DIC Epatopatia HIT. Lorenzo ALBERIO. Médecin chef Hématologie générale et Hémostase Service et Laboratoire centrale d Hématologie CHUV, Lausanne

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1 DIC Epatopatia HIT Lorenzo ALBERIO Médecin chef Hématologie générale et Hémostase Service et Laboratoire centrale d Hématologie CHUV, Lausanne

2 Disseminated Intravascular Coagulation

3 Coagulation studies PT (Quick) 23 % aptt 57.8 sec FII:C 92 % FV:C 59 % FVII:C 47 % FX:C 111 % TT Reptilase Fibrinogen D-dimers 59.8 sec no clot 0.20 g/l > ng/ml Legend: PT, prothrombin time; TT, thrombin time Pediatr Emerg Care 2010;26:932

4 DIC : Plasmin degrades FV and FVII FII:C 92 % FV:C 59 % FVII:C 47 % FX:C 111 % (D-dimers)

5 ISTH DIC score Clinical Underlying disorder Indispensable points + Laboratory Platelets 100 G/L 1 50 G/l 2 Prothrombin time < 60% 3 sec prolonged 1 < 45% 6 sec prolonged 2 Fibrinogen 1 g/l 1 Fibrinolysis marker moderate > ng/ml increase 2 (D-dimers) strong > increase ng/ml 3 Overt DIC 5 Thromb Haemost 2001;81:1327

6 Conditions associated with DIC Sepsis and severe infection - e.g. meningococcemia Trauma - e.g. severe head injury Organ destruction - e.g. pancreatitis, brain injury, burns Malignancy - solid tumors, promyelocytic leukaemia Obstetric complications - amniotic fluid embolism, placental abruption, pre-eclampsia Vascular abnormalities - large haemangiomata, vascular aneurysm Severe liver failure Toxic insults - snake bite, recreational drugs Immunological insults - ABO transfusion incompatibility, transplant rejection Purpura fulminans Br J Haematol 2009;145:24

7 Purpura fulminans... is characterized by hemorrhagic skin necrosis It is usually seen in association with: 1) homozygous protein C or S deficiency (neonatal) 2) acquired protein C deficiency (meningococcemia) What about varicella zoster virus?

8 Protein S deficiency in VZV Acquired, transient (1-3 months) auto-antibodies increasing PS clearance How frequent? Antibodies 60% PS deficiency 20% Purpura rare develops 7-10 days after the onset of VZV-infection J Pediatr 1995;127:355

9 DOAC in DIC? A 75-year-old man aortic dissection and thoracic aortic aneurysm, treated conservatively with a stent Chronic DIC: Platelet count 20 G/l ( G/l) Fibrinogen level 0.8 g/l ( g/l) D-dimers 9750 ng/ml (<500 ng/ml) Purpura Rivaroxaban 10 mg/d p.os Ann Intern Med 2014;161:158

10 DOAC in DIC? Ann Intern Med 2014;161:158

11 DIC Diagnosis Aetiology Treatment DOAC ISTH score, FV&FVII << FII&FX DIC is a symptom, not a disease Aetiologic + supportive Chronic DIC (e.g., vascular) Monitor [drug] & efficacy!

12 Liver disease

13 Hemostasis von Willebrand factor (VWF) & Platelets Coagulation factors Endogenous antifibrinolytics ADAMTS13 NO and PGI 2 Endogenous anticoagulants Fibrinolysis Circulation 2011;124:e365

14 Cirrhosis and Coagulation Digestion 2016;93:149

15 Cirrhosis and Coagulation VWF & FVIII Coagulation factors & Platelets (Quick, aptt, fibrinogen) JTH 2011;9:1713

16 Endogenous Thrombin Potential Legend: ETP, Endogenous Thrombion Potential TM, Thrombomodulin (activates protein C) JTH 2011;9:1713

17 Cirrhosis and ETP Gastroenterology 2009;137:2105

18 Cirrhosis and Risk of VTE Thromb Haemost 2017;117:139

19 Digestion 2016;93:149 Cirrhosis with PVT : Anticoagulation Cirrhotic patients with portal vein thrombosis

20 Cirrhosis & Anticoagulation VKA - Baseline INR? - Monitor factors (e.g. II and VII) - D-dimers LMWH - Acquired antithrombin (AT) deficiency! - Monitor anti-xa (test based on patient AT) - D-dimers DOAC -?

21 Cirrhosis & DOAC De Gottardi A et al. Liver Int 2016; Oct 25. doi: /liv

22 Cirrhosis Coagulopathy Procoagulant! Correlates w/ Child stage FVIII & Protein C Anticoagulation DOAC Indicated Tc >50G/l Exclude esophageal varices Possible Clinical study Monitor [drug] & efficacy!

23 DD : DIC versus Liver disease FVIII N/ D-dimers N/

24 Heparin-induced thrombocytopenia

25 HIT : definitions and clinical presentations HIT type I = non immune-mediated, heparin-associated HIT trombocytopenia develops within 4 days from start heparin and is transient (disappears while on heparin) NO thrombotic risk HIT type II = heparin-induced, immune-mediated HIT HIGH thrombotic risk Typical onset: 5-14 days after start heparin Mechanism: de novo anti-pf4/heparin antibodies Rapid-onset: first 24 hours of heparin-treatment Mechanism: circulating anti-pf4/heparin antibodies Requirement: heparin exposure in the preceding 1(-3) months Delayed: Mechanism: 5-40 days after stop heparin de novo and high titre anti-pf4/heparin antibodies

26 HIT pathogenesis 1. Heparin/PF4 2. Heparin/PF4 IgG 3. Tc Activation 4. - Degranulation - Aggregation - Procoagulant 5. Endothel - Procoagulant 6. Coagulation activation N Engl J Med 1995;332:1374

27 HIT is a clinico-pathologic syndrome Clinical clues and Laboratory evidence 4 +1 T Think of (h)it! HIT-Abs Thrombin D-dimers are both necessary for the diagnosis of HIT

28 Clinical clues : 4T score Thrombocytopenia >50% drop of platelet count 0 2 Time 5 10 days after start heparin 0 2 Thrombosis while on heparin 0 2 other causes for Tc penia excluded 0 2 Score 0-3 Score 4-5 Score 6-8 low intermediate high Br J Haematol 2003;121:535

29 Can the 4T score predict HIT? A low 4T score almost excludes HIT A high 4T score cannot diagnose HIT Blood 2012;120:4160 Haematologica 2012;97:89

30 Laboratory evidence Immunoassays ELISA PaGIA-H/PF4 Chemiluminescence (AcuStar) Can rapid immunoassays for anti-pf4/heparin antibodies predict the results of the gold standard functional assays? Functional assays Platelet activation

31 True-positive Rate (Sensitivity) Assessing the the ability to predict a disease B A A : Test result with a 100% NPV (i.e. excludes the disease) C B: Best cut-off C: Test result with a 100% PPV (i.e. predicts the disease) False-positive Rate (1-Specificity) Legend: NPV, Negative Predictive Value PPV, Positive Predictive Value

32 Can the PaGIA predict HiPAT result? A: Titer of 1 B: Titer of 4 C: Titer of 32 Legend: A: Test result with a NPV of 100% C: Test result with a PPV of 100% Haematologica 2012;97:89

33 Comparison : ELISA vs. AcuStar vs. PaGIA PaGIA A: Titer of 1 B: Titer of 4 C: Titer of 16 AcuStar A: 0.12 B: 0.6 C: 3.0 Legend: A: Test result with a NPV of 100% C: Test result with a PPV of 100% Work in progress

34 Rapid diagnosis of HIT: combine clinical pre-test probability with the magnitude of a rapid HIT-immunoassay (AcuStar or PaGIA)

35 HIT treatment principles A. Remove all sources of heparin B. Avoid platelet transfusion C. Postpone Vit. K-Antagonists nn(cave: coumarin necrosis) D. Alternative anticoagulants nn(e.g. Direct IIa Inhibitors) Stop in vivo thrombin generation

36 HIT : Alternative anticoagulants Danaparoid (Orgaran ) Bivalirudin (Angiox ) Argatroban (Argatra ) Chemistry Action Half-life Excretion Monitoring Anti-Xa (spec.) Dose Glycosaminoglycan Hirudin analogue Synthetic Anti-Xa Direct anti-iia Direct anti-iia AT (free + bound) (free + bound) 24 hours ~ min ~ min Renal Proteolysis/Renal Hepatic bolus 2250 U 400 U/h for 4h 300 U/h for 4h U/h TT/Anti-IIa (spec.) TT/Anti-IIa (spec.) 0.06 mg/kg/h 1.0 μg/kg/min

37 Argatroban : starting dose Patients with normal hepatic function - Stable, non-critically ill 1.0 μg/kg/min - Unstable, critically-ill 0.5 μg/kg/min (heart failure, multiple organ dysfunctions) Patients with impaired hepatic function - bilirubin >25.5 μmol/l - ALAT >3x upper norm - Slightly impaired 0.25 μg/kg/min - Severely impaired contraindicated Patients with anasarca Critical Care 2015;19:396 contraindicated (accumulation in 3 rd space ) J Transl Sci 2015;1:37

38 La storia di Igea A 77-year-old woman ER: CT-scan: Lab: Treatment: Follow-up: History: New Dg: dyspnea and cough, hypoxia pulmonary embolism & bilateral DVT Hb 137 g/, Hct 0.40 l/l, Lc 13.1 G/l, Tc 77 G/l ICU, LMWH Tc 35 G/l 3 weeks earlier: pain left lower leg Therapeutic nadroparine for 5 days Duplex & MRI : Backer cysts, no DVT 4T score 7/8 (high) Anti-PF4/heparin abs: AcuStar 128 U/ml Delayed-onset HIT

39 La storia di Igea Argatroban 1.0 μg/kg/min target : [argatroban] (<1.5) μg/ml Despite therapeutic argatroban: multiple arterial thromboembolism with critical ischemia both lower limbs and left upper limb How to proceed?

40 HIT treatment principles (2) Remove the HIT antibodies A. Intravenous immunoglobulins B. Plasma-exchange

41 Plasma-exchange A single plasmapheresis treatment only removes about two-thirds of the HIT antibodies (IgG antibodies are distributed between the extravascular and intravascular spaces) Anesth Analg 2010;110:30 J Cardiothoracic Vasc Anesth 2016;doi.org/ /j.jvca

42 La storia di Igea Argatroban 1.0 μg/kg/min target : [argatroban] (<1.5) μg/ml Despite therapeutic argatroban: multiple arterial thromboembolism with critical ischemia lower limbs bilateral and left upper limb New ttt: Plasma exchange daily for 3 days disappearance of anti-pf4/heparin antibodies normalisation of platelet count Embolectomy Follow-up: Rivaroxaban increasing D-dimer, low [rivaroxaban] Apixaban decraesing D-dimer, therapeutic [apixaban]

43 HIT Pathophysiology Increased in vivo thrombin generation Diagnosis Treatment DOAC Combine clinical probability (4T) with the quantitative result of a rapid IA for anti-pf4/h abs (100% NPV/PPV) Alternative anticoagulant drugs Remove HIT-abs (PEX, IvIg) Possible Sub-acute HIT Monitor [drug] & efficacy!

44 My HIT MD-students Sabine KIMMERLE (MD 2003) Hyunju KIM (MD 2005) Martina TSCHUDI (MD 2009) Lara CHILVER-STAINER (MD 2004) Sabine SCHNEITER (MD 2008) Thomas HOFER (MD 2014) Vanessa NELLEN (MD 2011) Matteo MARCHETTI (work in progress) Niels RITECO (MD 2015)

45 DIC Epatopatia HIT Grazia! Grazie! Merci! Danke! Thank you!