immunologic reactions.Recreational drugsTransplant rejection

DIC

An acquired syndrome characterized by:The intravascular activation of

coagulation.Activated platelets (PL) for thrombin

formationConsumption 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

activation of coagulation

Thrombotic obstruction

Hamper blood supply

Multiple organ dysfunction

consumption of Coagulation

Serious bleeding

Impaired fibrynolysis

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

&TMPro-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

.iSingle.

.iiSensitive.

.iiiSpecific.

.ivSimple.

.vRapid for non-overt DIC.

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 venepunctureFreeze-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

Direct endothelial injury Mononuclear cells

IL1β ,TNF& E-selection

Sepsis( lipopolysaccharide)

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.