Hematologic Aspects of Cardiac Surgery 마취통증의학과 R3 임 태 완

1. Hematologic Aspects of Cardiac Surgery 마취통증의학과 R3 임 태 완

2. Introduction(1) 심장수술환자에서의 hematologic management - complex balance between extreme degrees of anticoagulation & restoration of normal hemostasis after the procedure : preop. disease state, op. duration, CPB use, desired hemostasis 에 따라 careful management 필요 CPB 중의 최적 anticoagulation - minimized coagulation PLT kept quiescent → extracorporeal circuit에 microvascular clot이 형성되지 않도록 preop. Frequent heparin use - heparin resistance, heparin-induced thrombocytopenia유발 → alternative anticoagulation agents 필요성 제기

3. Introduction(2) CPB후에, coagulation abnor., PLT dysfunction, fibrinolysis발생 : hemostatically impaired, hemostasis monitoring 필요 fibrinolysis –antifibrinolytic Tx사용하여 막을 수 있음 uncontrolled hemorrhage –activated Factor VII사용 off-pump cardiac surgery : coagulation & inflamm.의 activation이 early postop. Period에 발생 hypercoagulation potential 최소화 필요 anti-thrombotic medication & anti-PLT medication : 심혈관계 환자에서 수술전, 수술후 사용 bleeding related Cx , bleeding 증가

4. Biocompatibility(1) CPB circuit의 bio-incompatibility pump & cardiotomy suction에 의한 blood trauma → homeostatic systems disruption 초래 Major three homeostatic systems affected : coagulation, fibrinolysis, inflamm. Cascade 이들 cascade 활성화를 감소시키면 morbidity감소, outcome 개선 coated circuit with heparin or others – inflammatory response to CPB ↓ WBC & Complement activation 의 marker 감소 atrial fibrillation 발생 감소 cf) overt improvement in outcome – marker와 연관성 찾기 힘듬

5. Biocompatibility(2) cardiotomy suction - blood cell 에 traumatic effect suction 사용 안하면, PLT function protection, inflamm. Marker ↓ cf) neurologic outcome – cerebral embolic phenomenon 감소, but not definitely improved thrombin activation during CPB - thrombin 활성화시, anticoagulant protease 분비되고 fibrin cross-linkage, fibrinolysis, PLT 활성화 일어남 : thrombin activation prevention이 CPB 관리의 주요 목적이 됨 heparin alone use - thrombin deactivation하는데 inadequate

6. Heparin resistance preop. Heparin Tx받는 환자 : 일정 level의 anticoagulation 위해 larger dose heparin 필요 → heparin resistance d/t def. In the level or activity of antithrombin III d/t enhanced factor VIII activity and PLT activation : lead to a decrease in ACT response to heparin Montes & Levy : in vitro addtion of antithrombin III → enhance ACT response to heparin Lemmer : ACT로 측정시, heparin resistance는 preop. ATIII level와 no correlation cf) ATIII concentrate – ATIII def. 환자 치료에 사용중

7. Heparin induced thrombocytopenia(1) HIT - heparin 투여환자 5 – 28 %에서 발생 HIT type I : PLT count mild decrease proaggregatory effect of heparin on PLT 가 원인 HIT type II : more severe form heparin 투여 5일이상후에 발생(평균9일후 onset) heparin과 PLT factor 4(PF4)간에 형성된 complex에 결합하는 Antibody에 의해 mediation associated immune-mediated endothelial inj.와 complement activation이 PLT clot(white clot) 형성 thrombotic Cx 20% , mortality rate 40%

8. Heparin induced thrombocytopenia(2) HIT type II Dx – heparin-induced proaggregation of PLT 입증 입증방법 예 : heparin-induced serotonin release assay specific heparin-induced PLT activation assay highly specific enz.-linked immunoassay for the heparin/PF4 complex risk & course of HIT type II –unclear 이유 : HIT type II에서, Ab가 heparin DC후 종종 수주간 undetectable heparin 계속 써도 항상 생기지는 않고 연용해도 저절로 없어짐 많은 환자가 결코 + lab에도 불구, DIC나 thrombosis가 안생김 따라서, HIT는 preop. Heparin Tx받는 환자에서 intraop. Heparin resistance의 DDx로 고려해야 함

9. Heparin induced thrombocytopenia(3) HIT Tx –몇 주간 heparin DC some types of LMWH prostacyclin, iloprost, ASA, ASA+dipridamole : PLT 억제 plasmapheresis : Ab 제거 hirudin / bivalirudin으로 anticoagulation

10. Hirudin : isolated from the salivary gl. Of the medicinal leech potent inhibitor of thrombin ATIII 와는 무관하게 작용 clot-bound thrombin & fluid-phase thrombin 억제 cofactor 불필요. Not susceptible to neutralization by PF4 PLT activation & thrombosis가 disease hallmark인 환자에서 유용 kidney elimination easily hemo-filtered at the end of CPB R-hirudin - 0.25 mg/kg bolus & infusion to maintain hirudin conc. At 2.5 mcg/ml by ecarin clotting time I

11. Bivalirudin(1) : small 20-A.A. molecule with plasma half-life of 24 mins synthetic derivatives of hirudin direct thrombin inhibitor binds to both catalytic binding site and the anion-binding exosite on fluid phase and clot-bound thrombin thrombin에 결합하는 분자는 thrombin에 의해 cleavage 용도 –interventional cardiology에서 heparin 대용 heparin + PLT inhibitor와 비교시, less bleeding & equivalent ischemic outcome → d/t anti-thrombin anticoagulant & anti-thrombin at the level of the PLT

12. Bivalirudin(2) e.g. Merry et al in off-pump cardiac surgery, 0.75 mg/kg bolus, 1.75 mg/kg/hr infusion same bleeding outcome improvement in graft flow after off-pump op monitoring –ecarin clotting time : ACT보다 anti-Iia activity & plasma drug level과 더 연관성

13. Anti-Platelet Therapies(1) glycoprot. IIbIIIa(GPIIbIIIa) receptor : mediating PLT-PLT aggregation via fibrinogen bridging GPIIbIIIa receptor 억제제 : Abciximab(ReoproⓇ), Eptifibatide(IntegrilinⓇ), Tirofiban(AggrastatⓇ) interventional cardiology에서 thrombus formation 막는데 사용 percutaneous angioplasty & stent 에서 re-thrmobosis, infarction rate 감소 Abciximab – large monoclonal Ab GPIIbIIIa receptor에 결합해 permanent dysfunction유발 prolonged op.time to achieve hemostasis increased incidence of PLT transfusion Eptifibatide, Tirofiban– small molecule competitive blocker, half-life 2hr bleeding risk 증가 없음, MI rate 감소 예 보고

14. Anti-Platelet Therapies(2) thienopyridine derivatives : ticlopidine and clopidogrel(PlavixⓇ, Sanofi) non-competitive antagonism at one of the PLT ADP receptor, P2Y12 receptor cf) ADP receptor subtype P2X – Ca channel P2Y1 – Ca influx and subsequent aggregation 조절 P2Y12 – cAMP 생산 억제, PLT aggregation 강화 anti-PLT activity duration– P2Y12 receptor이 영구변화되므로 PLT life span이 됨 Plavix + ASA –synergistic, excessive postop. Bleeding 가능 → 수혈 증가, 출혈로 인한 재수술 증가 Monitoring – PLT function monitoring

15. Platelet function monitoring : Thromboelastography, Hemostatus(Medtronic, MN) Platelet Function Analyzer, UltegraⓇ, Clot Signature Analyzer – high negative predictive value not specific when positive for PLT dysfunction Ultegra : GPIIaIIIb inhibitor 효과 측정시, accurate, specific Antifibrinolytic therapy aminocaproic acid(EACA), tranexamic acid, aprotinin - CPB후 수혈요구량 & bleeding 감소 d/t fibrinolysis inhibition & direct inhibition of plasmin’s anti PLT effects microvascular bleeding 발생위험높은 환자에서 효과 두드러짐 cf) Aprotinin –효과 좋으나 cost-benefit analysis 필요

17. Recombinant activated factor VII recombinant activated factor VII(Novo Seven, Novo Nordisk) - effective for restoring hemostasis from severe hemorrhagic Cx after CPB 처음엔 hemophilia A 치료용으로 도입 기전 – 1.locally expressed tissue factor에 결합해 bleeding site에 직접 작용함 → factor X(common pathway) 활성화 → factor IX(intrinsic pathway) 활성화 → thrombin 생산 증가(systemic activation of coagulation 없이) : hypercoagulability, thrombotic event 드문이유 2.tissue factor와 무관하게 PLT function enhancement cf) severe uncontrolled bleeding의 경우, 다른 방법이 다 실패했을때 Novo Seven이 효과적이라는 보고가 있음