Disseminated Intravascular Coagulation

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Disseminated Intravascular Coagulation

• Galila Zaher
• MRCPath 2005

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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

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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

• Secondary fibrinolysis
• Platelets Consumption
• coagulation factors and inhibitors Consumption.

• Thrombin generation
• Widespread microvascular thrombosis

Thrombin generation, fibrinolysis and inhibition
of fibrinolysis ? thrombosis and/or bleeding
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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
• Acute pulmonary microembolism syndrome
• Late pulmonary microembolism syndrome ? ARDS ,
  Microatelectasis and capillary leakage
• Acute renal failure
• Oligouria or anuria
• Microscopic or macroscopic hematuria

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Symptoms And Sings

• Cerebral dysfunction Confusion Blurring of
  consciousness
• Dermal changes microthrombosis / bleedings
• Focal hemorrhagic necroses face peripheral
  extremities.
• Petechiae and/or ecchymoses.
• Additional symptoms can result from dysfunction
  of the liver, endocrine glands and other organs.

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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

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Factors Accelerating DIC

• Shock
• Acidosis
• Hypoxemia
• Stasis
• Dehydration
• Hyperthermia

• Chronic renal insufficiency
• Chronic hepatic insufficiency
• Malnutrition
• Impaired anti-coagulation activity
• Impaired fibrinolytic activity
• Phagocytic dysfunction

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Laboratory Diagnosis
Analysis Early changes Late changes
Platelets ?/?? ???
APTT ? ???
Fibrinogen ? ???
D-dimer ?? ???
FII,VII,X ? ???
Protein C ? ???
Anti-thrombin ? ???
TAT complex ?? ???
Soluble fibrin ?? ???
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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

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Scoring System For DIC
Risk assessment Underlying disorder known to be associated with DIC YES Continue Global coagulation tests NO Stop
Platelet count (gt 100 0, lt 100 1, lt 50 2)
Soluble fibrin/D-dimer (no increase 0), ? moderate increase 2, ? ? strong increase 3
Prolongation of PT (lt3 sec 0 gt3 -6 sec 1 gt6 sec 2)
Fibrinogen level (gt 1.0 g/l 0 lt 1.0 g/l 1)
Calculate score
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Calculated Score

• Patient scores is gt5 compatible with overt DIC,
  (decompensated hemostasis) repeat scoring daily
• Patient scores is lt5 suggestive (not
  affirmative) for non-overt DIC, repeat next 1-2
  days
• Taylor, Thromb Haemostas
  2001861327-1330

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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 1. Risk assessment Does the patient have an underlying disorder known to be associated with DIC? If yes proceed 1. Risk assessment Does the patient have an underlying disorder known to be associated with DIC? If yes proceed 1. Risk assessment Does the patient have an underlying disorder known to be associated with DIC? If yes proceed 1. Risk assessment Does the patient have an underlying disorder known to be associated with DIC? If yes proceed 1. Risk assessment Does the patient have an underlying disorder known to be associated with DIC? If yes proceed 1. Risk assessment Does the patient have an underlying disorder known to be associated with DIC? If yes proceed 1. Risk assessment Does the patient have an underlying disorder known to be associated with DIC? If yes proceed
2. General criteria 2. General criteria 2. General criteria 2. General criteria 2. General criteria 2. General criteria 2. General criteria 2. General criteria
Platelet count gt100 x 109/L 0 lt100 x 109/L 1 Rising -1 Stable 0 Falling 1 Score
PT prolongation lt 3 s gt 3 s Falling -1 Stable 0 Rising 1
Soluble fibrin or FDPs Normal Raised Falling -1 Stable 0 Rising 1
3. Specific criteria 3. Specific criteria 3. Specific criteria 3. Specific criteria 3. Specific criteria 3. Specific criteria 3. Specific criteria 3. Specific criteria
Antithrombin Normal -1 Low 1
Protein C Normal -1 Low 1
TAT complexes Normal -1 High 1
4. Calculate score


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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

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Supportive Treatment

• Supportive treatment of MODS
• Shock fluids, catecholamines
• Hypoxemia oxygen, mechanical ventilation
• Renal failure diuretics, renal replacement
  therapy
• Severe anemia blood transfusion

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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

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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

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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-a, IL-Iß (cytokine and receptor
  upregulation)

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Sepsis
Pro-inflammatory cytokines
IL-6
TNF-a
Depression of fibrinolysis due to high levels
of PAI-1.
TF- activation of coagulation
Inhibition of physiological anticoagulant
pathways
Enhanced fibrin formation
Impaired fibrin removal
Microvascular thrombosis
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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.

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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.
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Scoring system for DIC
NO Stop YES Continue Underlying disorder known to be associated with DIC
Platelet count - (gt 100 0, lt 100 1, lt 50 2)..
Soluble fibrin/D-dimer - (normal 0), ? 2, ? ? 3).
Prolongation of PT - (lt 3s 0, 3-6s 1, gt 6 2).
Fibrinogen - (gt 1g/1 0, lt 1g/1 1)...
Calculate score
When the patient scores gt5 it is DIC
If the calculated score is gt5 compatible with overt DIC, repeat scoring daily lt5 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 2001861327-1330.
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DIC Subcommittee of the ISTH

• Dr Galila Zaher
• Consultant Haematologist
• MRCPath

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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 .

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Inflammatory cells
IL-B TNF
TPI
TF-VIIa
TM-IIa
II?IIa
PC?APC
Fibrinogen ?Fibrin
Va,VIIIa?Vi,VIIIi
Fibrinolysis
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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

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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.

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DIC

• Pro-inflammatory pro-hemostatic.
• Non-overt DIC.
• Overt DIC.
• Multiple organ dysfunction .
• Decreased survival potential
• ISTH
  SSC

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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.

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Reasons for such a distinction

• Earlier diagnosis.
• Earlier management.
• Assess natural history .
• Management triggering (antibiotics ,APC )
• Assess treatment response (APC).

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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.

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Diagnostic scoring criteria for DIC

• General criteria
• Platelets count lt100.
• PT prolongation gt3s.
• FDPs raised.
• Specific criteria
• Anti-thrombin.
• Protein C.
• TAT complex.
• If gt5 compatible with overt DIC ,if lt5reapet
  scoring daily suggestive of non overt DIC.

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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).

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The gold standard

1. Single.
2. Sensitive .
3. Specific.
4. Simple.
5. Rapid for non-overt DIC.

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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).

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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.

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APTT BPW

• Not influenced by analytical variables
• Time from venepuncture
• Freeze-thawing .
• Platelet count .
• APTT reagent .
• Not associated with medication or plasma
  expanders.

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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 .

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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.

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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.

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New Modalities In DIC

• APC concentrate .
• Heparin.
• Anti-thrombin concentrates .
• TFPI.
• rNAPc2.
• rIL-10 .

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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.

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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.

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• rNAPc2Inhibitor of the ternary complex (TF-
  VIIa and activated factor X).
• Derived from nematode anticoagulant proteins.
• rIL-10 abrogate the endotoxin-induced affects
  on coagulation

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• 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.

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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.

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• Thanks

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Sepsis( lipopolysaccharide)
Mononuclear cells
Direct endothelial injury
IL1ß ,TNF E-selection
Activation of coagulation
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• 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.