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This activity reviews the general principles in anticoagulation therapy, with highlights on the different types, indications, and perioperative impact of anticoagulants. Hemostasis involves an interplay of clotting factors and the vessel wall. Abnormalities of the vessel wall and the clotting factors result in the conversion of soluble fibrinogen to insoluble fibrin leading to clot formation (coagulation). Different anticoagulant options exist, and providers make expert decisions on which anticoagulant to use based on the indication, patient preference, the efficacy of individual anticoagulants in specific clinical settings, and the general treatment guidelines. This activity reviews different anticoagulation therapies, their indications, contraindications, and highlights the role of the interprofessional team in improving care for patients requiring anticoagulation. Objectives: Review the principles of anticoagulation with a brief description of the clotting cascade. Describe different anticoagulation therapies and their clinical indications. Identify different modalities used in the reversal of anticoagulation. Summarize the interprofessional strategies in improving care for patients requiring anticoagulation. Access free multiple choice questions on this topic.

Hemostasis is defined as the process of clot formation. It is divided into four stages. The first stage involves the creation of a platelet plug consequent from disruption of the vascular endothelium from injuries due to diabetes, hypertension, smoking as well as vascular wall tear. Following damage to the vascular wall, the Von Willibrand factor (VWF) is released by the endothelial cells and megakaryocytes, which mediates platelet adhesion to the damaged vascular surface, and aggregation of platelets. The second stage involves the propagation of clots by activation of various proenzymes to their active form.[1] This clotting cascade is a regulatory process of the clotting system initiated by the extrinsic pathway and propagated via the intrinsic pathway.[1] The extrinsic pathway is initiated by factor 3 (tissue factor), a membrane-bound glycoprotein that is present in the subendothelial tissues and fibroblast. Tissue factor is activated by exposure from vascular disruption or damage. Exposed tissue factor binds to factor 7 and calcium, which then converts factor 10 to activated factor 10.[2] The intrinsic pathway results from activation of factor 11 by factor 12, HMW Kininogen, and prekallikrein. Activated 11 then activates factor 9. Activated factor 9 in conjunction with its cofactor (factor 8), leads to the activation of factor 10.[3] The coagulation cascade has a common pathway that bridges the intrinsic and extrinsic pathways. Activated factor 10 with its cofactor (factor 5) in conjunction with calcium, tissue, and platelet phospholipids, converts prothrombin to thrombin. Thrombin breaks circulating fibrinogen to fibrin and activates factor 13, which crosslinks fibrin leading to a stable clot. The third stage in the clotting process is the termination of clot formation and the antithrombin control mechanism which are designed to prevent and mediate the extent of clot formation, thereby preventing processes that can lead to thrombosis, vascular inflammation, and tissue damage. This phase in the clotting pathway ensures the fluidity of blood.[1] Removal of the clot by fibrinolysis is the last stage in clot formation. This stage ensures the removal of organized clots by plasmin as well as wound healing and tissue remodeling.

The third stage in the clotting process is the termination of clot formation and the antithrombin control mechanism which are designed to prevent and mediate the extent of clot formation, thereby preventing processes that can lead to thrombosis, vascular inflammation, and tissue damage. This phase in the clotting pathway ensures the fluidity of blood.[1] Removal of the clot by fibrinolysis is the last stage in clot formation. This stage ensures the removal of organized clots by plasmin as well as wound healing and tissue remodeling. Anticoagulation or clot prevention can be directed at different sites of the coagulation pathway, with overlaps at multiple points. Direct thrombin inhibitors and direct factor 10a inhibitors can inhibit the formation of a fibrin clot. Other mechanisms through which anticoagulation can be achieved include inhibition of vitamin K-dependent factors by preventing their synthesis in the liver or modification of their calcium-binding properties. The use of anticoagulation in pregnancy is an important consideration; pregnancy is associated with a five-fold increase in the risk of venous thromboembolism, with the risk rising to twenty-fold or more during puerperium.[4] The risk further increases if underlying thrombophilia is present. The risk of venous thromboembolism persists until nearly 12 weeks postpartum.[4]

Bleeding Risk on Anticoagulation Several factors can increase the risk of bleeding in patients receiving anticoagulation therapy. The risks can be anticoagulant-related or patient-related. Providers need to consider other factors or errors that can increase the risk of bleeding in patients.[22][23] Anticoagulant-Related Risks Studies have shown that the risk of significant bleed is higher with warfarin than with direct oral anticoagulants.[24] Dose of anticoagulant Concomitant use of other medications (e.g., antiplatelet agents) that independently increase the risk of bleeding Patient-Related Risks Age Race (risk increased in Black/Brown population) Underlying medical conditions Recent surgery Coagulopathy Anticoagulation Reversal The initial step for any condition requiring urgent reversal of anticoagulation is always to discontinue the anticoagulant. Other standard measures that can be applied to most anticoagulants in certain significant and life-threatening bleeding situations include: a) Use of activated charcoal with 2 hours of the last dose of anticoagulant b) Hemodialysis c) Red blood cell transfusion for anemia d) Platelet transfusion if thrombocytopenic e) Some cases may warrant surgical or endoscopic intervention Different anticoagulants have specific reversal agents that act to counteract their effects. Unfractionated Heparin: Protamine sulfate counteracts the anti-10a activity of unfractionated heparin. Protamine sulfate has a short half-life and is usually administered intravenously. The ideal dose to achieve full resolution of anti-10a action can be calculated by 1 mg/100units of heparin remaining in the blood. The amount of heparin remaining in the blood can be estimated based on the previous dose of heparin, the interval since the last treatment, considering its half-life of one to two hours (doses of 50mg or 25mg via slow intravenous infusion). Low Molecular Weight (LMW) Heparin: Protamine sulfate is indicated for bleeding in patients on LMW heparin, although not as effective as with bleeding associated with unfractionated heparin. It is known to neutralize the larger molecules of the LMW heparin, which are the culprits in bleeding. Direct Oral Anticoagulants (Dabigatran): Idarucizumab is an anti-dabigatran monoclonal antibody fragment used in patients treated with dabigatran presenting with life-threatening bleeding. Its dose is 5 grams intravenously.

Low Molecular Weight (LMW) Heparin: Protamine sulfate is indicated for bleeding in patients on LMW heparin, although not as effective as with bleeding associated with unfractionated heparin. It is known to neutralize the larger molecules of the LMW heparin, which are the culprits in bleeding. Direct Oral Anticoagulants (Dabigatran): Idarucizumab is an anti-dabigatran monoclonal antibody fragment used in patients treated with dabigatran presenting with life-threatening bleeding. Its dose is 5 grams intravenously. Direct Oral Anticoagulants (Apixaban, Betrixaban, Edoxaban, Rivaroxaban): Andexanet alfa can be given as 800 mg bolus at 30 mg/minute followed by 960 mg infusion at 8 mg/minute or half of this dose depending on the dose of anticoagulation and last dose of direct oral anticoagulant received above 8 hours. Other Agents: Other nonspecific reversal agents that can be used if andexanet is not available are; 4-factor activated prothrombin complex concentrate (4-factor PCC), factor eight inhibitor bypassing activity (FEIBA), antifibrinolytic agents (tranexamic acid, epsilon-aminocaproic acid), or desmopressin (DDAVP).[25]

The perioperative management of anticoagulation for hospitalized and ambulatory adult patients on anticoagulation for various reasons requires expert clinical judgment tailored to the patients' needs. The decision to hold, bridge, or resume anticoagulant therapy for a patient is based on the patient's clinical condition, and established guidelines. This article focuses on recommendations formulated to assist providers in developing periprocedural antithrombotic management plans.[22] When managing surgical patients on chronic anticoagulation, providers must address the estimated risk of thromboembolism, bleeding, the timing of anticoagulation, and if anticoagulation bridging is necessary.[30][31] Patients with mitral valve prosthesis, recent cerebrovascular accident (CVA), and pulmonary embolism (PE), have a higher estimated risk for thromboembolic events and may benefit from a delay in planned surgical intervention. When considering patients with more than one predisposing thromboembolic risk, it is recommended that the condition with the highest thromboembolic risk receive precedence. The consequences of a significant thromboembolic event for patients with estimated high risk are more long-lasting when compared to the effects of a major bleed. The patient's risk for a thromboembolic event is increased depending on the interval since diagnosis, the number of predisposing conditions, and age. Patients with recent CVA or PE are likely to benefit from a delay in surgical interventions until the risk reverts to baseline.[30][32][22] Duration of Anticoagulation Therapy Treatment duration with anticoagulation should be individualized based on recurrence and risk of bleeding.[33][34] When the first episode of venous thromboembolism (provoked or unprovoked), treatment for a minimum of 3 months. Persisting or reversible risk factor, treatment may be extended to 6 or 12 months. If unprovoked proximal DVT and symptomatic PE, indefinite anticoagulation for life. When recurrent venous thromboembolism with or without anticoagulation, indefinite anticoagulation for life.

Educate at-risk patients on the disease condition and precautionary measures to minimize bleeding risk like avoiding suppositories, careful tooth brushing. Encourage ambulation and activities to keep patients in chairs and out of bed for hospitalized patients or use mechanical compression devices if no contraindication. Skin and mucosal inspection for petechiae, purpura, and open wounds.

Encourage close monitoring of patients on anticoagulation suspected of bleeding. This includes: Monitoring hemoglobin serially Monitoring heart rate and blood pressure, and electrocardiogram Administering blood products if indicated Monitor for indicators of internal bleeding like back, joint, or flank pain Monitor for dark or smoky colored urine Minimize unnecessary intravenous line placement or venipuncture