ISTH DIC subcommittee communication on anticoagulation in COVID19

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.

## | introduc ti on
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. [bib_ref] Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia, Cui [/bib_ref] [bib_ref] Incidence of thrombotic complications in critically ill ICU patients with COVID-19, Klok [/bib_ref] One of the key interventions that appears to be effective in reducing mortality associated with thrombosis in non-COVID-19 settings is anticoagulant therapy. [bib_ref] Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019..., Tang [/bib_ref] 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. The following recommendations are for adult patients only.

## | unfr ac ti onated heparin or low molecul ar weig ht heparin?
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). [bib_ref] Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019..., Tang [/bib_ref] The use of LMWH reflects the evolving practice worldwide toward LMWH becoming the standard of care for the prevention and treatment of thromboembolism versus UFH because of better bioavailability, fixed dosing, decreased risk of heparin-induced thrombocytopenia (HIT), and osteoporosis. [bib_ref] Heparin and low-molecular weight heparin: mechanism of action, pharmacokinetics, dosing, monitoring, efficacy..., Hirsh [/bib_ref] [bib_ref] Parenteral anticoagulants: American College of Chest Physicians evidence-based clinical practice guidelines, Hirsh [/bib_ref] However, LMWH can accumulate with renal impairment and has a longer half-life than UFH. [bib_ref] Heparin and low-molecular weight heparin: mechanism of action, pharmacokinetics, dosing, monitoring, efficacy..., Hirsh [/bib_ref] [bib_ref] Parenteral anticoagulants: American College of Chest Physicians evidence-based clinical practice guidelines, Hirsh [/bib_ref] 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 preanalytic issues (sample collection and processing), and reagent differences can influence activated partial thromboplastin time (aPTT) measurements. [bib_ref] Guidance for the practical management of the heparin anticoagulants in the treatment..., Smythe [/bib_ref] The aPTT may be prolonged in some COVID-19 patients because of consumptive coagulopathy in the most critically ill and possibly from the 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 anticardiolipin and anti- 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.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. [bib_ref] Postinjury hyperfibrinogenemia compromises efficacy of heparin-based venous thromboembolism prophylaxis, Harr [/bib_ref] Heparin resistance is defined as the requirement of high doses of UFH (daily dose in excess of 35 000 units/d) to achieve a therapeutic range. 14 This phenomenon occurs because of heparin's ability to bind to various acute-phase plasma proteins (increased in COVID-19), as well as macrophages and endothelial cells, [bib_ref] Review article: heparin sensitivity and resistance: management during cardiopulmonary bypass, Finley [/bib_ref] 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%. [bib_ref] Abnormal coagulation parameters are associated with poor prognosis in patients with novel..., Tang [/bib_ref] [bib_ref] Clinical controversies in anticoagulation monitoring and antithrombin supplementation for ECMO, Chlebowski [/bib_ref] However, Ranucci et al did report antithrombin levels <60% in two of 16 patients in their analysis of COVID-19 critically ill subjects. [bib_ref] The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome, Ranucci [/bib_ref] In addition, thrombocytosis, which has been noted in COVID-19, possibly from excessive thrombopoietin production of the liver, has also been suggested as a reason for heparin resistance. [bib_ref] Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019..., Tang [/bib_ref] [bib_ref] Heparin resistance and excessive thrombocytosis, Koster [/bib_ref] A practical solution for "overcoming" heparin resistance is to measure both aPTT and a concomitant anti-factor Xa heparin level. [bib_ref] Guidance for the practical management of the heparin anticoagulants in the treatment..., Smythe [/bib_ref] If monitoring is impractical, alternate agents such as longer-acting, non-aPTT adjusted subcutaneous fondaparinux or danaparoid may be alternatives if the renal function is normal. [bib_ref] Anticoagulant failure in coagulopathic patients: PTT confounding and other pitfalls, Warkentin [/bib_ref] [bib_ref] Argatroban and bivalirudin for perioperative anticoagulation in cardiac surgery, Koster [/bib_ref] Prophylactic-dose LMWH (dalteparin) has been studied in critically ill patients even with markedly impaired renal function without monitoring and no adverse effects. [bib_ref] PROTECT investigators for the Canadian critical care trials group and the Australian..., Cook [/bib_ref] 

## | s tandard prophyl ac tic-dos e anti coag ul ati on?
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. [bib_ref] Incidence of thrombotic complications in critically ill ICU patients with COVID-19, Klok [/bib_ref] In an update of this cohort, the cumulative incidence of arterial and venous thromboembolism was 49% (95% confidence interval, 41-57). [bib_ref] Confirmation of the high cumulative incidence of thrombotic complications in critically ill..., Klok [/bib_ref] Other studies have found similarly marked increase in the incidence of venous thromboembolism (VTE) in patients requiring intensive care unit (ICU) care that exceed similarly cared for ICU patients without COVID-19, including comparison to past influenza patients. [bib_ref] High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter..., Helms [/bib_ref] [bib_ref] Association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with..., Paranjpe [/bib_ref] This could be due to 3. 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 [bib_ref] Confirmation of the high cumulative incidence of thrombotic complications in critically ill..., Klok [/bib_ref] [bib_ref] High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter..., Helms [/bib_ref] 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 hazard ratio of 0.86 per day; 95% confidence interval, 0.82-0.89; P < .001). [bib_ref] Association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with..., Paranjpe [/bib_ref] In addition, the higher dose reduced the incidence of mechanically ventilated patients (in-hospital mortality of 29.1% compared with 62.7% in those who did not receive anticoagulation). [bib_ref] Association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with..., Paranjpe [/bib_ref] However, this retrospective review of hospital system data 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. [bib_ref] Confirmation of the high cumulative incidence of thrombotic complications in critically ill..., Klok [/bib_ref] 

## | patients with renal impairment
Abnormalities in renal function are rare at least in the early phases of the COVID-19 infection. [bib_ref] Abnormal coagulation parameters are associated with poor prognosis in patients with novel..., Tang [/bib_ref] 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. If the patient is receiving LMWH in treatment doses, the amount should be adjusted based on anti-Xa measurements to avoid drug accumulation. [bib_ref] How useful is the monitoring of (low molecular weight) heparin therapy by..., Favaloro [/bib_ref] 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. [bib_ref] Guidance for the practical management of the heparin anticoagulants in the treatment..., Smythe [/bib_ref] Alternatives to UFH include renally adjusted dose danaparoid, argatroban, or bivalirudin. 32

## | s pecial patient p opul ati on: ob e s it y
Obesity with body mass index > 35 in patients with COVID-19 appears to be a poor prognostic indicator. [bib_ref] Obesity as a predictor for a poor prognosis of COVID-19: a systematic..., Tamara [/bib_ref] 

## | heparin -induced thromboc y topenia
The use of heparin can be associated with HIT, a well-known side effect of this drug. [bib_ref] American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced..., Cuker [/bib_ref] 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. [bib_ref] Heparin-induced thrombocytopenia, Arepally [/bib_ref] Because thrombocytopenia is uncommon in patients with COVID-19, a significant drop in platelet count that begins 5 or more days after starting UFH or LMWH should raise suspicion for 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. [bib_ref] Think of HIT when thrombosis follows heparin, Warkentin [/bib_ref] 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. [bib_ref] American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced..., Cuker [/bib_ref] Recently, high-dose intravenous immunoglobulin has been advocated as an adjunctive treatment for severe HIT, 45 and used with anecdotal success in deteriorating patients with COVID-19 infection. 46

## | limitati on s of the pub lis hed s tudie s on anticoag ul ation in cov i d -19
Overall, all of the existing studies about anticoagulation type and

## Ack n owled g em ents

## None

## Co n fli c t o f i nte r e s t
[fig] TA B L E 1: the prophylactic dose of heparin (especially in critical care patients)*,** *Note 1: This issue is still controversial and half of the experts recommed intensification of anticoagulation. **Note 1: If possible, this should be done in the setting of a clinical trail or by using the best available data to guide dosing adjustments. Bleeding adverse events under anticoagulation in COVID-19 patients [/fig]