DISSEMINATED INTRAVASCULAR COAGULATION (DIC) Pichika Chantrathammachart MD Division of Hematology, Department of Medicine Ramathibodi Hospital

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1 DISSEMINATED INTRAVASCULAR COAGULATION (DIC) Pichika Chantrathammachart MD Division of Hematology, Department of Medicine Ramathibodi Hospital

2 Disseminated intravascular coagulation (DIC) Disseminated intravascular coagulation (DIC) is a syndrome characterized by Systemic activation of blood coagulation Organ dysfunction Severe bleeding

3 Pathogenesis of DIC

4 DIC : phenotypes APL Ob complications Aortic aneurysm Major surgery, trauma Sepsis

5 Causes of DIC

6 DIC : Diagnosis - Scoring system ISTH overt DIC score Risk assessment : does the patient have an U/D known to be associated with overt DIC? Order global coagulation tests Score global coagulation test results Platelet count : >100 = 0; <100 = 1; <50 = 2 Elevated fibrin related marker (e.g. D-dimers, FDPs) : no increased = 0; moderate increased = 2; strong increased = 3) Prolonged PT : < 3 sec = 0; > 3 but < 6 sec = 1; > 6 sec = 2 Fibrinogen level : > 1 g/l = 0; < 1 g/l = 1 Calculate scores If > 5 : compatible with overt DIC > repeat score daily If < 5 : suggestive (not affirmative) for non-overt DIC > repeat next 1-2 days

7 Comparison of the diagnostic criteria ( 3 DIC scores)

8 JSTH s DIC diagnostic criteria :revised Wada et al. Thrombosis Journal (2017) 15:17

9 DIC : Diagnosis - Laboratory test Coagulation tests (GCT global coagulation tests) PT Platelet count Fibrinogen level Fibrin-related markers (FRMs) e.g. FDP, D-dimer Hemostasis molecular markers (HMMs) Natural anticoagulants : antithrombin, protein C Others e.g ADAMTS13, stm, PAI-1 and vwf Siluble fibrin, TAT, F1+2

10 Wada et al. Journal of Intensive Care 2014, 2:15 Laboratory tests for DIC OF, organ failure type of DIC; BL, bleeding type of DIC; MB, massive bleeding type of DIC; NS, non-symptomatic type of DIC.

11 Treatment of DIC Treatment of the underlying disease Blood transfusion Heparin : UFH, LMWH Anti-Xa agents : Fondaparinux and Danaparoid sodium Synthetic protease inhibitors e.g Gabexate mesilate, Nafamostat Natural protease inhibitor - AT concentrate - Recombinant human thrombomodulin (rhtm) - Recombinant human activated protein C (rhapc) Antifibrinolytic treatment

12 Treatment of the underlying disease : APL Hemostatic changes in APL

13 Treatment of the underlying disease : APL Initiation of therapy with ATRA and/or ATO Upon morphologic or clinical suspect of APL, therapy with ATRA and/or ATO should be started without waiting for genetic confirmation of diagnosis Transfusional supportive care Platelets /L Fibrinogen >1.5 g/l. Strict monitoring of blood count and coagulation profile (every 6 h in highrisk patients) Other hemostatic agents antifibrinolytic, anticoagulant (heparins) and procoagulant (e.g. recombinant activated Factor VII) agents is controversial

14 Treatment of the underlying disease : sepsis Intravascular thrombus formation in sepsis MCP-1, IL-6 Thrombin FVIIa, FXa Thrombin IL-6, IL-8 Iba T et.al. J Thromb Haemost 2017

15 Treatment of sepsis-dic : antithrombin (AT) Physiological anticoagulant, inhibit 80% of the coagulation activity against thrombin and other coagulation factors (FX, IX, VII, XI, and XII) Commonly decreased during sepsis Excessive thrombin generation Increased vascular permeability Degraded acceleration of AT Impaired synthesis of AT in the liver. Interaction between AT and vascular endothelial cells (ECs) Protection of ECs by binding to the glycosaminoglycans, and suppressing capillary leakage. AT binding to the glycosaminoglycans exerts an anti-inflammatory effect in sepsis.

16 Anti-inflammatory effects of antithrombin Toshiaki Iba, Jecko Thachil Int J Hematol (2016) 103:

17 Comparison of survival after the use of AT Iba T et al. Crit Care Sep 15;18(5):497.

18 Treatment of sepsis-dic : thrombomodulin (TM) TM accelerates the thrombin-catalyzed conversion of protein C to activated protein C Inhibits monocyte and macrophage activation Suppresses the production of inflammatory cytokines such as TNF-α and IL-1β Anti-inflammatory effects >>>>

19 Anti-inflammatory effects of thrombomodulin Toshiaki Iba, Jecko Thachil Int J Hematol (2016) 103:

20 rhtm vs. no rhtm: all-cause mortality at days A. RCTs, B. observational studies Yamakawa K et al. J Thromb Haemost 2015; 13:

21 rhtm vs. no rhtm: DIC resolution rate on day 7 A. RCTs, B. observational studies Yamakawa K et al. J Thromb Haemost 2015; 13:

22 Concomitant Versus Individual administration : AT - rhtm Adjusted estimated survival curves according to the types and presence of anticoagulant therapy Concomittant No treatment Umemura Y. et.al. Clin Appl Thromb Hemost Jan 1

23 Treatment of the underlying disease : TIC Trauma-induced coagulopathy Coagulation activation 1. Procoagulants in the systemic circulation 2. Impairment of endogenous anticoagulant activity 3. Thrombin generation in the systemic circulation Hyperfibrino(geno)lysis 1. Acute release of t-pa-induced hyperfibrino(geno)lysis 2. Coagulation activation-induced fibrino(geno)lysis Consumption coagulopathy Ayakawa et al. Journal of Intensive Care (2017) 5:14

24 Procoagulants circulating in the systemic circulation Thrombin generation (TG) Control vs trauma Spontaneous TG Ayakawa et al. Journal of Intensive Care (2017) 5:14

25 Treatment of the underlying disease : TIC Trauma-induced coagulopathy Coagulation activation 1. Procoagulants in the systemic circulation 2. Impairment of endogenous anticoagulant activity 3. Thrombin generation in the systemic circulation Hyperfibrino(geno)lysis 1. Acute release of t-pa-induced hyperfibrino(geno)lysis 2. Coagulation activation-induced fibrino(geno)lysis Consumption coagulopathy Plasma PAI activity has not yet increased enough Non-suppressed fibrino(geno)lysis consumes α2-plasmin inhibitor > accelerates the dysregulation of fibrino(geno)lysis Ayakawa et al. Journal of Intensive Care (2017) 5:14

26 Treatment of the underlying disease : TIC Trauma-induced coagulopathy ayakawa Journal of Intensive Care (2017) 5:14

27 Treatment summary of DIC in 4 types of DIC Wada et al. Journal of Intensive Care 2014, 2:15

28 Blood products In DIC patients with active bleeding at high risk of bleeding requiring invasive procedures Threshold : depends on clinical state e.g. Platelet count < /L : active bleeding patients Platelet count /L : non-bleeding patients Other blood products FFP Cryoprecipitate

29 Heparin (UFH, LMWH) No RCTs demonstrating that the use of heparin in patients with DIC results in improvements in clinically relevant outcomes. Not recommended in bleeding type of DIC > Recommended in nonsyptomatic patients for VTE prophylaxis

30 Conclusions DIC is clinical syndrome * not disease Treatment Mainly treat underlying disease Supportive treatment : depends on clinical menifestations e.g. Bleeding, organ failure Transfusion support : patients with active bleeding high risk of bleeding require invasive procedure Treatment vs disease-specific