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Xét Nghiệm Đánh Giá Khi Dùng Thuốc Chống Đông Đường Uống Và Đường Tiêm

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Xét Nghiệm Đánh Giá Khi Dùng Thuốc Chống Đông Đường Uống Và Đường Tiêm XÉT NGHIỆM ĐÁNH GIÁ KHI DÙNG THUỐC CHỐNG ĐÔNG ĐƯỜNG UỐNG VÀ ĐƯỜNG TIÊM TS. Trần thị Kiều My Trưởng phòng Đông máu-Khoa Huyết học BV Bạch mai 1 NHẮC LẠI CƠ CHẾ ĐÔNG CẦM MÁU • 3 giai đoạn: • Các thành phần tham - Cầm máu ban đầu gia: - Đông máu huyết tương - Thành mạch - Tiêu sợi huyết - Tiểu cầu - Yếu tố đông máu huyết tương - Hệ thống tiêu sợi huyết - Các yếu tố chống đông sinh lý 2 CẦM MÁU BAN ĐẦU 3 CẦM MÁU BAN ĐẦU CHỨC NĂNG TIỂU CẦU Platelet . Dính . Nhờ glycoprotein (GP) . Thay đổi hình dạng . Từ dạng đĩa thành dạng amip . Phóng thích các chất . ADP, thromboxane A2, vWF . Ngưng tập . Nhờ glycoprotein (GP) 4 CẦM MÁU BAN ĐẦU CHỨC NĂNG TIỂU CẦU ligand receptor . dính vWF GP Ib/IX/V collagen GP Ia/IIa . ngưng tập fibrinogen GP IIb/IIIa 5 Yếu tố Von Willebrand Ngưng tập Dính bám Lớp dưới nội mạc 6 Coagulation cascade Intrinsic system (surface contact) Extrinsic system (tissue damage) XII XIIa Tissue factor XI XIa IX IXa VIIa VII VIII VIIIa X Xa V Va (Prothrombin) II IIa (Thrombin) Fibrinogen Fibrin TIÊU SỢI HUYẾT 8 9 ĐẠI CƯƠNG VỀ THUỐC CHỐNG ĐÔNG VÀ CHỐNG HUYẾT KHỐI • Thuốc chống ngưng tập tiểu cầu • Thuốc chống các yếu tố đông máu huyết tương • Thuốc tiêu sợi huyết và huyết khối • Các chất chống đông không phải là thuốc dùng trong xét nghiệm 10 THUỐC CHỐNG NGƯNG TẬP TIỂU CẦU 11 Thuốc chống ngưng tập tiểu cầu Đường sử Xét nghiệm theo dõi dụng Nhóm thuốc ức chế Glycoprotein IIb/IIIa: TM VerifyNow Abciximab, ROTEM Tirofiban SLTC, Hb, Hct, APTT, Clotting time Eptifibatide, ACT, aPTT, TT, and PT Nhóm ức chế receptor ADP /P2Y12 Uống NTTC, phân tích chức +thienopyridines năng TC bằng PFA, Clopidogrel ROTEM Prasugrel VerifyNow Ticlopidine +nucleotide/nucleoside analogs Cangrelor Elinogrel, TM Ticagrelor TM+uống ƯC ADP Uống Nhóm Prostaglandin analogue (PGI2): Uống NTTC, phân tích chức Beraprost, năng TC bằng PFA, ROTEM Iloprost (Illomedin), Xịt hoặc VerifyNow truyền TM Prostacyclin,Treprostinil 12 Nhóm ức chế COX: Uống NTTC, phân tích Acetylsalicylicacid/Aspirin#Aloxiprin,Carbasalate, chức năng TC bằng calcium, Indobufen, Triflusal PFA, ROTEM VerifyNow Nhóm ức chế Thromboxane: Uống NTTC, phân tích +thromboxane synthase inhibitors chức năng TC bằng Dipyridamole (+Aspirin), Picotamide PFA, ROTEM +receptor antagonist : Terutroban† VerifyNow Nhóm ức chế Phosphodiesterase: Uống NTTC, phân tích Cilostazol, Dipyridamole, Triflusal chức năng TC bằng PFA, ROTEM VerifyNow Nhóm khác: Uống NTTC, phân tích Cloricromen, Ditazole, Vorapaxar chức năng TC bằng PFA, ROTEM VerifyNow 13 THUỐC CHỐNG YẾU TỐ ĐÔNG MÁU HUYẾT TƯƠNG 1. Nhóm thuốc kháng các yếu tố phụ thuộc vitamin K 2. Heparin (UH, LMWH) 3. Nhóm thuốc kháng trực tiếp yếu tố IIa, Xa (đường uống mới-NOACs) 4. Các thuốc khác 14 Development of anticoagulants over the past century Unfractionated heparins: antithrombin-dependent inhibition of FXa & FIIa in 1:1 ratio Vitamin K antagonists: indirectly affect synthesis of multiple Low-molecular weight heparin: indirect/direct clotting factors inhibition of FXa > FIIa (2:1 to 4:1) Direct thrombin inhibitor Indirect factor Xa inhibitors Direct thrombin inhibitor Direct factor Xa inhibitors 1930s 1940s 1980s 1990s 2000s 2010s Parenteral Oral Coagulation cascade Intrinsic system (surface contact) Extrinsic system (tissue damage) XII XIIa Tissue factor XI XIa IX IXa VIIa VII VIII VIIIa X Xa V Va II IIa (Thrombin) Fibrinogen Fibrin Coagulation cascade Intrinsic system (surface contact) Extrinsic system (tissue damage) XII XIIa Tissue factor XI XIa IX IXa VIIa VII VIII VIIIa Activated partial thromboplastin time X Xa (APTT) V Va Targets of heparin II IIa (Thrombin) Fibrinogen Fibrin Coagulation cascade Intrinsic system (surface contact) Extrinsic system (tissue damage) XII XIIa Tissue factor XI XIa IX IXa VIIa VII VIII VIIIa Activated partial thromboplastin time X Xa (APTT) V Va Targets of heparin II IIa Thrombin time (Thrombin) (TT) Fibrinogen Fibrin Coagulation cascade Intrinsic system (surface contact) Extrinsic system (tissue damage) XII XIIa Tissue factor XI XIa IX IXa VIIa VII VIII VIIIa X Xa V Va Vitamin K dependant factors II IIa (Thrombin) Fibrinogen Fibrin Coagulation cascade Intrinsic system (surface contact) Extrinsic system (tissue damage) XII XIIa Tissue factor XI XIa Prothrombin time IX IXa VIIa VII VIII VIIIa X Xa V Va Vitamin K dependant factors II IIa (Thrombin) Fibrinogen Fibrin Xét nghiệm theo dõi thuốc chống đông cổ điển Loại thuốc Yếu tố đích Các test dùng theo dõi và hoặc đánh giá hoạt tính heparin không Anti-thrombin activity • APTT phân đoạn(UH) (and to lesser extent anti- • Anti-Xa FXa, FIXa and FXIa • Thrombin time activity) Kháng Vitamin K Các yếu tố phụ thuộc • PT / INR vitamin K(i.e. II, VII, IX, X) Favaloro EJ, et al. Pathology 2011;43(7):682-692 Coagulation cascade Intrinsic system (surface contact) Extrinsic system (tissue damage) XII XIIa Tissue factor XI XIa IX IXa VIIa VII VIII VIIIa X Xa Main target of LMWH V Va II IIa (Thrombin) Fibrinogen Fibrin Coagulation cascade Intrinsic system (surface contact) Extrinsic system (tissue damage) XII XIIa Tissue factor XI XIa IX IXa VIIa VII VIII VIIIa X Xa V Va II IIa Main target of LMWH (Thrombin) Fibrinogen Fibrin Xét nghiệm theo dõi thuốc chống đông cổ điển Loại thuốc Yếu tố đích Các test dùng theo dõi và hoặc đánh giá hoạt tính heparin không +ATIII (ức chế XIIa, Xia, • APTT phân đoạn(UH) Ixa, Xa, IIa) • Anti-Xa • Thrombin time Kháng Vitamin K Các yếu tố phụ thuộc • PT / INR vitamin K(i.e. II, VII, IX, X) LMWH Ức chế trực tiếp Xa (tác • anti-Xa dụng ức chế thrombin ít) Favaloro EJ, et al. Pathology 2011;43(7):682-692 Xét nghiệm theo dõi thuốc chống đông khác Loại thuốc/đường Yếu tố đích Các test dùng theo dõi và hoặc dùng đánh giá hoạt tính Fondaparinux Ức chế gián tiếp nhưng • Anti-Xa (TDD) chọn lọc FXa qua ATIII Lepirudin (hirudin) Ức chế trực tiếp • APTT (1.5-2.5 x baseline APTT) (TM) thrombin • ECT Bivalirudin Ức chế trực tiếp • ACT (oligopeptide of thrombin hirudin) (TM) Favaloro EJ, et al. Pathology 2011;43(7):682-692 Thuốc kháng đông đường uống mới ( NOACs) Xa Rivaroxaban Apixaban Edoxaban THROMBIN Dabigatran Tests for Dabigatran: Semi- quantitative Normal aPTT = no pharmacologically relevant anticoagulation • median peak level ~2-fold that of control after 150mg BID • ~1.5-fold prolongation at trough expected after 150 mg BID aPTT • ~2–3-fold prolongation at trough → higher bleeding risk May‏ show false prolonged measures in first 2–3 days after surgery May‏ be prolonged by heparin and its derivatives Normal ECT = no pharmacologically relevant anticoagulation ECT 3−4-fold elevation at trough → higher bleeding risk or TT Normal TT = no clinically relevant anticoagulant activity May be prone to substantial interlaboratory variability aPTT = activated partial thromboplastin time, ECT = escarin clotting time, TT = thrombin time Assessment before Surgery & Intervention • Activated partial thromboplastin time (aPTT) • Thrombin time (TT) Pernod G, Albaladejo G, et al. 2013 Pernod G, Albaladejo G, et al. 2013 NOACs : General and specific assays Test Dabigatran Rivaroxaban Apixaban Edoxaban Drug dTT Specific Anti-FXa Anti-FXa Anti-FXa Specific ECT aPTT ↑↑↑ ↑ ↑ ↑ PT ↑ ↑↑ ↑ ↑↑ General TT ↑↑↑↑ - - - Cannot be Cannot be Cannot be Cannot be INR used used used used aPTT = activated partial thromboplastin time; dTT = diluted thrombin time; ECT = ecarin clotting time; INR = international normalized ratio; FXa = coagulation Factor Xa; PT = prothrombin time; Theo dõi đông máu và các xét nghiệm Labo với NOACs • Không đòi hỏi theo dõi điều trị thường quy • Xét nghiệm về các tác dụng của thuốc khi: – Trước mổ hoặc các thủ thuật xâm nhập – Chấn thương – Nghi ngờ quá liều – tương tác thuốc, suy thận – Bệnh nhân có chảy máu • Chảy máu nặng –Tác dụng quá mức của thuốc • Chảy máu do nồng độ thuốc quá cao hay do lý do khác? Khi bệnh nhân chảy máu • Tìm nguyên nhân chảy máu • Kiểm tra đếm tế bào máu, đông máu, chức năng thận, chức năng gan • Thời điểm dùng thuốc cuối cùng - có sự liên quan nào với tác dụng chống đông của NOACs ? • Ngừng ngay loại thuốc NOACs đang dùng. • Xác định vị trí và mức độ chảy máu • Cứu chữa tích cực • Ngăn chặn tác dụng chống đông của thuốc Loại bỏ NOACs • Dùng than hoạt tính • Uống than hoạt tính nếu uống thuốc trong vòng 4 giờ • >99% Dabigatran bị hấp phụ trên in vitro • Lọc máu • Dabigatran có thể lọc được vì nó gắn khá lỏng lẻo với protein huyết tương(∼35%) • Mức độ loại bỏ của thuốc trung bình - 62% sau 2 h và 68% sau 4 h • Rivaroxaban/Apixaban – gắn rất mạnh với albumin, KHÔNG lọc được Am. J. Hematol. 87:S141–S145, 2012 Loại trừ tác dụng của NOACs • Không có thuốc giải độc đặc hiệu cho các loại thuốc này • Huyết tương, HT tươi đông lạnh, tủa lạnh sẽ không ngăn chặn được NOAC vì nó sẽ ức chế ngay thrombin / yếu tố Xa trong chế phẩm truyền vào. • Chất có tiềm năng để ngăn chặn được là yếu tố VIIa tái tổ hợp, phức hợp prothrombin cô đặc (4Factor PCC) , Feiba. • Chưa có nhiều dữ liệu về hướng dẫn điều trị biến chứng chảy máu của thuốc Chất có tiềm năng “ngăn chặn”- phức hợp Prothrombin cô đặc 4 yếu tố • Phức hợp Prothrombin cô đặc (PCCs) thường dùng để điều trị chảy máu do thuốc kháng Vitamin K. • Loại 4 yếu tố - có đủ FII, FVII, FIX và FX • Loại 3 yếu tố - nồng độ FVII rất thấp Rivaroxaban Ở người – Thời gian PT kéo dài đã bị đảo ngược lại và đưa chức năng đông máu trở về bình thường ở những người tình nguyện khỏe mạnh.
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