key: cord-0857427-4vw1xgnf
authors: Thachil, Jecko; Juffermans, Nicole P.; Ranucci, Marco; Connors, Jean M.; Warkentin, Theodore E.; Ortel, Thomas L.; Levi, Marcel; Iba, Toshiaki; Levy, Jerrold H.
title: ISTH DIC Subcommittee Communication on Anticoagulation in COVID‐19
date: 2020-07-13
journal: J Thromb Haemost
DOI: 10.1111/jth.15004
sha: 6ae433db19a59e3f322499e415970e80f26e4d80
doc_id: 857427
cord_uid: 4vw1xgnf

Hypercoagulability is an increasingly recognized complication of SARS‐CoV‐2 infection. As such, anticoagulation has become part and parcel of comprehensive COVID‐19 management. However, several uncertainties exist in this area including the appropriate type and dose of heparin. In addition, special patient populations, including those with high body mass index and renal impairment, require special consideration. Although the current evidence is still insufficient, we provide a pragmatic approach to anticoagulation in COVID‐19, but stress the need for further trials in this area.

Morbidity and mortality secondary to COVID-19 is increasing worldwide. Venous thromboembolism (including pulmonary embolism), arterial thrombosis, and microvascular thrombi appear to contribute to adverse outcomes. 1, 2 One of the key interventions that appears to be effective in reducing mortality associated with thrombosis in non-COVID-19 settings is anticoagulant therapy. 3 Accordingly, the International Society on Thrombosis and Haemostasis (ISTH) published an interim guideline which recommended the use of prophylactic anticoagulation with low-molecular-weight heparin (LMWH) in all patients admitted with COVID-19 in the absence of contraindications. 4 With the increasing experience of health care providers in managing COVID-19 patients, several questions have arisen about the use of anticoagulation that we address in this practice communication. Although possible solutions are suggested, we stress the need for well-designed randomized studies (performed rapidly) to produce evidence-based recommendations. It should be noted that the following recommendations are for adult patients only.

In the study by Tang et al, a minority of all COVID-19 patients received LMWH in prophylactic doses, with relatively few given unfractionated heparin (UFH). 3 The use of LMWH reflects the evolving practice worldwide towards LMWH becoming the standard of care for the prevention and treatment of thromboembolism versus UFH due to better bioavailability, fixed dosing, decreased risk of heparin-induced thrombocytopenia (HIT), and osteoporosis. 5, 6 However, LMWH can accumulate with renal impairment and

This article is protected by copyright. All rights reserved has a longer half-life than UFH. 5, 6 Hence in patients with severe renal impairment, at a high-risk of bleeding, or the need to undergo invasive procedures, UFH is preferred, which may be particularly relevant in critically ill COVID-19 patients, in whom coagulopathy is the most severe.

When using UFH, however, numerous variables ranging from pre-analytic issues (sample collection and processing), and reagent differences can influence activated partial thromboplastin time (aPTT) measurements. 7 The aPTT may be prolonged in some COVID-19 patients due to consumptive coagulopathy in the most critically ill and possibly, due to presence of a lupus anticoagulant. A recent report implicating antiphospholipid antibodies in COVID-19 patients with thrombotic events found elevated aPTT levels and presence of anti-cardiolipin and anti-β 2 -glycoprotein antibodies, although lupus anticoagulant tests were negative. 8 Another paper noted 20% of patients had a prolonged aPTT, most of which were due to lupus anticoagulants. 9 A French group observed 45% positivity in lupus anticoagulant tests in 56 patients diagnosed with COVID-19. 10 Whether these antibodies are pathogenic and result in thrombosis (including arterial thrombosis) remains to be determined.

One potential concern with the use of UFH in COVID 19 patients is the possible development of heparin resistance in the setting of an acute phase response. In COVID-19 and other inflammatory states, acute phase reactants, including fibrinogen 11 and C-reactive protein, 12 are elevated. It has been shown that increased fibrinogen levels and other heparin-binding acute-phase reactants create a prohemostatic environment that can antagonize the anticoagulant effects of heparin, with hyperfibrinogenemia a key factor causing heparin resistance. 13 Heparin resistance is defined as the requirement of high doses of UFH (daily dose in excess of 35,000 units/day) to achieve a therapeutic range. 14 This phenomenon occurs due to the ability of heparin to bind to various acute-phase plasma proteins (increased in COVID- 19) , and also macrophages and endothelial cells, 15 which are both activated in COVID-19. Although low antithrombin levels are another potential reason for heparin resistance, moderate to severe decreased antithrombin levels are unusual in COVID-19 patients, with most patients having plasma levels within the low-normal range of ~80%. 11, 16 However, Ranucci et al did report antithrombin levels less than 60% in two out of 16 patients in their analysis of COVID-19 critically ill subjects. 17 In addition, thrombocytosis, which has been noted in COVID-19 possibly due to excessive thrombopoietin production from the liver, has also been suggested as a reason for heparin resistance. 3, 18 A practical solution for 'overcoming' heparin resistance is to measure both aPTT and a concomitant anti-factor Xa heparin level. 7 If monitoring is impractical, alternate agents like a longer-acting, non-aPTT adjusted subcutaneous fondaparinux or danaparoid may be alternatives if the renal function is normal; 19, 20 Prophylactic-dose LMWH (dalteparin) has been studied in critically-ill patients even with markedly impaired renal function without monitoring and no adverse effects. 21

This article is protected by copyright. All rights reserved Clinical experience in COVID-19 suggests there are anticoagulation failures in patients already receiving prophylactic anticoagulation. In a recently published study, despite systematic thromboprophylaxis, 31% of the 184 patients in critical care units with COVID-19 developed thrombotic complications. 2 In an update of this cohort, the cumulative incidence of arterial and venous thromboembolism was 49% (95% confidence interval [CI] 41-57%). 22 Other studies have found similarly marked increase in the incidence of VTE in patients requiring ICU care that exceed similarly cared for ICU patients without COVID-19, including comparison to past influenza patients. 23, 24, 25 This could be due to several reasons including i) COVID-19 specific coagulation changes with extensive coagulation activation for which prophylactic dosing may be insufficient, ii) thromboembolism had already developed prior to starting anticoagulation, or iii) inadequate dosing (high body-mass index or inaccurate dosing). In the setting of critically ill patients requiring mechanical ventilation, immobilization can occur due to deep sedation and muscle paralysis. Also, the use of high pressure ventilation settings resulting in high intrathoracic pressure may impair pulmonary perfusion. Significant controversy has developed regarding an empiric increase in the dose of heparin, especially in the following situations (also see figure 1 ): a) Worsening of the clinical picture, manifest as increasing oxygen requirements, which may be due to pulmonary microthrombi b) Suspicion of pulmonary thromboembolism based on abrupt development of hypoxemia, new tachycardia, and right heart strain seen on echocardiogram. Heightened suspicion should be maintained in ALL patients; c) Need for ICU care and ventilatory support as the cumulative incidence of VTE in ICU patients has been found to be higher than those not requiring ICU care 22, 23, 24 If imaging can be performed, and there is definite evidence of thrombi, therapeutic anticoagulation should be administered. In those patients for whom pulmonary thromboembolism is highly likely based on clinical findings but imaging is not feasible, an increase to therapeutic-dose anticoagulation may be appropriate.

Therapeutic-dose anticoagulation in a large cohort of hospitalized patients with COVID-19 was associated with a reduced risk of mortality (adjusted HR of 0.86 per day, 95% confidence interval 0.82-0.89, p<0.001). 25 In addition, the higher dose reduced the incidence of mechanically ventilated patients (inhospital mortality of 29.1% compared to 62.7% in those who did not receive anticoagulation). 25 However, this retrospective review of hospital system data, however, has many limitations, including lack of information on patient selection for therapeutic-dose anticoagulation, indication for anticoagulation, severity of illness, and other unknown confounding variables. Other centers are using "intermediate dose"

anticoagulation in patients who have no evidence of VTE but require ICU care based on the increased incidence of VTE despite standard-dose thromboprophylaxis. 22 If therapeutic anticoagulation with UFH is chosen, the issue of "aPTT confounding" should be considered -the situation where an underlying condition (e.g., liver impairment or lupus anticoagulant) may cause pretreatment aPTT elevations and patients may have "therapeutic" aPTT values, but where the anticoagulant level is actually sub-therapeutic. 19

Healthcare providers are noticing in COVID-19 patients, an increase in filter occlusion and thrombosis with extracorporeal circuits including haemofiltration or extracorporeal membrane oxygenation, despite routine anticoagulation. 27 Contact activation and the complement system are both involved in thrombin generation in patients who require dialysis or ECMO. 28, 29 Since the inflammatory process is closely linked to both these pathways, intense inflammation in COVID-19 could predispose to filter clots or occlusion. 29, 30 Possible management approaches include administration of higher doses of heparin as well as more accurately assessing the anticoagulant effects of heparin. Additional therapies that may also be considered include complement inhibitors and possibly agents that can inhibit the contact pathway of the coagulation cascade. For patients on ECMO or with CVVH, therapeutic anticoagulation may be appropriate if there is evidence of clots in the extracorporeal circuits.

Abnormalities in renal function are rare at least in the early phases of the COVID-19 infection. 11 But there may be patients who already have known kidney problems or can develop renal impairment secondary to the critical illness or the use of hydroxychloroquine. I the patient is receiving LMWH in treatment doses, the amount should be adjusted based on anti-Xa measurements to avoid drug accumulation. 31 Some experts recommend switching to UFH in this clinical situation, which may be reasonable, but as discussed before, ensuring rapid and adequate anticoagulation is imperative. 7 Alternatives to UFH include renally-adjusted dose danaparoid, argatroban, or bivalirudin. 32

Obesity with body-mass index >35 in patients with COVID-19 appears to be a poor prognostic indicator. 33 A possible explanation is the higher susceptibility to inflammation and thrombotic complications in obese patients. Debate exists about the appropriate dose for prophylaxis in obese patients with limited data to guide care. These patients should be given a weight-adjusted appropriate prophylactic dose at admission,

This article is protected by copyright. All rights reserved with an increase to intermediate intensity or full therapeutic dose based on clinical parameters ( figure   1 ). 34, 35 Treatment doses also require adjustment for weight. 36, 37 The role of point of care testing Point of care testing, including viscoelastic testing, has been used in the critical care setting to guide transfusion of blood products in patients undergoing cardiothoracic surgery, liver transplantation surgery, massive transfusion protocols for trauma, and postpartum haemorrhage. 38 Point of care testing has never been validated for use in patients to predict risk of bleeding or thrombosis, although several studies have examined this aspect. 39 Ranucci et al. reported hemostatic changes in patients with COVID-19 pneumonia using Quantra Hemostasis analyser (Quantra® System, HemoSonics LLC, Charlottesville, VA), using a device based on lower manipulation of the samples since blood is directly suctioned from citrated vials. 17 The study reported increased clot firmness consistent with hypercoagulability, but decreased biomarkers with a higher level of anticoagulation; and clopidogrel if platelet count > 400,000 cells/μL. This small study provides important initial information, but requires validation using larger patient numbers. TEG parameters in an Italian study of 24 patients were also suggestive of hypercoagulability as shown by decreased R time and K value, and increased K angle and MA. 40 ROTEM analysis by Pavoni and colleagues also demonstrated a state of severe hypercoagulability not obvious on standard coagulation parameters. 41

The use of heparin can be associated with HIT -a well-known side effect of this drug. 42 HIT is also more common in patients who have associated inflammatory conditions, a finding that may reflect increased platelet activation in patients receiving UFH or therapeutic doses of LMWH. 43 Since thrombocytopenia is uncommon in patients with COVID-19, a significant drop in platelet count that begins five or more days after starting UFH or LMWH should raise the suspicion of HIT, especially if additional explanations such as bacterial superinfection or consumption coagulopathy has been excluded. Moreover, development of clinically-evident venous or arterial thrombosis in a patient receiving heparin should also prompt consideration of HIT. 44 Until the diagnosis of HIT can be confirmed, heparin exposure that includes line flushes should be discontinued and substituted with an alternate anticoagulant such as danaparoid, fondaparinux, bivalirudin, or argatroban. 42 Recently, high-dose intravenous immunoglobulin (IVIG) has been advocated as an adjunctive treatment for severe HIT 45 , and used with anecdotal success in deteriorating patients with COVID-19 infection. 46

This article is protected by copyright. All rights reserved 

Thrombosis is a major problem in patients with COVID-19 requiring hospitalization. Anticoagulation is important in these patients but questions have arisen about the appropriate type, dose, and timing of anticoagulation. Existing guidelines and consensus documents are providing general suggestions on the LMWH dose based on the severity of the disease and the thrombotic risk, but a link between coagulation markers and anticoagulation regimen is still lacking. Many clinical trials addressing these questions are in progress; participation in these trials is encouraged to determine the best management strategies for 

This article is protected by copyright. All rights reserved 

Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. JTH epublished April 9

Incidence of thrombotic complications in critically ill ICU patients with COVID-19

Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy

ISTH interim guidance on recognition and management of coagulopathy in COVID-19

Accepted Article This article is protected by copyright. All rights reserved

Heparin and low-molecular weight heparin: mechanism of action, pharmacokinetics, dosing, monitoring, efficacy and safety

Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

Guidance for the practical management of the heparin anticoagulants in the treatment of venous thromboembolism

Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19

Lupus Anticoagulant and Abnormal Coagulation Tests in Patients with Covid-19

Lupus anticoagulant is frequent in patients with Covid-19

Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia

Clinical Characteristics of Coronavirus Disease 2019 in China

Postinjury hyperfibrinogenemia compromises efficacy of heparinbased venous thromboembolism prophylaxis

A randomized trial comparing activated thromboplastin time with heparin assay in patients with acute venous thromboembolism requiring large daily doses of heparin

Review article: heparin sensitivity and resistance: management during cardiopulmonary bypass

Clinical controversies in anticoagulation monitoring and antithrombin supplementation for ECMO. Crit Care

The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome

Accepted Article This article is protected by copyright. All rights reserved

Heparin resistance and excessive thrombocytosis

Anticoagulant failure in coagulopathic patients: PTT confounding and other pitfalls

Argatroban and Bivalirudin for Perioperative Anticoagulation in Cardiac Surgery

PROTECT investigators for the Canadian Critical Care Trials Group and the Australian and New Zealand Intensive Care Society Clinical Trials Group,. Dalteparin versus unfractionated heparin in critically ill patients

Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis

Incidence of venous thromboembolism in hospitalized patients with COVID-19

High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study

Association of Treatment Dose Anticoagulation With In-Hospital Survival Among Hospitalized Patients With COVID-19

Clinical Characteristics of Covid-19 in New York City

Fibrinolysis Shutdown Correlates to Thromboembolic Events in Severe COVID-19 Infection

Contact system: a vascular biology modulator with anticoagulant, profibrinolytic, antiadhesive, and proinflammatory attributes

Role of Complement-Related Inflammation and Vascular Dysfunction in Hypertension

Coagulation factor XII in thrombosis and inflammation

How useful is the monitoring of (low molecular weight) heparin therapy by anti-Xa assay? A laboratory perspective

American College of Chest Physicians evidence based clinical practice guidelines

Obesity as a Predictor for a Poor Prognosis of COVID-19: A Systematic Review

Efficacy of standard dose unfractionated heparin for venous thromboembolism prophylaxis in morbidly obese and non-morbidly obese critically Ill patients

Unfractionated heparin infusion for treatment of venous thromboembolism based on actual body weight without dose capping

Intravenous unfractionated heparin dosing in obese patients using anti-Xa levels

Enoxaparin Dosing at Extremes of Weight: Literature Review and Dosing Recommendations

The use of viscoelastic haemostatic assays in the management of major bleeding: A British Society for Haematology Guideline

A critical appraisal of point-of-care coagulation testing in critically ill patients

Hypercoagulability of COVID-19 patients in Intensive Care Unit. A Report of Thromboelastography Findings and other Parameters of Hemostasis

Evaluation of coagulation function by rotation thromboelastometry in critically ill patients with severe COVID-19 pneumonia

American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia

ISTH interim guidance on recognition and management of coagulopathy in COVID-19

A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia

Chinese expert consensus on diagnosis and treatment of coagulation dysfunction in COVID-19

Recommendations on antithrombotic treatment during the COVID-19 pandemic. Position statement of the Working Group