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2. DisseminatedIntravascular CoagulationD I C Hemostasis and Coagulation Conference Meredith Lann, MD Dec 1, 2005

4. What is DIC? • A syndrome characterized by systemic intravascular activation of coagulation and widespread deposition of fibrin in the circulation leading to overwhelming consumption of coagulation factors • Dx is suggested by clinical presentation, confirmed by laboratory studies • Always secondary to an underlying process

5. Clinical presentation of DIC

6. Conditions associated with DIC • Sepsis/severe infection • Trauma • Organ destruction (eg, severe pancreatitis) • Malignancy (solid tumors, hematologic) • Obstetrical calamities (amniotic fluid embolism, abruptio placentae) • Vascular abnormalities (Kasabach-Merritt Syndrome, large vascular aneurysms • Severe hepatic failure • Severe toxic or immunologic reactions (snake bites, rec drugs, transfusion rxns, transplant rej.)

7. Conditions associated with DIC From Wada H. Disseminated intravascular coagulation. Clinica Chemica Acta 2004 Jun; 344(2): 13-21.

8. Significance of DIC 1% • Constitutes approximately 1% of all hospital admissions in U.S. • Mortality is 40 - 80% (trauma, sepsis, burn) • Independent risk factors for death: age, organ failure, hemostatic abnormalities 80%

9. Scoring Systems for Diagnosis Fujita M, et al. Protein C Inhibitor as an Anti-DIC agent – Mechanism and modification. Current Medicinal Chemistry: Cardiovascular and Hematological Agents. 2004 Mar 2(1): 21-27.

10. Alternative scoring systems • Simple calculation that can be computed quickly at the bedside • Accurate, effective • Minimize lab tests • Provide prognostic value • Account for dynamic nature of evolving disease example: Kinasewitz et al 2005

11. Pathophysiology of clinical manifestations of DIC www.uptodate.com

12. Overt/Acute DIC Easier to diagnose, clear criteria/scoring systems exist Uncompensated state with  levels of hemostatic components Clinical findings: bleeding, oozing, petechiae, purpura. Microthrombosis 60-75% (ARF, resp failure,liver failure, necrotic skin lesions Variations of DIC – Overt

13. Variations of DIC – Non-overt • Non-overt/Chronic DIC • Difficult to dx as no clear criteria • Compensated state that is prone to develop in certain medical conditions such as disseminated malignancy, advanced liver disease, immunologic disorders • Coag studies may be normal • Normal or  clotting factors (esp if APR) • Recommend following SERIAL tests to evaluate the course (progressive, resolving, chronic)

14. Acute v Chronic DIC www.uptodate.com

15. Lab tests in DIC – what do they really mean? •  platelet count - thrombin activation and clearance, destruction, endotoxemia-induced suppression •  D-Dimer - secondary lysis of crosslinked fibrin •  PT, aPTT – reduction of clotting factors •  fibrinogen – thrombin converts to fibrin •  thrombin clotting time – inhibition of fibrin polymerization by FDPs

16. No one single test… • D Dimer is more sensitive than FDPs • High negative predictive value • good screening test • Formerly only +/-, newer quantitative test is more helpful • Monoclonal antibody or ELISA Lehman CM et al.Am J Clin Pathol 2004;122:178-184 www.uptodate.com

17. Pre-DIC • Difficult to dx • Allows for earlier Rx • Sensitive tests: TAT complex, PPIC, SF and D-Dimer • In 2002 ISTH subcommittee proposed global coagulation tests, PC and AT activity, TAT complex levels, aPTT biphasic waveform (but was not adopted)

18. Biphasic Transmittance Waveform in the aPTT Coagulation Assay • Change in light transmittance due to formation of Ca++dependent complex of CRP with VLDL • Indicates greater capacity to generate THROMBIN From Toh CH et al. Blood, Sep 2002; 100: 2522 - 2529.

20. Normal Hemostasis- Thrombogenesis PT APTT http://www.frca.co.uk/images/clotting_cascade.gif

21. Normal Hemostasis - Fibrinolysis http://upload.wikimedia.org

22. Abundant presence of TF or inflammatory mediator Activation of extrinsic pathway leads to TF-FVIIa complex formation Role of sytemic inflammatory mediators Continues down cascade, eventual THROMBIN generation State worsened by consumption of clotting factors, secondary fibrinolysis Derangements of hemostasis in DIC – activation of coagulation

23. Tissue Factor Pathway Inhibitor insufficency - less inhibition of TF/FVIIa complex Antithrombin system ( levels of AT) Consumption by complex formation Degraded by elastases Impaired synthesis Capillary leakage  Protein C system ( levels of PC or  capacity of APC) Enhanced consumption Impaired liver synth. Vascular leakage Activation of cytokine network (TNF-alpha) results in  TM and  free Protein S Derangements at control pathways

24. Impact on anticoagulant mechanisms during sepsis Levi M. Disseminated Intravascular Coagulation: What’s New? Critical Care Clinics 2005 Jul; 21(3): 449 – 467.

25. Changes in secondary fibrinolysis in DIC • Fibrinolysis starts clearly after coagulation is activated • Fibrin deposition/endotoxemia stimulates release of plasminogen activators (tPA) • Leads to PLASMIN generation • Plasmin “chews up” fibrin  FDPs • Suppressed by PAI-1 ( in sepsis)

26. Gram neg sepsis LPS endotoxin initiates an inflammatory reaction Stimulates TLR, interacts with CD14 inc production of NF-kB  levels of CYTOKINES (IL-1, TNF), ELASTASE and CRP Gram pos sepsis Peptidoglycan initiates inflammatory reaction, much like LPS  production of CYTOKINES (IL-1, TNF) as well as TF DIC in sepsis http://www.conceptdraw.com/ http://www.nature.com/

27. Mechanisms for pathogenesis of DIC in sepsis Fujita M et al. Protein C Inhibitor as an Anti-DIC agent – Mechanism and modification. Current Medicinal Chemistry: Cardiovascular and Hematological Agents. 2004 Mar 2(1): 21-27.

28. Low TAT complex (binds, inhibits FIXa, FXa) Prothrombin fragment 1+2 (F1.2) Soluble fibrin monomer APC-PC inhibitor complex TF levels (free, leuk) TFPI-factor complexes TF mRNA Upside: high sens, spec Downside: Expensive, require sophisticated equipment Often have long turnaround time Possible future lab tests – Thrombogenic effects in DIC

29. PAI-1 levels GE-XDP PPIC (also PAP), not as useful as anticipated tPA AT, PC levels (prognostic value) Unfortunately these tests may not be realistic -?Fluctuating course -?tech difficult, more expensive, less sensitive than current tests Possible future lab tests – Fibrinolytic effects of DIC

30. Treatment of DIC • Aggressive treatment for underlying condition • Support with blood products • Follow serial labs • Therapeutic heparin or argatroban (HIT) if risk/ evidence of thrombosis (this is debatable) • Recombinant activated Protein C (both anti-inflammatory and anti-coagulant effects)

31. PROWESS, 2001 Bernard GR, et al. performed RCT – based on premise that suppression of the protein C system may contribute to DIC Phase II RCT - APC in patients with severe sepsis reduced D-Dimer, IL-6 Phase III - stopped early as it showed huge reduction in mortality in the treated patients as(RRR 19.4% (24.7% v 30.8%) -Subgroup analysis showed benefit in virtually all subgroups (age, type, site, disease severity) Clinical Trials - APC

32. Clinical Trials – Antithrombin Previous bench studies showed AT  TF, IL-6 in LPS-stimulated mononuclear cells, HUVECs, WB KYBERSEPT 2001, Warran BL et al. RCT showed high-dose ATIII in patients with severe sepsis resulted in increased mortality (38.9% v 38.7%)

33. Clinical Trials - TFPI OPTIMIST 2003, Abraham E et al. In previous mouse models TFPI appeared to protect against the onset of DIC/sepsis Phase II for recombinant TFPI (tifacogin) supported this Phase III however showed increased mortality (34.2% v 33.9%)

34. Therapies under construction Theoretically the following should work: Rx directed against TF TFPI, inactivated FVIIa, recomb NAPc2 Restoring anticoagulant pathways AT concentrates (animal studies, Kybersept trial) antifibrinolytics – gabexate mesilate, nafamostat mesilate (x-ind) Selectively inhibit granulocyte elastase sivelestat sodium hydrate

35. Summary DIC is a syndrome where widespread thrombosis due to underlying condition leads to consumption of coagulation factors, as well as derangement of various control pathways, puts the patient at risk of clotting complications and/or bleeding diathesis. Treatment aims to improve the causative condition and support the patient. Many people are working towards improvement in diagnosis and treatment of this condition.

36. References • Levi M. Disseminated Intravascular Coagulation: What’s New? Critical Care Clinics 2005 Jul; 21(3): 449 – 467. • Wada H. Disseminated intravascular coagulation, review. Clinica Chemica Acta 2004 Jun; 344(2): 13-21. • Goodnight SH, Hathaway WE. Disorders ofHemostasis and Thrombosis, 2nd ed. Mc-Graw Hill, Inc 2001 • Kinasewitz GT, Zein JG, Lee G, Nazir SA, Taylor FB. Prognostic Value of a simple evolving disseminated intravascular coagulation score in patients with severe sepsis. Critical Care Medicine 2005 Oct; 33(10): 2214-2221. • Lehman CM, Wilson LW, Rodgers GM. Analytic Validation and Clinical Evaluation of the STALIATEST Immunoturbidimetric D-Dimer Assay for the Diagnosis of Disseminated Intravascular Coagulation. Am J Clin Pathol 2004;122:178-184 • Fujita M, Izutani W, Takahashi K. Protein C Inhibitor as an Anti-DIC agent – Mechanism and modification. Current Medicinal Chemistry: Cardiovascular and Hematological Agents 2004 Mar 2(1): 21-27. • Toh CH, Samis J, Downey C et al. Biphasic transmittance waveform in theAPTT coagulation assay is due to the formation of a Ca-dependent complex of C-reactive protein with very-low–density lipoprotein and is a novel marker of impending disseminated intravascular coagulation. Blood, Sep 2002; 100: 2522 - 2529. • DIC, Cause or Consequence of an unfavourable outcome in Sepsis? Summaries from a Satellite Symposium sponsored by bioMerieux at the XIXth Congress of the ISTH. Birmingham, UK, July 2005 • www.uptodate.com, www.biomerieux.com

37. Questions?

38. Thank you.