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.