The administration of a drug to inhibit blood coagulation is called anticoagulation ( Greek ἀντί anti “against” and Latin coagulatio “ agglomeration , clotting”). The drug used is called an anticoagulant ( anticoagulant , anticoagulant, antithrombotic ; plural: anticoagulants , outdated: anticoagulants ). The effect is based on influencing the plasmatic coagulation, i.e. the coagulation factors in the plasma . There are direct anticoagulants that work directly with coagulation factorsinhibit, differentiated from indirect anticoagulants, which either require a cofactor to inhibit coagulation or inhibit the synthesis of the coagulation factors. Typical representatives of direct anticoagulants are hirudin and the active ingredients also known as direct oral anticoagulants (DOAC) (synonymous with new oral anticoagulants, NOAC) such as apixaban , dabigatran , edoxaban and rivaroxaban . Classic representatives of indirect anticoagulants are the vitamin K antagonists phenprocoumon , acenocoumarol or warfarin as well as the heparins .
The anticoagulants are to be distinguished from the platelet aggregation inhibitors such as acetylsalicylic acid (ASA), clopidogrel , prasugrel and ticagrelor which act by inhibiting the function of the blood platelets and thus disrupt the ability of the blood platelets to clump together.
The colloquial term blood thinners is misleading for both the anticoagulants and the platelet aggregation inhibitors, as these agents do not make the blood thinner in the sense of a lower viscosity , but rather reduce its coagulability. An actual blood thinning is the hemodilution , a method for the targeted reduction of the hematocrit , e.g. B. by infusing liquids.
Reasons for anticoagulation
Anticoagulation is necessary in diseases or conditions in which there is a tendency to form blood clots ( thrombi ). The administration of anticoagulants can prevent thromboses or embolisms in the arteries or veins . The second reason for anticoagulant treatment is to treat pre-existing thromboses or embolisms.
Preventive ( prophylactic indication )
Anticoagulants are often used before, during and after operations as well as when bedridden for other reasons to avoid thrombosis and pulmonary embolism . In cardiac catheter interventions and blood sampling for stem cell apheresis as well as (outside the human body) in tube systems ( dialysis , heart-lung machine ) or blood transport tubes, blood clotting is often required.
For treatment ( therapeutic indication )
The most common reason for therapeutic anticoagulation, the non-valvular atrial fibrillation or flutter . With this cardiac arrhythmia there is an increased risk of stroke and embolism, which in many patients can be reduced by anticoagulation. The second most common reason is thrombosis (usually of the leg veins). Here, anticoagulation in the acute phase is intended to prevent the further expansion of the thrombosis and later recurrence ( relapse ). While treatment is only required for a few months in most patients after a thrombosis, lifelong anticoagulation may be required in individual cases (e.g. recurrent thrombosis or congenital blood clotting disorders such as APC resistance ). Special consultations on coagulation at large clinics and centers can give patients important recommendations here. Patients after heart valve surgery always need anticoagulation, with biological valve prostheses often only for a few weeks or months, with artificial valves but usually for life.
Less common causes of anticoagulation can an advanced atherosclerosis (z. B. coronary heart disease , peripheral vascular disease or narrowing of the carotid artery ), a heart wall aneurysm or an atypical hemodynamics (eg. B. after palliative -OP in congenital heart defects ) to be.
Anticoagulant and risk of bleeding
The main risk of drug anticoagulation is the risk of bleeding. Patients on long-term anticoagulants bleed longer. They are prone to bruising and are at greater risk of bleeding from the genitourinary or gastrointestinal tract. Cerebral haemorrhage is particularly feared . Bleeding under anticoagulant therapy often occurs spontaneously after trauma . The more intensive the anticoagulant (high dose of anticoagulants or a combination of several anticoagulants), the greater the risk of bleeding. There are also patient-side factors that increase the risk of bleeding.
According to Danish registry data, the incidence of bleeding requiring hospital admission under newly started antithrombotic therapy in patients after myocardial infarction is 4.6% over 1.3 years. The risk with the various antithrombotics or their combinations varies:
|Type of anticoagulant||Probability of bleeding (over 1.3 years)|
|simple platelet function inhibition with ASA||2.6%|
|double antiplatelet function (ASA + clopidogrel)||3.7%|
|oral anticoagulation with vitamin K antagonist||4.3%|
|Combination of ASA + vitamin K antagonist||5.1%|
|Triple therapy: ASA + clopidogrel + vitamin K antagonist||12%|
If you add bleeding that does not require hospital treatment to these figures, then around one in five patients on oral anticoagulants should expect a bleeding complication every year. In the RE-LY study, in which the vitamin K antagonist warfarin was compared with two different doses of the thrombin inhibitor dabigatran for the indication of atrial fibrillation, annual bleeding rates (major and minor bleeding) of 13.6% (2 × 110 mg dabigatran), 16.4% (2 × 150 mg dabigatran) and 18.1% (warfarin) found. With regard to the probability of bleeding, there is therefore a clear correlation between the dose used and the quality of the INR setting for vitamin K antagonists .
Various risk scores are also used to assess the risk of bleeding, e.g. B. the HAS-BLED Score or the HEMORR 2 HAGES Score .
|HAS Bled Score (ESC guidelines 2010)|
|H||H ypertension||Hypertension (RR systolic over 160 mmHg )||1|
|A.||A BNORMAL renal and liver function||Severe liver / kidney dysfunction (1 point each)||1-2|
|S.||S dry||History of stroke||1|
|B.||B leeding||Have had any bleeding or have a tendency to bleed||1|
|L.||L abile INRs||unstable setting (<60% of the INR values in the target range)||1|
|E.||E lderly||Age over 65 years||1|
|D.||D rugs or alcohol||Drugs such as non-steroidal anti-inflammatory drugs or alcohol abuse||1-2|
Above a score of 3 there is an increased risk of bleeding, which requires particular caution when prescribing anticoagulants (selection of substances, if necessary dose reduction) and their monitoring (regular family doctor consultations and laboratory checks). Critics point out that more than half of the complications associated with anticoagulant therapy can be traced back to errors in medication management. The most common medication errors are disregarding drug interactions , treatment with an anti-coagulant that is unsuitable for the patient, unreliable medication intake (therapy adherence ), inadequate therapy monitoring , incorrect indication and dosage, and loss of information between the treating physicians.
Risk / benefit balance
When deciding on anticoagulant therapy, the risk of bleeding must be balanced by an appropriate therapeutic benefit. For example, oral anticoagulation in patients with atrial fibrillation reduces the risk of stroke by more than 60%. If a patient is at high risk of stroke, e.g. B. 6% per year (estimate using the CHA 2 DS 2 -VASc score , for example ), then the risk of significant bleeding during antithrombotic therapy can be significantly lower than the resulting benefit. Patients should therefore be aware of the potential benefit of the therapy as well as the risk. The treatment guidelines of the European Society for Cardiology (ESC) for atrial fibrillation therefore also recommend discussing all aspects of therapy with anticoagulants with the patient in order to then reach a participatory decision (shared decision-making) and informed consent . : informed consent) to come.
Medicines and essential properties
The drugs can be divided into direct and indirect anticoagulants according to the principle of action. A further division can be made according to the type of application into orally applicable and non-orally applicable anticoagulants.
Indirect anticoagulants do not directly inhibit plasmatic coagulation.
Coumarins (vitamin K antagonists)
The so-called oral anticoagulation with coumarins (active ingredients: phenprocoumon , acenocumarol , warfarin ) works by depleting the vitamin K -dependent coagulation factors II, VII, IX and X (Eselsbrücke 1972 ). These are no longer sufficiently formed and the bleeding time increases. The effect can be measured using the bleeding times. Today based on a determination of the INR (formerly Quick value ). The degree of anticoagulation depends not only on the dose taken, but also on the diet and metabolism of the patient. Vitamin K-rich foods such as B. kale or broccoli can lead to a weakening of the coumarin effect. In addition, coumarins are extensively metabolized in the body. They are modified by a large number of enzymes both when they are absorbed into and when they are eliminated from the body. Due to the varying degrees of activity of these enzymes (slow, fast, ultrafast metabolizer), a patient's need for coumarin cannot be foreseen. Therapy is therefore started slowly, with constant INR controls. When the target INR is reached, a maintenance dose is set and recorded in a coagulation card. Some patients only need 2 tablets per week, others 8. Another disturbance is drug interactions . Many comedic drugs, including phytopharmaceuticals , directly and indirectly influence the effects of coumarins. The most important interactions are listed in the relevant technical information .
Oral anticoagulation with coumarins takes the form of regular tablet intake. The dose is determined by the treating physician. The higher the INR, the more intense the anticoagulation. Some indications require a less strong anticoagulant (eg INR 2–3, for non-valvular atrial fibrillation), others a much stronger one (eg INR 3.5–4 for certain artificial heart valves). The higher the INR, the higher the risk of bleeding and the more fluctuating the INR setting, the higher the risk of complications from the therapy (thrombosis, embolism and bleeding). In the case of reliable patients, INR monitoring should therefore be transferred to the patient in the form of coagulation self-management after appropriate training. The necessary test devices are paid for by the health insurance companies under certain conditions. This allows the patient to determine the correct dosage independently.
However, around a third of patients have problems with coumarin treatment. The INR fluctuates strongly, the intake is unreliable, the patients fall more frequently or have spontaneous bruises. This often leads to the fact that the therapy is stopped or not started at all for safety reasons, although the patients would have a great benefit. Another problem is that the effect of the coumarins lasts for several days, which can be very disadvantageous in the event of bleeding or surgery . In this case, vitamin K can be added. The coagulation then normalizes within several hours. The administration of vitamin K is not, however, a coumarin antidote in the classical sense . In an emergency, the missing coagulation factors (e.g. prothrombin complex ) can also be infused.
The heparins, which can only be administered parenterally , are glycosaminoglycans whose anticoagulant effect is due to an increase in the activity of endogenous antithrombin . Antithrombin leads to inactivation of the coagulant factor Xa . According to the molar mass , a distinction can be made between unfractionated heparin (UFH) and low molecular weight heparin (LMWH). While unfractionated heparin also accelerates the inactivation of the clotting-promoting thrombin , low-molecular-weight heparins with a molar mass of 5400 u lose this ability.
The molar mass influences the pharmacokinetics of the individual substances. In general, the lower the molar mass, the greater the bioavailability and the half-life . In addition, the laboratory-chemical verifiability of the effect differs due to the named mechanisms of action. While the effect of unfractionated heparin can be tested by determining the partial thromboplastin time , low molecular weight heparins can only be tested using the anti-factor Xa activity . The administration of fractionated heparin therefore does not affect the INR.
Unfractionated heparin is administered subcutaneously 2–3 times a day or, then usually as a continuous infusion , intravenously. The half-life is 30 to 60 minutes. The effect of unfractionated heparin quickly wears off and can be quickly reversed by protamine .
Low molecular weight (= fractionated) heparins are obtained from unfractionated heparin. Representatives of this group Certoparin , dalteparin , enoxaparin , nadroparin , reviparin and tinzaparin . Depending on the indication and preparation, heparins are administered subcutaneously 1–2 times a day. Depending on the LMWH preparation used, the effect can be temporarily reversed by 50 to 85% by protamine.
Direct oral anticoagulants (DOAK or DOAKs)
Direct oral anticoagulants used to be referred to as new oral anticoagulants ( NOAC ). Now that they are used routinely, the name direct oral anticoagulants should be better used, as this nomenclature also explicitly emphasizes the mechanism of action that deviates from the group of coumarins. These drugs intervene directly in the coagulation cascade and directly inhibit individual coagulation factors. Direct inhibitors of the Stuart Prower factor (coagulation factor Xa) and thrombin (coagulation factor IIa) are currently on the market.
Factor Xa inhibitors
Factor IIa inhibitors
- Dabigatran etexilate - trade name Pradaxa
- Argatroban - trade name Argatra
- Ximelagatran was withdrawn from the market worldwide in February 2006 due to liver damage.
DOAC are increasingly replacing coumarins. They have the practical advantage that the coagulation values do not have to be checked regularly. Patients take a fixed dose once (rivaroxaban, edoxaban) or twice daily (dabigatran, apixaban). Disadvantages are their significantly higher price (approx. 15 times higher than with phenprocoumon) and that the lack of information about the intensity of the antithrombotic therapy due to the unnecessary INR controls, so the therapy is more or less blind. The regular family doctor visits for INR control and the associated clinical controls are also eliminated.
Most studies have shown that DOAC can reduce strokes about as effectively as with coumarins with slightly fewer bleeding complications overall, especially cerebral haemorrhage. In these studies, however, a coumarin that is unusual in Germany and Austria was used (warfarin) and the quality of the INR setting was unsatisfactory (hardly any self-management). That could have skewed the result in favor of the DOAK. From the point of view of the Drugs Commission of the German Medical Association ( AkdÄ ), there is therefore no benefit from a therapy with a DOAC for patients with atrial fibrillation who can be treated well with a coumarin. DOAC are therefore a valuable option for specific contraindications to coumarins, if there is an increased risk of coumarin-specific drug interactions, strongly fluctuating INR values or if regular monitoring of the INR value is difficult for understandable reasons.
When choosing the DOAK, medical aspects such as accompanying diseases, co-medication, potential interactions and kidney function should be decisive. In addition, the detailed results of the individual substances must be taken into account in the respective approval studies. The fact that there has so far only been an antidote for a single DOAC (dabigatran) should also be taken into account when selecting the drug. The DOAK must therefore by no means be viewed in the same way. A complicated differential indication is increasingly emerging and not all questions have been answered by a long way.
One problem with the DOAC is careless handling of these seemingly easily controllable anticoagulants. Der Arzneimittelbrief, for example, criticizes an increasingly flawed and too lax handling of the DOAC, which is likely to cancel out the low clinical advantages over vitamin K antagonists. Frequent avoidable errors that lead to serious side effects are a non-existent indication for anticoagulation ( over-therapy ), ignorance or disregard of drug interactions , treatment with an anticoagulant that is unsuitable for the patient or an incorrect dose, unreliable medication intake and a insufficient therapy monitoring. Other frequent problems in connection with the DOAK are training deficits among patients, insecurities from scandalous media reports, self-medication with non-prescription preparations with interaction potential, the downplaying marketing of the DOAK manufacturers, which understates the advantages and risks, and the loss of contact between general practitioners and patients due to the lack of INR controls.
Based on the recommendations of the European Heart Rhythm Association (EHRA), structured follow-up care is proposed to improve therapy safety with DOAK. Accordingly, the first prescriber should issue an anti- coagulant ID card or emergency passport that is as uniform as possible even in the event of treatment with DOAK . The follow-up intervals and content are specified as follows:
- first check-up one month after the first prescription: query of thrombotic, embolic or bleeding events; of side effects and adherence to intake; Checking the comedication for interactions; Evaluation of the suitability of the selected DOAC and the dose; Determination of the next follow-up appointment and the necessary laboratory controls. Patient education.
- In addition, clinical follow-up visits approximately every 3 months (maximum 6 months), depending on patient factors such as age, kidney function and concomitant diseases. Contents of the visits as for the first check-up.
All patients with DOAC should receive a laboratory check at least once a year (kidney function, liver function, blood count). Patients ≥75 years of age (especially if they are receiving dabigatran) and frail patients more often, at least every 6 months. Renal insufficiency patients with creatinine clearance ≤ 60 ml / min should receive a blood test x-monthly, according to the formula: x = creatinine clearance / 10 (i.e. at 30 ml / min = 3-monthly). Laboratory controls are also recommended for all conditions that can impair kidney or liver function. Routine determinations of DOAC serum levels are not recommended.
In contrast to the coumarins, the DOAC have specific antidotes . Such an antidote has been approved for dabigatran since November 2015 under the name Idarucizumab (trade name Praxbind). It only works against dabigatran and completely eliminates its effects within a few minutes in the case of life-threatening bleeding. In May 2018, the recombinant Andexanet alfa (trade name AndexXa) was approved as an antidote for the factor Xa antagonists rivaroxaban and apixaban . It was approved in Europe in April 2019, subject to further clinical studies.
If intracranial bleeding occurred during therapy with dabigatran, apixaban or rivaroxaban , the following measures were recommended:
- Stopping (or pausing) the DOAK
- If you have taken dabigatran or rivaroxaban in the last two hours: give activated charcoal
- PPSB at a dosage of 30 U / kg body weight
- When taking rivaroxaban, the administration of activated prothrombin complex or recombinant factor VIIa can also be considered
- Keep systolic blood pressure below 140 mmHg.
Other active ingredients
- Fondaparinux - trade name Arixtra®, factor Xa inhibitor for subcutaneous use
- Danaparoid - trade name Orgaran®
- Hirudin , a thrombin inhibitor (used by leeches ), discovered in 1884 as the first anticoagulant principle.
- Lepirudin , recombinant hirudin (no longer commercially available)
- Bivalirudin , hirudin obtained from leeches
- Calcium complexing agents , for example citrate or EDTA , which bind the calcium ( chelate complex ) to prevent the blood from clotting. Citrate anticoagulation in particular is increasingly used in continuous kidney replacement procedures. The advantage is that the patient himself is excluded from the anticoagulation; anticoagulation only takes place in the extracorporeal circuit. This means that patients who cannot tolerate heparin (HIT II, SHT) or who are septic can also be treated.
- Otamixaban , a factor Xa inhibitor, for intravenous administration
In the laboratory ( in vitro )
When examining blood, anticoagulants such as EDTA , citrate , ammonium heparinate , lithium heparinate or acid-citrate-dextrose (ACD) are added in order to be able to examine blood that has not clotted. The blood tubes used to take the blood are already equipped with one of these anticoagulants.
The anticoagulants, known colloquially as blood thinners, are to be distinguished from active substances that actually thin the blood , the plasma expanders , since anticoagulants neither significantly reduce the viscosity of the blood nor the concentration of blood cells and total blood protein .
- Plasma expanders cannot be swallowed as tablets , they are infused .
- Plasma expanders also reduce the blood's ability to clot, which is an often unpleasant side effect here. This side effect is different depending on the substance class, depending on
- Plasma expanders have two main areas of application:
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