Secondary hemostasis . Cell-based model representation of coagulation with three phases: initiation , amplification , and propagation , leading to the formation of fibrin. vWF: von Willebrand Factor [6, 7, 9]. Adapted from: “Vine AK. Recent advances in haemostasis and thrombosis. Retina. 2009;29(1):1–7.” 
The fibrinolytic system aims degradation of fibrin, because after thrombus formation, its excess must be removed to restore blood flow .
The activation of plasminogen, a circulating inactive precursor to plasmin, is the beginning of fibrinolysis. This activation can occur via two pathways: one mediated by tissue plasminogen activator and urokinase-type plasminogen activator, substances released by endothelial cells after activation of coagulation, limiting unnecessary progression of thrombus [11, 12].
Plasmin does not restrict its action on fibrin. Plasmin is also able to break the degrading fibrinogen, factor V, and factor VIII .
The fibrinolytic process is regulated by natural inhibitors system : (1) plasminogen activator inhibitor 1 and plasminogen activator inhibitor 2, which act directly on plasminogen; (2) α2-antiplasmin and α2-macroglobulin, which inhibit plasmin. In addition to the thrombin-activatable fibrinolysis inhibitor, tissue plasminogen activator act by preventing to bind to the fibrin, thereby decreasing fibrinolysis [9, 12] (Fig. 4.2).
Fibrinolysis and its natural inhibitors system . Tissue plasminogen activator and urokinase-type plasminogen activator activates the fibrinolytic system by converting plasminogen to plasmin, thus leading to a degradation of fibrin into fibrin degradation products. This process is modulated by plasminogen activators 1 and 2, α2-antiplasmin, α2-macroglobulin, and thrombin-activatable fibrinolysis inhibitor [9, 11, 12]. Adapted from: “Batty P, Smith G. Anticoagulation. Surgery (Oxford). 2010;28(6):243–7.” , “Vaughan D, Declerck P. Fibrinolysis and its regulation. 1998.” and “Rau J, Beaulieu L, Huntington J, Church F. Serpins in thrombosis, hemostasis and fibrinolysis. Journal of Thrombosis and Haemostasis. 2007;5(s1):102–15.”
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What is it? Unfractionated heparin , known as standard heparin or simply heparin , is an anticoagulant drug , heterogeneous with respect to molecular size, anticoagulant action, and pharmacokinetic aspects . This drug is composed of proteins of various molecular weights, which have different kidney clearance. Only one-third of heparin molecules contain the high-affinity pentasaccharide required for anticoagulant activity. These are some aspects that justify the heterogeneous activity of the drug. Heparin acts mainly by indirect inhibition of thrombin and factor Xa .
Indications : Heparin is a commonly used medication worldwide since it is essential in the prophylaxis and treatment of thromboembolic disorders . It is indicated for the prevention and treatment of venous thromboembolism and treatment of acute coronary syndrome and other arterial conditions as well .
Dose : Heparin must be given parenterally. It is usually administered subcutaneously or by continuous intravenous infusion. When it is used for therapeutic purposes, the intravenous route is most often used [15, 16, 17]. To prescribe the appropriate heparin dose, the physician should consider the patient’s weight and associated comorbidities, as the dose of heparin depends on these factors. The initial dose of heparin for treatment of venous thromboembolism is weight based: 80 U/kg bolus and 18 U/kg/h infusion . The most used commercial presentation of unfractionated heparin for intravenous use is 5000 U/mL .
Monitoring : Since heparin has a variable anticoagulant response, the anticoagulant effect of heparin must be monitored when therapeutic doses are employed, and doses should be adjusted accordingly. The activated partial thromboplastin time (aPTT) or anti-factor Xa assay is the appropriate laboratory test. The goal is to reach an activated partial thromboplastin time within the therapeutic range of 1.5–2.5 times higher than control [13, 18–26]. The activated partial thromboplastin time should be measured approximately 6 h after the initial dose, and the continuous intravenous dose of heparin is altered in agreement with the result of the test (Table 4.1).
80 U/kg bolus, then 18 U/kg/h
aPTT, <35 s
80 U/kg bolus, then increase 4 U/kg/h
aPTT, 35–45 s
40 U/kg bolus, then increase 2 U/kg/h
aPTT, 46–70 s
aPTT, 71–90 s
Decrease infusion rate by 2 U/kg/h
aPTT, >90 s
Hold infusion 1 h, then infusion rate by 3 U/kg/h
Adverse effects : Main adverse effect of heparin is bleeding. The risk of extensive bleeding with hemodynamic consequences increases with higher doses and interaction with other medications, such as antiplatelet or fibrinolytic agents. Heparin’s antidote is protamine sulfate, and it should be used in patients experiencing major bleedings during heparin treatment: 1 mg protamine intravenous neutralizes approximately about 100 U of heparin . Another important adverse effect is heparin-induced thrombocytopenia . Heparin-induced thrombocytopenia is a dangerous adverse drug reaction that promotes antibody-mediated-platelet activation. It is defined as a relative reduction in platelet count of 50 % occurring within 5–14 days after initiation of the therapy. The diagnosis of heparin-induced thrombocytopenia is challenging and is based on the clinical probability and laboratory tests for the detection of heparin-induced thrombocytopenia antibodies. Heparin must be discontinued immediately in case of a clinical suspicion for heparin-induced thrombocytopenia . Heparin-induced thrombocytopenia has been estimated to develop in 1–5 % of the postoperative patients receiving unfractionated heparin . Ambulatory patients develop heparin-induced thrombocytopenia in frequencies lower than 1 % .
Other adverse effects are osteoporosis, which has been reported in up to 30 % of patients given long-term heparin treatment [31–34], and elevated levels of transaminases, which occur in approximately 15 % of the patients .
Contraindications/ precautions : Important limitations are the deficient bioavailability in small doses, dose-dependent clearance, and variable anticoagulant response. The use of heparin is limited in patients with osteopenia .
Heparin is contraindicated in the presence of active bleeding or disease states with an increased risk of bleeding. Patients using other drugs that can affect the clotting process should be monitored closely since the interaction between drugs may increase the chance of bleeding. In cases of spinal injection or puncture, it is necessary to seek specialist advice before considering intrathecal, epidural analgesia, anesthesia, or lumbar puncture, due to the risk of epidural hematoma, which may cause paralysis. Heparin is also contraindicated in cases of severe hepatic disease. All heparins are Australian category C in pregnancy because they are medicines that cause or may cause harmful effects to the human fetus and neonate . However, they do not cause malformations [14, 37, 38]
Low Molecular Weight Heparins
What is it? Low molecular weight heparins consist of smaller fragments of heparin and are prepared from unfractionated heparin by controlled enzymatic or chemical depolymerization. Low molecular weight heparins have a mean molecular weight of 4000–5000 (about one-third of the molecular weight of unfractionated heparin) [13, 39]. Low molecular weight heparins have advantages over heparin: better bioavailability, dose-independent clearance, predictable anticoagulant response, lower risk for heparin-induced thrombocytopenia and osteoporosis. Therefore, heparin is replaced for most indications. Low molecular weight heparins act inhibiting antithrombin and, mainly, factor Xa . Enoxaparin, dalteparin, and tinzaparin are representatives of this class of drug.
Indication: Low molecular weight heparin has the same indications of heparin: prevention and treatment of venous thromboembolism, acute pulmonary embolism, acute coronary syndromes, and other arterial conditions.
Dose : Low molecular weight heparin is typically administrated in fixed doses, subcutaneously, for thromboprophylaxis, or in body weight-adjusted doses for full therapeutic effect. For prophylaxis purposes, once-daily doses of 2500 U are recommended for moderate risk patients and 5000 U for high-risk patients. Treatment of venous thromboembolism requires doses of 100 U/kg once-daily for 5–10 days . Laboratory monitoring is generally not necessary, except in patients with kidney disease and severe obesity [40–43]. The test that evaluates the anticoagulant activity is the dosage anti-Xa activity. A more globally responsive test is the Heptest [43, 44].
Adverse effects : Main adverse effect of low molecular weight heparins is also bleeding. Heparin-induced thrombocytopenia and osteoporosis are less common with low molecular weight heparins than with unfractionated heparin (less than 1 % of patients exposed to low molecular weight heparin develop heparin-induced thrombocytopenia) [39, 45–47].
Bleeding complications can be handled with protamine sulfate. Protamine is an antidote to heparin, but it has incomplete action on low molecular weight heparins because protamine sulfate binds only the longer fragments of the chemical structure of the substance . Protamine neutralizes approximately 60 % of the anti-factor Xa activity of low molecular weight heparin [49–52].
Currently, the following scheme has been recommended :
If low molecular weight heparin was administered for less than 8 h: 1 mg of protamine per 100 anti-factor Xa units low molecular weight heparin (1 mg of low molecular weight heparin equals approximately 100 anti-factor Xa units). If the bleeding continues a second dose is recommended: 0.5 mg of protamine per 100 anti-factor Xa units.
If low molecular weight heparin was administered more than 8 h: smaller doses are needed for neutralization.
Contraindications/ precautions : The use of low molecular weight heparins in patients with creatinine clearance < 30 mL/min should be carefully monitored with anti-factor Xa. The treatment dose in cases of patients with a creatinine clearance < 30 mL/min who have acute coronary syndromes or venous thromboembolism or another acute arterial condition is half of usual dose . Severe thrombocytopenia or heparin-induced thrombocytopenia induced by heparin contraindicates the use of low molecular weight heparins. The medication is also contraindicated in case of active bleeding or disease states with an increased risk of bleeding. The concomitant use with others drugs that increase the bleeding risk should be avoided. Caution is also required in patients with thrombocytopenia, severe uncontrolled hypertension, and spinal injection or puncture. Low molecular weight heparins are also contraindicated in cases of a severe hepatic disease. In surgical patients, unless prophylactic doses are used, the risk of excessive bleeding during the procedure is increased for up to 12 h after intravenous heparin administration and up to 36 h after low molecular weight heparin administration . All heparins are Australian category C in pregnancy because they are medicines that cause or may cause harmful effects to the human fetus and neonate. However, they do not cause malformations [14, 37].
What is it? Fondaparinux is a synthetic and selective anticoagulant which blocks factor Xa. It is an alternative to heparin and low molecular weight heparins for thromboprophylaxis and treatment or venous thromboembolism . Fondaparinux has higher bioavailability and plasma half-life after subcutaneous administration in comparison to low molecular weight heparin [55, 56].
Indications: Fondaparinux is indicated for the prevention and treatment of venous thromboembolism and is accepted in the treatment of unstable angina and acute myocardial infarction [57, 58]. It has also been used in patients with heparin-induced thrombocytopenia . For initial treatment of patients with deep vein thrombosis or pulmonary embolism, it appears as effective as standard treatment (heparin or low molecular weight heparin followed by oral anticoagulation with vitamin K antagonists) with similar rates of bleeding [59, 60].
Dose: Fondaparinux is administered subcutaneously. Dosages and treatment duration varies depending on the therapeutic objectives. For venous thromboembolism prophylaxis in abdominal and orthopedic surgery, a dose of 2.5 mg once daily is recommended, initiating at least 6–8 h after surgery and continued for at least 5–9 days. For prophylaxis in high-risk medical patients, the same dose is given once daily for 6–14 days .
The dose used for the treatment of venous thromboembolism is presented in Table 4.2. Treatment is usually continued for 5–9 days and followed by oral anticoagulation .
Doses of fondaparinux for the treatment of venous thromboembolism 
Patient body weigh
Single dose 5 mg/day
>50 and <100 kg
Single dose 7.5 mg/day
Single dose 10 mg/day
The doses of fondaparinux may need to be reduced in patients with renal impairment .
The treatment does not require laboratory control. Unlike heparin, there is no specific antidote for fondaparinux .
Adverse effects : Main adverse effect of fondaparinux is bleeding. Hemorrhagic complications imply the discontinuation of treatment and, if necessary, consider blood or fresh plasma transfusion and plasma exchange. Thrombocytopenia and allergic reactions are infrequent side effects occurring in <1 % .
Contraindications/ precautions : Fondaparinux is eliminated renally and should be used with caution in patients with renal impairment. It is contraindicated in patients with creatinine clearance (CC) below 30 mL/min, and in patient with CC between 30 and 50 mL/min this drug should be used with caution .
It is also contraindicated for treatment and prophylaxis in cases of severe active bleeding, severe uncontrolled hypertension, and severe thrombocytopenia . Caution is recommended when treating patients with bodyweight below 50 kg and elderly patients due to a higher risk of bleeding . It is category C used in pregnancy because they are medicines that cause or may cause harmful effects to the human fetus and neonate. However, they do not cause malformations .
Fondaparinux should be used cautiously in those with a history of heparin-induced thrombocytopenia, and it should not be given to patients who had thrombocytopenia with heparin and who also have a positive in vitro platelet aggregation test (i.e., cross-reactivity) in the presence of fondaparinux itself .
Direct Thrombin Inhibitors
Direct thrombin inhibitors include Argatroban, Bivalirudin Danaparoid and Lepirudin and Desirudin- both recombinants forms of Hirudin. These medicine agents bind directly to thrombin and block its interaction with its substrates. Table 4.3 shows some important aspects of these drugs.
Dose, use, and considerations about the parenteral direct thrombin inhibitors
Initial dose of 1–2 mg/kg/min and the dose is adjusted to maintain the aPTT ratio in the 1.5–2.5 range
– Licensed for treatment and prevention of HIT-associated thrombosis and for anticoagulation during percutaneous coronary interventions when heparin is contraindicated because of a recent history of HIT
– Use with caution in patients with hepatic insufficiency because it has hepatic metabolism 
– It is not renally excreted, so it is particularly useful in patients with HIT with severe renal impairment
– It has a plasma half-life about 45 min
Dose should be adjusted to maintain aPTT 1.5–3 times the control
– Can also prolong the INR 
Bolus of 0.75 mg/kg followed by an infusion of 1.75 mg/kg/h for the duration of the procedure
– Licensed as an alternative to heparin in patients undergoing percutaneous interventions for unstable angina or non-ST-elevation or ST-elevation myocardial infarction and in patients with HIT (with or without thrombosis) who require percutaneous coronary interventions 
– It has a plasma half-life of about 25 min ; excreted via the kidneys
– Danaparoid is the only agent that has been evaluated for HIT in a randomized clinical trial, wherein it was reported to be significantly better than dextran
– It acts catalyzing the inhibition of factor Xa in an AT-dependent fashion
– Danaparoid does not prolong the INR
Hirudin recombinant form: Desirudin
15 mg twice daily without monitoring
– Approved in Europe and the United States for postoperative thromboprophylaxis in patients undergoing elective hip arthroplasty
– Cleared via the kidneys (dose must be reduced when the CrCl is 60 mL/min and it is contraindicated in patients with renal failure)
– It has a plasma half-life of 60 min
Hirudin recombinant form: Lepirudin
0.15 mg/kg/h with or without an initial bolus of 0.4 mg/kg
– Licensed for the treatment of thrombosis complicating HIT
– Cleared via the kidneys (dose must be reduced when the CrCl is 60 mL/min and it is contraindicated in patients with renal failure)
– Plasma half-life of 60 min
– Some patients developing antibodies against the drug that, in rare cases, can cause serious bleeding 
– Can be monitored through aPTT (dose should be adjusted to maintain aPTT 1.5–2.5 times the control)
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