Disseminated Intravascular Coagulation

1. Disseminated Intravascular Coagulation Nigel S. Key, MD Professor Division of Hematology/Oncology

2. What Is DIC?

3. DIC: Definition �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�

5. Severe Sepsis: A Complex Clinical Syndrome High mortality rate (28%-50%) Heterogeneous patient population Severe sepsis is a complex and unpredictable clinical syndrome with mortality ranging from 28% to 50%. The mortality increases with the degree of organ dysfunction. Patients presenting with sepsis are a heterogeneous population varying in: Age Gender Infecting organism Comorbidities Genetic background Immune status, etc. Although the severity of sepsis is related to the degree of organ dysfunction, progression is often unpredictable. Although advances in molecular biology, immunology, and hemostasis have significantly contributed to our understanding of the nature of severe sepsis, there are many points that remain to be clarified concerning its etiology and pathogenesis. Severe sepsis can be thought of as a triad of systemic inflammation, coagulation, and impaired fibrinolysis. Angus DC, Linde-Zwirble WT, Lidicker J, et al. Incidence, cost, outcome of severe sepsis in the United States. Crit Care Med. 2001 (In Press). Wheeler AP, Bernard GR. Treating patients with severe sepsis. N Engl J Med. 1999;340:207-14. Zeni F, Freeman B, Nathanson C. Anti-inflammatory therapies to treat sepsis and septic shock: a reassessment. Crit Care Med. 1997;25:1095-100. Severe sepsis is a complex and unpredictable clinical syndrome with mortality ranging from 28% to 50%. The mortality increases with the degree of organ dysfunction. Patients presenting with sepsis are a heterogeneous population varying in: Age Gender Infecting organism Comorbidities Genetic background Immune status, etc. Although the severity of sepsis is related to the degree of organ dysfunction, progression is often unpredictable. Although advances in molecular biology, immunology, and hemostasis have significantly contributed to our understanding of the nature of severe sepsis, there are many points that remain to be clarified concerning its etiology and pathogenesis. Severe sepsis can be thought of as a triad of systemic inflammation, coagulation, and impaired fibrinolysis. Angus DC, Linde-Zwirble WT, Lidicker J, et al. Incidence, cost, outcome of severe sepsis in the United States. Crit Care Med. 2001 (In Press). Wheeler AP, Bernard GR. Treating patients with severe sepsis. N Engl J Med. 1999;340:207-14. Zeni F, Freeman B, Nathanson C. Anti-inflammatory therapies to treat sepsis and septic shock: a reassessment. Crit Care Med. 1997;25:1095-100.

10. Role of Anticoagulation in DIC No clear benefit of heparin demonstrated in any of the handful of RCTs, but� Consider for those patients with documented thromboembolic event acral ischemia purpura fulminans

12. APL: Intracerebral Hemorrhage

13. DIC; Are We Dealing with Apples and Oranges?

14. Mechanisms of Bleeding in DIC Hyper-acute process leading to uncompensated rapid consumption of clotting factors and platelets (e.g. Obstetric causes) Hyper-fibrinolytic bleeding due to ectopic production of plasminoegn activators

15. Hyperfibrinolysis in APL (AML-M3)

16. Therapeutic Effects of ATRA in AML-M3

17. Impact of ATRA on Early Deaths in APL

18. Frequency of Bleeding in DIC Varies with Cause and Presence of Hyperfibrinolysis

19. Role of Blood Products in DIC No randomized trials; not even true consensus guidelines Do not use routine blood product prophylaxis, but�. Consider blood products for those who are actively bleeding or about to undergo an invasive procedure. Goals: platelets >50,000 fibrinogen > 1g/L PT and aPTT as close to normal as possible

20. DIC: Phases Overt DIC Decompensated form Non-overt DIC More subtle hemostatic dysfunction

21. Defining DIC: Relevance Pathogenesis: To define more completely the sequence of events that determines the evolution of biochemical or non-overt DIC to overt DIC Prognostication: To propose targets, based on a more complete understanding of the sequence along this possible continuum, for possible intervention to block progression to overt DIC

22. The Ideal Algorithm for the Diagnosis of DIC Simple ? Based primarily on clinical and global tests of coagulation as well as a screening assay for intravascular soluble fibrin formation Practical ? Detailed understanding of hemostasis biochemistry not required to use the diagnostic paradigm

23. The Ideal Algorithm for the Diagnosis of DIC Flexible ? Diagnosis of DIC (whether overt or non-overt) should be coupled with diagnosis and staging of the underlying disorder based on clinical signs and symptoms (e.g. SIRS) Reliable ? The paradigm (particularly when used with available molecular marker data) authenticates appropriate and timely therapeutic intervention

27. ISTH Non-Overt DIC Score ****

31. Coagulation as an important denominator of outcome in sepsis. NEJM 1999; 341: 586 DIC independent predictor of mortality in sepsis & trauma.Chest 1992; 101: 8 reversing cause does not always ameliorate DIC. BMJ 2003; 327: 974

32. Activated Protein C Improves Survival in Severe Sepsis (The PROWESS Trial)

34. ISTH Overt DIC Score: an Important Predictor of 28-day Mortality in Severe Sepsis in the PROWESS Study*

35. Effect of rhAPC on Mortality by Baseline Overt DIC Status

36. Interpretation The ISTH overt DIC scoring system may identify severe sepsis patients at high risk of death, with a favorable response profile to rhAPC??

38. Influence of DIC (Overt or Non-Overt) on AT Responsiveness in Sepsis (Kybercept Trial)

39. Interpretation High dose AT without concomitant heparin in septic patients with DIC may result in a significant mortality reduction??

40. Conclusions The ISTH �Overt DIC� and �Non-overt DIC� scoring systems provide a new framework for the diagnosis and severity scoring of DIC These templates have been prospectively validated in independent patient populations (both as a tool to define diagnostic scores for DIC, and as a method to demonstrate prognostic associations for overt and non-overt DIC with mortality risk) These scoring systems offer new opportunities for objective assessment of therapeutic interventions in DIC As yet, it is unclear how well the scoring systems perform for all forms of DIC