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Xử Trí Quá Liều Thuốc Chống Đông XỬ TRÍ QUÁ LIỀU THUỐC CHỐNG ĐÔNG TS. Trần thị Kiều My Bộ môn Huyết học Đại học Y Hà nội Khoa Huyết học Bệnh viện Bạch mai TS. Trần thị Kiều My Coagulation cascade TIÊU SỢI HUYẾT 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 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 truyền VerifyNow TM Prostacyclin,Treprostinil 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 chức +thromboxane synthase inhibitors năng TC bằng PFA, Dipyridamole (+Aspirin), Picotamide ROTEM +receptor antagonist : Terutroban† VerifyNow Nhóm ức chế Phosphodiesterase: Uống NTTC, phân tích chức Cilostazol, Dipyridamole, Triflusal năng TC bằng PFA, ROTEM VerifyNow Nhóm khác: Uống NTTC, phân tích chức Cloricromen, Ditazole, Vorapaxar năng TC bằng PFA, ROTEM VerifyNow Dược động học một số thuốc chống đông thường dùng Nhóm Thuốc Đường dùng Thời gian Thời gian bán Đặc tính gắn Cơ quan thải trừ đạt đỉnh thải protein Chống NTTC Aspirin Uống 1-2h 4-6h 80 – 90%, Thận Thận, đường tiêu Clobidogrel Uống 1h 4 – 6h Phần lớn hóa Ticargelor Uống 1-1,5h 2-8h 99,7% Đường tiêu hóa Kháng Vitamin Sintrom Uống 1-3h ( td 8-11h (sau dừng 97% Thận, đường tiêu K sau 36-72h thuốc còn td 2-3 hóa dùng) ngày) Heparin UFH Truyền TM 20-30p 1-6h Gắn tối đa LMWH Tiêm dưới da 3-4h 18-24h Không gắn Thận (Lovenox) NOACs Dabigatran Uống 0,5-2h 12-14h 30% Thận (Pradaxa) Rivaroxaban Uống 2-4h Trẻ: 5-9h 92-95% Thận (Xarelto) Già: 11-13h Xử trí quá liều Nếu lâm sàng BN có chảy máu nghi ngờ do quá liều các thuốc chống ngưng tập tiểu cầu, cần ngưng sử dụng thuốc. Tìm các nguyên nhân khác song song với việc xử trí chảy máu. Khi cần có thể cân nhắc truyền khối tiểu cầu cho bệnh nhân. Nếu bệnh nhân dùng các thuốc tác động lên Glycoprotein IIb-IIIa hay ức chế Thromboxane, có thể dùng yếu tố VIIa tái tổ hợp nếu có chảy máu nặng (liều bolus truyền TM 90 µmg/kg, có thể lặp lại sau 2 – 6h đến khi ngừng chảy máu.). 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-DOACs) 4. Các thuốc khác Development of anticoagulants over the past century Vitamin K antagonist Antidote: Vitamin K, HTTĐL, PCC. Dược động học một số thuốc chống đông thường dùng Nhóm Thuốc Đường dùng Thời gian Thời gian bán Đặc tính gắn Cơ quan thải trừ đạt đỉnh thải protein Chống NTTC Aspirin Uống 1-2h 4-6h 80 – 90%, Thận Thận, đường tiêu Clobidogrel Uống 1h 4 – 6h Phần lớn hóa Ticargelor Uống 1-1,5h 2-8h 99,7% Đường tiêu hóa Kháng Vitamin Sintrom Uống 1-3h ( td 8-11h (sau dừng 97% Thận, đường tiêu K sau 36-72h thuốc còn td 2-3 hóa dùng) ngày) Heparin UFH Truyền TM 20-30p 1-6h Gắn tối đa LMWH Tiêm dưới da 3-4h 18-24h Không gắn Thận (Lovenox) NOACs Dabigatran Uống 0,5-2h 12-14h 30% Thận (Pradaxa) Rivaroxaban Uống 2-4h Trẻ: 5-9h 92-95% Thận (Xarelto) Già: 11-13h Xử trí quá liều o Đối với các chảy máu nguy hiểm đến tính mạng: BN cần nhập viện ngay và sử dụng phức hệ Prothrombin cô đặc (PCC), liều 25 – 50 u/kg 5 mg vitamin K1 truyền tĩnh mạch Yếu tố VIIa tái tổ hợp không được khuyến cáo. Huyết tương tươi đông lạnh được khuyến cáo khi không có các chế phẩm được chỉ định nêu trên. Đối với chảy máu không nguy hiểm đến tính mạng: vitamin K1 truyền tĩnh mạch liều 1 – 3mg. BN không có chảy máu: INR > 5.0: dừng 1,2 liều sau đó lập lại chống đông và giảm liều, tìm nguyên nhân. INR > 8.0: vitamin K1 đường uống 1 – 5mg. Heparin Standard HMWK XII XIIa TF Kallikrein VIIa VII XI XIa AT III (Heparin) IX IXa + VIIIa X Xa + Va Prothrombin Thrombin (IIa) Fibrinogen Fibrin Tỷ lệ anti IIa:Xa=1:1 XIII XIIIa Fibrin ổn định Cơ chế tác động của UFH Antidote: Protamine sunfate (>80%) LMWH HMWK XII XIIa TF Kallikrein VIIa VII XI XIa ATIII (LMWH) IX IXa + VIIIa X Xa + Va Prothrombin Thrombin (IIa) Fibrinogen Fibrin XIII XIIIa Tỷ lệ anti IIa:Xa= 1:2 đến 1:4 Fibrin ổn định Cơ chế tác động của LMWH Antidote: Protamine sulfate (60%) Dược động học một số thuốc chống đông thường dùng Nhóm Thuốc Đường dùng Thời gian Thời gian bán Đặc tính gắn Cơ quan thải trừ đạt đỉnh thải protein Chống NTTC Aspirin Uống 1-2h 4-6h 80 – 90%, Thận Thận, đường tiêu Clobidogrel Uống 1h 4 – 6h Phần lớn hóa Ticargelor Uống 1-1,5h 2-8h 99,7% Đường tiêu hóa Kháng Vitamin Sintrom Uống 1-3h ( td 8-11h (sau dừng 97% Thận, đường tiêu K sau 36-72h thuốc còn td 2-3 hóa dùng) ngày) Heparin UFH Truyền TM 20-30p 1-6h Gắn tối đa LMWH Tiêm dưới da 3-4h 18-24h Không gắn Thận (Lovenox) NOACs Dabigatran Uống 0,5-2h 12-14h 30% Thận (Pradaxa) Rivaroxaban Uống 2-4h Trẻ: 5-9h 92-95% Thận (Xarelto) Già: 11-13h Protamine Sulfate 1mg protamin sulphat có thể trung hoà được 100IU Heparin. Protamin chỉ trung hoà được hiệu lực chống Thrombin nhưng không trung hoà được hiệu lực chống Xa của Heparin. Các liều thông thường được sử dụng theo đường tĩnh mạch ở người lớn là: • 3ml (= 3.000 UAH) protamin nếu sự trung hoà được thực hiện trong vòng 6 giờ đầu kể từ khi tiêm liều Heparin cuối cùng. • 2ml (= 2.000 UAH) protamin nếu sự trung hoà được thực hiện sau 6 giờ đầu kể từ khi tiêm liều Heparin cuối cùng. Có thể sử dụng lặp lại sau mỗi 2 hoặc 3 giờ cho đến 12 giờ sau nếu chưa trung hoà hết toàn bộ lượng Heparin. Thuốc kháng đông đường uống mới ( DOACs) Rivaroxaban Apixaban Edoxaban Thrombin Andexanet Alfa, Dabigatran ciraparantag Idarucizumab DOACs : General and specific assays Rivaroxaba Test Dabigatran Apixaban Edoxaban n Drug dTT. Anti IIa 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 DOACs 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 DOACs? Ngừng ngay loại thuốc DOACs 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 DOACs • 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 4h • Rivaroxaban/Apixaban – gắn rất mạnh với albumin, KHÔNG lọc được Loại trừ tác dụng của DOACs • Antidote tuỳ loại chống đông • Huyết tương, HT tươi đông lạnh, tủa lạnh sẽ không ngăn chặn được DOAC 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. Antidote Dabigatran: Idarucizumab (Praxbind). • Bản chất: Là mảnh Fab từ kháng thể đơn dòng được tìm thấy ở người được điều trị Dabigatran. • Cơ chế: Ức chế hoàn toàn tác dụng của dabigatran in vitro và in vivo • Liều: duy nhất 2,5g/50ml x 2 lọ IV (5g bolus IV). Các thuốc ức chế trực tiếp Xa (Rivaroxaban, Apixaban, Endoxaban): Andexanet Alfa (PRT064445-Andex Xa), Ciraparantag (PER977). Andexanet Alfa • Bản chất: Là protein tái tổ hợp ở dạng bất hoạt của yếu tố Xa • Cơ chế: Có tác dụng gắn vào tất cả các loại chất ức chế yếu tố Xa.
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