🫀 Interná medicína · 62

Antikoagulačná a antiagregačná liečba

Definícia

• Antikoagulačná liečba tlmí zrážanie krvi pôsobením na koagulačné faktory (patria sem napr. heparíny, fondaparinux, perorálne inhibítory faktora Xa, inhibítory trombínu a warfarín). Antiagregačná liečba tlmí funkciu trombocytov (patria sem napr. kyselina acetylsalicylová, klopidogrel, prasugrel, tikagrelor a inhibítory GP IIb/IIIa).

Etiológia a patogenéza

• Warfarín (antagonista vitamínu K) inhibuje vitamín K epoxid reduktázu (VKORC1), a tým znižuje pečeňovú syntézu na vitamíne K závislých koagulačných faktorov II, VII, IX a X a proteínov C a S.
• Nefrakcionovaný heparín (NFH) aj nízkomolekulový heparín (LMWH) katalyzujú účinok antitrombínu: NFH inhibuje faktor Xa aj trombín, LMWH najmä faktor Xa (v menšej miere trombín); parenterálny fondaparinux inhibuje iba faktor Xa.
• Priame perorálne antikoagulanciá (DOAC) zahŕňajú perorálne inhibítory faktora Xa (napr. apixabán, edoxabán, rivaroxabán) a priamy inhibítor trombínu dabigatran-etexilát.
• Kyselina acetylsalicylová (ASA) ireverzibilne inhibuje COX-1, a tým syntézu tromboxánu A2 v trombocytoch; klopidogrel je prodrug (aktivácia cez CYP, napr. CYP2C19), ktorý ireverzibilne blokuje trombocytový receptor P2Y12 pre ADP.

Klinický obraz

• Fibrilácia predsiení (FP): perorálna antikoagulácia sa odporúča pri klinickej FP so zvýšeným tromboembolickým rizikom; indikátorom je skóre CHA2DS2-VA ≥ 2 (pri skóre 1 sa má zvážiť).
• FP: DOAC sa odporúčajú prednostne pred antagonistami vitamínu K, okrem pacientov s mechanickými chlopňami alebo so stredne ťažkou až ťažkou mitrálnou stenózou – u nich sa DOAC ako skupine treba vyhnúť.
• FP: antiagregačná liečba sa neodporúča ako alternatíva antikoagulácie na prevenciu ischemickej cievnej mozgovej príhody.
• Akútny koronárny syndróm (AKS) bez indikácie antikoagulácie: predvolenou stratégiou je 12-mesačná duálna antiagregačná liečba (DAPT) – ASA s inhibítorom P2Y12 (prednostne prasugrel alebo tikagrelor), ak nie je vysoké riziko krvácania; klopidogrel, ak prasugrel a tikagrelor nie sú dostupné, nie sú tolerované alebo sú kontraindikované (zvážiť ho možno aj u starších pacientov).

Diagnostika

• Warfarín: dávka sa titruje podľa INR; cieľové INR pri FP aj pri liečbe hlbokej venóznej trombózy je 2,0–3,0.
• NFH: monitorovanie pomocou aPTT (príp. ACT); anti-Xa aktivita sa používa napr. u pacientov, u ktorých je monitorovanie aPTT nespoľahlivé.
• LMWH: monitorovanie globálnymi koagulačnými testami nie je spoľahlivé (LMWH ich výrazne nepredlžujú); odpoveď na dávku je predvídateľná.
• FP na warfaríne: ak sa nedarí udržať dostatočný čas v terapeutickom rozmedzí (TTR < 70 %), odporúča sa u vhodných pacientov prechod na DOAC.

Liečba

• Venózny tromboembolizmus (VTE): apixabán a rivaroxabán možno nasadiť ako monoterapiu hneď po diagnóze; prechod na edoxabán alebo dabigatran vyžaduje najmenej 5 dní liečby LMWH.
• Hlboká venózna trombóza v gravidite: LMWH je liečbou prvej línie; warfarín prechádza placentou a je možnosťou liečby hlbokej venóznej trombózy u pacientov, ktorí nie sú gravidní.
• FP: pridanie antiagregačnej liečby k perorálnej antikoagulácii sa na prevenciu ischemickej cievnej mozgovej príhody neodporúča.
• Podozrenie na HIT (trombocytopénia s novou trombózou alebo pokles trombocytov o > 50 %): ihneď vysadiť všetky formy heparínu a nasadiť neheparínové antikoagulans (napr. argatroban, bivalirudín, apixabán, rivaroxabán, fondaparinux); LMWH nepoužiť (skrížená reaktivita protilátok), warfarín nasadiť až po úprave počtu trombocytov.

Komplikácie a prognóza

• Krvácanie je najčastejšou komplikáciou antikoagulancií; pri aktívnom krvácaní u pacienta s FP sa odporúča prerušiť antikoaguláciu a hľadať a riešiť príčinu krvácania.
• Zvrátenie účinku: heparíny – protamín (účinnejší pri NFH, LMWH neutralizuje len čiastočne); warfarín – vitamín K, pri závažnom krvácaní koncentrát protrombínového komplexu (PCC), mrazenú plazmu možno použiť, ak PCC nie je dostupný.
• DOAC: pri život ohrozujúcom krvácaní alebo krvácaní do kritickej lokality zvážiť špecifické antidotum, napr. idarucizumab pri dabigatrane.
• Heparínom indukovaná trombocytopénia (HIT) typu II: imunitne podmienená reakcia (protilátky proti komplexu heparín–PF4), zvyčajne po 5–14 dňoch podávania heparínu (pri expozícii v posledných 100 dňoch aj od 1. dňa); namiesto krvácania skôr paradoxné artériové a venózne trombózy; častejšia pri NFH ako pri LMWH.

Kľúčové pojmy

antikoagulanciá	anticoagulantia
antiagreganciá	antiaggregantia
antagonista vitamínu K (warfarín)	antagonista vitamini K
nefrakcionovaný heparín	heparinum
nízkomolekulový heparín
priame perorálne antikoagulanciá (DOAC)
kyselina acetylsalicylová	acidum acetylsalicylicum
duálna antiagregačná liečba (DAPT)
medzinárodný normalizovaný pomer (INR)
fibrilácia predsiení	fibrillatio atriorum
heparínom indukovaná trombocytopénia
protamín	protaminum

📎 Zdroje:

MSD Manual Professional: Medications for Deep Venous Thrombosis (Anticoagulants – rozdelenie)Low molecular weight heparins (LMWHs) Unfractionated heparin (UFH) Factor Xa inhibitors: oral (eg, rivaroxaban, apixaban, edoxaban) and parenteral (fondaparinux) Direct thrombin inhibitors: oral (dabigatran etexilate) and parenteral (argatroban, bivalirudin, desirudin) Warfarin
MSD Manual Professional: Medications for Acute Coronary Syndromes (Antiplatelet Agents)Aspirin, clopidogrel, prasugrel, ticagrelor, and glycoprotein (GP) IIb/IIIa inhibitors are examples of antiplatelet agents.
Warfarin - StatPearls - NCBI Bookshelf (Mechanism of Action)Warfarin competitively inhibits the vitamin K epoxide reductase complex subunit 1 (VKORC1), an enzyme essential for activating available vitamin K.
Warfarin - StatPearls - NCBI Bookshelf (Mechanism of Action – faktory)The hepatic synthesis of coagulation factors II, VII, IX, and X, as well as coagulation regulator proteins C and S, requires vitamin K.
MSD Manual Professional: Medications for Deep Venous Thrombosis (heparíny a fondaparinux – mechanizmus)However, there are also parenteral agents that inhibit both factor Xa and thrombin (unfractionated heparin), that inhibit mainly factor Xa (LMWH), or that inhibit only factor Xa (fondaparinux).
MSD Manual Professional: Medications for Deep Venous Thrombosis (LMWH – antitrombín)Like UFH, LMWHs catalyze the action of antithrombin (which inhibits coagulation factor proteases), leading to inactivation of coagulation factor Xa and, to a lesser degree, factor IIa.
MSD Manual Professional: Medications for Deep Venous Thrombosis (DOAC)Oral factor Xa inhibitors and direct thrombin inhibitors are sometimes referred to as direct oral anticoagulants (DOACs).
Aspirin - StatPearls - NCBI Bookshelf (Mechanism of Action – COX-1)Aspirin irreversibly inhibits cyclooxygenase-1 (COX-1), abolishing its cyclooxygenase activity
Aspirin - StatPearls - NCBI Bookshelf (Mechanism of Action)This mechanism also results in irreversible inhibition of thromboxane A2 synthesis in platelets, thereby preventing platelet aggregation.
Clopidogrel - StatPearls - NCBI Bookshelf (Mechanism of Action)Clopidogrel is an irreversible inhibitor of the platelet P2Y12 adenosine diphosphate receptor.
Clopidogrel - StatPearls - NCBI Bookshelf (Mechanism of Action – prodrug)Clopidogrel is an inactive prodrug that requires enzymatic activation via various CYP enzymes, including the CYP2C19 and CYP3A4 enzymes, through a 2-step bioactivation process.
2024 ESC Guidelines for the management of atrial fibrillation (Eur Heart J 2024;45:3314–3414, PDF) (Recommendation Table 6)Oral anticoagulation is recommended in patients with clinical AF at elevated thromboembolic risk to prevent ischaemic stroke and
2024 ESC Guidelines for the management of atrial fibrillation (Eur Heart J 2024;45:3314–3414, PDF) (Recommendation Table 6 – CHA2DS2-VA ≥ 2)A CHA2DS2-VA score of 2 or more is recommended as an indicator of elevated thromboembolic risk for decisions on initiating oral
2024 ESC Guidelines for the management of atrial fibrillation (Eur Heart J 2024;45:3314–3414, PDF) (Recommendation Table 6 – CHA2DS2-VA = 1)A CHA2DS2-VA score of 1 should be considered an indicator of elevated thromboembolic risk for decisions on initiating oral
2024 ESC Guidelines for the management of atrial fibrillation (Eur Heart J 2024;45:3314–3414, PDF) (Recommendation Table 7 – DOAC vs. VKA)Direct oral anticoagulants are recommended in preference to VKAs to prevent ischaemic stroke and thromboembolism, except in patients
2024 ESC Guidelines for the management of atrial fibrillation (Eur Heart J 2024;45:3314–3414, PDF) (Recommendation Table 7 – výnimky)with mechanical heart valves or moderate-to-severe mitral stenosis.
2024 ESC Guidelines for the management of atrial fibrillation (Eur Heart J 2024;45:3314–3414, PDF) (6.2.1 – DOAC pri chlopňových chybách)Direct oral anticoagulants as a class should be avoided in specific pa
2024 ESC Guidelines for the management of atrial fibrillation (Eur Heart J 2024;45:3314–3414, PDF) (6.2.1 – DOAC pri chlopňových chybách, pokračovanie)tient groups, such as those with mechanical heart valves or
2024 ESC Guidelines for the management of atrial fibrillation (Eur Heart J 2024;45:3314–3414, PDF) (Recommendation Table 6 – antiagreganciá nie ako alternatíva)Antiplatelet therapy is not recommended as an alternative to anticoagulation in patients with AF to prevent ischaemic stroke and
2023 ESC Guidelines for the management of acute coronary syndromes (Eur Heart J 2023;44:3720–3826, PDF) (6.3.3 – predvolená DAPT)Twelve-month DAPT (preferably
2023 ESC Guidelines for the management of acute coronary syndromes (Eur Heart J 2023;44:3720–3826, PDF) (6.3.3 – predvolená DAPT, pokračovanie)with prasugrel or ticagrelor) remains the default strategy for patients
2023 ESC Guidelines for the management of acute coronary syndromes (Eur Heart J 2023;44:3720–3826, PDF) (Recommendation Table 5 – P2Y12 inhibítor 12 mesiacov)oral LD followed by an MD for 12 months unless
2023 ESC Guidelines for the management of acute coronary syndromes (Eur Heart J 2023;44:3720–3826, PDF) (Recommendation Table 5 – výnimka HBR)there is HBRc
2023 ESC Guidelines for the management of acute coronary syndromes (Eur Heart J 2023;44:3720–3826, PDF) (Figure 10 – klopidogrel)Clopidogrel is recommended for 12 months DAPT if prasugrel and ticagrelor are not available, cannot be tolerated, or are contraindicated, and may be considered in older ACS patients (typically defined as older than 70–80 years of age)
2024 ESC Guidelines for the management of atrial fibrillation (Eur Heart J 2024;45:3314–3414, PDF) (Recommendation Table 7 – cieľové INR)A target INR of 2.0–3.0 is recommended for patients with AF prescribed a VKA for stroke prevention to ensure safety and effectiveness.
MSD Manual Professional: Medications for Deep Venous Thrombosis (Warfarin – INR)Therapeutic goal is an international normalized ratio (INR) of 2.0 to 3.0 (1). INR is monitored weekly for the first 1 to 2 months of warfarin treatment and monthly thereafter; the dose is adjusted to maintain the INR within this range.
Heparin - StatPearls - NCBI Bookshelf (Monitoring)Therapeutic monitoring of heparin involves measuring aPTT and ACT, both of which are prolonged with therapeutic doses of heparin.
Heparin - StatPearls - NCBI Bookshelf (Monitoring – anti-Xa)Another form of monitoring involves measuring anti–factor Xa activity levels, with therapeutic levels considered to be between 0.3 and 0.7 international units per milliliter. This method is often reserved for patients in whom aPTT monitoring is unreliable
MSD Manual Professional: Medications for Deep Venous Thrombosis (LMWH – monitorovanie)Monitoring is not reliable because LMWHs do not significantly prolong the results of global tests of coagulation. Furthermore, they have a predictable dose response
2024 ESC Guidelines for the management of atrial fibrillation (Eur Heart J 2024;45:3314–3414, PDF) (Recommendation Table 7 – TTR)Switching to a DOAC is recommended for eligible patients that have failed to maintain an adequate time in therapeutic range on a VKA
2024 ESC Guidelines for the management of atrial fibrillation (Eur Heart J 2024;45:3314–3414, PDF) (Recommendation Table 7 – TTR <70 %)(TTR <70%) to prevent thromboembolism and intracranial haemorrhage.
MSD Manual Professional: Medications for Deep Venous Thrombosis (Factor Xa inhibitors – začatie liečby)Rivaroxaban and apixaban can be started as monotherapy immediately upon diagnosis or used in transition from an injectable heparin at any time without overlap
MSD Manual Professional: Medications for Deep Venous Thrombosis (LMWH – prechod na perorálne antikoagulanciá)Transition to edoxaban or dabigatran requires at least 5 days of LMWH treatment, but no overlap is needed.
MSD Manual Professional: Medications for Deep Venous Thrombosis (LMWH – gravidita)The primary indications for LMWH as a first-line therapy are for DVT in pregnant patients and for breakthrough DVT in patients taking warfarin, in which case it is preferred over DOACs
MSD Manual Professional: Medications for Deep Venous Thrombosis (Warfarin)Warfarin is a treatment option for patients with DVT who are not pregnant.
Warfarin - StatPearls - NCBI Bookshelf (Pregnancy considerations)Warfarin crosses the placental barrier, causing fetal plasma levels similar to maternal values.
2024 ESC Guidelines for the management of atrial fibrillation (Eur Heart J 2024;45:3314–3414, PDF) (Recommendation Table 8 – nepridávať antiagregans k OAK)Adding antiplatelet treatment to oral anticoagulation is not recommended in AF patients for the goal of preventing ischaemic stroke or
MSD Manual Professional: Thrombocytopenia: Other Causes (Heparin-induced thrombocytopenia)Heparin should be stopped immediately in any patient who becomes thrombocytopenic and develops a new thrombosis or whose platelet count decreases by more than 50% pending results of tests done to detect antibodies to heparin bound to platelet factor 4.
Heparin-Induced Thrombocytopenia - StatPearls - NCBI Bookshelf (Treatment / Management)The first step in the treatment is the discontinuation of all forms of heparin, including heparin flushes, heparin-coated catheters, and heparin in the dialysate.
MSD Manual Professional: Thrombocytopenia: Other Causes (Heparin-induced thrombocytopenia)Anticoagulation with a nonheparin anticoagulant (eg, argatroban, bivalirudin, apixaban, rivaroxaban, fondaparinux) should be substituted at least until platelet recovery.
MSD Manual Professional: Thrombocytopenia: Other Causes (Heparin-induced thrombocytopenia)is ten-fold less immunogenic than unfractionated heparin but cannot be used to anticoagulate patients with heparin -induced thrombocytopenia because most HIT antibodies cross-react with LMWH.
MSD Manual Professional: Thrombocytopenia: Other Causes (Heparin-induced thrombocytopenia)In patients who require subsequent warfarin anticoagulation, warfarin should be started only after the platelet count has recovered.
MSD Manual Professional: Medications for Deep Venous Thrombosis (Bleeding During Use of Anticoagulants)Bleeding is the most common complication of anticoagulants and ranges on a continuum from minor to severe, life-threatening hemorrhage.
2024 ESC Guidelines for the management of atrial fibrillation (Eur Heart J 2024;45:3314–3414, PDF) (Recommendation Table 13 – aktívne krvácanie)Interrupting anticoagulation and performing diagnostic or treatment interventions is recommended in AF patients with active bleeding until
MSD Manual Professional: Medications for Deep Venous Thrombosis (Anticoagulant reversal – heparíny)With the heparins, bleeding can be stopped or slowed with protamine
MSD Manual Professional: Medications for Deep Venous Thrombosis (Anticoagulant reversal – protamín)It is more effective on unfractionated heparin (UFH) than on low molecular weight heparin (LMWH) because protamine only partially neutralizes LMWH inactivation of factor Xa.
MSD Manual Professional: Medications for Deep Venous Thrombosis (Anticoagulant reversal – vitamín K)Warfarin anticoagulation can be reversed with vitamin K
MSD Manual Professional: Medications for Deep Venous Thrombosis (Anticoagulant reversal – warfarín)If hemorrhage is severe, prothrombin complex concentrate should be given; fresh frozen plasma may be used if prothrombin complex concentrate is unavailable.
2024 ESC Guidelines for the management of atrial fibrillation (Eur Heart J 2024;45:3314–3414, PDF) (Recommendation Table 13 – špecifické antidotá)Specific antidotes should be considered in AF patients on a DOAC who develop a life-threatening bleed, or bleed into a critical site, to
MSD Manual Professional: Medications for Deep Venous Thrombosis (Anticoagulant reversal – dabigatran)With dabigatran, a humanized monoclonal antibody idarucizumab is an effective antidote to bleeding
Heparin-Induced Thrombocytopenia - StatPearls - NCBI Bookshelf (Etiology)Type II HIT is an immune, antibody-mediated reaction. Because it takes time for the antibodies to form, this reaction usually occurs after 5 to 14 days of receiving heparin.
Heparin-Induced Thrombocytopenia - StatPearls - NCBI Bookshelf (Etiology – reexpozícia)However, if a patient has been exposed to heparin within the last 100 days, antibodies may remain in the system, causing this reaction to manifest as soon as day one of re-exposure to heparin.
Heparin-Induced Thrombocytopenia - StatPearls - NCBI Bookshelf (Pathophysiology)PF4 binding to heparin may trigger the formation of IgG, IgA, or IgM antibodies specific to the heparin-PF4 complex.
MSD Manual Professional: Thrombocytopenia: Other Causes (Heparin-induced thrombocytopenia)Bleeding rarely occurs, but more commonly platelets clump excessively, causing vessel obstruction, leading to paradoxical arterial and venous thromboses, which may be life threatening
MSD Manual Professional: Medications for Deep Venous Thrombosis (Unfractionated heparin – komplikácie)Complications of UFH are similar to those of LMWHs, except that heparin-induced thrombocytopenia, which is rare and may be life-threatening, is more common with UFHs.

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Kartičky

Vymenujte zložky skóre CHA2DS2-VA (ESC 2024) s ich bodovým hodnotením a uveďte, pri akom skóre sa odporúča perorálna antikoagulácia.

Najprv si odpoveď povedz nahlas alebo v duchu – až potom ju odkry.

Aké sú hlavné zásady postupu pri podozrení na heparínom indukovanú trombocytopéniu (HIT)?

Najprv si odpoveď povedz nahlas alebo v duchu – až potom ju odkry.