dic - up.ac.za · 11/3/2011 · diagnosis and management of disseminated intravascular coagulation....

DIC

Bert Vandewiele

Fellow Critical Care

23 May 2011

Dissiminated Intravascular Coagulopathie

2 Dr. Bert Vandewiele 11/3/2011

Dissiminated Intravascular Coagulopathie

= Consumption coagulopathie

= Defibrination syndrome

• Incidence: – 1 % Hospital Admissions

• Prognosis ≈ Underlying disease – 40-80% mortality in patients with severe sepsis,

trauma or burns

• DIC is NOT a disease, it is a complication of an underlying disorder


DIC

1. Pathogenesis

2. Etiology

3. Clinical Features

4. Diagnosis

5. Treatment


1. Pathogenesis

Bleeding Trombosis


Acute or chronic

The clotting Cascade

11/3/2011 Dr. Bert Vandewiele 6

Furie B, Furie B.C. Mechanisms of Thrombus Formation N Engl J Med 2008; 359:938-949

1. Pathogenesis: trombosis


1. Pathogenesis: bleeding

• Coagulation factor deficiency – Consumption of coagulation factors

– Compensatory mechanisms compromised • Liver

• Vit K deficiency

– Increased losses due to bleeding

• Thrombocytopenia – Thrombin induced platelet aggregation

– Microangiopathic hemolytic anemia


Akca, S., Haji-Michael, P., de, M.A., Suter, P., Levi, M. & Vincent, J.L. (2002) Time course of platelet counts in critically ill patients. Critical Care Medicine, 30, 753–756.

1. Pathogenesis: Bleeding


• PLASMIN

– FIBRIN DEGRADATION PRODUCTS (FDP) • Interfere with normal fibrin

polymerization

• Bind to glycoprotein IIb/IIIa fibrinogen receptor on platelets

– PROTEOLYTIC ACTIVITY • Proteolytic degradation of fibrinogen

• Proteolytic degradation of clotting factors

1. Pathogenesis


1. Pathogenesis: Acute versus chronic DIC

Chronic

Event

• Slow activation

Propagation

• Production procoagulants

• Liver compensates clotting factors

• Bone marrow compensates platelets

effect

• trombosis

• Trousseau Syndrome

Acute

Event

• Brisk

• Explosive

Propagation

• Depletion of clotting factors

• Depletion of platelets and fibrinogen

• FDP interfere with hemostasis

effect

• Bleeding diathesis

• Microangiopathic hemolytic anemia


2. Etiology

• Sepsis/severe infection (any microorganism) • Trauma (e.g. polytrauma, neurotrauma, fat embolism).. • Organ destruction (e.g. severe pancreatitis). • Malignancy:

– solid tumours – myeloproliferative/lymphoproliferative malignancies.

• Obstetrical calamities: – amniotic fluid embolism – abruptio placentae.

• Vascular abnormalities: – Kasabach–Merrit syndrome – large vascular aneurysms

• severe hepatic failure. • Severe toxic or immunological reactions:

– snake bites – recreational drugs – transfusion reactions – transplant rejection.

Levi M, Toh CH, Thachil J, Watson HG. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology. Br J Haematol 2009; 145:24.


Etiology (alternatively

aetiology) is the study

of causation, or

origination. The word

is derived from the

Greek αἰτιολογία,

aitiologia, "giving a

reason for" (αἰτία,

aitia, "cause"; and -

λογία, -logia).

2.1 Sepsis

• Incidence – 30-50% Gram negative sepsis – Meningococcal sepsis – (Gram positive sepsis/viral infections)

• Pathophysiology – Tissue FactorThrombin generation

(direct via endotoxins or other membrane LPS, IL6-mediated, high levels of microparticles with TF)

– Suppression of normal antithrombotic mechanisms (TNFα) – Associated conditions

• Reduced blood flow • Tissue damage • Impaired hepatic perfusion (decreased hepatic clearance of

procoagulants)


2.2 Trauma and extensive surgery

• Incidence

– > 50% in trauma patients with SIRS

– 25-40 % patients with severe head injury

• Pathophysiology

– Tissue enzymes from damaged tissue

– Phospholipids from damaged tissue

– Activation of cytokine networks

– Associated conditions


2.3 Malignancy

• Incidence

– 15% Acute promyelocytic leukemia (bleeding)

– Common in solid tumors Trousseau’s syndrome

• Pathophysiology

– Tissue factor expressed on circulating tumor cells

– Cancer procoagulant: activates factor X directly


2.4 Obstetrical complications

• Incidence

– > 50% Amniotic fluid embolism

– > 50% Abruptio Placenta

– 20% HELLP

– 7% Preeclampsia

– Septic abortion/dead fetus syndrome

• Pathophysiology

– Leakage of tromboplastin like material


3. Clinical features

• Bleeding (64%)

• Renal Dysfunction (25%)

• Hepatic dysfunction (19%)

• Respiratory dysfunction (16%)

• Shock (14%)

• Thromboembolism (7%)

• Central nervous system involvement (2%)


3. Clinical features: bleeding

• Petechiae and ecchymoses • Blood oozing:

– Wound sites – Intravenous lines/catheters – Mucosal surfaces – Life-Threatening: GASTROINTESTINAL/LUNGS/CNS

• Post-surgical blood oozing: – Catheters – Drains – Tracheostomies – Serous cavities


3. Clinical features: Acute renal failure

• 25-40% of patients

• Two mechanisms – Microthrombosis of afferent arterioles Cortical ischemia and necrosis

– Hypotension and or sepsis Acute tubular necrosis

• Differentiate from TTP-HUS!


DIC vs TTP-HUS


Test DIC TTP

Platelet count Decreased Decreased

Fibrinogen Decreased Normal

Fibrin Degradation Products (FDP)

Increased Normal

D-dimer Increased Normal

Antithrombin Decreased Normal

Schistocytes Present Present

Plasma clotting times Prolonged Normal

Euglobin Lysis time Shortened Normal

Schistocyte


3. Clinical features: hepatic dysfunction

• Jaundice – Increased bilirubin production secondary to

hemolysis

– Due to the underlying disease


3. Clinical features: Pulmonary disease

• Primary due to damage to the pulmonary vascular endothelium

• As a consequence of the underlying disease.


4. Diagnosis

• Which tests to use?

• Acute DIC vs Chronic DIC

• Differential diagnosis

– Acute DIC versus severe liver disease

– DIC versus TTP-HUS

– DIC versus fibrinogenolysis

– DIC versus Heparin Induced Thrombocytopenia


4. Diagnosis

• There is no single laboratory test to diagnose DIC!

• DIC is an extremely dynamic situation!

• The whole clinical picture + ?

• Laboratory tests


4. Diagnosis

1. Platelet count

2. Fibrin Degradation products and D-dimers

3. PT and aPTT

4. Fibrinogen

5. Blood film

6. Other markers of hemostasis

7. Scoring system


4.1 Platelet count

• Reduction in platelet count or clear downward trend – Sensitive

• (Thrombocytopenia 98% patients with DIC) • (Platelet count <50.000 in 50% DIC patients)

– Not specific • (Sepsis/Leukemia/... thrombocytopenia)

• Correlates strongly with markers of thrombin generation (thrombin-induced platelet aggregation is mainly responsible for platelet consumption).


4.2 Fibrin Degradation products and D-dimers

• Increased fibrinolytic activity

– Fibrin Degradation Products – FDP (not specific)

– D-dimer (more specific)

• BUT

– Other disease associated with FDP and D-dimers

– Liver and kidney impairment influence the levels

• Maybe

– Soluble Fibrin Monomer (Is only generated intravascularly by the thrombin action on fibrinogen)


4.3 PT and aPTT

• Prolonged in about 50-60% of cases of DIC, due to consumption, impaired synthesis and loss of coagulation proteins

• PT measures extrensic and common pathway – Factor VII, X, V and prothrombin (II)

• aPTT measures intrinsic and common pathway – XII, XI, IX and VIII, X, V and prothrombin (II)

• Sometimes shortened – Circulating activated clotting factors)

• PT ≠ INR (Only validated for OAC monitoring)


4.4 Fibrinogen

• Theoretically useful BUT

• It is an acute phase reactant (fibrinogen levels were normal in up to 58% patients with DIC)

• Interference on the assay for fibrinogen level by FDP

• Sequential measurements might be more useful


4.5 Blood film

• Fragmented Red blood cells

– Not specific

– Not sensitive

• Consider other causes of TMA (thrombotic microangiopathy)


4.6 Other markers of haemostasis

• Natural anticoagulants

– Antithrombin

– Protein C

– Protein S

• TEG

• Atypical light transmittance profile on the aPTT


4.7 Scoring System


Taylor, F.B., Jr, , Toh, C.H., Hoots, W.K., Wada, H. & Levi, M. (2001) Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Journal of Thrombosis and Haemostasis., 86, 1327–1330.

4. Diagnosis: Acute versus chronic DIC

Parameter Acute Decompensated DIC Chronic Compensated DIC

Platelet count Reduced Variable

Prothrombin time Prolonged Normal

Activated partial tromboplastin 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 (FDP)

Elevated Elevated

D-dimer Elevated Elevated


4. Diagnosis: Differential

• Acute DIC versus severe liver disease

• DIC versus TTP-HUS

• DIC versus fibrinogenolysis

• DIC versus Heparin Induced Thrombocytopenia


5. Treatment

• The underlying disease

• The Underlying disease



•The Underlying disease


5. Treatment: Besides the underlying disease

1. Platelets

2. Plasma

3. Anticoagulants

4. Anticoagulant factor concentrates

5. Antifibrinolytic treatment


5.1 Platelets

• Dont make the decision on laboratory results!

• There is no evidence to support the administration of platelets in non bleeding patients or patients not at high risk of bleeding – Platelets < 50.000 + bleeding OK

– Platelets < 20.000 + non bleeding OK

– Patient at high risk for bleeding/procedure ??

• Dose: 1-2 units / 10kg / day

• Monitor the respons of component therapy


5.2 Plasma

• Dont make the decision on laboratory results! • Bleeding? Risk for bleeding? Procedure? • Dose: 15-30 ml / kg / day (Average male 1.2 – 2.4

liter FFP / day ) – Coagulation factor concentrates

• Small volumes • Lack factor V • Risk for worsening DIC due to activated clotting factors

– Cryoprecipitate as source of fibrinogen (3000 mg) if fibrinogen < 1g/l)

• Monitor the respons of component therapy


5.3 Anticoagulants

• There are no clinical randomised controlled trials proving an improvement in clinically relevant outcomes

• Theoretically and experimentally heparin can at least partly inhibit the activation of coagulation in DIC. (anti factor Xa and thrombin activity)

• VTE prophylaxis with UFH or LMWH has become standard care in patients with DIC

• Tissue Factor Pathway Inhibitor (TFPI), was promising, but no benefit in phase III trial


5.4 Anticoagulant factor concentrates

• Antithrombin concentrate

– Laboratory changes

– No clinical changes

• aPC = Activated Protein C

– Effective in patients with DIC AND Sepsis

– Stop if invasive procedures necessary

– Risk for major bleeding

– Severe thrombocytopenia is a contraindication

• Dose: Continuous infusion 24 µg/kg/h for 4 days


5.5 Antifibrinolytic treatment

• Generally not recommended

• Exception: if primary or secondary hyperfibrinolysis dominates the clinical picture

– Acute Promyelocytic Leukemia

– Prostate cancer

• Dose: lysine analogue, tranexamic acid 1g every 8 hours


References

• Furie B, Furie B.C. Mechanisms of Thrombus Formation N Engl J Med 2008; 359:938-949

• Levi M, Toh CH, Thachil J, Watson HG. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology. Br J Haematol 2009; 145:24.

• Akca, S., Haji-Michael, P., de, M.A., Suter, P., Levi, M. & Vincent, J.L. (2002) Time course of platelet counts in critically ill patients. Critical Care Medicine, 30, 753–756.

• Levi, M. & Ten, C.H. (1999) Disseminated intravascular coagulation. New England Journal of Medicine, 341, 586–592.

• Taylor, F.B., Jr, , Toh, C.H., Hoots, W.K., Wada, H. & Levi, M. (2001) Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Journal of Thrombosis and Haemostasis., 86, 1327–1330. 11/3/2011 Dr. Bert Vandewiele 45

dic - up.ac.za · 11/3/2011 · diagnosis and management of disseminated intravascular coagulation....

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