Coagulation – Hemostatic Agents – Thromboprophylaxis English

About Coagulation

Administering thrombolysis and preventing thromboembolisms is common in conditions such as acute coronary syndromes, stroke, and other thromboembolic diseases. Hemostatic drugs are primarily used in trauma and surgeries with significant bleeding but can also be used in obstetric bleeding, pathological bleeding due to coagulation disorders, or in cases of overdose with antithrombotic medications. A detailed description of the coagulation mechanism is beyond the scope of this handbook and is referred to specialized literature.

During traumatic tissue injury with bleeding, the three stages of hemostasis begin: primary hemostasis, plasma coagulation, and fibrinolysis. In primary hemostasis, vasoconstriction is initiated, along with stimulation of platelet adhesion to form a clot. Platelets attach to an endothelial injury in the collagen via von Willebrand factor and release thromboxane A2 and serotonin. Adequate hemostasis typically requires an Hb > 100 g/L. Platelets release vWF, FV, FXIII, and fibrinogen. Platelets are bound together by fibrinogen into a platelet plug, which is later reinforced by fibrin. Fibrinogen is thus essential for proper hemostasis in cases of major bleeding. Numerous coagulation factors circulate in inactive form in the blood. These are activated during traumatic injuries or by activated cells like platelets, endothelial cells, and monocytes. When the vascular endothelium is damaged, coagulation factors are activated through an initiation of plasma coagulation. This results in the Xa/Va factor complex converting prothrombin into thrombin, leading to the reinforcement phase of clot formation. The thrombin formed during initiation activates circulating platelets and coagulation factors. Prothrombin is converted into thrombin on the surface of activated platelets in large quantities. Meanwhile, several inhibitors limit coagulation to the injured area, such as antithrombin, protein C, and tissue factor pathway inhibitor (TFPI). Antithrombin prevents excessive clot formation within the vessel lumen. Activated protein C (APC) and its cofactor protein S inactivate FVa and FVIIIa, significantly reducing thrombin production.

The role of fibrinolysis is to dissolve formed fibrin and maintain balance in hemostasis. Plasminogen activates plasmin, which breaks down fibrin into fibrin degradation products (FDP). Plasminogen is activated by several factors such as t-PA, u-PA, PAI-1, and PAI-2. Plasminogen is produced in the liver and circulates freely in plasma. Plasminogen is activated on the surface of a clot, and fibrinolysis occurs only on the clot’s surface. t-PA is continuously released from endothelial cells, PAI-1 is produced in the liver but is also found in endothelial cells and platelets. Factor XIII binds soluble fibrin into a stable network and incorporates antiplasmin into the clot. Platelet aggregation is halted when platelets come into contact with intact endothelium by agents like NO, PGI2, and negatively charged heparan sulfates. Balanced coagulation is necessary for healing tissue injuries without forming harmful thrombi and emboli. In clinical practice, several tests are used to assess coagulation system function and activity. Common tests include Hb, PK/INR, APTT, TPK, fibrinogen, antithrombin, and graphical analysis methods such as thromboelastography. Bleeding time is no longer a commonly used test. APTT (activated partial thromboplastin time) is measured in seconds and reveals any deficiencies in coagulation protein activity, except for factor VII and factor XIII. Low molecular weight heparins only marginally affect APTT time.

Besides deranged coagulation factors, several other critical parameters affect hemostasis, including body temperature. Coagulation capacity begins to deteriorate below 36.5°C, and at temperatures below 33°C, coagulation capacity is halved. Low pH, below 7.2, reduces coagulation capacity, as does Hb below 90 g/L. Low calcium concentration impairs coagulation, and free calcium should be maintained above 1.0 mmol/L. High blood pressure increases bleeding, with optimal blood pressure considered systolic between 80 and 100 mm Hg but must be related to the body’s other vital organ perfusion needs.

In treating bleeding, volume replacement is initiated with crystalloid and colloidal solutions. Please refer to the chapter on bleeding and fluid replacement for optimal tissue perfusion. Bleeding substitution is typically provided in the form of blood components such as erythrocyte concentrates (SAG), plasma, and platelets to achieve optimal Hb (90-120 g/L) and ensure the best rheology and hemostasis. Erythrocyte concentrate is generally administered in acute bleeding exceeding 500 ml in a healthy small person and normovolemia, over 800 ml in a normal-sized person, and over 1 liter in a large person, but this can be adjusted individually based on the patient’s general condition and current Hb. Moderate bleeding usually does not require plasma, platelets, or specific medications for adequate hemostasis. A rule of thumb suggests administering blood and plasma in a 1:1 ratio after a blood loss greater than 20% of the blood volume, with the addition of platelets after a loss equivalent to the patient’s entire blood volume. Factor concentrates are used when the content in regular plasma is insufficient without causing excessive volume overload with blood components. The administration of blood components is guided by clinical and current laboratory values (PK/INR, APTT, fibrinogen, TPK, TEG).

Benchmarks for Good Hemostasis:

• Hb > 90 g/L
• TPK > 100 x 10⁹ /L
• Fibrinogen > 2.0 g/L
• PK/INR < 1.5
• Normal APTT

INR = international normalized ratio; indicates the patient’s coagulation time compared to normal coagulation time. PK (INR) is not a test but a way of reporting the analysis. PK (prothrombin complex) measures factors II, VII, and X. APTT (activated partial thromboplastin time) measures factors XII, XI, X, IX, VIII, V, prothrombin, and fibrinogen.

In cases of massive sudden bleeding, it is possible to initially administer 4 units of erythrocyte concentrate, 4 units of plasma, 1 unit of platelet concentrate, 2 g of fibrinogen, and 2 g of Cyklokapron. Body temperature should be maintained above 36 degrees. Overtransfusion should be avoided, and normovolemia should be pursued. Follow blood gases and other metabolic parameters such as lactate carefully.

Actilyse (alteplase)

Alteplase is a recombinant human tissue plasminogen activator, a glycoprotein, which activates plasminogen to plasmin. After intravenous administration, alteplase remains relatively inactive in systemic circulation. Activation occurs upon binding to fibrin, leading to the conversion of plasminogen to plasmin, which in turn dissolves the fibrin thrombus.

Indication: Acute myocardial infarction, pulmonary embolism, ischemic stroke.

Side effects: Hypotension, bradycardia, respiratory failure.

Concentration: 1 mg/ml. Infusion substance 10 mg, 20 mg, and 50 mg (I+II).

Dosage: For the treatment of acute myocardial infarction with symptom onset < 6 hours, 100 mg is given to people over 65 kg. 15 mg as a bolus, then 50 mg over 30 minutes, and then 35 mg over 60 minutes. For people under 65 kg, 15 mg as a bolus, then 0.75 mg/kg IV over 30 minutes, and then 0.5 mg/kg over 60 minutes.

For treatment of acute myocardial infarction with symptom onset 6-12 hours, 100 mg is given to people over 65 kg. 10 mg as a bolus, followed by 50 mg over 60 minutes, and then 40 mg over 120 minutes. For people under 65 kg, 1.5 mg/kg is given.

For treatment of acute pulmonary embolism, 100 mg is administered over 2 hours (120 minutes). For people under 65 kg, a maximum of 1.5 mg/kg is given. For those over 65 kg, 100 mg is given. Administer 10 mg (10 ml) as a bolus, followed by 90 mg over 2 hours.

Warning: Actilyse is contraindicated where there is a high risk of bleeding.

Aggrastat (tirofiban)

Tirofiban is a direct thrombin inhibitor for the prevention of thromboembolic disease. It inhibits platelet aggregation by blocking the binding to the GPIIb/IIIa receptor on activated platelets. Tirofiban has a rapid onset of action and a relatively short duration. Coagulation is normalized 4-8 hours after the end of infusion. The effect can be measured as a lower value in the TRAP test, which is part of the platelet function test in Multiplate.

Dosage: First, a bolus dose of 25 micrograms/kg over 3 minutes, followed by 0.15 micrograms/kg/min for up to 18 hours. Reduced dose in renal failure, 0.075 micrograms/kg/min.

Indication: Thromboprophylaxis in thrombotic heart disease (NSTE-ACS), such as acute coronary syndromes with impending heart attack. Can be used preoperatively before PCI and stenting of coronary arteries.

Concentration: Infusion solution, 50 micrograms/ml.

Warning: Contraindicated in ongoing bleeding. Caution in liver failure or thrombocytopenia.

Arixtra (fondaparinux)

Fondaparinux is a synthetic and selective inhibitor of activated factor X (Xa). The antithrombotic effect of fondaparinux is due to antithrombin III (ATIII)-mediated selective inhibition of factor Xa. It inhibits both thrombin formation and thrombus development. Fondaparinux does not inactivate thrombin and has no effect on platelets.

• Factor Xa inhibitor
• Once daily subcutaneously
• Long half-life – 17 hours
• Not for use in renal impairment
• Safe in liver failure
• Antidote available

Dosage: 2.5 mg daily via subcutaneous injection, six hours after surgery. For acute myocardial infarction or angina, 2.5 mg daily subcutaneously.

Indication: Prophylaxis of thromboembolic disease in surgical settings. Treatment of acute myocardial infarction (non-STEMI) or angina.

Side effects: Bleeding, bleeding complications, anemia, allergic reaction, nausea, vomiting.

Concentration: 1.5 mg/0.3 ml, 2.5 mg/0.5 ml, 7.5 mg/0.6 ml.

Warning: EDA/Spinal should not be administered to patients treated with fondaparinux. Fondaparinux should not be administered to patients with an EDA catheter. For patients undergoing coronary bypass surgery (CABG), fondaparinux should, if possible, not be given 24 hours before surgery. Treatment can be resumed 48 hours postoperatively. Must not be given intramuscularly.

ASA (acetylsalicylic acid)

COX-1 inhibitor. Acetylsalicylic acid has an inhibitory effect on platelet aggregation. Although the mechanism of action is not fully understood, the effect appears to be mainly due to acetylation and thus irreversible inactivation of the enzyme cyclooxygenase, which is involved in the formation of thromboxane A2 in platelets and prostacyclin in vascular endothelium. Salicylates inhibit platelet function and enhance the effect of anticoagulants. The effect on platelets is permanent, as they cannot regenerate cyclooxygenase. Therefore, the effect lasts throughout the platelet’s life cycle, which is 7-10 days. Acetylsalicylic acid also inhibits renal prostacyclin synthesis.

Dosage: 75 mg daily orally. For the treatment of acute coronary syndromes, an initial loading dose of 150-500 mg is given, followed by 75 mg daily.

Indication: Prevention of thrombotic events in patients with ischemic stroke, unstable angina, acute myocardial infarction, TIA prophylaxis.

Side effects: Dyspepsia, bleeding, bleeding complications, nosebleeds, anemia, allergic reactions, skin reactions, dizziness, tinnitus.

Concentration: Tablet 75 mg, tablet 160 mg, tablet 500 mg.

Warning: A pharmacodynamic interaction between clopidogrel and acetylsalicylic acid is possible, leading to an increased risk of bleeding. Caution should be exercised during simultaneous treatment. People with known allergies or asthma are at increased risk of hypersensitivity reactions to ASA.

Brilique (ticagrelor)

ADP receptor inhibitor. Ticagrelor belongs to the chemical class of cyclopentyltriazolopyrimidines (CPTP) and is a selective ADP receptor antagonist that can prevent platelet activation and aggregation.

Dosage: Initially 180 mg orally, then 90 mg twice daily. Patients taking Brilique should also take ASA daily unless specifically contraindicated.

Indication: Prevention of thrombotic events in patients with unstable angina, acute myocardial infarction, including those treated medically and those undergoing percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG).

Side effects: Bleeding, bleeding complications, nosebleeds, anemia, bradycardia, dyspnea, rash, confusion.

Concentration: Tablet 90 mg.

Warning: EDA/Spinal should not be administered to patients treated with ticagrelor. Ticagrelor should not be administered to patients with an EDA catheter. The coagulation effect of ticagrelor is not visible in a standard thromboelastogram (TEG).

Confidex (coagulation factor concentrate)

Bleeding inhibitor, hemostatic. Coagulation factor concentrate. Coagulation factors II, VII, IX, and X, synthesized in the liver with the help of vitamin K, are called the prothrombin complex. In addition to coagulation factors, CONFIDEX contains the protein C and protein S.

Dosage: The dose is based on INR before treatment and the target INR value. The INR before treatment should be measured as close to the time of dosing as possible to calculate the appropriate dose of Confidex.

Indication: Major bleeding, bleeding in liver failure.

• Treatment of bleeding and perioperative bleeding prophylaxis in acquired deficiency of prothrombin complex coagulation factors, such as deficiency due to treatment with vitamin K antagonists, or in overdose of vitamin K antagonists, when rapid correction of the deficiency is required.
• Treatment of bleeding and perioperative prophylaxis in congenital deficiency of one of the vitamin K-dependent coagulation factors when purified specific coagulation factor products are not available.

Concentration: Powder for solution 250/500/1000 IU. Reconstitutes as 250 IU/10 ml.

Side effects: Thromboembolic events including myocardial infarction and pulmonary embolism. Lack of effect. Headache. Elevated body temperature.

Warning: Patients receiving vitamin K antagonists may have an underlying condition of hypercoagulability, and infusion of prothrombin complex concentrate may

worsen this. There is a risk of thrombosis or disseminated intravascular coagulation in patients, whether congenital or acquired deficiency, treated with human prothrombin complex concentrate, especially with repeated dosing.

Contraindications: Known allergy to heparin or history of heparin-induced thrombocytopenia. In cases of disseminated intravascular coagulation, treatment with prothrombin complex preparations should be given only after the consumptive phase has passed.

Cyklokapron (tranexamic acid)

Fibrinolysis inhibitor. Tranexamic acid inhibits fibrinolysis by preventing the activation of plasminogen to plasmin. Tranexamic acid does not cause thrombosis, but it inhibits the dissolution of existing clots.

Dosage: Initially, a slow (10 minutes) intravenous injection of 1-2 g IV, can be repeated after 4-6 hours. Infusion can be given at a dose of 70-700 mg/hour. Cyklokapron can also be administered orally, applied topically on mucous membranes, in the oral cavity, and in the nose.

Indication: During surgery and bleeding in patients with increased bleeding tendency. In operations with increased fibrinolysis, such as surgeries on mucous membranes, mammoplasty, thoracic and liver surgery, and prostate surgery. In operations on patients with an increased risk of bleeding, such as known platelet defects, von Willebrand disease, and hemophilia. Can be tried in cases of major bleeding related to severe trauma.

Concentration: Injection solution 100 mg/ml.

Side effects: In DIC and microthrombotic syndromes, tranexamic acid can reduce the breakdown of fibrin in the microcirculation and thus increase the risk of organ failure.

Contraindications: Cyklokapron should be avoided during the first six months following acute thrombosis. In cases of severe massive bleeding, single doses of tranexamic acid may be administered, but prolonged treatment for several days should be avoided. Bleeding in the urinary tract is a contraindication due to the risk of obstructive clot formation.

Efient (prasugrel)

ADP receptor inhibitor. Prasugrel inhibits platelet activation and aggregation by irreversibly binding its active metabolite to the P2Y₁₂ group on platelets’ adenosine diphosphate receptors (ADP).

Dosage: Treatment should begin with a single loading dose of 60 mg and then continue with a dose of 10 mg once daily.

Indication: Prevention of thrombotic events in patients with unstable angina, acute myocardial infarction, including patients treated medically and those undergoing percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG).

Side effects: Bleeding, bleeding complications, nosebleed, anemia, bradycardia, dyspnea, skin rash, confusion.

Concentration: Tablet 10 mg.

Warning: EDA/Spinal should not be given to patients treated with prasugrel. Prasugrel should not be given to patients with an EDA catheter. Coagulation effects of prasugrel do not appear in a standard thromboelastogram (TEG).

Eliquis (apixaban)

Apixaban is a potent, oral, reversible, direct, and highly selective inhibitor of factor X (Xa). Apixaban inhibits free and clot-bound factor Xa and prothrombinase activity. Apixaban indirectly inhibits platelet aggregation. By inhibiting factor Xa, apixaban prevents the formation of thrombin and the development of thrombi. By inhibiting FXa, apixaban prolongs coagulation times such as prothrombin time (PT), INR, and activated partial thromboplastin time (APTT). Changes observed in these coagulation tests at the expected therapeutic dose are small and highly variable. Apixaban has indications similar to warfarin. Serum concentration of apixaban can be measured with peak levels about 3 hours after administration and trough levels just before the next dose.

Dosage: 10 mg orally twice daily for the first 7 days, followed by 5 mg orally twice daily.

Indication: Prophylaxis of thromboembolic disease in patients with atrial fibrillation. Treatment of deep vein thrombosis and pulmonary embolism. Prophylaxis of DVT and PE.

Contraindication: Recent brain, spinal, or eye surgery. Concurrent treatment with other anticoagulants.

Side effects: Bleeding, bleeding complications, nosebleed, anemia, skin rash. Allergic reactions are less common.

Strength: 5 mg per tablet.

Warning: Apixaban should be discontinued 1-2 days before surgery. EDA/Spinal should not be given to patients treated with apixaban. Experiences with apixaban and neuraxial blockades are limited, but it is recommended to stop apixaban 4-6 half-lives, i.e., 3-4 days before placing a block. Apixaban should not be given to patients with an EDA catheter. Apixaban can be resumed 24-48 hours after EDA catheter removal. Treatment with apixaban can be restarted 48 hours postoperatively.

Fibrinogen (Riastap)

Human fibrinogen concentrate. Hemostatic agent.

Dosage: To calculate the individual dose, the functional fibrinogen level should be determined. If the patient’s fibrinogen level is unknown, an IV dose of 70 mg per kg of body weight is recommended. The target level (>2 g/l) for major bleeding (e.g., head trauma or intracranial hemorrhage) should be maintained for seven days. Dose of fibrinogen (mg/kg body weight) to be administered = [target level (g/l) – measured level (g/l)]/ 0.017 (g/l per mg/kg body weight). Typically, 1-2-4 g IV is given per occasion, repeated as needed after monitoring bleeding parameters. One gram of fibrinogen increases plasma value by about 0.5 g/l.

Indication: Major bleeding, traumatic bleeding. Treatment of bleeding in patients with congenital hypo- or afibrinogenemia with a tendency to bleed. The normal fibrinogen level in plasma is 1.5-4.5 g/l. The critical fibrinogen level in plasma, below which bleeding may occur, is 0.5-1.0 g/l. For major surgical procedures, it is essential to closely monitor replacement therapy with coagulation assays.

Concentration: Powder for solution 1 g.

Side effects: Thromboembolic events, including myocardial infarction and pulmonary embolism. Lack of effect.

Warning: An increased risk of thrombosis exists in patients with congenital deficiency when treated with human fibrinogen concentrate, especially at high doses or repeated doses. Patients receiving human fibrinogen concentrate should be closely monitored for signs and symptoms of thrombosis.

Contraindications: Hypersensitivity to the active substance or any excipient.

Fragmin (dalteparin)

Dalteparin sodium is the sodium salt of low molecular weight heparin (LMWH). The antithrombotic effect of dalteparin is due to its ability to enhance antithrombin’s inhibition of factor Xa and thrombin, reducing blood clot formation. The effect of Fragmin can be monitored by analyzing plasma levels of anti-Xa/ml.

Dosage: Thromboprophylaxis; 2500/5000 IU subcutaneously once daily, usually in the evening.

DVT: 200 IU/kg body weight is administered once daily subcutaneously. Hemodialysis: IV bolus injection of 30-40 IU/kg body weight, followed by IV infusion of 10-15 IU/kg body weight per hour.

Pulmonary embolism: 100-120 IU/kg body weight twice daily every 12 hours.

Indication: Thromboprophylaxis, deep vein thrombosis (DVT), pulmonary embolism, intravascular coagulation, hemodialysis, unstable angina, and non-Q wave myocardial infarction.

Side effects: Bleeding, thrombocytopenia, transient liver impairment.

Concentration: Solution 2500 IU/ml, solution 10,000 IU/ml, solution 25,000 IU/ml. Pre-filled syringes: 2500 IU/ml, 5000 IU/ml, 7500 IU/ml, 10,000 IU/ml, 12,500 IU/ml, 15,000 IU/ml, 18,000 IU/ml.

Warning: Dalteparin is contraindicated in cases of high risk of bleeding. Caution is recommended in thrombocytopenia and platelet function defects, as well as in severe liver and kidney insufficiency, uncontrolled hypertension, hypertensive or diabetic retinopathy. Fragmin can cause heparin-induced thrombocytopenia (HIT type II). In HIT, the patient develops antibodies, usually of the IgG type, directed against complexes of heparin and platelet factor 4.

In anticoagulant therapy combined with epidural/spinal anesthesia, there is a risk of developing epidural or spinal hematoma, which can result in long-term or permanent paralysis. The risk increases if the epidural catheter remains in place postoperatively or when it is removed. Epidural anesthesia during labor is absolutely contraindicated in women treated with dalteparin.

Haemate (FVIII/VWF)

Human coagulation factor concentrate. Hemostatic agent. Contains Factor VIII and von Willebrand factor in a 1:2.4 ratio. Bleeding prophylaxis during surgery or major trauma: To prevent extensive bleeding during or after surgery, administration should begin 1 to 2 hours before the procedure. The infusion is repeated with an adequate dose every 12-24 hours.

Dosage: 40-50 IU/kg in case of severe bleeding.

Indication: Major bleeding, traumatic bleeding. Treatment of bleeding in patients with congenital bleeding tendency. Von Willebrand disease in mild or severe form. Massive bleeding with ongoing hemorrhage. Hemophilia A with Factor VIII deficiency.

Side effects: Thromboembolic events, including myocardial infarction and pulmonary embolism. Lack of effect.

Concentration: Powder for solution 1000 IU Factor VIII and 2400 IU von Willebrand factor. Powder for solution 500 IU Factor VIII and 1200 IU von Willebrand factor.

Warning: During treatment, it is recommended to measure factor VIII levels to adjust dose and dosing intervals. Hypersensitivity reactions can occur. There is an increased risk of thrombosis.

Contraindications: Hypersensitivity to the active substance or any excipient.

Heparin (heparin)

Heparin, which is normally found in the body bound to protein, is a strongly acidic, sulfated glycosaminoglycan (mucopolysaccharide) with a potent anticoagulant effect. In combination with the co-factor, antithrombin III, heparin affects several steps in the coagulation mechanism, producing an anticoagulant effect. Heparin is administered in the treatment of thromboembolic events such as pulmonary embolism or deep vein thrombosis.

Dosage:

• For the treatment of deep vein thrombosis, a bolus dose of 5000 IU (1 ml) IV is given for a weight under 85 kg.
• For a weight over 85 kg, a bolus of 7500 IU (1.5 ml) IV is given.
• For the treatment of pulmonary embolism, a bolus of 7500 IU (1.5 ml) IV is given
• For massive DVT/PE: larger bolus (100-150 IU/kg).
• In cases of increased bleeding risk, a bolus of 2500 IU IV is given, except in cases of massive pulmonary embolism/DVT. For suspected pulmonary embolism, a bolus and infusion are administered while awaiting diagnosis. A continuous infusion of heparin, heparin drip, is then started. 15,000 IU (3 ml) is added to 500 ml 0.9% NaCl, or 7500 IU (1.5 ml) is added to 250 ml 0.9% NaCl. The drip is started simultaneously with the bolus dose.
• For weight > 60 kg and age < 65 years, 42 ml/hour is given. For other adults, 36 ml/hour is given. Treatment effect is monitored by APTT control. First APTT control after 6 hours.
• APTT should be 1.5-3 times the reference value, i.e., 60-120 seconds, but for increased bleeding risk, 50-80 seconds.

Indication: Anticoagulation. Deep vein thrombosis (DVT), pulmonary embolism. Intravascular coagulation, peritendinitis crepitans. Extracorporeal circulation in cardiovascular surgery and hemodialysis.

Side effects: Bleeding, thrombocytopenia, transient liver impairment.

Concentration: 5000 IU/ml, 25,000 IU/ml.

Warning: Heparin is contraindicated in cases of high risk of bleeding. Caution is recommended in thrombocytopenia and platelet function defects (including drug-induced) and in severe liver and kidney insufficiency.

Innohep (tinzaparin)

Innohep acts as an anticoagulant by enhancing antithrombin III’s inhibition of activated coagulation factors, mainly factor Xa. Innohep is a low molecular weight heparin of porcine origin. The effect of Innohep can be monitored by analyzing plasma levels of anti-Xa/ml.

Dosage: Thromboprophylaxis; in general surgery 3500 IU subcutaneously once daily, usually in the evening. In orthopedic surgery, usually 4500 IU daily subcutaneously. Pulmonary embolism and deep vein thrombosis: 175 anti-Xa units per kg body weight administered subcutaneously once daily.

Indication: Thromboprophylaxis, deep vein thrombosis (DVT), pulmonary embolism.

Concentration: Solution 10,000 IU/ml, solution 20,000 IU/ml, Pre-filled syringes; 2500 IU/ml, 3500 IU/ml, 4500 IU/ml, 10,000 IU/ml, 14,000 IU/ml, 18,000 IU/ml.

Side effects: Bleeding, thrombocytopenia, transient liver impairment, various skin reactions.

Warning: Tinzaparin is contraindicated in cases of high risk of bleeding. Caution is recommended in thrombocytopenia and platelet function defects, as well as in severe liver and kidney insufficiency, uncontrolled hypertension, hypertensive or diabetic retinopathy. Tinzaparin may cause heparin-induced thrombocytopenia (HIT type II). In HIT, patients develop antibodies, usually of the IgG type, directed against complexes of heparin and platelet factor 4.

In anticoagulant therapy combined with epidural/spinal anesthesia, there is a risk of developing epidural or spinal hematoma, which can result in long-term or permanent paralysis. The risk increases if the epidural catheter remains in place postoperatively or during removal of the epidural catheter. Epidural anesthesia during childbirth is absolutely contraindicated in women treated with tinzaparin.

Integrilin (eptifibatide)

Integrilin is an antiplatelet agent that works by blocking the binding of fibrinogen, von Willebrand factor, and other adhesive ligands to glycoprotein (GP) IIb/IIIa receptors. Inhibition is reversible 4 hours after the end of infusion with normal renal function.

Dosage: Bolus dose of 180 micrograms/kg followed by a continuous infusion of 2 micrograms/kg/min for up to 72 hours. After PCI, Integrilin is usually administered for 24 hours, up to a total of 96 hours pre- and post-PCI.

Indication: Early myocardial infarction in adults, unstable angina at high risk of developing infarction.

Concentration: Infusion solution 0.75 mg/ml. Injection solution 2 mg/ml.

Side effects: Bleeding, thrombocytopenia, cerebral ischemia, hematuria, skin rash. Anaphylactic reactions are very rare.

Warning: Eptifibatide is contraindicated in cases of high risk of bleeding. Patients with renal impairment have an increased risk of bleeding. Caution is recommended in thrombocytopenia and platelet function defects, as well as in severe liver and kidney insufficiency, uncontrolled hypertension, hypertensive or diabetic retinopathy.

Infusion with Integrilin must be stopped if the patient is to undergo thrombolysis treatment or emergency coronary bypass surgery.

In anticoagulant therapy combined with epidural/spinal anesthesia, there is a risk of developing epidural or spinal hematoma, which can result in long-term or permanent paralysis. The risk increases if the epidural catheter remains in place postoperatively or during removal of the epidural catheter.

Klexane (enoxaparin)

Klexane acts as an anticoagulant by enhancing antithrombin III’s inhibition of activated coagulation factors, mainly factor Xa. Klexane is a low molecular weight heparin of porcine origin. Klexane also works by inhibiting factor VIIa, inducing the release of endogenous TFPI (Tissue Factor Pathway Inhibitor), as well as reducing the release of vWF (von Willebrand factor). The effect of Klexane can be monitored by analyzing plasma levels of anti-Xa/ml (should be in the range of 0.5-1.2 IU anti-Xa/ml). Protamine can be used as an antidote in case of overdose.

Dosage: Thromboprophylaxis; in general surgery, 20 or 40 mg once daily, usually in the evening. In orthopedic surgery, usually 40 mg daily subcutaneously. Pulmonary embolism and deep vein thrombosis: 1.5 mg/kg (150 IU/kg) as a subcutaneous injection once daily. A two-dose regimen, with a dose of 1 mg/kg (100 IU/kg) twice daily, is recommended for patients with severe thromboembolic conditions.

Indication: Thromboprophylaxis, deep vein thrombosis (DVT), pulmonary embolism. Treatment of unstable angina and non-Q-wave infarction in combination with ASA (acetylsalicylic acid).

Side effects: Bleeding, thrombocytopenia but also thrombocytosis, transient liver impairment, various skin reactions.

Concentration: Solution 100 mg/ml. Pre-filled syringes; 100 mg/ml, 150 mg/ml.

Warning: Enoxaparin is contraindicated in cases of high risk of bleeding. Caution is recommended in thrombocytopenia and platelet function defects, as well as in severe liver and kidney insufficiency, uncontrolled hypertension, hypertensive or diabetic retinopathy. Enoxaparin may cause heparin-induced thrombocytopenia (HIT type II). In HIT, patients develop antibodies, usually of the IgG type, directed against complexes of heparin and platelet factor 4.

In anticoagulant therapy combined with epidural/spinal anesthesia, there is a risk of developing epidural or spinal hematoma, which can result in long-term or permanent paralysis. The risk increases if the epidural catheter remains in place postoperatively or during removal of the epidural catheter. Epidural anesthesia during childbirth is absolutely contraindicated in women treated with enoxaparin.

Lixiana (edoxaban)

Edoxaban is a highly selective, direct, and reversible inhibitor of factor Xa, the serine protease at the end of the common pathway in the coagulation cascade. Edoxaban inhibits free factor Xa and prothrombinase activity. Inhibition of factor Xa in the coagulation cascade reduces thrombin formation, prolongs coagulation time, and decreases the risk of thrombus formation.

Dosage: The recommended dose is 60 mg edoxaban once daily.

Indication: Edoxaban is used as prophylaxis for stroke and systemic embolism in adult patients with atrial fibrillation with one or more risk factors, such as chronic heart failure, hypertension, age ≥75 years, diabetes mellitus, previous stroke or transient ischemic attack (TIA).

Concentration: Tablets 15, 30, or 60 mg.

Warning: Contraindicated in active bleeding. Edoxaban increases the risk of bleeding and may cause severe, potentially fatal bleeding. Lixiana, like other anticoagulants, should be used with caution in patients with an increased risk of bleeding.

Novastan (argatroban)

Novastan (argatroban) is a selective, reversible, intravenous thrombin inhibitor. Novastan generally increases bleeding risk. No specific antidote is available. T 1/2 is about 36-68 minutes depending on renal function. Clearance is impaired by liver dysfunction. The drug effect may persist for about 5 hours. Reversal in case of severe bleeding can be done with prothrombin complex concentrate (Confidex/Ocplex) or NovoSeven.

• Direct thrombin inhibitor
• Only continuous intravenous administration
• Short half-life
• Rapid onset – about 30 minutes
• Steady state after 1-3 hours
• Independent of renal function and age
• No antibodies

Indication: Anticoagulation in adult patients with heparin-induced thrombocytopenia type II requiring parenteral antithrombotic therapy.

Side effects: Bleeding, bleeding complications, nosebleed, anemia, thrombocytopenia, leukopenia, hypoglycemia, hyponatremia, atrial fibrillation.

Concentration: Solution 100 mg/ml.

Dosage: The initial dosage in adult patients without liver dysfunction for HIT type II is 2 micrograms/kg/min, given as a continuous infusion.

• Baseline APTT should be measured
• Start with 2 micrograms/kg/min
• Steady state within 3 hours
• Target APTT 1.5-3 times baseline but under 100 sec
• Check APTT 2 hours after start
• Then once daily
• Maximum dose is 10 micrograms/kg/min

Warning: EDA/Spinal should not be given to patients treated with argatroban. Argatroban should not be given to patients with an EDA catheter.

Novoseven (eptacog alfa)

Hemostatic agent. Activated recombinant coagulation factor VII.

Dosage: An initial dose of 90 µg/kg body weight is recommended. The dose should be repeated every 2 hours and then at 2–3 hour intervals for the first 24–48 hours, depending on the procedure and the patient’s general condition.

Indication: Major bleeding. Novoseven is indicated for the treatment of major bleeding and for the prevention of bleeding during surgical or invasive procedures in specific risk groups. These risk groups include congenital or acquired hemophilia, isolated factor VII deficiency, Glanzmann’s thrombasthenia.

Concentration: Solution 1 mg/ml. Prepare the solution and administer it as an intravenous injection over 2–5 minutes.

Side effects: Arterial thromboembolic events (cerebral arterial occlusion, cerebrovascular event), venous thromboembolic events (pulmonary embolism, hepatic artery embolism, and deep vein thrombosis), angina pectoris, nausea, fever, erythematous skin rash. Lack of effect.

Warning: In conditions where tissue factor may be present in higher than normal amounts, there may be a risk of thrombotic disease or induction of disseminated intravascular coagulation (DIC).

Contraindications: Hypersensitivity to the active substance or to mouse, hamster, or bovine protein.

Ocplex (Prothrombin Complex Concentrate)

Hemostatic agent. Prothrombin complex concentrate. The coagulation factors II, VII, IX, and X, synthesized in the liver with the help of vitamin K.

Dosage: The dose is determined by the INR before treatment and the target INR. Normally, 2-3000 IU Ocplex is administered. A single dose should not exceed 3000 IU (120 ml Ocplex).

Indication: Major bleeding, bleeding in liver failure. Treatment of bleeding and perioperative bleeding prophylaxis in acquired deficiency of the prothrombin complex coagulation factors, such as deficiency caused by vitamin K antagonists (Warfarin) or overdose of Warfarin when rapid correction of the deficiency is required. Correction of elevated PK/INR.

Concentration: Powder for solution 500 IU.

Side effects: Thromboembolic events including myocardial infarction and pulmonary embolism. Lack of effect.

Warning: Patients receiving vitamin K antagonists may have an underlying condition of hypercoagulability, and infusion of prothrombin complex concentrate may exacerbate this. In rare cases (>0.01% and <0.1%), substitution therapy can lead to the formation of circulating antibodies that inhibit one or more of the human prothrombin complex factors.

Contraindications: Known allergy to heparin or history of heparin-induced thrombocytopenia.

Octaplas (SD Plasma)

SD plasma is a cell-free, blood group-specific human plasma with standardized levels of coagulation factors. Octaplas contains reduced levels of labile coagulation factors, FVIII and factor V, and essentially stable levels of other coagulation factors.

SD plasma is virus-inactivated using the solvent detergent (SD) method. It contains a slightly lower but standardized amount of coagulation factors compared to blood bank plasma. SD plasma is a registered pharmaceutical product ordered through pharmacies. The product is blood group-specific and cell-free. SD plasma is prepared from over 1,000 blood donors. Some loss of coagulation factors occurs during manufacturing.

Dosage: To provide adequate plasma factors for effect, about 30% of the patient’s estimated plasma volume must be administered (20-30 mL/kg body weight). To ensure sufficient levels of FV and FVIII, at least 50% must be FFP. The minimum effective transfusion volume is 10-15 mL/kg. To increase fibrinogen concentration from 0.5 g/L to 1.5 g/L, at least 4 units of plasma are needed (increase of 0.25 g/L per unit of plasma). Since the desired fibrinogen level in severe bleeding is >2.5 g/L, plasma treatment often needs to be supplemented with fibrinogen concentrate.

Indication: Peri- or postoperative bleeding. Complex deficiency of coagulation factors. Shortening or normalization of prolonged bleeding time in uremia, liver cirrhosis, and prolonged bleeding time without identifiable cause. For rapid reversal of the effects of oral anticoagulants (coumarin or indanedione).

Side effects: Risk of hypervolemia and heart failure, possibly increased risk of certain malignant diseases, risk of edema.

Volume: 200 mL/unit.

Warning: Patients with latent heart failure may develop overt heart failure and pulmonary edema.

Contraindications: Unstable angina pectoris, decompensated heart failure.

Octostim (desmopressin)

Hemostatic agent. Structural analog of the natural posterior pituitary hormone arginine vasopressin (ADH).

Dosage: 0.3 μg/kg diluted in physiological saline to 10 ml as an intravenous injection over 10 minutes or 0.3 μg/kg as a subcutaneous injection.

Indication: Bleeding. Shortening or normalization of prolonged bleeding time in uremia, liver cirrhosis, congenital or drug-induced platelet dysfunction, and in patients with prolonged bleeding time without identifiable cause. If a positive effect is obtained, the initial dose of Octostim can be repeated 1-2 times at 6-12 hour intervals.

Concentration: Solution 15 μg/ml.

Side effects: Risk of reduced urine output, water retention, and hyponatremia with accompanying symptoms, headache, nausea, vomiting, weight gain, reduced serum sodium, and in severe cases, seizures.

Warning: Small children and elderly patients, in conditions requiring diuretic treatment, in cases of disturbed fluid and/or electrolyte balance, and in cases of risk for increased intracranial pressure.

Contraindications: Unstable angina pectoris, decompensated heart failure, von Willebrand disease type 2B.

Plavix (clopidogrel)

ADP receptor inhibitor. Clopidogrel (Plavix) is a prodrug, and one of its metabolites is a platelet aggregation inhibitor that can prevent platelet activation and aggregation. Since the binding is irreversible, exposed platelets are affected for the remainder of their lifespan (approximately 7-10 days), and normal platelet function is recovered at a rate corresponding to platelet turnover.

Dosage: 75 mg daily. In the treatment of acute coronary syndromes, a loading dose of 300 mg is first administered, followed by 75 mg daily. Patients taking Plavix should generally also take ASA daily, but not more than 100 mg daily.

Indication: Prevention of thrombotic events in patients with ischemic stroke, unstable angina, acute myocardial infarction, including patients treated medically and those undergoing percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG), atrial fibrillation, and peripheral ischemic arterial insufficiency.

Concentration: tablet 75 mg, tablet 300 mg.

Side effects: Bleeding, bleeding complications, nosebleeds, anemia, thrombocytopenia, leukopenia, eosinophilia, TTP, headache, gastrointestinal bleeding, dyspepsia, abdominal pain.

Warning: EDA/Spinal should not be given to patients treated with clopidogrel. Clopidogrel should not be administered to patients with an EDA catheter. In rare cases, thrombotic thrombocytopenic purpura (TTP) has been reported during treatment with clopidogrel. Clopidogrel is not recommended during the first 7 days after acute ischemic stroke. The coagulation effects of clopidogrel are not visible in a standard thromboelastogram (TEG).

Pradaxa (dabigatran)

Dabigatran (Pradaxa^®) is a potent, oral, competitive, reversible direct thrombin inhibitor. Dabigatran etexilate is a small prodrug molecule without pharmacological activity. After oral administration, dabigatran etexilate is rapidly absorbed and converted to dabigatran through esterase-catalyzed hydrolysis in plasma and liver. Medication effect lasts 2-3 days. T_1/2 is approximately 15 hours and dependent on renal function. Reversal in case of severe bleeding is achieved with Idarucizumab (Praxbind^®). Praxbind dosing: 5.0 g IV total dose (given in two separate doses of 2.5 g with 15 minutes between). Alternatives to consider if Praxbind is not available: Tranexamic acid (Cyklokapron^®) 25 mg/kg IV or desmopressin (Octostim^®) 0.3 mcg/kg SC or IV, limited to 2 IV doses (12-24 hours apart).

Dosage: 220 mg daily. Two capsules of 110 mg daily for 10 days. 150 mg daily in case of reduced renal function.

Indication: Prevention of thrombotic events in patients undergoing orthopedic surgery with total hip or knee replacement.

Concentration: capsule 75 mg, capsule 110 mg, capsule 150 mg.

Side effects: Bleeding, bleeding complications, nosebleeds, anemia, thrombocytopenia, bronchospasm, abdominal pain, dyspepsia, liver impairment.

Warning: The risk of spinal or epidural hematoma may be increased with traumatic or repeated puncture and with prolonged use of epidural catheters. At least 2 hours should elapse after catheter removal before administering the first dose of dabigatran etexilate. Frequent monitoring of neurological function and symptoms of spinal or epidural hematoma is required for these patients.

Protamin (protamine sulfate)

Antidote to heparin. Protamine sulfate contains basic peptide sulfates that complex with heparin. For low-molecular-weight heparin (LMWH), anti-IIa activity is fully neutralized and anti-Xa activity is partially neutralized. The degree of neutralization varies between different LMWHs. The effect is almost immediate.

Dosage: Bolus dose of 5 ml (50 mg) is given IV over 10 minutes, which neutralizes approximately 7,000 IU of heparin. One ml of protamine neutralizes 1400 IU of heparin. If possible, APTT or ACT (activated clotting time) is checked immediately before and 15 minutes after administration.

Indication: Overdose and severe bleeding with heparin or LMWH. To reverse heparin effect before emergency surgery. To neutralize heparin effect during cardiopulmonary bypass.

Concentration: injection solution 1400 IU/ml.

Side effects: Excess can cause bleeding and APTT prolongation.

Warning: Hypersensitivity to protamine or fish allergy. Thrombocytopenia after cardiopulmonary bypass may worsen.

Reopro (abciximab)

Abciximab is the Fab fragment of the chimeric monoclonal antibody 7E3. It is directed against the glycoprotein (GP) IIb/IIIa (alpha_IIbbeta₃) receptor on the surface of human platelets. Abciximab inhibits platelet aggregation by blocking the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to the GPIIb/IIIa receptor on activated platelets.

Dosage: 0.25 mg per kg body weight as an intravenous

bolus dose, followed immediately by a continuous intravenous infusion of 0.125 mcg/kg/min (up to a maximum of 10 mcg/min).

Indication: Prevention of thrombotic events in patients with unstable angina and patients undergoing percutaneous coronary intervention (PCI).

Concentration: injection solution, infusion solution 2 mg/ml.

Side effects: Bleeding, bleeding complications, hypotension, anemia, thrombocytopenia, bradycardia, fever, headache, gastrointestinal bleeding, dyspnea, abdominal pain.

Contraindication: Active internal bleeding, cerebrovascular injury within the past two years, intracranial or intraspinal injury, or major surgery within the last two months.

Warning: EDA/Spinal should not be given to patients treated with abciximab. Abciximab should not be administered to patients with an EDA catheter. In rare cases, thrombocytopenia has been reported with abciximab treatment. Abciximab is not recommended within the first 7 days after an acute ischemic stroke. Coagulation effects of abciximab can be measured with Multiplate.

Streptase (streptokinase)

Streptase is a highly purified streptokinase, produced from the culture filtrate of beta-hemolytic streptococci. Activation of the endogenous fibrinolytic system begins with the formation of a streptokinase-plasminogen complex. This complex has activating properties and converts free plasminogen into proteolytically and fibrinolytically active plasmin.

Dosage: Streptase dissolved in 100 ml physiological saline is infused over 30-60 minutes, alternatively 1.5 million IU Streptase dissolved in 250 ml physiological saline is infused over 60 minutes. Initially, 250,000 IU Streptase dissolved in 100-300 ml physiological saline is infused over 30 minutes. Immediately following the initial dose, both at standard and individual dosing, a maintenance dose of 100,000 IU Streptase per hour is administered over a period of 72 hours.

Indication: Acute myocardial infarction. Recent venous and arterial thrombosis. Pulmonary embolism. Ischemic stroke.

Side effects: Blood pressure drop, allergic reactions, bleeding, transient liver impairment, myalgia.

Concentration: powder for solution 1.5 million units

Warning: Streptase is contraindicated where there is a high risk of bleeding. Caution should be exercised in the following conditions:

• Traumatic procedures, such as puncture of non-compressible vessels, intramuscular injections should be avoided.
• Risk of serious local bleeding, e.g., with aortography via the lumbar route.
• Cardiopulmonary resuscitation.
• Intubation.
• Recent childbirth or abortion.
• Urogenital diseases where bleeding or the risk of bleeding is present, e.g., with an implanted bladder catheter.
• Severe atherosclerotic vascular degeneration.
• Cavernous lung disease, such as tuberculosis.
• Previous streptokinase treatment (>5 days <6 months). In rare cases, elevated antibody titers may persist for up to 12 months or longer, and the effect may be reduced.
• Mitral valve disease with atrial fibrillation.
• Sepsis with disseminated intravascular coagulation.

Tranexamic acid (Cyklokapron/Statraxen)

Fibrinolysis inhibitor. Tranexamic acid inhibits fibrinolysis by preventing the activation of plasminogen to plasmin. Tranexamic acid does not cause thrombosis, but it inhibits the dissolution of existing thrombi.

Dosage: Initially, a slow (10 minutes) intravenous injection of 1-2 g IV is given, which can be repeated after 4-6 hours. Infusion can be administered at a dose of 70-700 mg/hour. Cyklokapron can also be given orally, in local treatment on mucous membranes, in the oral cavity, and in the nose.

Indication: Used during surgery and bleeding in patients with increased bleeding tendency. For surgeries with increased fibrinolysis, such as operations on mucous membranes, breast augmentation, thoracic and liver surgery, and prostate surgery. For surgery in patients with increased bleeding risk, such as those with known platelet defects, von Willebrand disease, and hemophilia. Can also be used for severe bleeding in trauma cases.

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Concentration: injection solution 100 mg/ml.

Side effects: In cases of DIC and microthrombotic syndromes, tranexamic acid can reduce the dissolution of fibrin in the microcirculation, thereby increasing the risk of organ failure.

Contraindications: Cyklokapron should be avoided during the first six months after acute thrombosis. In cases of severe major bleeding, single doses of tranexamic acid may be administered, but prolonged treatment over several days should be avoided. Bleeding in the urinary tract constitutes a contraindication due to the risk of obstructive clot formation.

Platelet Concentrate (platelets)

A platelet unit is prepared from whole blood by pooling platelets from 4-6 donors. Platelet concentrates are always leukocyte-depleted and contain < 1 x 10⁶ leukocytes per unit. The concentrate is prepared from buffy coat, which is obtained by centrifugation of whole blood. It also contains 100 ml of plasma.

• 350 ml of nutrient solution and plasma
• Contains over 240 x 10⁹ platelets
• Leukocyte-depleted
• Usually pooled from 4-6 donors
• Increases platelet count by 15-30 x 10⁹ within 10 minutes

Dosage: One to two units per 4 red blood cell concentrates in cases of severe bleeding. The expected platelet increase in an adult patient is 15-30 x 10⁹/L per transfused unit.

Indication: Severe bleeding or symptomatic thrombocytopenia. A guideline for good hemostasis is a platelet count > 100 x 10⁹/L. Over 60 x 10⁹/L generally provides stable hemostasis. The platelet count should always be kept above 20 x 10⁹/L if there is no bleeding and always above 40 x 10⁹/L if there is bleeding.

Side effects: Can cause thrombosis of micro or macro vessels. Can cause allergic reactions. Thrombocytopenia in TTP can worsen.

Concentration: Content: > 240 x 10⁹ platelets per unit suspended in approximately 350 ml of nutrient solution and plasma.

Warning: The most common transfusion complication is mild allergic reactions, usually caused by plasma or plasma proteins in the platelet concentrate. Anaphylactic reactions are rare (<1/100,000 transfusions), but when they occur, they are usually caused by plasma. Use special filters with small drip chambers when transfusing platelets.

Thrombosis Prophylaxis in Child Immobilization

• No immobilization prophylaxis in children before puberty

• After this, Fragmin about 100 U/kg once daily up to normal adult doses

• When treating an existing thrombosis, higher doses are often required, especially for small children. Monitor anti-Xa (should be 0.5–1.0)

• We also check antithrombin and maintain a value > 0.7 during all heparin treatment

Vitamin K (Phytomenadione)

Vitamin K is required for the synthesis of the vitamin K-dependent clotting factors II, VII, IX, X as well as proteins C and S into active clotting factors.

Dosage: In acute bleeding conditions, 10-20 mg Konakion is given intravenously. The effect begins to appear after 4-6 hours. The injection is given slowly over at least 30 seconds.

Indication: Elevated PK(INR) with bleeding risk or ongoing bleeding. Accelerate the reduction of PK(INR) before a procedure when treated with coumarin preparations (Waran). Malnutrition with liver or intestinal disease.

Concentration: injection solution 10 mg/ml.

Side effects: Thromboembolic complications. Exercise caution in patients with an increased risk of thromboembolism or a mechanical heart valve.

Warning: Injection of Konakion may cause a drop in blood pressure, so caution must be exercised when treating patients in shock.

Xarelto (Rivaroxaban)

Rivaroxaban is a synthetic, potent, oral, direct, and highly selective inhibitor of factor X (Xa). Rivaroxaban inhibits free and clot-bound factor Xa and prothrombinase activity. Rivaroxaban indirectly inhibits platelet aggregation. By inhibiting factor Xa, rivaroxaban prevents the formation of thrombin and the development of thrombi. Through FXa inhibition, rivaroxaban prolongs the prothrombin time (PT). The activated partial thromboplastin time (aPTT) and HepTest are also dose-dependently prolonged. The

effect should not be measured using PK-INR. In clinical practice, there is no need to monitor coagulation parameters during treatment with rivaroxaban. Serum concentrations of rivaroxaban can be measured, with a peak value approximately 3 hours after ingestion and a trough value just before the next dose.

Dosage: 10 mg orally once daily.

Indication: Prophylaxis of thromboembolic disease in patients undergoing selective hip or knee replacement surgery. The initial dose should be taken 6 to 10 hours after surgery, provided that hemostasis has been established.

Contraindication: Active bleeding. Severe liver disease.

Side effects: Bleeding, bleeding complications, nosebleeds, anemia, thrombocytopenia, skin rashes, tachycardia. Allergic reactions are less common.

Strength: 2.5, 10, 15, 20 mg per tablet.

Warning: It should be noted that rivaroxaban 10 mg may contribute to an elevated INR value. When switching from Waran to rivaroxaban 10 mg, the INR value (International Normalized Ratio) will be falsely elevated after taking rivaroxaban 10 mg.

INR is not a valid method for determining the anticoagulant effect of Xarelto 10 mg and should therefore not be used. Rivaroxaban should be discontinued one day (24 hours) before surgery. EDA/Spinal anesthesia should not be given to patients being treated with rivaroxaban. Experience with rivaroxaban and neuraxial blocks is limited, but a discontinuation interval of 4-6 half-lives, i.e., 3 days, is recommended before administering a block. Rivaroxaban should not be given to patients with an epidural catheter. Rivaroxaban can be resumed 24-48 hours after the removal of an epidural catheter. Treatment with rivaroxaban can be resumed 48 hours postoperatively.