Heparin-induzierte Thrombozytopenie Wann daran denken? Wie behandlen?

Transcription

1 Heparin-induzierte Thrombozytopenie Wann daran denken? Wie behandlen? Andreas Greinacher S. Felix Institut für Immunologie und Transfusionsmedizin Universitätsmedizin Greifswald Medizinische Klinik der königlichen Universität Greifswald

2 Heparansulfate Heparin PF4 B-L Thrombocytopenia EC Tissue factor Thrombin Thrombosis HIT Greinacher A, Chong BH, Warkentin TE; in Michelson A; Platelets 3rd ed; 2012

3 platelet count (x10 9 /L) Platelet count decrease > 50% and/or new thrombotic complications between day trauma surgery T T T day

4 How to diagnose HIT? HIT in surgical patients

5 Platelets (x 10 9 /L) 400 Platelet fall in first 4 days is USUALLY NOT HIT 300 CPB Pre-Op Day 3 Day 4 Day 5-6 Day 7-8 Day 9-11 Pouplard C et al. Br J Haematol. 2005;128:837-41

6 Platelets (x 10 9 /L) 400 Platelet fall on day 5-10 = HIT unless proven otherwise 300 CPB Pre-Op CPB Day 3 Day 4 Day 5-6 Day 7-8 Day 9-11 Pouplard C et al. Br J Haematol. 2005;128:837-41

7 Constant production of thrombopoietin in the liver (free thrombopoietin) free thrombopoietin Bone marrow megakaryocytopoiesis

8 romiplostim Wang B, et al. Clin Pharmacol Ther. 2004;76:628-38

9 An early fall in platelet counts to 60, ,000/µL until day 4 after major surgery is normal Major surgery resets the clock for the 5-14 day time window

10 Diagnosis - Pretest Probability: the 4 T s Scoring points: A Thrombocytopenia >50% 30-50% nadir 20 G/L nadir G/L <30% nadir 10 G/L B Timing (onset) day 5-10 (d1 if recent heparin) > day 10, or unclear before day 4 C Thrombosis new thrombosis progressive thrombosis None D OTher cause for thrombocytopenia no other cause possible definite 0-3 low score 4-6 medium score 7-8 high score Lo et al. J Thromb Haemost 2006;4:759-65

11 Antigen tests detect IgG, IgM, IgA Functional test detect IgG Optimal is a combination of both tests

12 Number of patients EIA-SRA Relationship N = NOT HIT (SRA <50% release) HIT (SRA >50%) EIA-GTI Warkentin et al. J Thromb Haemost 2008;6:

13 PF4/heparin antigen tests have a high negative predictive value There is no substitute for a functional washed platelet assay to confirm the diagnosis of HIT HIPA test or 14 C-SRA

14 How to diagnose HIT? HIT for the medical expert

15 HIT differs from Classical Antibody Responses Cumulative Percent numeric labels are shown only for IgG IgG IgA IgM Day Greinacher A et al Blood. 2009;113: Warkentin & Kelton. N Engl J Med 2001;344:

16 PF4 binds to bacteria and PF4/H abs enhance phagocytoses bacteria polyanions Krauel K, et al. Blood 2011

17 One antibody specificity recognizes a large HIT is a misdirected host defense variety of bacteria = innate humoral immune defense PF4 MZ B-cell heparin activated platelet anti-pf4/polyanion IgG granulocyte HIT

18 % of events % of events Anti-PF4/heparin Immune Response requires additional signals = UFH = LMWH Major Surgery n = 222 Minor Surgery n = All seroconversions HIPA + EIA IgG IgG ELISA positiv Clinical HIT HIT All seroconversions HIPA + EIA IgG pos HIT Lubenow et al. BLOOD 2010

19 31 year old female admitted with severe head ache. Upper respiratory tract infection that began 10 days earlier. Otherwise healthy, no medications. INR 1.4, aptt 34s, fibrinogen 0.6 g/l, D- dimer >35mg/L (<0.5), platelets 31,000/µL, no bleeding, no signs of infection normal CT head scan (to exclude sinus vein thrombosis). Greinacher A, BLOOD 2014

20 4 g fibrinogen and LMWH thrombosis prophylaxis. Next day: platelet count 15,000/µL New DVT; persistent headache Although HIT seemed implausible, platelet decrease and new thrombosis during LMWH prompted HIT testing Greinacher A, BLOOD 2014

21 Anti-PF4/heparin IgG ELISA strongly positive OD >2.5 HIPA test strongly positive also in the sample without addition of heparin. Pre-LMWH admission sample: same results Immediate start of therapeutic-dose danaparoid anticoagulation she deteriorated neurologically the same day, and massive sinus vein thrombosis associated with intracerebral bleeding was demonstrated by repeat CT imaging.

22 Spontaneous HIT or Autoimmune HIT 10 patients reported in the literature 6 after orthopedic surgery (no heparin) 3 after infection 1 no obvious trigger Warkentin et al. BLOOD 2014 Greinacher BLOOD 2014 HALLMARK: positive HIPA without heparin HIT during fondaparinux, rivaroxaban, dabigatran

23 heparin-dependent HIT danger PF4/heparin complexes on heparin-coated platelets PF4/polyanion complexes PF4/polyanion complexes on bacteria danger (MZ) B-cells high affinity antibodies clustering PF4 PF4 complexes formed by poorly-defined non-heparin triggers Greinacher A, BLOOD 2014 danger danger heparin-independent HIT

24 Platelet-activating anti-pf4/heparin IgG antibodies Heparin treatment Platelet-activating IgG antibodies with heparin without heparin Typical HIT yes 100% acute phase (day 1-5) ~30% Delayed onset HIT 5-14 days before 100% 100% Spontaneous HIT or Autoimmune HIT No (often, infection or major surgery 5-14 days prior) 100% 100%

25 How to treat patients with HIT?

26 heparin anticoagulatory factors procoagulatory factors 1. steady state of haemostasis 2. heparinized patient heparin HIT-related clotting activation HIT-related clotting activation 3. HIT-patient (still on heparin) therapeutic dose danaparoid/fondaparinux/ argatroban 4. HIT-patient heparin stop Protein C deficiency HIT-related clotting activation 5. acute HIT-patient (on compatible anticoagulant) 6. acute HIT-patient avoid early start of VKA

27 Alternative Anticoagulants in HIT Lepirudin Danaparoid Argatroban Fondaparinux Bivalirudin North America, intermittendly in Europe Dabigatran Rivaroxaban Apixaban Edoxaban

28 Monitoring of DTIs Low prothrombin? liver impairment, DIC; pretreatment with vit K antagonists Yes No Monitor by prothrombin independent assay, e.g. ECA test Monitor by aptt x baseline, but not >80s**

29 Platelet count x 10 9 /L Lepirudin infusion rate (mg/h) 400 Coronary bypass surgery (40,000 U heparin) Diluted thrombin time Pulmonary embolism Ischemic necrosis (4 fingers, both feet) Platelet transfusions 4 0 UFH (therapeuticdose) APTT Lepirudin Days after starting heparin Greinacher A and Warkentin TE; Thromb Haemost 2008; 99:

30 Heparin-induced Thrombocytopenia in 2014 HIT still exists Major surgery, cardiac surgery Medical intensive care patients New: Autoimmune HIT/Spontaneous HIT Treatment: argatroban, danaparoid, fondaparinux, bivalirudin, (rivaroxaban, apixaban, dabigatran)

31 T. Thiele T. Bakchoul K. Selleng A. Sümnig K. Althaus S. Czekay University Hospital Greifswald