DISSEMINATED INTRAVASCULAR COAGULATION

DIC is one condition that always trouble patients and doctor, though its a nightmare for any clinician , its also a potent question in both UG and PG exams. I hope this will help you in answering those questions well.

1. DISSEMINATED INTRAVASCULAR COAGULATION DR AKSHAYA TOMAR , MD IMMUNOHEMATOLOGY AND BLOOD TRANSFUSION AFMC, PUNE

2. INTRODUCTION Clinicopathologic syndrome characterized by:

3. DEFINITION According to International Society on Thrombosis and Haemostasis , - 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

4. HISTORICAL ASPECTS First description in 1950 ,by Walter H Seegers Lecture named “ Factors in the Control of Bleeding ” where he postulated that thromboplastin may be associated with the hemorrhage that are seen with amniotic fluid embolism .

5. HISTORICAL ASPECTS Later Ratnoff , Pritcher and Colopy in an article entitled “ Hemorrhagic States During Pregnancy ” described about the hemorrhagic syndromes of pregnancy now called DIC After a mid-1960s DIC became a clinically accepted and recognized syndrome

6. NORMAL HEMOSTASIS AND FIBRINOLYSIS

7. NORMAL HEMOSTASIS

8. ROLE OF ENDOTHELIUM

9. CELL BASED MODEL OF COAGULATION

10. THROMBIN

11. FIBRINOLYTIC SYSTEM

12. PATHOPHYSIOLOGY

13. PATHOPHYSIOLOGY MASSIVE TISSUE DESTRUCTION SEPSIS ENDOTHELIAL INJURY RELEASE OF TISSUE FACTOR Widespread microvascular thrombosis Platelet aggregation Activation of plasmin FIBRINOLYSIS Proteolysis of clotting factors BLEEDING Consumption of platelets and clotting factors FDP PLATELET AGGREGATION THROMBOSIS FIBRIN POLYMERISATION VASCULAR OCCLUSION

14. CAUSES AND TYPES OF DIC

15. CAUSES OF DIC

16. CAUSES Sepsis    Bacterial   Staphylococci, streptococci, pneumococci , meningococci , gram-negative bacilli   Viral   Mycotic   Parasitic   Rickettsial Trauma and tissue injury    Brain injury (gunshot)    Extensive burns   Fat embolism   Rhabdomyolysis Vascular disorders   Giant hemangiomas (Kasabach-Merrit syndrome)    Large vessel aneurysms (e.g., aorta) Obstetric complications    Abruptio placentae    Amniotic fluid embolism   Dead fetus syndrome   Septic abortion Cancer   Adenocarcinoma (prostate, pancreas, etc)    Hematologic malignancies (acute promyelocytic leukemia) Immunologic disorders    Acute hemolytic transfusion reaction   Organ or tissue transplant rejection   Graft-versus-host disease Drugs   Fibrinolytic agents   Aprotinin   Warfarin (especially in neonates with protein C deficiency)    Prothrombin complex concentrates   Recreational drugs (amphetamines) Envenomation   Snake   Insects Liver disease   Fulminant hepatic failure   Cirrhosis   Fatty liver of pregnancy Miscellaneous   Shock   Respiratory distress syndrome   Massive transfusion

17. CAUSES

18. ACUTE VS CHRONIC DIC ACUTE DIC CHRONIC DIC Due to consumption and inhibition of clotting factors Thrombocytopenia Faster rate of consumption Sudden exposure of massive amount of thromboplastin ex: Abruptio placenta, extensive tissue trauma,meningococcimea Due to overcompensation of clotting factors Thrombocytosis or normal platelets Slower rate of consumption Blood is continuously exposed to small amount of thromboplastin ex: prostate and pancreatic adenocarcinoma , aortic aneurysms

19. CLINICAL FEATURES

20. CLINICAL MANIFESTATION Related to the magnitude of imbalance of hemostasis , to the underlying disease or to both Most common is bleeding ranging from oozing from venipuncture sites,petechiae and ecchymoses Severe hemorrhage from GIT , lung or CNS In chronic DIC , bleeding symptoms are discrete & restricted to skin & mucosal surfaces Microvascular occlusion and resultant organ failure

21. CLINICAL MANIFESTATIONS Bleeding from at least 3 unrelated sites is particularly suggestive of DIC. Patients with pulmonary involvement can present with dyspnea , hemoptysis , and cough . Comorbid liver disease as well as rapid hemolytic bilirubin production may lead to jaundice. Neurologic changes ( eg , coma, obtunded mental status, and paresthesias ) are also possible .

22. SIGNS

23. SIGNS

24. DERMATOLOGICAL SIGNS Hemorrhagic bulla Echymosis Petechiae Acral cyanosis and superficial skin necrosis

25. DIFFERENTIAL DIAGNOSIS

26. DIAGNOSIS AND MANAGEMENT OF DIC

27. INTRODUCTION Clinicopathologic syndrome characterized by:

28. PATHOPHYSIOLOGY MASSIVE TISSUE DESTRUCTION SEPSIS ENDOTHELIAL INJURY RELEASE OF TISSUE FACTOR Widespread microvascular thrombosis Platelet aggregation Activation of plasmin FIBRINOLYSIS Proteolysis of clotting factors BLEEDING Consumption of platelets and clotting factors FDP PLATELET AGGREGATION THROMBOSIS FIBRIN POLYMERISATION VASCULAR OCCLUSION

29. DIAGNOSIS No single test is diagnostic of DIC It is the overall clinical picture supported by some investigations, which should guide the management. Of these tests , thrombocytopenia and hypofibrinogenemia (or a 50% drop in either value) are the most sensitive in making a laboratory diagnosis of DIC.

30. SCORING SYSTEM The International Society on Thrombosis and Haemostasis (ISTH) developed a simple scoring system for the diagnosis of overt DIC that makes use of laboratory tests available in almost all hospital laboratories

31. ISTH CRITERIA FOR DIC

32. IMPORTANCE OF SCORING SYSTEM A score of 5 or higher indicates overt DIC, whereas a score of less than 5 does not rule out DIC but may indicate DIC that is not overt. The sensitivity of the DIC score for a diagnosis of DIC is 91-93%, and the specificity is 97-98%.

33. COMMON LAB FINDINGS Prolongation of PT/ aPTT Thrombocytopenia (often <1lac/µl 3 ) or a rapid decline in platelet number Peripheral blood smear – Schistocytes (fragmented RBC) Increased FDP levels (most sensitive test), DIC is unlikely in presence of normal FDP Elevated D- Dimer

34. SPECIALIZED LAB TESTS Excess thrombin generation - Increased thrombin- antithrombin complexes - Increased fibrinopeptides - Increased prothrombin fragments 1 and 2 Decreased protein C / protein S and antithrombin Increased fibrinolysis - Increase in plasmin - Decreased plasminogen levels - Decrease in α 2 antiplasmin - High levels of plasminogen activators inhibitors

35. SPECIALIZED LAB TESTS Newer markers (signifying thrombosis-inflammation cross-link) - Increased soluble thrombomodulin - Decreased ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13)

36. D- Dimer D- dimers are little chunks of broken up fibrin, like FDPs, but with an important difference: they contain an extra linkage. When fibrin seals up a clot, factor XIII creates cross-links between the fibrin molecules When the fibrin in a clot breaks, some of the resulting fragments will contain these cross-links. These fragments contain one “E” fibrin subunit and two “D” subunits and are called D- dimers .

37. D- Dimer D- dimers are more specific for actual clots than FDPs are – because you only get D- dimers from the breakdown of real clots (not from the breakdown of fibrinogen). Serial monitoring of D- dimer assays are of value in evaluation of response to therapy.

38. MANAGEMENT OF DIC

39. GENERAL CONSIDERATION Morbidity & Mortality is mainly related to underlying disease rather than the complications of DIC. Control or elimination of underlying cause should be the primary concern. Attempts to teat DIC without accompanying treatment of causative disease are likely to fail.

40. Management of hemorrhagic symptoms Marked thrombocytopenia (<10,000/µl 3 ) and PT> 1.5 X Normal require replacement therapy. Low levels of fibrinogen (<100mg/dl) -> Cryoprecipitate 1U/10kg Replacement of 10U of Cryoprecipitate for every 2-3 U of FFP is sufficient to correct hemostasis . Platelet concentrate 1-2U/10kg -> severe thrombocytopenia. Clotting factors conc. are not recommended for control of bleeding in DIC ;limited efficacy

41. Replacement of coagulation and fibrinolysis inhibitors Heparin (5-10U/kg/hr) may be effective in low grade DIC associated with – Solid tumor/Acute Promyelocytic Leukemia/Recognized thrombosis/some cases of purpura fulminans (dead fetus syndrome) In acute DIC, heparin can aggravate bleeding EACA/ Tranaexemic acid may reduce bleeding in DIC and confirmed hyperfibrinolysis , however they can increase the risk of thrombosis & concomitant use of heparin is indicated. Activated protein C concentrate to treat Purpura Fulminans (In Protein C deficiency and meningococcemia) proven efficacious.

42. In the acute coagulopathy of trauma, in which hyperfibrinolysis predominates, antifibrinolytic agents are beneficial for those with persistent bleeding after adequate replacement of fresh frozen plasma . Another clinical situation is massive postpartum hemorrhage, for which fibrinolysis is a prime pathophysiological factor in the coagulopathy and tranexamic acid has been demonstrated to be beneficial.

43. NEW THERAPEUTIC STRATEGIES

44. Activated Protein C In a phase III clinical trial of recombinant APC ( rAPC ) in patients with severe sepsis in a dose of 24 μg /Kg/h over 96 h, significant reduction in 28 day mortality was seen. Most significant complication was bleeding It is recommended in patients with severe sepsis Clinical efficacy of APC in severe sepsis was demonstrated in a Large randomized controlled trial (the protein C worldwide evaluation In severe sepsis [PROWESS] trial), in which its use was Associated with a reduced mortality (24.7%) compared with that of The placebo (30.8%) with highest benefit for those who had DIC.

45. Antithrombin III (AT III) In a large double blind placebo controlled multicentre phase III trial ( Kybersept trial) AT was used in a dose of 30,000 IU over 4 days. There was no difference in mortality between the treatment and the placebo group. More bleeding complications.

46. Tissue factor pathway inhibitor(TFPI) It was tested in a phase III trial in patients with severe sepsis. Tifacogin (TFPI) was given in a dose of .025mg/kg/hr for 96 hrs. There was no effect on mortality and the risk of bleeding was increased.

47. Protease inhibitors Gabexate mesylate is a synthetic inhibitor of serine proteases, including thrombin and plasmin . It seems to be a potentially useful agent In a limited number of patients, the drug (2mg/kg/hr x 7 days) could not inhibit coagulation or fibrinolysis

48. C1- Inhibitor (C1- Inh ) Activation of factor XIa leads to a thrombin burst , therefore inhibition of factor XIa by C1 inhibitor might be beneficial. In a pilot study with limited number of patients C1- Inh was administered to patients with severe sepsis or septic shock Organ dysfunction improved significantly but no effect on mortality was observed due to small number of patients.

49. Synthetic Inhibitors Heparin treatment may be ineffective because it requires antithrombin for anticoagulant activity Direct thrombin inhibitors may be more effective as they do not require antithrombin . Recombinant hirudin reduces thrombin activity in DIC, but clinical benefit has not yet been evaluated. Desirudin and related compounds, might be more effective than heparin, and experimental studies have had promising results.

50. REFERENCES Rossi’s Principles of Transfusion Medicine 5 th edition. Harrison’s principles of Internal medicine 19 th edition Vol 1 Transfusion Therapy: Clinical Principles and Practice 3 rd Edition- Paul D Mintz Colman Basic Principles of Hemostasis and Thrombosis 5 th edition Robin’s Basic Pathology 9 th edition. DIC current concepts by R kumar and V Gupta; Indian journal of pediatrics 2008.

51. Thank you