1. Disseminated Intravascular Coagulation Robert R. Zaid D.O. Genesys Regional Medical Center PGY-I

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3. Disseminated Intravascular Coagulation - Background - Pathophysiology -Etiology -Clinical Manifestations -Diagnosis -Treatment -Xigris Primarily a thrombotic process –Systemic process producing both thrombosis and hemorrhage –Also called consumption coagulopathy and defibrination syndrome 1 –Its clinical manifestation may be widespread hemorrhage in acute, fulminant cases 2. 1. Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179, HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY 2. Uptodote, 2005, www.utdol.com, Clinical feadures, diagnosis and teratment of disseminated intravascular coagulationwww.utdol.com

5. Disseminated Intravascular Coagulation - Background - Pathophysiology -Etiology -Clinical Manifestations -Diagnosis -Treatment -Xigris Basic pathophysiology –Entry into the circulation of procoagulant substances Trigger systemic activation of the coagulation system and platelets Lead to the disseminated deposition of fibrin- platelet thrombi. –Procoagulant stimulus is tissue factor (most cases) Lipoprotein Not normally exposed to blood. –Tissue factor gains access to blood by Tissue injury, Malignant cells, Expression on the surfaces of monocytes and endothelial cells by inflammatory mediators. Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179, HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY

6. Stein B, Fuster V, Israel DH, et al. Platelet inhibitor agents in cardiovascular disease: an update. J Am Coll Cardiol. 1989;14:813–836.

7. Disseminated Intravascular Coagulation - Background - Pathophysiology -Etiology -Clinical Manifestations -Diagnosis -Treatment -Xigris Tissue factor triggers –Thrombin Protease Induces fibrin formation and platelet activation Other procoagulants –Cysteine protease –Mucin –Trypsin Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179, HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY

8. Disseminated Intravascular Coagulation - Background - Pathophysiology -Etiology -Clinical Manifestations -Diagnosis -Treatment -Xigris Acute DIC –Coagulation factors are consumed at a rate in excess of the capacity of the liver to synthesize them, –Platelets are consumed in excess of the capacity of bone marrow megakaryocytes to release them. Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179, HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY

9. Disseminated Intravascular Coagulation - Background - Pathophysiology -Etiology -Clinical Manifestations -Diagnosis -Treatment -Xigris Laboratory manifestations –Prolonged prothrombin time (PT) –Prolonged Activated partial thromboplastin time (aPTT) –Thrombocytopenia. –Increased fibrin formation Stimulates compensatory process of secondary fibrinolysis, Plasminogen activators generate plasmin to digest fibrin (and fibrinogen) into fibrin(ogen) degradation products (FDPs). –FDPs are potent circulating anticoagulants that contribute further to the bleeding manifestations of DIC. Intravascular fibrin deposition can cause fragmentation of red blood cells and lead to the appearance of schistocytes in blood smears Hemolytic anemia is unusual in DIC. Microvascular thrombosis in DIC can compromise the blood supply to some organs and lead to multiorgan failure Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179, HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY

10. Disseminated Intravascular Coagulation - Background - Pathophysiology -Etiology -Clinical Manifestations -Diagnosis -Treatment -Xigris

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12. Disseminated Intravascular Coagulation - Background - Pathophysiology -Etiology -Clinical Manifestations -Diagnosis -Treatment -Xigris DIC always has an underlying etiology –Must be identified and eliminated to treat the coagulopathy successfully. –The development of DIC in many of these disorders is associated with an unfavorable outcome 1. Occurs in 1% of hospitalized patients 2 Mortality rate approaches 40-80% 1. Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179, HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY 2. Uptodote, 2005, www.utdol.com, Clinical feadures, diagnosis and teratment of disseminated intravascular coagulationwww.utdol.com

13. Disseminated Intravascular Coagulation - Background - Pathophysiology -Etiology -Clinical Manifestations -Diagnosis -Treatment -Xigris Causes –Infection Most common cause of DIC. The syndrome particularly is associated with gram-negative or gram-positive sepsis Can be triggered by a variety of other –Bacterial –Fungal –Viral –Rickettsial, and protozoal microorganisms. Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179, HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY

14. Disseminated Intravascular Coagulation - Background - Pathophysiology -Etiology -Clinical Manifestations -Diagnosis -Treatment -Xigris Obstetrics –The placenta and uterine contents are rich sources of Tissue factor Other procoagulants that normally are excluded from the maternal circulation Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179, HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY

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16. Disseminated Intravascular Coagulation - Background - Pathophysiology -Etiology -Clinical Manifestations -Diagnosis -Treatment -Xigris –Clinical manifestations of DIC may accompany obstetric complications, especially in the third trimester. These syndromes range from –Acute, fulminant, and often fatal DIC in amniotic fluid embolism »Blood is exposed to large amounts of tissue factor in a short period of time creating large amounts of thrombin »Multiorgan failure –Chronic or subacute DIC with a retained dead fetus. »Exposure to small amounts of tissue factor Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179, HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY

17. Disseminated Intravascular Coagulation - Background - Pathophysiology -Etiology -Clinical Manifestations -Diagnosis -Treatment -Xigris –Other obstetric problems associated with DIC include Abruptio placentae Toxemia Septic abortion. Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179, HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY

18. Disseminated Intravascular Coagulation - Background - Pathophysiology -Etiology -Clinical Manifestations -Diagnosis -Treatment -Xigris Clinical manifestations –Determined by Nature Intensity Duration of the underlying stimulus. –Chronicity Low-grade DIC is often asymptomatic –Diagnosed only by laboratory abnormalities. –Bleeding is most common clinical finding »Generalized or widespread ecchymoses Chronic disease –Thrombotic complications »Trousseau's syndrome in cancer »Gangrene of the digits or extremities »Hemorrhagic necrosis of the skin »Purpura fulminans –Enhanced by Coexistence of liver disease Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179, HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY

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20. Disseminated Intravascular Coagulation - Background - Pathophysiology -Etiology -Clinical Manifestations -Diagnosis -Treatment -Xigris Diagnosis of severe, acute (easy) –Prolongation of PT, aPTT and Thrombin time Due to consumption and inhibitiion of clotting factors –Thrombocytopenia –Fibrin degradatin products Increased due to secondary fibrinolysis –Measured by latex agglutination or D-dimer assays. –Schistocytes may be seen in the peripheral blood smear Neither sensitive nor specific for DIC. Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179, HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY

21. Disseminated Intravascular Coagulation - Background - Pathophysiology -Etiology -Clinical Manifestations -Diagnosis -Treatment -Xigris Chronic or compensated forms of DIC –Highly variable patterns of abnormalities in "DIC screen" coagulation tests. –Increased FDPs and prolonged PT are generally more sensitive measures than are abnormalities of the aPTT and platelet count. –Overcompensated synthesis of consumed clotting factors and platelets in some chronic forms Cause shortening of the PT and aPTT and/or thrombocytosis Though, elevated levels of FDPs indicate secondary fibrinolysis in such cases. Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179, HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY

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23. Disseminated Intravascular Coagulation - Background - Pathophysiology -Etiology -Clinical Manifestations -Diagnosis -Treatment -Xigris Treatment –Identify underlying cause and treat –All other therapies are temporizing Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179, HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY

24. Disseminated Intravascular Coagulation - Background - Pathophysiology -Etiology -Clinical Manifestations -Diagnosis -Treatment -Xigris Asymptomatic patients with self- limited DIC –Have only laboratory manifestations of the coagulopathy –No treatment may be necessary. Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179, HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY

25. Disseminated Intravascular Coagulation - Background - Pathophysiology -Etiology -Clinical Manifestations -Diagnosis -Treatment -Xigris Actively bleeding or who are at high risk of bleeding, –Blood component treatments of choice Transfusions of platelets –Improve the thrombocytopenia Fresh-frozen plasma (FFP) –Replace all consumed coagulation factors and correct the prolonged PT and aPTT. Large volumes of plasma in severe cases –The theoretical concern that these blood products may "fuel the fire" and exacerbate the DIC has not been supported by clinical experience Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179, HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY

26. Disseminated Intravascular Coagulation - Background - Pathophysiology -Etiology -Clinical Manifestations -Diagnosis -Treatment -Xigris Special cases –Profound hypofibrinogenemia Additional transfusion of cryoprecipitate, Plasma concentrate enriched in fibrinogen –Sepsis Infusion of antithrombin III concentrate may be considered as an adjunctive measure Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179, HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY

27. Disseminated Intravascular Coagulation - Background - Pathophysiology -Etiology -Clinical Manifestations -Diagnosis -Treatment -Xigris Pharmacologic inhibitors of coagulation and fibrinolysis –Heparin –Theoretical benefit It blocks thrombin and the secondary fibrinolysis. Might exacerbate the bleeding tendency –Usually reserved for –Forms manifested by »Thrombosis »Acrocyanosis »Cancer »Vascular malformations »Retained dead fetus »Acute promyelocytic leukemia.

28. Disseminated Intravascular Coagulation - Background - Pathophysiology -Etiology -Clinical Manifestations -Diagnosis -Treatment -Xigris Antifibrinolytic agents, –ε-aminocaproic acid and tranexamic acid –Generally are contraindicated May precipitate thrombosis –May be effective in decreasing life- threatening bleeding

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30. Disseminated Intravascular Coagulation - Background - Pathophysiology -Etiology -Clinical Manifestations -Diagnosis -Treatment -Xigris XIGRIS® (Lilly) Drotrecogin alfa (activated) –Recombinant form of human Activated Protein C

31. Disseminated Intravascular Coagulation - Background - Pathophysiology -Etiology -Clinical Manifestations -Diagnosis -Treatment -Xigris General Pharmacology Activated Protein C –Antithrombotic effect –Inhibits Factors Va and VIIIa. Indirect profibrinolytic activity through its ability to inhibit plasminogen activator inhibitor-1 (PAI-1) Limits generation of activated thrombin- activatable-fibrinolysis-inhibitor. In vitro data indicate that Activated Protein C may exert an anti-inflammatory effect by inhibiting human tumor necrosis factor production by monocytes –Blocks leukocyte adhesion to selectins –Limits the thrombin-induced inflammatory responses within the microvascular endothelium.

32. Disseminated Intravascular Coagulation - Background - Pathophysiology -Etiology -Clinical Manifestations -Diagnosis -Treatment -Xigris Clinical study (PROWESS) –1690 patients with severe sepsis –Entry criteria included a systemic inflammatory response presumed due to infection and at least one associated acute organ dysfunction –The study was terminated after a planned interim analysis due to significantly lower mortality in patients on Xigris than in patients on placebo (210/850, 25% vs. 259/840, 31% p=0.005).

33. Disseminated Intravascular Coagulation - Background - Pathophysiology -Etiology -Clinical Manifestations -Diagnosis -Treatment -Xigris INDICATIONS AND USAGE –Xigris is indicated for the reduction of mortality in adult patients with severe sepsis (sepsis associated with acute organ dysfunction) who have a high risk of death (APACHE II)

34. Disseminated Intravascular Coagulation - Background - Pathophysiology -Etiology -Clinical Manifestations -Diagnosis -Treatment -Xigris Contraindications –Active internal bleeding –Recent (within 3 months) hemorrhagic stroke –Recent (within 2 months) intracranial or intraspinal surgery, or severe head trauma –Trauma with an increased risk of life- threatening bleeding –Presence of an epidural catheter –Intracranial neoplasm or mass lesion or evidence of cerebral herniation

35. Disseminated Intravascular Coagulation - Background - Pathophysiology -Etiology -Clinical Manifestations -Diagnosis -Treatment -Xigris Warnings –Concurrent therapeutic dosing of heparin to treat an active thrombotic or embolic event –Platelet count <30,000 × 10 6 /L, even if the platelet count is increased after transfusions –Prothrombin time-INR >3.0 –Recent (within 6 weeks) gastrointestinal bleeding –Recent administration (within 3 days) of thrombolytic therapy –Recent administration (within 7 days) of oral anticoagulants or glycoprotein IIb/IIIa inhibitors –Recent administration (within 7 days) of aspirin >650 mg per day or other platelet inhibitors –Recent (within 3 months) ischemic stroke –Intracranial arteriovenous malformation or aneurysm –Known bleeding diathesis –Chronic severe hepatic disease –Any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location.

36. Disseminated Intravascular Coagulation - Background - Pathophysiology -Etiology -Clinical Manifestations -Diagnosis -Treatment -Xigris DOSAGE AND ADMINISTRATION –Xigris should be administered intravenously at an infusion rate of 24 µg/kg/hr for a total duration of infusion of 96 hours.

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