DIC Bert Vandewiele Fellow Critical Care 23 May 2011
Dissiminated Intravascular Coagulopathie 11/3/2011 Dr. Bert Vandewiele 2
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 11/3/2011 Dr. Bert Vandewiele 3
DIC 1. Pathogenesis 2. Etiology 3. Clinical Features 4. Diagnosis 5. Treatment 11/3/2011 Dr. Bert Vandewiele 4
1. Pathogenesis Acute or chronic Bleeding Trombosis 11/3/2011 Dr. Bert Vandewiele 5
The clotting Cascade Furie B, Furie B.C. Mechanisms of Thrombus Formation N Engl J Med 2008; 359:938-949 11/3/2011 Dr. Bert Vandewiele 6
1. Pathogenesis: trombosis 11/3/2011 Dr. Bert Vandewiele 7
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. 11/3/2011 Dr. Bert Vandewiele 8
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 11/3/2011 Dr. Bert Vandewiele 9
11/3/2011 Dr. Bert Vandewiele 10
1. Pathogenesis 11/3/2011 Dr. Bert Vandewiele 11
1. Pathogenesis: Acute versus chronic DIC Chronic Acute Event Slow activation Event Brisk Explosive Propagation Production procoagulants Liver compensates clotting factors Bone marrow compensates platelets Propagation Depletion of clotting factors Depletion of platelets and fibrinogen FDP interfere with hemostasis effect trombosis Trousseau Syndrome effect Bleeding diathesis Microangiopathic hemolytic anemia 11/3/2011 Dr. Bert Vandewiele 12
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. 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). 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. 11/3/2011 Dr. Bert Vandewiele 13
2.1 Sepsis Incidence 30-50% Gram negative sepsis Meningococcal sepsis (Gram positive sepsis/viral infections) Pathophysiology Tissue Factor Thrombin 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) 11/3/2011 Dr. Bert Vandewiele 14
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 11/3/2011 Dr. Bert Vandewiele 15
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 11/3/2011 Dr. Bert Vandewiele 16
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 11/3/2011 Dr. Bert Vandewiele 17
3. Clinical features Bleeding (64%) Renal Dysfunction (25%) Hepatic dysfunction (19%) Respiratory dysfunction (16%) Shock (14%) Thromboembolism (7%) Central nervous system involvement (2%) 11/3/2011 Dr. Bert Vandewiele 18
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 11/3/2011 Dr. Bert Vandewiele 19
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! 11/3/2011 Dr. Bert Vandewiele 20
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 11/3/2011 Dr. Bert Vandewiele 21
Schistocyte 11/3/2011 Dr. Bert Vandewiele 22
3. Clinical features: hepatic dysfunction Jaundice Increased bilirubin production secondary to hemolysis Due to the underlying disease 11/3/2011 Dr. Bert Vandewiele 23
3. Clinical features: Pulmonary disease Primary due to damage to the pulmonary vascular endothelium As a consequence of the underlying disease. 11/3/2011 Dr. Bert Vandewiele 24
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 11/3/2011 Dr. Bert Vandewiele 25
4. Diagnosis There is no single laboratory test to diagnose DIC! DIC is an extremely dynamic situation! The whole clinical picture +? Laboratory tests 11/3/2011 Dr. Bert Vandewiele 26
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 11/3/2011 Dr. Bert Vandewiele 27
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). 11/3/2011 Dr. Bert Vandewiele 28
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) 11/3/2011 Dr. Bert Vandewiele 29
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) 11/3/2011 Dr. Bert Vandewiele 31
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 11/3/2011 Dr. Bert Vandewiele 32
4.5 Blood film Fragmented Red blood cells Not specific Not sensitive Consider other causes of TMA (thrombotic microangiopathy) 11/3/2011 Dr. Bert Vandewiele 33
4.6 Other markers of haemostasis Natural anticoagulants Antithrombin Protein C Protein S TEG Atypical light transmittance profile on the aptt 11/3/2011 Dr. Bert Vandewiele 34
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. 11/3/2011 Dr. Bert Vandewiele 35
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 11/3/2011 Dr. Bert Vandewiele 36
4. Diagnosis: Differential Acute DIC versus severe liver disease DIC versus TTP-HUS DIC versus fibrinogenolysis DIC versus Heparin Induced Thrombocytopenia 11/3/2011 Dr. Bert Vandewiele 37
5. Treatment The underlying disease The Underlying disease The Underlying disease The Underlying disease The Underlying disease 11/3/2011 Dr. Bert Vandewiele 38
5. Treatment: Besides the underlying disease 1. Platelets 2. Plasma 3. Anticoagulants 4. Anticoagulant factor concentrates 5. Antifibrinolytic treatment 11/3/2011 Dr. Bert Vandewiele 39
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 11/3/2011 Dr. Bert Vandewiele 40
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 11/3/2011 Dr. Bert Vandewiele 41
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 11/3/2011 Dr. Bert Vandewiele 42
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 11/3/2011 Dr. Bert Vandewiele 43
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 11/3/2011 Dr. Bert Vandewiele 44
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