Coagulation

Mechanisms of Coagulation

Posted by Kai Knudsen, Senior Physician in Anesthesia & Intensive Care, Sahlgrenska University Hospital.
Updated 2019-06-12


Thrombolysis and prevention of thromboembolism are common in acute coronary artery syndrome, stroke and other thromboembolic diseases. Bleeding-inhibiting drugs are used mainly in trauma and major bleeding due to surgery but can also be used for example in obstetric bleeding, pathological bleeding during coagulation disorders or overdose with antithrombotic drugs. A detailed description of the coagulation mechanism is outside of this framework and is referenced to specialized literature.

In case of traumatic tissue injury with hemorrhage, hemostasis starts in three parts, primary hemostasis, plasma coagulation and fibrinolysis. In the primary hemostasis, a vasoconstriction is initiated, and stimulation of platelet adhesion to form a clot. The platelets attach to an endothelial injury in the collagen with the von Willebrand factor and release thromboxane A2 and serotonin. For effective hemostasis, Hgb values > 10 g/dL is usually required. From the platelets, vWF, F-V, F-XIII and fibrinogen are released. The platelets are bound together by fibrinogen into a platelet plug which is then amplified by fibrin. Therefore, fibrinogen is necessary for a good hemostasis during severe bleeding. In the blood, a whole lot of coagulation factors are constantly circulating in inactive form. These are activated by traumatic injury or by activated cells such as platelets, endothelial cells and monocytes. When the vessel is damaged, coagulation factors are activated via a so-called initiation of plasma coagulation. This leads to the fact that the factor complex Xa/Va converts prothrombin into thrombin which leads to a boosting phase of a clot. The thrombin generated during initiation, in turn, activates circulating platelets and coagulation factors. In the activated platelets, prothrombin converts to thrombin in large amounts. At the same time, there are a number of inhibitors that restrict the clotting to the injured area, e.g. antithrombin, protein C and tissue factor pathway inhibitor (TFPI). Antithrombin prevents excessive clot formation free in the vessel lumen. Activated protein C (APC) and its cofactor protein S inactivate F-Va and F-VIIIa, which greatly reduces thrombin formation.

Figure 1. To determine treatment with antithrombin in cases with acute liver failure. If the antithrombin value is below the line at a measured INR value, it is indicated to administer antithrombin. If the value is above the line, no supply of antithrombin is required. The higher the value of INR, the lower the values ​​of antithrombin are accepted.

The task of fibrinolysis is to dissolve formed fibrin and balance the hemostasis. Plasminogen activates plasmin which, in turn, breaks down fibrin to fibrinogen degradation products (FDP). Plasminogen, in turn, 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 a fibrinolysis occurs only on the surface of a clot and not generally. T-PA is released continuously from endothelial cells, PAI-1 is formed in the liver but is also present in endothelial cells and in platelets. Factor XIII binds the soluble fibrin to a stable network and binds antiplasmin into the coagulum. Platelet aggregation is stopped when the platelets come into contact with undamaged endothelium of, for example, NO, PGI-2 and negatively charged heparan sulfates. Well balanced coagulation is necessary to cure tissue damage and do not form harmful thromboembolism and embolism. In clinical practice, a variety of tests are used to gain an understanding of the function and activity of the coagulation system. Common tests that are checked are Hgb, INR, PTT, platelets, fibrinogen, antithrombin and various graphical analysis methods of the entire coagulation such as a thromboelastogram (Rotem). Bleeding time is no longer a commonly used test. PTT (partial thromboplastin time) is measured in seconds and reveals any deficiencies in the activity of coagulation proteins in addition to factor VII and factor XIII. Low molecular weight heparins only affect the APT time marginally. In addition to depleted blood samples, there are several other essential parameters that affect hemostasis, including body temperature. Already below 36.5 degrees, the coagulation capacity decreases and below 33 degrees the coagulation capacity is halved. At low pH, below 7.2, the coagulation ability decreases as well as at Hgb values below 90 g/L. Low calcium concentration decreases the coagulation and free calcium should be kept above 1.0 mmol/L. High blood pressure increases bleeding and optimal blood pressure is considered to be systolic between 80 and 100 mm Hg but must be compared to the body’s other needs for vital organ perfusion. In the treatment of bleeding, volume substitution is initiated with crystalloid and colloidal solutions, see the chapter on bleeding and fluid replacement for optimal tissue perfusion. Blood components are normally given in the form of transfusions such as erythrocyte concentrates (SAG), plasma and platelets for optimal Hgb (90-120 g/L) and for the best rheology and best haemostasis. Generally, erythrocyte concentrate is given to an otherwise healthy small person in acute bleeding above 500 ml and normovolemia, to a normal-sized person in bleeding over 800 ml and to a large person in bleeding over 1 liter, but this can be adjusted individually according to the patient’s general condition and current Hgb. Moderate bleeding usually does not require replacement with plasma, platelets or any special pharmacological intervention to achieve good hemostasis. A rule of thumb recommends the supply of blood and plasma in the 1:1 relationship after a bleeding volume greater than 20% of the blood volume with the addition of platelets following a bleeding corresponding to the patient’s entire blood volume. Factor concentrates are used when the contents of normal plasma are not enough without the blood pressure of the blood components becoming too large. The supply of blood components is controlled by the clinical pictures and current lab values ​​(INR, PTT, fibrinogen, platelets, TEG). Guidelines for good hemostasis are Hgb > 9 g/dL, platelets > 100 x 109/L, fibrinogen > 2.0 g/L, INR < 1.5 and normal PTT. In case of massive sudden bleeding, 4 units of erythrocyte concentrate, 4 units of plasma, 1 unit of platelet concentrate, 2 g of fibrinogen and 2 g of tranexamic acid can be given initially. Body temperature should be maintained above 36 degrees. Overtransfusion should be avoided and normovolemia sought for. Follow blood gases, S-Ca and other metabolic measurements as lactate carefully.


Abciximab (Reopro®)

Abciximab (Reoppro) is the Fab fragment of the chimeric monoclonal antibody 7E3. It is targeted to the glycoprotein (GP) IIb/IIIa (alphaIIbbeta3) receptor located on the surface of human platelets. Abciximab inhibits platelet aggregation by blocking the binding of fibrinogen, von Willebrand factor and other adhesion molecules to the GPIIb/IIIa receptor on activated platelets.

Dosage: 0.25 mg per kg body weight as intravenous bolus dose, followed immediately by a continuous intravenous infusion of 0.125 μg/kg/min (up to 10 μg/min).

Indication: Prevention of thrombotic events in patients with unstable angina and patients treated with 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, shortness of breath, abdominal pain.

Contraindications: Active internal bleeding, cerebrovascular injury less than two years ago, intracranial or intraspinal injury or major surgery less than two months ago.

Caution: Epidural/Spinal anesthesia should not be given to patients treated with abciximab. Abciximab should not be given to patients who have an epidural catheter. In rare cases, thrombocytopenia has been reported during treatment with abciximab. Abciximab is not recommended during the first 7 days following acute ischemic stroke. The coagulation effect of abciximab can be measured with Multiplate.


Alteplas (Actilyse®)

Alteplas is a recombinant human tissue plasminogen activator, a glucoprotein that activates plasminogen to plasmin. Following intravenous administration, alteplas remains relatively inactive in the system circulation. After binding to fibrin, an activation occurs which leads to the conversion of plasminogen to the plasmin, which in turn leads to the dissolution of the fibrin thrombus.

Indication: Acute myocardial infarction. Pulmonary embolism. Ischemic stroke

Side effects: Blood pressure fall, bradycardia, respiratory distress.

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

Dosage: In the treatment of acute myocardial infarction with symptom debut < 6 hours, 100 mg is given to persons over 65 kg. 15 mg is given as a bolus, then 50 mg for 30 minutes and then 35 mg for 60 minutes. For persons under 65 kg, 15 mg is given as bolus, then 0.75 mg/kg i.v. for 30 minutes and then 0.5 mg/kg for 60 minutes. In the treatment of acute myocardial infarction with symptom debut 6-12 hours, 100 mg is given to persons over 65 kg. 10 mg is given as a bolus, then 50 mg for 60 minutes and then 40 mg for 120 minutes. For people under 65 kg, 1.5 mg/kg is given.

In the treatment of acute pulmonary embolism, 100 mg is given in 2 hours (120 min). Weighing less than 65 kg max 1,5 mg/kg is given. At weight over 65 kg, 100 mg is given. 10 mg (10 ml) is given as bolus, then 90 mg for 2 hours.

Caution: Actilyse is contraindicated when there is a high risk of bleeding.


Apixaban (Eliquis®)

Apixaban is a synthetic potent, oral, reversible, direct and highly selective factor X (Xa) inhibitor. Apixaban inhibits free and coagulant factor Xa and prothrombinase activity. Apixaban inhibits indirect platelet aggregation. By inhibiting factor Xa, apixaban prevents thrombin from forming and thrombus develops. By the FXa inhibition, apixaban prolongs coagulation values ​​such as prothrombin time (PTT), INR and activated partial thromboplastin time (aPTT). Changes observed in these coagulation tests at the expected therapeutic dose are small and of varying degrees. Apixaban has indications similar to Waran. Concentration determination in the serum of apixaban can be done at maximal value approximately 3 hours after intake and valley value 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. It’s used in the treatment of severe vein thrombosis and pulmonary embolism. Profylax of DVT and LE.

Contra indication: Recent review of brain, spinal or eye surgery. Another contra indication could be co-administration with other anticoagulants.

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

Concentration: 5 mg per tablet.

Caution: Apixaban should be postponed one to two days before surgery. Epidural/Spinal anesthesia should not be given to patients treated with apixaban. Experience with apixaban and neuraxial blockades is limited, but a range of 4-6 half-lives is recommended. 3-4 days before blocking. Apixaban should not be given to patients who have an epidural catheter. Apixaban can be reintroduced 24-48 hours after removal of an epidural catheter. Apixaban treatment may be re-initiated 48 hours post-operatively.


Argatroban (Novastan®)

Novastan (argatroban) is a selective, reversible, intravenous thrombin inhibitor. Novastan generally causes increased bleeding tendency. Specific antidote is missing. T1/2 is about 36-68 min depending on renal function. Clearance is impaired by hepatic impairment. The drug effect may last for about 5 hours. Reversal in severe bleeding with administration of prothrombin complex concentrate (Confidex/Ocplex) or NovoSeven.

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

Adverse reactions: Bleeding, bleeding complications, nose bleeding, anemia, thrombocytopenia, leukopenia, hypoglycaemia, hyponatraemia, atrial fibrillation.

Concentration: Solution 100 ml/ml.

Dosage: The initial dose in adult patients without hepatic impairment at HIT type II is 2 micrograms/kg/min, which is given as continuous infusion.

Caution: Epidural/spinal should not be given to patients treated with argatroban. Argatroban should not be given to patients who have an EDA catheter.


Bivalirudin (Angiox®)

Bivalirudin is a selective, reversible, intravenous thrombin inhibitor. Bivalirudin generally causes increased bleeding tendency. Specific antidote is missing. T1/2 is about 13-37 min depending on liver function. Clearance is impaired by hepatic impairment. The drug effect may last for about 3 hours. Reversal in severe bleeding with prothrombin complex concentrate (Confidex/Ocplex) or NovoSeven.

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

Side effects: Bleeding, bleeding complications, nose bleeding, anemia, thrombocytopenia, leukopenia, hypoglycaemia, hyponatraemia, atrial fibrillation.

Concentration: Powder for solution at 250 mg.

Dosage: The initial dose in adult patients without hepatic impairment at HIT type II is 2 micrograms/kg/min, which is given as continuous infusion.

Caution: Epidural/Spinal blocks should not be given to patients treated with argatroban. Argatroban should not be given to patients who have an epidural catheter.


Clopidogrel (Plavix®)

Clopidogrel is a prodrug, and one of its metabolites is a platelet aggregation inhibitor that can prevent platelet activation and platelet aggregation. Because the binding is irreversible, exposed platelets are affected for the rest of their life (approximately 7-10 days) and recovery of normal platelet function occurs at a rate corresponding to platelet turnover.

Dosage: 75 mg daily. In the treatment of acute coronary syndrome, a loading dose of 300 mg, then 75 mg daily is given. Patients taking Plavix should usually 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 with medication and patients treated with percutaneous coronary intervention (PCI) or coronary artery disease (CABG), atrial fibrillation and peripheral ischemic arterial insufficiency.

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

Caution: Epidural/Spinal anesthesia should not be given to patients treated with clopidogrel. Klopidogrel should not be given to patients who have an epidural catheter. In rare cases, thrombotic thrombocytopenia Purpura (TTP) has been reported during treatment with clopidogrel. Clopidogrel is not recommended during the first 7 days following acute ischemic stroke. The clotting effect of clopidogrel is not seen in a common thrombus stroke (TEG).


Dabigatran (Pradaxa®)

Dabigatran is a potent, oral, competitive, reversible, direct thrombin inhibitor. Dabigatran etexilate is a small pro drug molecule without pharmacological activity. After oral administration, dabigatran etexilate is rapidly absorbed and converted to dabigatran by ester-catalyzed plasma and liver hydrolysis. Drug effect lasts for 2-3 days. T1/2 is about 15 hours depending on renal function. Specific antidote is missing. Reversal in severe bleeding with prothrombin complex concentrate (Confidex/Ocplex) or NovoSeven.

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

Indication: Prevention of thrombotic events in patients who have undergone orthopedic surgery with hip or knee prosthesis.

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

Side effects: Bleeding, bleeding complications, nose bleeding, anemia, thrombocytopenia, bronchospasm, abdominal pain, dyspepsia, liver reaction.

Caution: The risk of spinal or epidural hematoma may be increased in traumatic or repeated punctures and in prolonged use of epidural catheters. After removal of the catheter, at least 2 hours should pass before the first dose of dabigatran etexilate is given. Severe observations of neurological function and symptoms of spinal or epidural hematoma are required for these patients.


Dalteparin (Fragmin®)

Dalteparin sodium is the sodium salt of low molecular weight heparin (LMWH). Daltparin’s antithrombotic effect is due to its ability to enhance antithrombin inhibition of factor Xa and thrombin, which reduces the formation of blood clots. The effect of Fragmin can be followed by analysis of plasma levels of anti-Xa/ml.

Dosage: Thromboprophylaxis; 2500/5000 IU subcutaneously 1 times daily, usually until evening. DVT: 200 IU/kg body weight is given once daily subcutaneously. Hemodialysis: Intravenous bolus injection of 30-40 IU/kg body weight, followed by intravenous infusion of 10-15 IU/kg body weight and hour. Pulmonary embolism: 100-120 IU/kg body weight twice daily was 12 hours.

Indication: Thrombosis prophylaxis, deep vein thrombosis (DVT), pulmonary embolism, intravasal coagulation, hemodialysis, unstable angina and non-Q-wave infarction.

Side effects: Haemorrhage, thrombocytopenia, transient liver effect.

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.

Caution: Dalteparin is contraindicated as there is a high risk of bleeding. Caution is advised in the case of thrombocytopenia and platelet function defects, as well as severe hepatic and renal insufficiency, uncontrolled hypertonia, hypertonia or diabetic retinopathy. Fragmine may cause heparin-induced thrombocytopenia (HIT type II). At HIT, the patient develops antibodies, usually of the IgG type directed against heparin complexes and platelet factor 4.

In anticoagulant therapy with epidural/spinal anesthesia there is a risk of developing an epidural or spinal hematoma, which may result in prolonged or permanent paralysis. The risk increases if the epidural catheter remains postoperatively or when removing an epidural catheter. Epidural anesthesia during childbirth is absolutely contraindicated in women treated with dalteparin.


Edoxaban (Lixiana®)

Edoxaban is a highly selective, direct and reversible factor Xa serine protease inhibitor at the end of the joint 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 the clotting time and reduces the risk of thromboembolism.

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

Indication: Edoxaban is given as prophylaxis of 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.

Caution: Contraindicated in case of ongoing bleeding. Edoxaban increases the risk of bleeding and can cause severe, potentially fatal bleeding. Lixiana, as well as other anticoagulants, should be used with great caution in patients with increased risk of bleeding.


Enoxaparin (Klexane®)

Enoxaparin (Klexane) appears anticoagulant by promoting antitrombin III inhibition of the activated coagulation factors, mainly factor Xa. Klexane is a low molecular weight heparin of porcine origin. Klexane also acts by inhibiting factor VIIa, induction of release of endogenous TFPI (Tissue Factor Pathway Inhibitor) as well as reduced release of vWF (von Willebrand factor). The effect of Klexane can be followed by analysis of plasma levels of anti-Xa/ml (should be in the range of 0.5-1.2 IU anti-Xa/ml). Protamine may be used as an antidote for overdose.

Dosage: Thrombosis prophylaxis; at general surgery 20 or 40 mg 1 times daily, usually until 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 a day. Two-dose procedure, with the dose of 1 mg/kg (100 IU/kg) 2 times a day, is recommended for patients with severe thromboembolic disease states.

Indication: Thrombosis prophylaxis, 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 effect, various skin reactions.

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

Caution: Enoxaparin is contraindicated when there is a high risk of bleeding. Caution is advised in the case of thrombocytopenia and platelet function defects, as well as severe hepatic and renal insufficiency, uncontrolled hypertonia, hypertonia or diabetic retinopathy. Enoxaparin may cause heparin-induced thrombocytopenia (HIT type II). At HIT, the patient develops antibodies, usually of the IgG type directed against heparin complexes and platelet factor 4.

In anticoagulant therapy with epidural/spinal anesthesia there is a risk of developing epidural or spinal hematoma, which may result in prolonged or permanent paralysis. The risk increases if the epidural catheter remains postoperatively or when removing an epidural catheter. Epidural anesthesia during childbirth is absolutely contraindicated in women treated with enoxaparin.


Eptifibatid (Integrilin®)

Integrilin is a platelet aggregation inhibitor that acts by blocking the binding of fibrinogen, von Willebrand factor and other adhesive ligands to glycoprotein (GP) IIb/IIIa receptors. The inhibition is reversible up to 4 hours after completion in patients with normal renal function.

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

Indication: Early myocardial infarction, unstable angina with high risk of developing infarction.

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

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

Caution: Eptifibatide is contraindicated when there is a high risk of bleeding. Patients with renal impairment have an increased risk of bleeding. Caution is advised in the case of thrombocytopenia and platelet function defects, as well as severe hepatic and renal insufficiency, uncontrolled hypertonia, hypertonia or diabetic retinopathy. Infusion with Integrilin must be discontinued if the patient is to undergo thrombolysis or acute coronary bypass surgery. In anticoagulant therapy with Epidural/spinal anesthesia there is a risk of developing Epidural or spinal hematoma, which may result in prolonged or permanent paralysis. The risk increases if the epidural catheter remains postoperatively or when removing epidural catheter.


Fondaparinux (Arixtra®)

Fondaparinux is a synthetic and selective factor X (Xa) inhibitor. The antithrombotic effect of fondaparinux is the result of antithrombin III (ATIII) -mediated selective inhibition of factor Xa. Inhibits both thrombin formation and thrombosis Fondaparinux does not disable thrombin and has no effect on platelets.

Dosage: 2.5 mg daily by subcutaneous injection six hours after completion of surgery. In the treatment of acute myocardial infarction or angina 2.5 mg daily s c.

Indication: 2.5 mg daily by subcutaneous injection six hours after completion of surgery. In the treatment of acute myocardial infarction or angina 2.5 mg daily, cProfylax of thromboembolic disease in conjunction with surgery. Treatment of acute myocardial infarction (non-STEMI) or angina. 

Side effects: Bleeding and 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.

Caution: Epidural/Spinal anesthesia should not be given to patients treated with fondaparinux. Fondaparinux should not be given to patients who have an Epidural catheter. In patients undergoing a coronary bypass operation (CABG) fondaparinux should, if possible, not be given 24 hours prior to surgery. Fundaparinux treatment may be re-initiated 48 hours post-operatively. The substance should not be given intramuscularly.


Heparin (Heparin®)

Heparin, which is usually found in the body complexed bound to proteines, is a highly acidic, sulphated glucosaminoglucan (mucopolysaccharide) with anticoagulant effect. In combination with the co-factor, antithrombin III, heparin affects several steps in the coagulation mechanism, which causes an anticoagulant effect. Heparin is given in the treatment of thromboembolic events such as pulmonary embolism or deep vein thrombosis.

Dosage

  • In the treatment of deep vein thrombosis, a bolus dose of 5000 E (1 ml) i.v. weighing less than 85 kg.
  • At a weight of more than 85 kg, a 7500 E (1.5 ml) bolus is given i.v. In the treatment of pulmonary embolism, a bolus of 7500 E (1.5 ml) i.v.
  • At massive DVT/PE: larger bolus (100-150 E/kg).
  • At increased bleeding risk, a bolus of 2500 E i.v. is given, except for massive pulmonary embolism/DVT.
  • In case of suspected pulmonary embolism, bolus and infusion are given pending the diagnosis. Subsequently, a continuous infusion of heparin, heparin body is given. 15000 E (3 ml) are added in 500 ml 0.9% NaCl or 7500 E (1.5 ml) in 250 ml 0.9% NaCl. The droplet is started at the same time as the bolus dose.
  • At weight > 60 kg and age <65 years, 42 ml/h is given. Other adults are given 36 ml/h. The treatment effect is monitored by PTT controls. First PTT check after 6 hours. PTT should be 1.5-3 times the reference value, that is, 60-120 sec (at increased bleeding risk 50-80 sec).

Heparin Dosing Schedule

aPTT value without increased bleeding risk (target value 60-120 sec)aPTT value at increased bleeding risk (target value 50-80 sec)Primary actionAdjust the drop rateNew sample checked
> 200 sec >160 secCheck the infusion mixture. Take a new test APTT sample, turn off the drop for 1 hour (not the first APTT after drip start)Reduce at 9 ml/hNew test after 4 hours
181-200 sec141-160 secReduce at 9 ml/hNew test after 6 hours
141-180 sec111-140 secReduce at 6 ml/hNew test after 6 hours
121-140 sec81-110 secReduce at 3 ml/hNew test after 6 hours
60-120 sec 50-80 secUnchanged infusion rateIf the first value after drip start, take a new test after 6 hours, or after 12 hours.
50-59 sec 40-49 secIncrease at 2 drops/min (= 6 ml/h)New test after 6 hours
< 50 sec < 40 secGive 2500 E of Heparin i.v. andIncrease infusion rate at 9 ml/hNew test after 6 hours

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

Side effects: Haemorrhage, thrombocytopenia, transient liver effect.

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

Caution: Heparin is contraindicated as there is a high risk of bleeding. Caution is advised in the event of thrombocytopenia and platelet function defects (including drug-induced) and severe liver and renal insufficiency.


Rivaroxaban (Xarelto®)

Rivaroxaban is a synthetic potent, oral, direct and highly selective factor X (Xa) inhibitor. Rivaroxaban inhibits free and coagulant factor Xa and prothrombinase activity. Rivaroxaban inhibits indirect platelet aggregation. By inhibiting factor Xa, rivaroxaban prevents thrombin from forming and thrombus develops. By the FXa inhibition, rivaroxaban prolongs the prothrombin time (PTT). The activated partial thromboplastin time (aPTT) and HepTest are also prolonged dose dependent. The effect should not be read through INR. In clinical practice there is no need to monitor coagulation parameters during treatment with rivaroxaban. Concentration determination in rivaroxaban serum can be done at maximal value approximately 3 hours after intake and valley 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 the operation, provided that haemostasis has been established.

Contraindications: Active bleeding. Severe liver disease.

Side effects: Bleeding, bleeding complications, nose bleeding, anemia, thrombocytopenia, rash, tachycardia. Allergic reactions are less common.

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

Caution: It should be noted that rivaroxaban 10 mg may contribute to an increased INR value. As patients switch from Waran to rivaroxaban 10 mg, the International Normalized Ratio (INR) value will be false increased 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 taken one day (24 hours) before surgery. epidural/spinal should not be given to patients treated with Rivaroxaban. Experience with Rivaroxaban and neuraxial blockades is limited, but a range of 4-6 half-lives is recommended. 3 days before blockade. Rivaroxaban should not be given to patients who have an epidural catheter. Rivaroxaban can be reintroduced 24-48 hours after removal of an epidural catheter. Rivaroxaban treatment may be re-initiated 48 hours post-operatively.


Salicylic Acid (ASA – Trombyl®)

Acetyl-Salicylic Acid has an inhibitory effect on platelet aggregation. Although the mechanism of action is not fully investigated, the effect appears to be mainly by acetylation and thus irreversible inactivation of the enzyme cyclooxygenase, which contributes to the formation of thromboxane A2 in platelets and of prostacycline in the vessel. Salicylates inhibit platelet function and enhance the effect of anticoagulants. The effect on platelets is persistent, as they lack the ability to recreate cyclooxygenase. The effect therefore remains the entire life cycle of the platelet, which is 7-10 days. Acetylsalicylic acid inhibits renal prostacyclin synthesis.

Dosage: 75 mg daily orally. In the treatment of acute coronary syndrome, a loading dose of 150-500 mg, then 75 mg daily is given.

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

Adverse reactions: Dyspepsia, bleeding, bleeding complications, nose bleeding, anemia, allergic reactions, skin reactions, dizziness, ear nuisance.

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

Caution: A pharmacodynamic interaction between clopidogrel and acetylsalicylic acid is possible, with consequent increased risk of bleeding. Caution should therefore be observed during concomitant treatment. People with known allergies or asthma are at increased risk of ASA hypersensitivity reactions.


Streptokinase (Streptase®)

Streptase is a high purity streptokinase, which is produced from culture filtrate from β-hemolysing streptococci. The activation of the endogenous fibrinolytic system begins with the formation of a streptokinase plasminogen complex. This complex has activating properties and transforms free plasminogen into proteolytic and fibrinolytically active plasmin.

Dosage: Streptase dissolved in 100 ml of saline is infused for 30-60 minutes, alternatively 1.5 million IU Streptase dissolved in 250 ml of saline saline infused for 60 minutes. Initially, 250,000 IU Streptase is dissolved in 100-300 ml of saline saline for 30 minutes. Immediate connection to the initial dose, both at standard and individual dosing, is given as maintenance dose 100,000 IU Streptase per hour for a 72 hour period.

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

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

Concentration: Powder to solution 1.5 million units

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

  • Traumatic surgery, eg puncture of non-compressible vessels, intramuscular injections should be avoided.
  • Risk of severe local bleeding, eg at aortography via lumbar route.
  • Cardiopulmonary rescue.
  • Recent childbirth or abortion.
  • Urogenital diseases where bleeding or bleeding risk is present, for example, in the case of implanted bladder catheters.
  • Severe atherosclerotic vascular degeneration.
  • Cavernous lung disease, for example tuberculosis.
  • Previous streptokinase treatment (> 5 days <6 months). In single patients, elevated antibody titers may last for up to 12 months or longer and the effect may then be reduced.
  • Mitral valve disease with atrial fibrillation.
  • Sepsis with disseminated intravasal coagulation.

Ticagrelor (Brilique®)

Ticagrelor is included in the chemical class cyclopentyltriazolopyrimidines (CPTP) which is a selective ADP receptor antagonist that can prevent platelet activation and platelet aggregation.

Dosage: Initially 180 mg orally, then 90 mg 2 times daily. Patients taking Brilique should also often take ASA daily, unless specifically contraindicated.

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

Side effects: Bleeding, bleeding complications, nose bleeding, anemia, bradycardia, dyspnoea, rash, confusion.

Concentration: 90 mg tablet.

Caution: Epidural/Spinal should not be given to patients treated with ticagrelor. Ticagrelor should not be given to patients who have an epidural catheter. The coagulation effect of ticagrelor is not seen in a common thromboplasty (TEG).


Tinzaparin (Inohep®)

Inohep appears anticoagulant by promoting antitrombin III inhibition of the activated coagulation factors, primarily factor Xa. Innohep is a low molecular weight heparin of porcine origin. The effect of Inohep can be followed by analysis of plasma levels of anti-Xa/ml.

Dosage: Thromboprophylaxis; in general surgery 3500 IU subcutaneously 1 times daily, usually until the evening. In orthopedic surgery usually 4500 IU daily subcutaneous. Pulmonary embolism and deep vein thrombosis: 175 anti-Xa units per kg body weight are administered subcutaneously once a day.

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

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

Side effects: Haemorrhage, thrombocytopenia, transient liver effect, various skin reactions.

Caution: Tinzaparine is contraindicated when there is a high risk of bleeding. Caution is advised in the case of thrombocytopenia and platelet function defects, as well as severe hepatic and renal insufficiency, uncontrolled hypertonia, hypertonia or diabetic retinopathy. Tinzaparin may cause heparin-induced thrombocytopenia (HIT type II). At HIT, the patient develops antibodies, usually of the IgG type directed against heparin complexes and platelet factor 4.

In anticoagulant therapy with Epidural/spinal anesthesia there is a risk of developing Epidural or spinal hematoma, which may result in prolonged or permanent paralysis. The risk increases if the Epidural catheter remains postoperatively or when removing Epidural catheter. Epidural anesthesia during childbirth is absolutely contraindicated in women treated with tinzaparin.


Tirofiban (Aggrastat®)

Tirofiban is a direct thrombin inhibitor to prevent thromboembolic disease. Tirofiban inhibits platelet aggregation by blocking the binding to the GPIIb/IIIa receptor on activated platelets. Tirofiban has a rapid onset effect and relatively short duration. The coagulation effect is normalized 4-8 hours after the completion of the infusion. The effect can be read as a lower value in the TRAP test that is part of the multiplate platelet function test.

Dosage: First given as a bolus dose of 25 μg/kg for 3 minutes. Thereafter 0.15 μg/kg/min up to 18 hours. Reduced dose at renal failure, 0.075 μg/kg/min.

Indication: Thrombotic prophylaxis of thrombotic heart disease (NSTE-ACS) as acute coronary syndrome with threatening myocardial infarction. Can be used preoperatively for PCI and stent of the coronary artery.

Concentration: infusion liquid, solution 50 μg/ml.

Caution: Contraindicated in case of ongoing bleeding. Caution in hepatic failure or thrombocytopenia.


Desmopressin (Octostim®)

Hemostatic (promoting blood clotting). Structural analogue to the posterior pituitary  hormone arginine vasopressin (ADH).

Dosage

0.3 μg/kg diluted in physiological saline to 10 ml as intravenous injection for 10 minutes or 0.3 μg/kg as subcutaneous injection.

Dosage of Desmopressin after Body Weight

Weight (kg)Dose (ml)
651.3
701.4
751.5
801.6
851.7
901.8
951.9
1002

Indication: Bleeding. Abbreviation or normalization of prolonged bleeding time in uremia, liver cirrhosis, congenital or drug induced platelet dysfunction as well as in patients with prolonged bleeding time without detectable etiology. If positive effect is obtained, the initial dose of Octostim may be repeated 1-2 times at 6 to 12 hours intervals.

Concentration: Solution 15 μg/ml

Side effects: Risk of decreased urine production, water retention and hyponatraemia with associated symptomatic pain, headache, nausea, vomiting, weight gain, decreased serum sodium and severe seizures.

Caution: Small children and elderly patients, in conditions requiring treatment with diuretics, in the event of a disrupted fluid and/or electrolyte balance, and at risk of increased intracranial pressure.

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


Eptacog Alfa (Novoseven®)

Hemostatic (blood clotting). Activated recombinant coagulation factor VII.

Dosage: An initial dose of 90 μg/kg body weight is recommended. The dose should be repeated after 2 hours and then 2-3 hours apart during the first 24-48 hours depending on the procedure and the patient’s general condition.

Indication: Large bleeding. Novoseven is indicated for the treatment of major bleeding and for prevention of bleeding in surgical or invasive surgery in particular risk groups. Among these risk groups are congenital or acquired haemophilia, isolated factor VII deficiency, Glanzmann’s thrombasti.

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

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

Caution: In stages of illness where tissue factor may be expected to occur more than normal, there may be a risk of thrombotic disease or induction of disseminated intravascular coagulation (DIC).

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


Fibrinogen (Riastap®)

Human fibrinogen concentrate.

Dosage: In order to calculate the individual dose, the functional fibrinogen level should be determined. If the patient’s fibrinogen level is unknown, an intravenous dose of 70 mg per kg body weight is recommended. Target level (> 2 g/l) for major bleeding (eg head injury or hemorrhage) should be maintained for seven days. Dose fibrinogen (mg/kg body weight) to be given = [target level (g/l) – measured level (g/l)]/0.017 (g/l per mg/kg body weight)]. Usually 1-2-4 g intravenously per occasion are given, repeated as needed after control of bleeding parameters. One gram of fibrinogen raises the plasma value by about 0.5 g/l.

Indication: Major bleeding, traumatic bleeding. Treatment of bleeding in patients with congenital hypo- or afibrinogenemia with bleeding tendency. The normal plasma fibrinogen level is 1.5-4.5 g/l. The critical fibrinogen level in plasma during which bleeding can occur is 0.5-1.0 g/l. In case of a major surgical procedure, it is essential to perform a precise monitoring of the replacement treatment by coagulation analysis.

Concentration: Powder for solution 1 g.

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

Caution: An increased thrombotic risk is present in patients with congenital deficiency when treated with human fibrinogen concentrate, especially at high dose or repeated dosing. Patients receiving human fibrinogen concentrate should be carefully monitored for signs and symptoms of thrombosis.

Contraindications: Hypersensitivity to the active substance or to any of the ingredients.


FVIII/VWF (Haemate®)

Human coagulation factor concentrate. Contains Factor VIII and von Willebrand factor in the ratio 1: 2.4. Bleeding prophylaxis during surgery or serious injury: To prevent extensive bleeding during or after surgical procedures, administration should commence 1 to 2 hours prior to surgical procedure. The infusion is repeated at an appropriate dose every 12-24 hours.

Dosage: 40-50 U/kg in severe bleeding.

Indication: Large bleeding, traumatic bleeding. Treatment of bleeding in patients with congenital haemorrhage. Hope Willebrand’s disease in mild or severe form. Massive bleeding with ongoing bleeding. 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.

Caution: During treatment, measurement of factor VIII levels is recommended to adjust dose and dose range. Hypersensitivity reactions occur. There is an increased risk of thrombosis.

Contraindications: Hypersensitivity to the active substance or to any of the excipients.


Fytomenadion (Vitamin K)

Vitamin K is needed so the K-vitamin-dependent coagulation factors II, VII, IX, X and proteins C and S may be synthesized into active coagulation factors.. 

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

Indication: Increased INR with bleeding risk or ongoing bleeding. Accelerate reduction of INR prior to surgery when co-administered with coumarin preparation (Waran). Malnutrition with liver or bowel disease.

Concentration: Injection fluid 10 mg/ml.

Side effects: Thromboembolic complications. Caution in patients with increased risk of thromboembolic or mechanical heart valve. 

Caution: Injection of Konakion may cause blood pressure drop, therefore caution must be observed when treating patients in shock.


Plasma (Human Plasma)

Contains centrifuged and separated human blood plasma from the blood bank with the addition of 63 mL citrate solution. Plasma contains reduced levels of the labile coagulation factors, FVIII and factor V, and substantially stable levels of other coagulation factors. Fresh-frozen plasma (FFP) is infected within 8 hours of vintage, and contains at least 70% of FVIII and other labile coagulation factors. Each plasma unit comes from a donor and the level of coagulation factors is not controlled and can vary. Takes 30-45 min to defrost and thus cannot be provided urgently. May be stored frozen for up to 3 years. In leukocyte-free/double-centrifuged units there are <1 x 106 leukocytes/unit. 

Dosage: In order for factors present in plasma to be supplied in an adequate amount to give effect, approximately 30% of the patient’s calculated plasma volume must be added (20-30 mL/kg body weight). In order to ensure adequate levels of FV and FVIII, at least 50% should 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 required (increase 0.25 g/L per unit of plasma). Since the desired fibrinogen level in severe bleeding is > 2.5 g/L, plasma treatment is often supplemented with fibrinogen concentrate. 

Indication: Per- or postoperative bleeding. Complex lack of coagulation factors such as coagulopathy due to severe liver failure or massive transfusion. As a replacement for lack of coagulation factor in acute situations when a specific coagulation factor concentrate such as factor V or XI is not available or when an exact laboratory diagnosis is not possible. To eliminate rapidly the effect of oral anticoagulants (coumarine or indanedion). In potentially dangerous bleeding associated with fibrinolysis treatment, e.g. with tissue plasminogen activators, in patients not responding to conventional treatment. In connection with plasma exchange, for example, thrombotic thrombocytopenic purpura (TTP).

Side effects: Risk of hypervolemia and heart failure, risk of transfusion-related acute pulmonary disease (TRALI), possibly increased risk of certain malignancies, risk of edema.

Volume: 210-280 mL/unit.

Caution: Patients with latent cardiac failure may develop manifest failure and pulmonary edema.

 Contraindications: Unstable angina pectoris, uncompensated heart failure.


Protamine Sulphate (Protamin®)

Protamine sulfate contains basic peptide sulfates that binds to heparin in a complex. To low molecular heparin (LMWH), anti-IIa activity is completely neutralized and anti-Xa activity in part. The degree of neutralization varies between different LMHs. The effect comes almost immediately.

Dosage: Bolus dose of 5 ml (50 mg) is given i.v. for 10 minutes which neutralizes about 7,000 IU of heparin. One ml of protamine neutralizes 1400 IU of heparin. If possible, aPTT or ACT (activation clotting time) is checked immediately before and 15 minutes after administration. 

Indication: Overdose and severe bleeding with heparin or LMH. To relieve heparin effect prior to emergency surgery. To neutralize heparin effect in conjunction with cardiopulmonary by-pass surgery. 

Concentration: Injection fluid 1400 IU/mL. 

Side effects: Excesses may cause bleeding and APTT prolongation. 

Caution: Hypersensitivity to protamine or fish allergy. Thrombocytopenia after cardiac lung can be exacerbated.


Prothrombin Complex Concentrate (Ocplex®)

Hemostatic (promoting blood clotting). The coagulation factors II, VII, IX and X, which are synthesized in the liver using vitamin K.

Dosage

The dose is determined by INR prior to treatment and the target value of INR. Usually 2-3000 IU Ocplex is given. The single dose should not exceed 3,000 IU (120 ml Ocplex).

Initial INR-valueDose (ml/kg)
(25 E/ml)
2 - 2,5 0,9 - 1,3
2,5 - 3 1,3 - 1,6
3 - 3,5 1,6 - 1,9
> 3,5 > 1,9

Indication: Major bleeding, hepatic failure with bleeding. Treatment of bleeding and perioperative bleeding prophylaxis in acquired deficiency of prothrombin complex coagulation factors, such as deficiency caused by treatment with vitamin K antagonists (Waran) or in case of overdose of Waran 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.

Caution: Patients receiving a vitamin K antagonist may have an underlying condition of hypercoagulability and infusion of prothrombin complex concentrates may exacerbate this. Substitution therapy may rarely (> 0.01% and <0.1%) lead to the formation of circulating antibodies that inhibit one or more of the human prothrombin complex factors.

Contraindications: Known heparin-related allergy to heparin-induced thrombocytopenia.


SD plasma (Octaplas®)

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

SD plasma is virus inactivated with the solvent detergent (SD) method. It has a somewhat lower but standardized content of coagulation factors compared to the plasma plasma. SD plasma is a registered drug ordered by the pharmacy. The product is blood-group specific and cell-free. SD plasma is produced from more than 1,000 blood donors. A certain loss of coagulation factors occurs in the manufacturing process.

Dosage: In order for factors present in plasma to be supplied in an adequate amount to give effect, approximately 30% of the patient’s calculated plasma volume must be added (20-30 mL/kg body weight). In order to ensure adequate levels of FV and FVIII, at least 50% should 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 required (increase 0.25 g/L per unit of plasma). Since the desired fibrinogen level in severe bleeding is > 2.5 g/L, plasma treatment is often supplemented with fibrinogen concentrate.

Indications: Per- or postoperative bleeding. Complex lack of coagulation factors. Abbreviation or normalization of prolonged bleeding time in uremi, liver cirrhosis, and prolonged bleeding time without detectable etiology. To quickly eliminate the effect of oral anticoagulants (coumarin or indanedion).

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

Volume: 200 mL/unit.

Caution: Patients with latent heart failure may develop manifest failure and pulmonary edema.

Contraindications: Unstable angina pectoris, uncompensated heart failure.


Thrombocyte Concentrate Batch (Platelets)

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

Dosage: One to two units per 4 erythrocyte concentrate in large bleeding. Expected platelet increase in an adult patient is 15-30 x 109/L per transfused unit.

Indication: Large bleeding or symptomatic thrombocytopenia. Guidelines for good hemostasis are TPC > 100 x 109/L. Over 60 x 109/L usually yield stable hemostasis. TPC should always be kept above 20 x 109/L if it does not bleed and always exceed 40 x 109/L if it bleeds.

Side effects: May cause thrombosis of micro or macro vessels. May cause allergic reactions. Thrombocytopenia at TTP may be exacerbated.

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

Caution: The most common transfusion complication is mild allergic reactions, usually caused by plasma or plasma proteins in the platelet concentrate. Anaphylactic reactions are uncommon (<1/100,000 transfusions), but when they occur, they are most commonly caused by plasma. Use special equipment with a small drip chamber at the transfusion of platelets.


Tranexamic acid

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

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

Indication: In surgery and bleeding in patients with increased bleeding tendency. For surgery with increased fibrinolysis such as mucosal, mammary, thoracic and liver surgery and prostate surgery. In the operation of patients with increased risk of bleeding such as known platelet deficiencies, von Willebrand’s disease and hemophilia. Can be tested for major bleeding in case of severe trauma.

Concentration: 100 mg/ml injection liquid.

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

Contraindications: Tranexamic acid should be avoided during the first six months after acute thrombosis. In case of severe bleeding, single doses of tranexamic acid may be given but several days of treatment should be avoided. Urinary tract bleeding is a contraindication due to risk of obstructive clot formation.


Thrombelastogram (TEG) is a viscoelastic assay method that in vitro illustrates the entire coagulation graphically in real time (showing global hemostasis). TEG provides an overall picture of how the blood coagulates during fibrin polymerization and shows the interaction between platelets, fibrin and fibrinolysis. Thrombelastogram is also called Rotation Thrombo Elasto Metry (ROTEM), NATEM or TEG (Thrombelastography).

Whole blood from the current patient is put into an analytical booth in a thrombelastograph for analysis (see image). A mechanical rotating sensor is dipped in the blood which detects hemostasis successively by the reduction of viscoelasticity gradually occurring in the clot. Typically, 0.36 ml of blood is transferred to an analyst and placed in the thrombelastograph. The blood should be analyzed within 3 minutes after sampling, preferably immediately. The thrombelastograph draws a curve while the blood coagulates and gives greater impact with a thicker curve, the more it coagulates in the test head. A straight line indicates non-coagulation. Within 5-10 minutes, an indication of current hemostasis is given that can provide guidance for the correct treatment of coagulation disorders. The result is read through a graphical reaction curve as well as numerical values. By adding different reagents, further analyzes can be made of the coagulation if necessary, the standard is called Natem. The subanalyses that can be done in addition to Natem are Extem, Fibtem, Intem, Aptem and Heptem.

Natem provides a classic thromboelastogram of whole blood made without additives. Provides a graphical analysis of global hemostasis.

Extem contains the addition of a tissue activator that gives the sample an information similar to INR. Analyzes the coagulation cascade when tissue factor (TF) is bound to FVII by activation via “extrinsic pathway”.

Fibtem uses cytokalasin D, a platelet inhibitor that blocks the contribution of platelets to coagulation to analyze the part of the fibrinogen in the coagulation.

Intimate content of phospholipids and ellagic acid as coagulation activators. Reflects coagulation activation via “Intrinsic pathway”. Intem provides an analytical response similar to aPTT. Intem is the subanalysis most similar to Natem.

Aptem is similar to Extem but can identify increased fibrinolysis via the addition of a fibrinolysis inhibitor that reverses the TEG change.

Heptem is used for heparinase analysis. Used in suspicion of the presence of heparin analogues in blood that impair the coagulation. These heparin analogues may be exogenous or endogenously administered. Upon addition of heparinase in the assay cup, these are broken down and the coagulation becomes fully or partially normalized. Heptem may be combined with Intem to distinguish heparin effect and coagulation factor deficiency.

Several numerical values ​​can be read in a trunk stroke. When analyzing a thromboelastogram, the findings are always set in relation to the usual lab values ​​that reflect the coagulation such as INR, aPTT, platelets and fibrinogen.

CT (s) is clotting time measured in seconds, usually 300-1000 sec. Reflects the time from the beginning of the measurement to the start of the coagulation with a minimum width of 2 mm in the diagram. CT is prolonged during heparin treatment or lack of coagulation factors. APTT is extended at long CT.

Alpha angle (a-angle) reflects the velocity of the clot formation. It is elevated in hypercoagulation and decreased in the absence of coagulation factors.

CFT (s) is Clotting Formation Time calculated in seconds. Measures the coagulation time in seconds until the throttle stroke has a width of 20 mm. CFT is usually 150-700 seconds. During this period, fibrin formation and stabilization of the clot with platelets and FVIII occurs. Amplitude of the thrombus chart is measured in mm at a given time (AX or A5). A5 is amplitude after 5 minutes. Amplitude provides a measure of the quality of the coagulation, where the platelet function is essential. Low amplitudes are seen in platelet deficiency or low fibrinogen levels. Fibrinolysis shows a gradual decrease in amplitude. Maximum Clot Firmness (MCF) is measured in mm and is a measure of the quality of the clog. Normal values ​​are between 40-65 mm. ML (maximum lysis) reflects fibrinolysis. This should normally be less than 15% after 1 hour. It is larger at, for example, increased fibrinolysis and DIC.



TEG (Rotem) with thrombocytopenia

TEG with thrombocytopenia (Natem = C). TEG curve has extended starting distance and long-term appearance. Both Extem, Intem and Aptem have a tapered appearance.



TEG with increased fibrinolysis

TEG with increased fibrinolysis (Fig D). The TEG curve will first have a normal amplitude, which in a short period of time decreases in amplitude when the coagulum is dissolved, the curve is narrowed heavily.


TEG with increased heparin activity

TEG with increased heparin activity. Intem gets an extended starting distance as well as Natem. This effect can be reversed with a fibrinolysis inhibitor.


ADP-test

The test’s reagent consists of ADP that activates platelets via ADP receptors. The test is sensitive to drugs such as Clopidogrel, Prasugrel and Ticagrelor. These drugs have a mechanism of action that passes through the P2Y12 receptor which is believed to be most important for ADP. The test is insensitive to ASA and NSAIDs. An alternative test for clopidogrel is ADP test HS (High sensitivity). In this test, Prostaglandin E1 is added to ADP. When clopidogrel is affected (but not by ASA), a flat curve is obtained in the ADP test against the normally high curve.


ASPI-test

The reagent of the test consists of arachidonic acid which is the substrate for the enzyme cyclooxygenase in the platelets. Cyclooxygenase converts arachidonic acid into thromboxane A2 which is a potent platelet activator. When cyclooxygenase is blocked, the formation of thromboxane A2 is inhibited and no or small platelet activation can occur. The test is sensitive to drugs that inhibit cyclooxygenase, GpIIb/IIIa antagonists, and lack of GpIIb/IIIa receptors. The test does not respond or only weakly on ADP receptor blocked as with clopidogrel or similar drugs. The test is primarily sensitive to ASA and NSAIDs. Clopidogrel, on the other hand, produces normal reaction and Reopro reduced response. As a result of ASA, you get a slight curve in the ASPI test against the normal high curve. Clopidogrel does not affect the appearance of the curve.


Reference values in Multiplate

Reference values of various  thrombocyte inhibiting agents in Multiplate’s various tests.

DrugTestBlood donor (U)Therapeutic level (U)Low responder (U)Non responder (U)
Acetylsalicylic AcidASPI65-119< 3030-65>65
ClopidogrelADP45-98< 3030-45>45
AbciximabTRAP80-160< 3030-80>80

Thrombocyte Functional Analysis

Multiplate is an analysis method with impedance technology that in vitro illustrates the platelet function graphically and numerically. Multiplate uses three different reagents (TRAP, ASPI and ADP) and is suitable for measuring the effect of drugs with anticoagulant effects. Examples of such drugs are acetylsalicylic acid (ASA), clopidogrel (Plavix) and abciximab (Reopro). Multiplate can be used to control the effect of certain anticoagulants, to control the effect of a dose increase and to check the residual effect after discontinuation. Multiplate consists of a double impedance meter that measures how whole blood platelets aggregate on the surface of a metal sensor and thereby affect the electrical resistance. Multiplate thereby measures the degree of the anticoagulant effect.

Multiplate consists of three separate tests, TRAP test, ASPI test and ADP test. Each test consists of a challenge of platelet aggregation with a reagent, TRAP, ASPI or ADP. The result appears as a graphical function over time that can be read in numerical values. The graph has a similar look for all three tests compared to a standard, see the figure below. The test drops graphically but can also be measured numerically and the answer is then measured in units (U). Normal values ​​are different for the three different tests.


Thrombocyte inhibiting medicines in Multiplate

Normal results of various  thrombocyte inhibiting agents in Multiplate’s various tests.

Multiplate Table 1

DrugsTRAPASPIADP
ASANormalReducedNormal
NSAIDNormalReducedNormal
PlavixNormalNormalReduced
ReoproReducedReducedReduced
Reference values AUC (U)94-15674-13653-122

TRAP-test

The test’s reagent consists of a thrombin receptor activating peptide (TRAP-6). The reagent is a potent platelet activator that stimulates platelet aggregation via thrombin receptors. The test is responsive to drugs that are GpIIb/IIIa antagonists. The TRAP reaction is inhibited by abciximab (Reopro) and tirofiban (Aggrastat) with little or no inhibition of ASA or clopidogrel. When numerical measurement is compared to a normal standard. Normal values ​​in the TRAP test are 80-160 U. Therapeutic level is given below 30 U. Low Responder 30-80 U and Non Responder> 80 U. The graphical curve remains high in the TRAP test under the influence of ASA or clopidogrel.


Discontinuation of Antithrombotic Medication before Surgery

SubstanceBrand NameMechanism of ActionSort of InhibitionHalf timeDiscontinuation time before planned operation
Abciximab ReoproGPIIb/IIIa Irreversible30 min 48 hours
Salicylic AcidTrombylCOX-1 Irreversible30 min 3 days
low dose (75-350 mg) as primary prophylaxis
(ASA in high dose - see table below)
30 min 3 days
as a secondary prophylaxisPatients with high thrombotic risk using ASA secondary prophylactically may continue with ASA, alternatively, abstain from ASA on the day of operation, after individual assessment.
Argatroban NovastanThrombinReversible1 hour2 2–4 hours
Bivalirudin Bivalirudin ThrombinReversible30 min4 hours
Cilostazol Cilostazol, PletalPDE3 Reversible10,5 hours5 days
Dabigatran PradaxaThrombin Reversible 12–17 hours24 hours3
Dipyridamol Dipyridamol, AsasantinAdenosineReversible10–12 hoursDiscontinuation not needed
Eptifibatid IntegrilinGPIIb/IIIa Reversible2,5 hours8 hours
Fondaparinux ArixtraFactor Xa Reversible17–21 hours36 hours
Heparin Heparin Factor IIa, IXa, Xa Reversible1–2 hours4 hours4
Iloprost Ilomedin, VentavisProstacycline analogue Reversible30 minuter 2 hours
Clopidogrel PlavixADP-receptor (P2Y12) Irreversible6–8 hours 5 days
Prasugrel EfientADP-receptor (P2Y12) Irreversible7 hours(2–15) 5 days
Rivaroxaban XareltoFactor Xa Reversible7–11 hours24 hours
Tirofiban AggrastatGPIIb/IIIa Reversible1,5 hours8 hours
Warfarin WaranProthrombine, Factor VII, IX, XReversibleR-warfarin 37–89 hours
S-warfarin 21–43 hours
3 days5
Low molecular weight heparin (therapy doses, subcutaneous), high intensity treatment
Dalteparine (>5000 E) FragminFactor IIa, Xa Reversible3–4 hours6 24 hours
Enoxaparine (>40 mg) KlexaneFactor Xa Reversible4 hours6(repeated dose, 7 hours) 24 hours
Tinzaparine (>4500 E) InohepFactor Xa Reversible3–4 hours624 hours
Low molecular weight heparin (therapy doses, subcutaneous), low intensity treatment
Dalteparine (≤5000 E) FragminFactor IIa, Xa Reversible3–4 hours6 10 hours
Enoxaparine (≤40 mg) KlexaneFactor Xa Reversible4 hours6 (repeated dose, 7 hours)10 hours
Tinzaparine (≤4500 E) InohepFactor Xa Reversible 3–4 hours6 10 hours
1 Patients with high thrombotic risk who use ASA secondary prophylactically may continue with ASA, alternatively, abstain from ASA on the day of operation, after individual assessment.
2 The efficacy of liver disease is greatly prolonged.
3The variation is large between different subpopulations
4Applies to the condition that the aPTT is normalized after the specified release time.
5Applies to therapeutic INR 2-3 and target INR prior to surgery <1.4.
6The task relates to anti-Xa activity.
 Link to Recommendations on the release of anticoagulants for neuroaxial blockade, epidural and spinal. Click here!

Discontinuation Times for Non Steroidal Anti-Inflammatory Agents (NSAID) before Surgery

SubstanceBrand NameMechanism of ActionSort of InhibitionHalf timeDiscontinuation time before planned operation
Salicylic Acid, high doseBamyl, Aspirin, TreoCOX-1 IrreversibleDose dependent, approximately 12 hours at therapeutic doses7 days
Celecoxib Celecoxib, CelebraCOX-2 Reversible8–12 hoursDiscontinuation not needed
Dexibuprofen Tradil COX-1 Reversible2 hours12 hours
Diclofenac Diclofenac, Voltaren, Arthrotec, Eeze, DicunoCOX-1 Reversible1–2 hours12 hours
Etoricoxib Etoricoxib, ArcoxiaCOX-2 Reversible22 hoursDiscontinuation not needed
Ibuprofen Brufen, Ipren, Ibumetin, Iprensa, Nurofen, IbumaxCOX-1 Reversible2 hours12 hours
Ketoprofen Orudis, SiduroCOX-1 Reversible2–3 hours12 hours
Ketorolak ToradolCOX-1 Reversible 5,3 hours24 hours
Meloxicam Meloxicam COX-1 Reversible20 hoursDiscontinuation not needed
Nabumeton RelifexCOX-2 Reversible20–25 hours Discontinuation not needed
Naproxen Naproxen, Naprosyn, Pronaxa, VimovoCOX-1 Reversible10–17 hours48 hours
Parecoxib DynastatCOX-2 Reversible22 min Discontinuation not needed
Piroxicam BrexidolCOX-1 Reversible50 hours2 weeks
Tenoxicam AlganexCOX-1 Reversible72 hours2 weeks

Apixaban (Eliquis®)

The half-life is approximately 12 hours

Reversal with: There is no specific antidote. Activated charcoal can be given orally if Eliquis has been ingested no later than 2 hours earlier.

Dosage: 100 g PO/oral tube.

Otherwise, consider treatment with:

  1. Tranexamic acid (Cyclocapron®) 25 mg/kg IV
  2. Prothrombin complex; Coagulation factor II + IX (Ocplex®) 50 units/kg IV; should not exceed 5,000 units (in single doses)
  3. Desmopressin (Octostim Injection®) 0.3 μg/kg SC or IV; should be limited to 2 IV doses (12 to 24 hours apart)

Licensing agents: Andexan alfa (AndexXa®) may be considered if available, 400 mg IV – at a bolus dose of 30 mg/min followed by continuous infusion at 4 mg/min for 120 minutes

FFP: not recommended RFVIIa (Novoseven®): not recommended


Dabigatran (Pradaxa®)

Pradaxa has a half-life of 12-14 hours but may be longer.

Reversal with: Idarucizumab (Praxbind®)

Dosage: 5.0 g IV in total dose (given in two separate doses at 2.5 g at 15 minutes intervals)

Options that may be considered if Praxbind is not available:

  1. Hemodialysis
  2. Activated charcoal; 100 g PO/oral tube if the ingestion time is less than 2 hours
  3. Tranexamic acid (Cyklokapron) 25mg/kg IV
  4. 4F-aPCC (FEIBA® – Prothrombin complex, activated) 50 Units/kg IV; may not exceed 5,000 units (in individual doses)
  5. Desmopressin (Octostim Injection®) 0.3 μg/kg SC or IV; should be limited to 2 IV doses (12 to 24 hours apart)
  • FFP: not recommended
  • RFVIIa (Novoseven®): not recommended

Enoxaparin (Klexane®)

Reversal with: Protamine Sulphate

Dosage: 1 mg per mg enoxaparin if the last injection is given within 8 hours.

0.5 mg per mg enoxaparin if the last injection is given more than 8 hours earlier.

0.5 mg per mg enoxaparin if bleeding persists 4 hours after first dose.

Single doses should not exceed 50 mg

Max infusion rate – 5 mg/min


Fondaparinux (Arixtra®)

Reversal with: Prothrombin complex, Coagulation factor II + IX (Ocplex®)

Dosage: 50 units/kg; should not exceed 5,000 units

Give one dose only .


Heparin

Reversal with: Protamine Sulphate

Protamine Sulphate is highly basic and binds acid heparin that forms a stable inactive complex.

Dosage: 1 mg per 100 units given heparin. The dose should not exceed 50 mg in total.

Max infusion rate – 5 mg/min.

Check APTT 5-15 minutes after initial dose and then after 2-8 hours.


Rivaroxaban (Xarelto®)

Rivaroxaban has a half-life of approximately 5-13 hours

Reversal with: Activated charcoal can be given if Xarelto is ingested within 2 hours. Dosage: 100 g PO/oral tube.

  1. Coagulation factor II + IX (Ocplex®) 50 units/kg IV; must not exceed 5,000 units (single doses)
  2. Tranexamic acid 25 mg/kg (Cyclocapron®) IV
  3. Desmopressin 0.3mcg/kg (Octostim Injection Fluid®) SC or IV; should be limited to 2 IV doses (12 to 24 hours apart)
  4. 4F-aPCC (FEIBA® – Prothrombin complex, activated) 50 Units/kg IV; should not exceed 5,000 units (in individual doses)

Licensed agents: Andexan alfa (Andex-Xa®) may be considered if available, 800 mg IV bolus below 30 mg/min followed by continuous infusion at 8 mg/min for 120 minutes

  • FFP: not recommended
  • RFVIIa (Novoseven®): not recommended

Warfarin (Waran®)

Reversal with: Prothrombincomplex, coagulation factor II + IX (Ocplex®) Dosage:

  • If INR 2 to <4: give 25 units/kg; The dose should not exceed 2500 units
  • If INR is 4 to 6: give 35 units/kg; do not exceed 3500 units
  • If INR> 6: give 50 units/kg; do not exceed 5000 units

If only one dose is given OR if Ocplex is not available then also provide:

  • Fresh-frozen plasma: 10-20 ml/kg plus
  • Vitamin K (Konakion): 5-10 mg in infusion (given slowly intravenously) with either Ocplex or FFP.

Repeat INR 30-60 minutes after administration of antidote.