Continuing Education Activity

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 the different anticoagulation therapies and their clinical indications.
• Identify the different modalities used in the reversal of anticoagulation.
• Summarize the complications of different anticoagulants, focusing on the importance of bridging anticoagulation and perioperative management of anticoagulants.

Introduction

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, 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 III (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 VII and calcium, which then converts factor X to activated factor X.[2]

The intrinsic pathway results from activation of factor XI by factor XII, HMW Kininogen, and prekallikrein. Activated XI then activates factor IX. Activated factor IX in conjunction with its cofactor (factor VIII), leads to the activation of factor X.[3]

The coagulation cascade has a common pathway that bridges the intrinsic and extrinsic pathways. Activated factor X with its cofactor (factor V) in conjunction with calcium, tissue and platelet phospholipids, converts prothrombin to thrombin. Thrombin breaks circulating fibrinogen to fibrin and activates factor XIII, 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 clot 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 Xa 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]

Anatomy and Physiology

Anticoagulants derive their effect by acting at different sites of the coagulation cascade. Some act directly by enzyme inhibition, while others indirectly, by binding to antithrombin or by preventing their synthesis from the liver (vitamin K dependent factors).

Available Anticoagulants

• Unfractionated Heparin (UFH): These include heparin, make complexes with antithrombin III, and inactivates various clotting factors. Its onset of action is rapid, a short half-life and can be monitored using activated partial thromboplastin (aPTT), activated clotting time, and anti-factor Xa activity. The recommended target ratio of aPTT is 1.5 to 2.2 times the patients' aPTT.

• Low Molecular Weight Heparin (LMWH): These are enoxaparin, dalteparin, tinzaparin, nadroparin, have a longer length of action, long half-life, and can be monitored using anti-factor Xa activity. However, monitoring is not indicated except in certain conditions like pregnancy and renal failure.

• Vitamin K Dependent Antagonists (VKA): Warfarin, one of the most common anticoagulants available. It acts by inhibiting vitamin K epoxide reductase (VKOR), which is needed for the gamma-carboxylation of vitamin K dependent factors (factors II, VII, IX, X, protein C and S). It has a narrow therapeutic window of dosing, and its effect is profoundly altered by certain factors including diet (leafy green vegetables, fruits like avocado, kiwi), medications, and genetic mutations in the VKOR complex which leads to resistance. It requires frequent monitoring with an international normalized ratio (INR).[5]

• Direct Thrombin Inhibitors: Bivalirudin, argatroban, and dabigatran are direct thrombin inhibitors; these inhibit the cleavage of fibrinogen to fibrin by thrombin. All products are renally metabolized.

• Direct Factor Xa Inhibitors: These include rivaroxaban, apixaban, edoxaban, and betrixaban. Mechanism of action involves inhibition of the cleavage of prothrombin to thrombin by binding directly to factor Xa. These products are only orally administered.

The terms direct oral anticoagulants (DOACs), new oral anticoagulants (NOACs), or target-specific oral anticoagulants (TSOACs) refer to those oral anticoagulants which specifically inhibit factors IIa (thrombin) or Xa. According to the International Society of Thrombosis and Haemostasis, DOACs is the preferred term. DOACs have been found to have similar effects when compared to other anticoagulants. Some studies have also shown possible decreased bleeding incidence with DOACs.[6][7] DOACs have increased ease of dosing with less susceptibility to dietary and drug interaction.

Indications

Indications for Anticoagulation: 

The choice of anticoagulation should be a shared decision and tailored to the patient's preference, risk stratification, and medical condition.[8][9] Anticoagulants are indicated in several conditions listed below. The main indications for anticoagulation include atrial fibrillation, venous thromboembolism, and post-heart valve replacement. Venous thromboembolism is important because they sometimes are the first sign in multiple medical conditions.[10][11][12]

• Acute Myocardial Infarction (AMI)

Early anticoagulation (AC) with heparin is indicated for all patients with a documented diagnosis of acute myocardial infarction or acute coronary syndrome. The choice of AC (heparin, unfractionated heparin (UFH), low-molecular-weight heparin, fondaparinux, or bivalirudin) depends on the therapy instituted. AC has been found to lower the risk of thrombus formation when it started early and continued for more than 48 hours. Heparin (UFH) is indicated for patients undergoing percutaneous coronary intervention (PCI). For those patients receiving fibrinolytic therapy, heparin is also indicated and continued for at least two days. Patients not undergoing PCI should be treated with low molecular weight heparin such as enoxaparin or parenteral heparin (UFH).

• Left Ventricular (LV) Thrombus

Studies have suggested the benefits of early initiation of anticoagulation in patients with documented LV thrombus to prevent embolization of thrombus.[13] Anticoagulation therapy should be continued for three to four months as the risk of embolization was found to be highest within the first 3-4 months. Although no extensive randomized studies have been conducted with the NOACs in this disease state, as compared to warfarin, it is recommended that NOACs be used due to the convenience of dosing. Vitamin K dependent anticoagulants like warfarin with a therapeutic target INR of 2-3, continue to be used most commonly.

•  Atrial Fibrillation

Anticoagulation reduces the embolic risk in patients with atrial fibrillation. The risk for embolization is the same for patients with paroxysmal, persistent, or chronic atrial fibrillation. Atrial fibrillation is an independent risk factor for stroke. It is present in approximately 20% of patients with a first-time stroke and contributes to increased mortality and disability.[14] The embolic risk for patients with atrial fibrillation can be assessed using scoring systems like the CHA2DS2-VASc score.

• Left Ventricular Aneurysm

A left ventricular aneurysm can be a complication of acute myocardial infarction. Patients with a left ventricular aneurysm are at high risk for a thromboembolic event. Among other medical therapies, anticoagulation reduces thromboembolic events, especially in those with arrhythmia.

• Prosthetic Heart Valve

Anticoagulation therapy is indicated in patients with a prosthetic heart valve. Vitamin K dependent anticoagulants are recommended for patients with prosthetic heart valves in addition to the use of unfractionated heparin or low-molecular-weight heparin at any point when vitamin K antagonist therapy is interrupted.[15] Direct oral anticoagulants are not indicated in patients with a prosthetic heart valve. The ideal level of vitamin K dependent anticoagulants varies depending on the diseased valve and the presence of additional thromboembolic risk factors. 

• Venous Thromboembolism Treatment

Anticoagulation is used in the treatment of venous thromboembolism (deep vein thrombosis and pulmonary emboli). The duration for anticoagulation in these clinical states depends on the precipitating circumstances, and additional thromboembolic risk and comorbidities.

• Venous Thromboembolism Prophylaxis

Anticoagulants are indicated for the prevention of venous thromboembolism in selected patient populations (hospitalized patients, post-operative state, cancer patients). Adverse events like thromboembolism are reduced in patients receiving prophylactic anticoagulation.[16]

• Treatment of Venous Thromboembolism in Patients with Cancer

Thromboembolism is a frequent complication in cancer patients due to the release of procoagulants from neoplastic cells. Several studies have demonstrated that LMWH is superior to VKAs in the treatment of VTE in cancer patients.[17]

• Heparin-Induced Thrombocytopenia

Although thrombocytopenia increases bleeding risk, it has been shown to predispose patients to venous thromboembolism. Heparin-induced thrombocytopenia is antibody-mediated with complications that include pulmonary embolism, acute myocardial infarction, and ischemic limb necrosis. Therefore, estimation of the bleeding risk before initiation of anticoagulation is essential. The use of argatroban, lepirudin, or danaparoid is recommended over other non-heparin anticoagulants.[18]

• Pregnancy

Anticoagulants are indicated in pregnancy for the treatment of acute venous thromboembolism, valvular heart disease, and pregnancy-related complications in women with antiphospholipid antibody syndrome, antithrombin deficiency, or other thrombophilias who had a prior VTE.[19] Warfarin is more efficacious than unfractionated heparin for the prevention of thromboembolism in pregnant ladies with mechanical valves. But, warfarin therapy in the first trimester of pregnancy is associated with a significant increase in fetal anomalies.

Contraindications

Anticoagulation should be avoided in patients with absolute contraindications, such as in the following conditions:

• Active bleeding
• Coagulopathy
• Recent major surgeries
• Acute intracranial hemorrhage
• Major trauma

Anticoagulation may be considered in those with relative contraindications such as the following conditions:

• Gastrointestinal bleed
• Low-risk surgeries
• Aortic dissection or aneurysm

Anticoagulation should be used cautiously in these patients:[20]

• Geriatrics
• Pregnant patients

Equipment

Laboratory Monitoring and Testing for Anticoagulation

Measurement and monitoring of anticoagulation levels and concentrations may be indicated in certain situations like:

1. Bleeding
2. Thrombosis
3. Urgent or elective invasive procedures
4. Thrombolysis
5. Overdose
6. Therapeutic levels for multiple conditions
7. Preoperative testing
8. Liver disease

Routine monitoring of direct oral anticoagulants (DOAC) levels is not generally indicated unless in certain conditions with high bleeding risk, such as neural procedures that require no anticoagulant effect. Assays for anti-Xa or anti-IIa activity are recommended methods in these conditions for quantitative information.[21]

The initial testing in any individual with suspected bleeding history is listed below. Several point-of-care tests (POCT) for anticoagulation are used in operating rooms. POCT can measure bleedings assays like prothrombin time (PT) and activated partial thromboplastin time (aPTT), fibrinogen assay, and whole blood platelet function test.

• CBC with platelet count and morphology
• Bleeding Time: An insensitive test that is not commonly in use. This test shows how quickly bleeding can stop. The test provides information on platelet disorder, vascular contractility, Von Willibrand disorder (VWD), and thrombocytopenia.
• Clotting Time: This is the time it takes for plasma to clot after the addition of different substrates in vitro under standard conditions using the capillary method. The average clotting time is between 8 to 15 minutes. Some studies have disputed the use of clotting time as a screening test.
• Prothrombin Time (PT)/INR: This is the initial test used to identify defects in secondary hemostasis. It is the time taken for blood to clot and generates thrombin. A delay in the PT or aPTT indicates the presence of either a deficiency or inhibitor of the clotting factor, except for the antiphospholipid antibody, which can result in delayed aPTT. The normal range for PT levels is approximately 11 to 13 seconds, although levels may vary depending on the laboratory.
• Activated Partial Thromboplastin Time (aPTT): Used to assess the intrinsic and common pathways of coagulation. The typical values range from 25 to 35 seconds, though this may vary between laboratories.
• Thrombin Time: This measures the final step in the clotting cascade. Abnormal thrombin time can be caused by thrombin inhibitor anticoagulants like heparin, dabigatran, argatroban, and any abnormalities in fibrinogen.
• Specific Clotting Factor Assays: This test is specific for individual factor deficiencies. It is done with the mixing study.
• Clot Solubility: This test is used to assess for deficiency of factor XIII. Factor XIII crosslinks the fibrin clot after its formation.
• Fibrin D-dimer: Released from the cleavage of fibrin cross-linked by plasmin.

Complications

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: 

1. Studies have shown that the risk of significant bleed is higher with warfarin than with direct oral anticoagulants.[24]
2. Dose of anticoagulant
3. Concomitant use of other medications (e.g., antiplatelet agents) that independently increase the risk of bleeding

• Patient-Related Risks:

1. Age
2. Race (risk increased in Black/Brown population)
3. Underlying medical conditions
4. Recent surgery
5. 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.

1. Unfractionated Heparin: Protamine sulfate counteracts the anti-Xa 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-Xa action can be calculated by 1mg /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).
2. 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.
3. 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. 
4. 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.
5. 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]

Clinical Significance

Bridging Anticoagulation

Perioperative and periprocedural anticoagulation management is a constant clinical dilemma for providers. Estimation of the risk of thromboembolism, bleeding, and timing of anticoagulation should be considered for patients undergoing elective procedures. Bridging anticoagulation, most commonly with low molecular weight heparin, should be considered in cases with considerable risk of thromboembolic events. For patients with low risk, bridging anticoagulation is not indicated. However, for patients with significant risk, bridging anticoagulation is indicated.[26][27][28] The American College of Cardiology (ACC), American Heart Association (AHA), and HRS (Heart Rhythm Society) recommendations are considered.[29]

Initiating Anticoagulation Treatment with Warfarin

• Nonvalvular Atrial Fibrillation: No bridging with heparin product is indicated when initiating therapy with warfarin for patients with uncomplicated nonvalvular atrial fibrillation. Bridging anticoagulation is not recommended for patients at low or moderate risk for thromboembolism.
• Mechanical Heart Valve: Bridging with heparin is indicated for patients with a mechanical heart valve.
• Recent Venous Thromboembolism (VTE) or Active Arterial Thromboembolism (TE): Bridging anticoagulation with a heparin product is indicated when initiating treatment for recent pulmonary emboli
• Coronary stenting within 12 weeks

Bridging overlap

Therapeutic doses of the direct oral anticoagulants are achieved within two to three hours of initiating treatment, and bridging therapy with heparin may be discontinued.

For oral Vitamin K antagonist, bridging overlap may last for up to 4 to 5 days before achieving a therapeutic level.

Enhancing Healthcare Team Outcomes

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.

Nursing, Allied Health, and Interprofessional Team Interventions

• 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 chair 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.

Nursing, Allied Health, and Interprofessional Team Monitoring

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