by Donna Castellone, MS, MT (ASCP) SH •
June 16, 2022
The interpretations below are provided by Donna Castellone, MS, MT (ASCP) SH for Aniara Diagnostica.
The Journal of Thrombosis and Thrombolysis has published an update guidance titled: "Thromboembolic prevention and anticoagulant therapy during the COVID-19 pandemic: updated clinical guidance from the anticoagulation forum'.1
Early on thromboembolism was found to be a complication of COVID-19 for hospitalized patients and early on the use of anticoagulation has been strongly encouraged. As the pandemic progressed and there were multiple clinical trials and larger observational studies more evidence has become available regarding anticoagulation for patients with COVID-19. This updated guidance is from the Anticoagulation Forum which is the leading North American organization of anticoagulation providers.
This will summarize the guidance document that covers ambulatory, in hospital and post thrombotic strategies as well as provide guidance for patients with thrombotic conditions receiving COVID vaccines. When writing a guidance document a statement with a strong evidence-based or expert consensus uses the word "recommend" whereas statement with less strong evidence or consensus are described as "suggest".1
Ambulatory patients with COVID-19:
The overall risk for thrombosis doesn't appear to be markedly elevated.2 A clinical trial conducted by the NIH compared placebo, aspirin and two doses of apixaban in non-hospitalized COVID patients. It was stopped due to a low number of thromboembolic events.3 It was also found in patients who currently take anticoagulation for AF, or prevention of CAD, unless their bleeding indication changes, they should stay on their anticoagulant regime.
The two guidance recommendations for ambulatory (non-hospitalized) adult patients with mild COVID-19 infection is to recommend against any specific antithrombotic preventative therapy who have no other indication for antithrombotic therapy and recommend patients on antithrombotic therapy prior to diagnosis of COVID-19 continue their antithrombotic therapy unless a significantly elevated risk of bleeding has developed.1
Non-Critically Ill Hospitalized Patients with COVID-19
Upon reviewing the results of several clinical trials which screened more than 13,000 patients, the use of therapeutic intensity heparin of primarily enoxaparin was found to be superior to usual care pharmacologic thromboprophylaxis primarily LMWH for increasing organ support free days (either noninvasive or invasive support). There was a reduction in secondary outcome of major thromboembolic events or death favoring therapeutic heparin and a higher risk of major bleeding with treatment dose heparin but did not reach statistical significance.4
Based on the results of the clinical trials the recommendation is that all patients hospitalized with COVID receive at least a standard dose of thromboprophylaxis. In patients admitted to the hospital for indications other than COVID but then found to have COVID it is recommended for them to receive one standard dose thromboprophylaxis with LMWH or UFH unless specific contraindications exist. It is also suggested that clinicians consider use the use of therapeutic intensity LMWH or UFH thromboprophylaxis for non-critically ill patients at increased risk of disease progression or thromboembolism and who are not at a high risk for anticoagulant related bleeding. There is a recommendation for intermediate intensity thromboprophylaxis and or antiplatelet agents only in the setting of a clinical trial for hospitalized patients with COVID-19.1
Critically Ill Hospitalized Patients with COVID-19
In patients that were admitted to the ICU and requiring organ support, invasive ventilation did not any experience benefit when receiving therapeutic intensity thromboprophylaxis when compared to usual care thromboprophylaxis.5
The use of intermediate intensity thromboprophylaxis was investigated in the INSPIRATION trial and there were no benefits observed when compared to standard dose in ICU patients.6 The recommendation for critically ill adult patients at the time of hospitalization is to receive standard dose thromboprophylaxis instead of intermediate- or therapeutic intensity thromboprophylaxis.1
There were two trials that looked at antiplatelet therapy in patient hospitalized with COVID. Patients were randomized to aspirin or usual care in RECOVERY trial or in ACTIVE-4a patient were randomized to heparin or heparin plus a P2Y12 inhibitor. The primary endpoint was organ free support. There was no difference in either of the groups. Therefore, the recommendation is that hospitalized patients with COVID-19 do not receive antiplatelet therapy.1
Hospital Transitions of Care
Patients with COVID-19 will require different levels of care while in the hospital and when transfered to different floors. There were no studies that compared different strategies when levels of care were changed, and patients were kept at the level of anticoagulation they were started. There is also no prospective clinical evidence to support the use of serial D-dimer testing to guide the intensity of D-dimer testing.7 The suggestion for these patients is they should remain on the intensity of VTE thromboprophylaxis that was initiated at hospital admission as long as their bleeding risk is not significantly elevated.1
There are conflicting reports as to the risk of post- hospital VTE in COVID-19 patients. In most reports it is similar to patients without COVID, but one study VTE was elevated in COVID patients.8 However the MICHELLE trial randomized 320 patients who were considered at an increased risk for post discharge events based on VTE scoring and D-dimer > 500ng/mL at discharge. They were randomized to rivaroxaban or no anticoagulation. The anticoagulation reduced the risk of VTE, stroke and cardiovascular death. But there were actually 997 patients that were screened in order to enroll 320 suggesting that post-hospital extended thromboprophylaxis is not appropriate for all.9 In the post-hospital patients it is recommended that clinicians not routinely use thromboprophylaxis after discharge from COVID for all patients including those who may have gotten therapeutic anticoagulation. It is also suggested to utilize 10mg rivaroxaban daily for 35 days post hospitalization for COVID-19 may be considered in patients with an increased risk for thrombosis without and increased risk of bleeding. The final recommendation for the post hospital period is clear documentation and communication of indication and intended duration of post-hospital thromboprophylaxis to providers and next care settings to avoid unnecessarily prolonged exposure to anticoagulation.1
Thromboprophylaxis for Pediatric Patients with COVID-19
Children infected with SARS-CoV-2 have milder infections than adults and most do not require hospitalization. Those with underlying medical conditions can have more severe COVID-19. Pediatric patients may also develop multisystem inflammatory syndrome (MIS-C). Rates of thrombotic complicated have not be well established. A small retrospective multi-center study confirmed venous or arterial thrombosis in 2.1% of children hospitalized with acute COVID-19 and MIS-C, of those the mortality rate was 28% suggesting thrombosis may contribute to mortality.10 There have been no randomized trials evaluating the efficacy and intensity of anticoagulant prophylaxis in COVID-19 pediatric patients. Suggestions have been made by the Pediatric/Neonatal Hemostasis and Thrombosis Scientific Subcommittee of the International Society on Thrombosis and Hemostasis expert-consensus based guidance for thromboprophylaxis in this population.11 It is suggested that clinicians consider LMWH in the range of 0.2 < 0.5 IU/mL hospitalized with acute COVID or MIS-C with one or more additional risk factor or a markedly high D-dimer without a bleeding risk. It is recommended against thromboprophylaxis in hospitalized children who are asymptomatic in the absence of other VTE risk factors and suggest that post- prophlyaxis be decided on a case by case basis.1
Thromboprophylaxis in Obstetric Patients with COVID-19
Randomized clinical trials in adult COVID-19 patients exclude pregnant women therefore there is no high quality evidence to support this cohort of patients. Pregnancy is a hypercoaguable state and complicated with COVID and reduced mobility may place women at a significant risk of VTE. In pregnant women who are not hospitalized with COVID, anticoagulation is not required, but it should be considered in hospitalized pregnancy taking into consideration patient characteristics such as obesity, renal function and time to labor and delivery.12 Recommendations include against thromboprophylaxis for pregnant women found to be COVID-19 positive and not requiring admission to the hospital however if they do require admission, anticoagulation should be used in accordance with existing obstetric guidelines for non-COVID-19 positive women. If a pregnant women is already receiving anticoagulant or treatment prior to admission for COVID it should be continued it is also suggested against routine post-discharge prophylaxis for COVID-19 OB patients unless they meet the criteria for non-COVID populations.
Thromboprophylaxis for Moderately Ill Patients in Long-term Care Facilities Who Are Not Transferred to the Hospital.
Due to many patients in long term care facilities having multiple comorbidities and advanced age, they present with an increased risk for thrombosis in particular during an acute illness such as COVID-19. The guidance document recommends that these patients that are ill enough yet remain in the long term facility should be offered standard intensity thromboprophylaxis for 10-14 days if this aligns with their goals of care.1
Thromboprophylaxis in Patients with Known Thrombophilia
Patients with known thrombophilia are at increased risk for VTE from any acute medical hospitalization. However, data regarding any diferential risk of thromboembolism while hospitalized with COVID-19 is lacking. The recommendation is that all adult patients with known thrombophilia receive standard intensity anticoagulation when hospitalized for COVID-19 unless already on chronic therapeutic intensity anticoagulation. The presence of a known thrombophilia lean towards a therapeutic intensity anticoagulant as long as the risk of bleeding is not high.1
Management of Patients on Anticoagulation Prior to Admission for COVID-19
In patients who are managed on anticoagulation for thromboembolic conditions such as AF, VTE or mechanical valves are still at risk during hospitalization for COVID-19 but they may also develop bleeding risks during this time due to acute renal failure, drug interactions or invasive procedures and it may require adjustment to their anticoagulant. Due to this. the recommendation is to be assessed for the use of ongoing outpatient anticoagulation and that this regimen be continued during the hospitalization for COVID-19 unless there are conditions that will preclude safe use. It is also recommended that patients receiving reduced or low dose anticoagulation prior to admission who are hospitalized receive either standard or therapeutic LMWH or UFH as clinically appropriate.1
Treatment for VTE is usually standard for between 3-6 months when it occurs due to a transient medical illness. It has not been well established that the risk of VTE from COVID-19 differs from this scenario. This would suggest that patients could be reevaluated at regular intervals and the recurrence risk is likely low once the COVID-19 infection resolves.13 As such the recommendation is that these patients should receive anticoagulation for a minimum of three to six months for VTE with a transient provoking risk factor and it is suggested that a finite course of anticoagulation (3-6 months) rather than continue anticoagulation long term for secondary prevention in patients with COVID-19 associated VTE.1
Vaccination for patients on anticoagulation or prior VTE/thrombophilia
Vaccination against COVID-19 has been the leading strategy to controlling the pandemic in preventing infection and severe illness. It is recommended that all eligible persons are vaccinated. There are rare reports of both typical and unusual site thromboembolism following COVID-19 vaccination. The benefit of the vaccine out weights the risk of thrombosis following the vaccine. The occurrence of Vaccine Induce Thrombosis and Thrombocytopenia (VITT) or Thrombosis and Thrombocytopenia Syndrome (TTS) is driven by an immune mediated process and not linked to a history of thrombosis, thrombophilia or current anticoagulation utilization.14 Current anticoagulant use should not impact vaccine selection, nor should anticoagulation be required prior to vaccine use. It is recommended that all patients be vaccinated even with those a history of thromboembolism. Thrombophilia or those on anticoagulation receive COVID-19 vaccine if eligible and that anticoagulation is not withheld for vaccine administration. If a patient is on anticoagulation, pressure should be held at the site of injection for 5 minutes to minimize any injection site bleeding. It is recommended that warfarin schedules should not be altered in relation to vaccine administration.1
The one thing that the COVID-19 has been consistently known for is that it is an ever changing entity. Between variants, symptoms, and how contagious this virus present itself, treatments and best practices have been moving targets. It is important that updates are evidence based as information can be supported by data from patients. These guidelines are the most recent from the Anticoagulation Forum and cover the most recent and available evidence on COVID-19.
Geofrey D Barnes1 · Allison Burnett2 · Arthur Allen3 · Jack Ansell4 · Marilyn Blumenstein5 · Nathan P Clark6 · Mark Crowther7 · William E Dager8 · Steven B. Deitelzweig9 · Stacy Ellsworth10 · David Garcia11 · Scott Kaatz10 · Leslie Rafni12 · Anita Rajasekhar13 · Andrea Van Beek14 · Tracy Minichiello1, Thromboembolic prevention and anticoagulant therapy during the COVID-19 pandemic: updated clinical guidance from the anticoagulation forum, Journal of Thrombosis and Thrombolysis, May 2022.
Roubinian NH, Dusendang JR, Mark DG et al (2021) Incidence of 30-Day Venous Thromboembolism in Adults Tested for SARSCoV-2 Infection in an Integrated Health Care System in Northern California. JAMA Intern Med 181:997.
Chow JH, Yin Y, Yamane DP et al (2021) Association of prehospital antiplatelet therapy with survival in patients hospitalized with COVID-19: A propensity score-matched analysis. J Thromb Haemost 19:2814–2824
Sholzberg M, Tang GH, Rahhal H et al (2021) Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial. BMJ n 2400
Investigators REMAP-CAP, Investigators ATTACC et al (2021) Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19. N Engl J Med 385:777–789
Investigators INSPIRATION, Sadeghipour P, Talasaz AH et al (2021) Efect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane Oxygenation Treatment, or Mortality Among Patients With COVID-19 Admitted to the Intensive Care Unit: The INSPIRATION Randomized Clinic. JAMA 325:1620
Investigators REMAP-CAP, Investigators ATTACC et al (2021) Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19. N Engl J Med 385:777–789.
Giannis D, Allen SL, Tsang J et al (2021) Postdischarge thromboembolic outcomes and mortality of hospitalized patients with COVID-19: the CORE-19 registry. Blood 137:2838–2847.
Ramacciotti E, Barile Agati L, Calderaro D et al (2021) Rivaroxaban versus no anticoagulation for post-discharge thromboprophylaxis after hospitalisation for COVID-19 (MICHELLE): an open-label, multicentre, randomised, controlled trial. Lancet (London England) 19.
Feldstein LR, Rose EB, Horwitz SM et al (2020) Multisystem Infammatory Syndrome in U.S. Children and Adolescents. N Engl J Med 383:334–346
Goldenberg NA, Sochet A, Albisetti M et al (2020) Consensusbased clinical recommendations and research priorities for anticoagulant thromboprophylaxis in children hospitalized for COVID-19–related illness. J Thromb Haemost 18:3099–3105.
Servante J, Swallow G, Thornton JG et al (2021) Haemostatic and thrombo-embolic complications in pregnant women with COVID19: a systematic review and critical analysis. BMC Pregnancy Childbirth 21:1–14.
Whyte MB, Barker R, Kelly PA et al (2021) Three-month follow-up of pulmonary embolism in patients with COVID-19. Thromb Res 201:113–115
Makris M, Pavord S, Lester W et al (2021) Vaccine-induced Immune Thrombocytopenia and Thrombosis (VITT). Res Pract Thromb Haemost 5:2–5