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. This clotting cascade is a regulatory process of the clotting system initiated by the extrinsic pathway and propagated via the intrinsic pathway. 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.
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.
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.
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. The risk further increases if underlying thrombophilia is present. The risk of venous thromboembolism persists until nearly 12 weeks postpartum.
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).
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. DOACs have increased ease of dosing with less susceptibility to dietary and drug interaction.
Indications for Anticoagulation:
The choice of anticoagulation should be a shared decision and tailored to the patient's preference, risk stratification, and medical condition. 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.
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).
Studies have suggested the benefits of early initiation of anticoagulation in patients with documented LV thrombus to prevent embolization of thrombus. 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.
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. The embolic risk for patients with atrial fibrillation can be assessed using scoring systems like the CHA2DS2-VASc score.
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.
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. 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.
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.
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.
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.
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.
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. 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.
Anticoagulation should be avoided in patients with absolute contraindications, such as in the following conditions:
Anticoagulation may be considered in those with relative contraindications such as the following conditions:
Anticoagulation should be used cautiously in these patients:
Laboratory Monitoring and Testing for Anticoagulation
Measurement and monitoring of anticoagulation levels and concentrations may be indicated in certain situations like:
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.
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.
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.
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
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.
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. The American College of Cardiology (ACC), American Heart Association (AHA), and HRS (Heart Rhythm Society) recommendations are considered.
Initiating Anticoagulation Treatment with Warfarin
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.
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.
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.
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.
Duration of Anticoagulation Therapy
Encourage close monitoring of patients on anticoagulation suspected of bleeding. This includes;
|||Mackman N,Tilley RE,Key NS, Role of the extrinsic pathway of blood coagulation in hemostasis and thrombosis. Arteriosclerosis, thrombosis, and vascular biology. 2007 Aug [PubMed PMID: 17556654]|
|||Butenas S,Orfeo T,Mann KG, Tissue factor in coagulation: Which? Where? When? Arteriosclerosis, thrombosis, and vascular biology. 2009 Dec [PubMed PMID: 19592470]|
|||Gailani D,Renné T, Intrinsic pathway of coagulation and arterial thrombosis. Arteriosclerosis, thrombosis, and vascular biology. 2007 Dec [PubMed PMID: 17916770]|
|||Marshall AL, Diagnosis, treatment, and prevention of venous thromboembolism in pregnancy. Postgraduate medicine. 2014 Nov [PubMed PMID: 25387211]|
|||Antoniou S, Rivaroxaban for the treatment and prevention of thromboembolic disease. The Journal of pharmacy and pharmacology. 2015 Aug [PubMed PMID: 26059702]|
|||Burnett AE,Mahan CE,Vazquez SR,Oertel LB,Garcia DA,Ansell J, Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE treatment. Journal of thrombosis and thrombolysis. 2016 Jan [PubMed PMID: 26780747]|
|||[PubMed PMID: 30298305]|
|||Zeballos-Palacios CL,Hargraves IG,Noseworthy PA,Branda ME,Kunneman M,Burnett B,Gionfriddo MR,McLeod CJ,Gorr H,Brito JP,Montori VM, Developing a Conversation Aid to Support Shared Decision Making: Reflections on Designing Anticoagulation Choice. Mayo Clinic proceedings. 2019 Apr [PubMed PMID: 30642640]|
|||Giustozzi M,Agnelli G,Quattrocchi S,Acciarresi M,Alberti A,Caso V,Vedovati MC,Venti M,Paciaroni M, Rates and Determinants for the Use of Anticoagulation Treatment before Stroke in Patients with Known Atrial Fibrillation. Cerebrovascular diseases extra. 2020 May 6 [PubMed PMID: 32375143]|
|||Pachón V,Trujillo-Santos J,Domènech P,Gallardo E,Font C,González-Porras JR,Pérez-Segura P,Maestre A,Mateo J,Muñoz A,Peris ML,Lecumberri R, Cancer-Associated Thrombosis: Beyond Clinical Practice Guidelines-A Multidisciplinary (SEMI-SEOM-SETH) Expert Consensus. TH open : companion journal to thrombosis and haemostasis. 2018 Oct [PubMed PMID: 31249964]|
|||[PubMed PMID: 31727694]|
|||Maraveyas A,Muazzam I,Noble S,Bozas G, Advances in managing and preventing thromboembolic disease in cancer patients. Current opinion in supportive and palliative care. 2017 Dec [PubMed PMID: 29068809]|
|||Leow AS,Sia CH,Tan BY,Loh JP, A meta-summary of case reports of non-vitamin K antagonist oral anticoagulant use in patients with left ventricular thrombus. Journal of thrombosis and thrombolysis. 2018 Jul [PubMed PMID: 29616407]|
|||Paciaroni M,Agnelli G,Caso V,Venti M,Milia P,Silvestrelli G,Parnetti L,Biagini S, Atrial fibrillation in patients with first-ever stroke: frequency, antithrombotic treatment before the event and effect on clinical outcome. Journal of thrombosis and haemostasis : JTH. 2005 Jun [PubMed PMID: 15892862]|
|||[PubMed PMID: 30947924]|
|||Mejilla A,Guirguis M,Koshman S,Bungard TJ, Venous Thromboembolism Prophylaxis on General Internal Medicine Units: Are Patients Well Served by Current Practice? The Canadian journal of hospital pharmacy. 2017 May-Jun [PubMed PMID: 28680173]|
|||Donnellan E,Khorana AA, Cancer and Venous Thromboembolic Disease: A Review. The oncologist. 2017 Feb [PubMed PMID: 28174293]|
|||Linkins LA,Dans AL,Moores LK,Bona R,Davidson BL,Schulman S,Crowther M, Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb [PubMed PMID: 22315270]|
|||[PubMed PMID: 23979047]|
|||Lin KJ,Singer DE,Glynn RJ,Blackley S,Zhou L,Liu J,Dube G,Oertel LB,Schneeweiss S, Prediction Score for Anticoagulation Control Quality Among Older Adults. Journal of the American Heart Association. 2017 Oct 5 [PubMed PMID: 28982676]|
|||Winter WE,Flax SD,Harris NS, Coagulation Testing in the Core Laboratory. Laboratory medicine. 2017 Nov 8 [PubMed PMID: 29126301]|
|||Nutescu EA,Wittkowsky AK,Burnett A,Merli GJ,Ansell JE,Garcia DA, Delivery of optimized inpatient anticoagulation therapy: consensus statement from the anticoagulation forum. The Annals of pharmacotherapy. 2013 May [PubMed PMID: 23585642]|
|||[PubMed PMID: 11742930]|
|||Su Z,Zhang H,He W,Ma J,Zeng J,Jiang X, Meta-analysis of the efficacy and safety of non-vitamin K antagonist oral anticoagulants with warfarin in Latin American patients with atrial fibrillation. Medicine. 2020 May [PubMed PMID: 32358343]|
|||Rowe AS,Dietrich S,Hamilton LA, Analysis of anticoagulation reversal survey (ARES). Hospital practice (1995). 2020 Apr 15 [PubMed PMID: 32295428]|
|||Lewin AR,Collins PE,Sylvester KW,Rimsans J,Fanikos J,Goldhaber SZ,Connors JM, Development of an Institutional Peri-procedural Management Guideline for Oral Anticoagulants. Critical pathways in cardiology. 2020 Apr 1 [PubMed PMID: 32243278]|
|||[PubMed PMID: 32067650]|
|||Bell BR,Spyropoulos AC,Douketis JD, Perioperative Management of the Direct Oral Anticoagulants: A Case-Based Review. Hematology/oncology clinics of North America. 2016 Oct [PubMed PMID: 27637308]|
|||Garcia DA,Regan S,Henault LE,Upadhyay A,Baker J,Othman M,Hylek EM, Risk of thromboembolism with short-term interruption of warfarin therapy. Archives of internal medicine. 2008 Jan 14 [PubMed PMID: 18195197]|
|||Bhalla V,Lamping OF,Abdel-Latif A,Bhalla M,Ziada K,Smyth SS, Contemporary Meta-Analysis of Extended Direct-Acting Oral Anticoagulant Thromboprophylaxis to Prevent Venous Thromboembolism. The American journal of medicine. 2020 Mar 6 [PubMed PMID: 32151593]|
|||[PubMed PMID: 32154260]|
|||Khan F,Rahman A,Carrier M,Kearon C,Weitz JI,Schulman S,Couturaud F,Eichinger S,Kyrle PA,Becattini C,Agnelli G,Brighton TA,Lensing AWA,Prins MH,Sabri E,Hutton B,Pinede L,Cushman M,Palareti G,Wells GA,Prandoni P,Büller HR,Rodger MA, Long term risk of symptomatic recurrent venous thromboembolism after discontinuation of anticoagulant treatment for first unprovoked venous thromboembolism event: systematic review and meta-analysis. BMJ (Clinical research ed.). 2019 Jul 24 [PubMed PMID: 31340984]|
|||Albertsen IE,Piazza G,Søgaard M,Nielsen PB,Larsen TB, Extended oral anticoagulation after incident venous thromboembolism - a paradigm shift? Expert review of cardiovascular therapy. 2020 Apr [PubMed PMID: 32276561]|
|||Girbea A,Sprynger M,Moonen M,Lancellotti P, [How Itreat ... extended duration of anticoagulation in lower-limb deep venous thrombosis]. Revue medicale de Liege. 2020 Apr [PubMed PMID: 32267106]|