Unfractionated heparin (UFH) is the anticoagulant of choice in acute settings (such as cardiovascular procedures or surgery) while both UFH and low-molecular-weight heparin (LMWH) are preferred agents in acute thrombosis. Heparin is an endogenously produced, linear polysaccharide that consists of repeating units of pyranosyluronic acid and glucosamine residues. Heparins contain an active pentasaccharide sequence that binds to the endogenous serin protease inhibitor antithrombin (AT), thus causing a conformational change of AT, which results in accelerated AT binding and inactivation of coagulation factors XIIa, IXa, XIa, Xa, and thrombin. Neither UFH nor LMWH have significant intrinsic fibrinolytic activity and neither provides direct thrombolysis. Most important for the clinical effect of heparin is the accelerated inhibition of thrombin and factor Xa. Once a heparin molecule has formed a complex with AT, it can easily dissociate and bind to other AT molecules, thus providing a continuous anticoagulant effect. The active pentasaccharide sequence (e.g., high-affinity-material) responsible for catalyzing AT is more prevalent in the chains of UFH than LMWH and only 30–50% of the UFH- and <20% of the LMWH molecules contain the specific and active pentasaccharide sequence. Fondaparinux is a fully synthetic analog of the naturally occurring pentasaccharide found in heparins, which selectively and irreversibly binds to AT. This results in neutralization of factor Xa, which ultimately inhibits thrombin formation and thrombus development.

Unfractionated heparin is administered either intravenously (IV) or subcutaneously. As with other medications, intravenously administered UFH achieves therapeutic plasma concentrations and its clinical effect more quickly compared to subcutaneous administration. Owing to its low bioavailability, subcutaneous UFH needs to be dosed more generously (>30,000 U/day) to reach a clinical effect. Intravenously administered heparin can be effectively monitored and adjusted based on infusion rates. To monitor the antiocoagulant effect of UFH, the activated partial thromboplastin time (aPTT) or the anti-factor Xa essay (range 0.3–0.7 IU/mL) are being utilized.

The clearance of UFH from the systemic circulation is dose-dependent and follows 2 independent mechanisms. The initial clearance is rapid and depends on saturable binding of UFH to endothelial cells, macrophages, and local proteins where UFH undergoes depolymerization. The second phase depends on renal-mediated clearance, is non-saturable, and results in non-linear UFH pharmacokinetics with anticoagulation increasing disproportionally at high therapeutic doses. At clinically effective doses, UFH is primarily cleared via depolymerization. However, if clearance becomes dependent on the kidney function and especially if the renal function is impaired, prolonged administration of UFH results in a disproportionate increase in both the intensity and the duration of the anticoagulant effect. In patients with moderate (creatine clearance [CrCl] 30–50 mL/min) to severe renal dysfunction (CrCl <30 mL/min), over-anticoagulation occurs once saturation of reticuloendothelial clearance is reached. Hospital-specific weight-based dosing nomograms are useful to streamline the administration of UFH and have been associated with shorter time to therapeutic UFH levels and no increase in bleeding events. Major complications of UFH therapy include bleeding and heparin-induced thrombocytopenia (HIT). Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder caused by antibodies to macromolecular complexes of platelet factor 4 (PF4), a positively charged platelet protein, and heparin, a negatively chared carbohydrate. Diagnostic tests for HIT consist of the platelet count (decrease of >50% from baseline), immunoassays, and functional assays. Immunoassays identify antibodies against heparin/platelet factor 4 (PF4) complexes and use an enzyme-linked immunosorbent assay (ELISA). Functional assays such as the serotonin release assay measure the platelet-activating capacity of PF4/heparin-antibody complexes. While functional assays have greater specificity than immunoassays they are also time-consuming and not as widely available.

Intracranial, intraspinal, intraocular, mediastinal, or retroperitoneal bleeding is typically classified as major bleeding and usually results in hospitalization, transfusion, possible organ failure, and death. Risk factors for major bleeding during anticoagulation with UFH include the intensity of the anticoagulant effect, increased age, female sex, history of gastrointestinal bleeding, concomitant use of other anticoagulants, and duration of therapy. Patients receiving long-term heparin therapy are also at increased risk to suffer from osteoporosis and may be prone to vertebral fractures.

Perioperative anticoagulation management is procedure-dependent and informed by the patient’s risk factors for bleeding and thrombosis. Evidence-based guidelines for the perioperative management of antithrombotic therapy contain specific recommendations. Bridging therapy is recommended in patients at moderate to high risk of thromboembolism (e.g., the prevention of thromboembolism outweighs the potential for increased surgical bleeding). For patients at low risk for thromboembolism, no bridging therapy is recommended. Preoperatively, UFH is routinely halted for 4 h prior to the surgical procedure and the effect is monitored with a normalization of the aPTT. Postoperatively, therapeutic UFH is restarted after about 12 h but will be delayed if surgical bleeding continues. One key advantage of UFH anticoagulation is that its effect may be rapidly reversed with protamine. Each mg of protamine can neutralize 100 U of heparin. Importantly, protamine is associated with development of a number of adverse effects, ranging from life-threatening anaphylactic complications in 0.16% of patients to minor reactions associated with systemic hypotension in 13% of patients. The incidence and severity of the reaction to protamine may depend on the rate of administration (maximum recommended administration rate is 5 mg/min). Patients at risk for a reaction to protamine may be pretreated with corticosteroids and anti-histamine medications.

Evidence-based guidelines help to provide safe regional anesthesia in patients receiving antithrombotic or thrombolytic therapy. As long as patients receive only low-dose UFH subcutaneously, there is no contraindication for neuraxial techniques. However, in the patient that is receiving intraoperative (and possibly high-dose) anticoagulation with UFH, therapy should be started at least 1 h after the neuraxial needle placement. The removal of indwelling catheters such as epidural catheters should not be performed unless the UFH therapy has been halted for at least 2–4 h and not without demonstration of an effect on the level of coagulation (see ◘ Table 14.1).

Low molecular weight heparin or UFH is routinely administered as high-dose (therapeutic), intermediate-dose, and low-dose (prophylactic). Prophylactic-dose LMWH is commonly prescribed to prevent venous thromboembolism (VTE) but is not sufficient in the prevention of arterial thromboembolism (e.g., stroke in atrial fibrillation). Due to the homogeneity of the polysaccharide chains, LMWHs have a superior pharmacodynamic and pharmacokinetic profile in comparison to UFHs. Other advantages of LMWH include the convenience of its fixed daily dosing regimens (once or twice), the fact that routine monitoring is not required and its track record of safety and efficacy in practice. The renal clearance for LMWH is dose-independent and the half-life is longer than for UFH (17–21 h). Anti-Xa testing is optional in high-risk patients (renal insufficiency, pregnancy, non-compliance) and its interpretation is product specific.

When administered subcutaneously, fondaparinux undergoes rapid and complete absorption and exhibits a half-life of 17–21 h and is excreted primarily unchanged in the urine in patients with normal renal function. Similar to LMWH and UHF, fondaparinux has been proven to be safe and effective for treatment of DVT and pulmonary embolism (PE). When studied in clinical trials, fondaparinux demonstrates superior efficacy in reducing VTE in various orthopedic surgeries but its incidence of major bleeding is higher compared with LMWH. Of note, the timing of fondaparinux administration has been shown to be associated with its efficacy and outcomes and the incidence of major bleeding. Fondaparinux currently does not have US Food and Drug Administration (FDA) approval for acute coronary syndromes.

The direct thrombin inhibitors (DTIs) lepirudin and hirudin are naturally occurring anticoagulants derived from the salivary glands of the medicinal leech and have demonstrated efficacy in models of thrombosis. The synthetic analogs of hirudin, bivalirudin, and desirudin exert their anticoagulant activity by direct, selective, and reversible binding to the active catalytic site and the anion-binding site of thrombin, which antagonizes the recognition and binding of fibrinogen at the anion binding exosite 1 of thrombin. Argatroban, which is derived from the amino acid arginine, is another smaller synthetic thrombin inhibitor, which also binds reversibly but non-covalently to an active thrombin site. The currently available DTIs vary significantly in regards to their pharmacologic profiles. Bivalirudin possesses a predictable, dose-dependent anticoagulant activity, has the shortest half-life, and therefore is the most suitable agent in the perioperative space. Patient-specific factors (age, cardiovascular function, and hepatic or renal dysfunction) dictate the choice of DTIs. Comorbidities and organ dysfunction in critically ill patients typically dictate lower infusion rates. Standard monitoring of DTI administration follows the aPTT, with a goal of 1.5–2.5 times control (bivalirudin) and 1.5–3 times control (argatroban) while desirudin does not require routine monitoring. As an alternative to aPTT levels and because of inconsistencies in aPTT measurements, the plasma-diluted thrombin time can be considered.

Platelets are essential to hemostasis and to the development of a pathological thrombus. In a multifactorial process, initial disruption of the endothelium exposes platelets to the adhesive proteins of the subendothelial matrix. Interactions between the matrix proteins and platelet-receptor glycoproteins enable platelet adhesion and subsequent activation of intracellular signaling pathways that trigger the release of activators such as ADP, serotonin, adrenaline, thrombin, and thromboxane A2. Via G-protein-coupled receptors, these agonists potentiate each other’s actions. Ultimately, the glycoprotein IIb/IIIa complexes on platelets bind to fibrinogen, a process that results in platelet aggregation and can culminate in thrombus formation (◘ Fig. 14.2). In summary, there are multiple steps involved in the adhesion, activation, and aggregation of platelets and more recently developed antiplatelet drugs either target platelet activating factors or associated receptors.