Thrombosis is a major cause of morbidity and mortality in severe COVID-19 illness. Deep vein thrombosis (DVT) (1), pulmonary embolism (PE) (2, 3), cerebral infarction (4), and myocardial infarction (MI) (5, 6) have all been reported in patients severely ill because of COVID-19 (7–9). Additionally, vascular access including dialysis catheters (10) and extracorporeal membrane oxygenation (ECMO) circuits (11) also fail at higher rates. D-dimer levels, a marker of fibrin breakdown (12) and intravascular clot burden (13), are increased in many patients with COVID-19. The degree of elevation correlates with disease severity (14) and it is particularly high in patients who died (15). Furthermore, widespread microthrombosis in the kidneys (16) and lungs (17), and other organs has been reported at autopsy. These observations strongly indicate that coagulopathy in COVID-19 infection contributes to organ dysfunction and mortality.

Anticoagulation appears to improve outcomes in critically ill COVID-19 patients, according to an early report from China (18), as well as a larger series from New York (19). However, two reports from France reported unexpected PE despite therapeutic anticoagulation (20, 21), presumably due to the severity of the hypercoagulability. Recently, a group in Italy reported that non-critically ill patients did not benefit from elevated doses of anticoagulation, though details were lacking about what agents and doses were administered (22). Additionally, an Italian group reported improved mortality in a retrospective cohort that received an “intermediate” dose of low molecular weight heparin (LMWH, 40–60 mg twice daily) (23). These findings were echoed in a report by five centers in New York City in which both prophylactic and therapeutic anticoagulation were associated with improved mortality, although there was not a significant difference between these groups (p = 0.07) (24). Despite these promising signs, a large randomized trial of therapeutic anticoagulation (NIH ACTIV-4) recently paused enrollment for lack of efficacy in critically-ill patients (25). At present, no randomized data is available to support one approach over another.

Despite the dearth of data, several professional societies have promulgated guidelines on anticoagulation in COVID-19. The American Society of Hematology (ASH) currently recommends against the use of therapeutic doses of heparin or LMWH in these patients in the absence of confirmed or suspected VTE (26). However, the International Society of Thrombosis and Hemostasis (ISTH) also recommends routine thromboprophylaxis with subcutaneous unfractionated heparin (UFH) or LMWH, with consideration for intermediate doses of LMWH in high-risk patients. The guidelines also state to consider a 50% increase in the dose of thromboprophylaxis in obese patients (27). Finally, current NIH treatment guidelines also indicate that there is not enough data available to recommend the use of anticoagulants at higher doses in these patients (28). Thus, new data are urgently needed.

During the early phase of the pandemic, our group observed severe arterial and venous thrombosis in COVID-19 patients despite routine, standard low-dose thromboprophylaxis. Based on these early observations, we hypothesized that escalated thromboprophylaxis for hypercoagulability (as indicated by elevated D-dimer levels) would limit thrombotic complications and improve outcomes in COVID-19 infection. We also suspected that many patients with increasing D-dimer levels had occult thromboses, either PE, or clots in other vascular beds. Therefore, we developed a protocol to escalate the level of anticoagulation, based on serum D-dimer levels, measured on a daily basis.

In the current report, we reviewed all of our COVID-positive, intubated patients (n = 240) admitted between February 7th, 2020 and May 17, 2020. We describe the 91 intubated COVID-19 intensive care unit (ICU) patients who received thromboprophylaxis based on this protocol, during the first wave of the pandemic in New York. At the peak of the pandemic, two of five ICUs at our institution had agreed on the escalated anticoagulation protocol; the 91 reported patients were admitted to these ICUs, based on pure chance availability of beds. This random assignment (a sort of “experiment of nature”) gives us the opportunity to understand whether escalated anticoagulation had a benefit, vs. routine care. We compared these patients to a cohort of 104 ICU patients who either received routine thromboprophylaxis or started full dose anticoagulation when standard clinical indications (e.g. DVT, PE) became apparent. Both groups were admitted to the hospital and ICU during the same time period, and their clinical care was otherwise similar.

Our study results indicate that an early-onset escalating thromboprophylaxis protocol based on daily D-dimer level is associated with significantly fewer thrombotic complications, preserved kidney function, and improved mortality in intubated patients with severe COVID-19 infection. The mortality in the ON-protocol cohort was 27%, compared to 58% in the OFF-protocol group, although this comparison needs to be made with caution, given the fact that this study is not a randomized trial, and it is possible there were unobserved differences between the groups that account for the differences in mortality. Nonetheless, the propensity-matched analysis also supports our core hypothesis, which should be confirmed in larger, randomized trials. The outcomes in the ON-protocol group are superior to those described in other published reports (33) and is probably due to both prevention of large-vessel thrombosis and improvement of kidney function, possibly by prevention of microthrombosis. Many fewer patient deaths in the ON-protocol group were attributed to large arterial or venous thrombotic complications, and clinically significant hemorrhage was not different between groups. On the contrary, thirteen patients in the OFF-protocol group died during their ICU course from probable PE, despite being administered standard low-dose thromboprophylaxis.

Our findings are generally consistent with the reported high incidence of thrombotic complications in COVID-19 ICU patients (7–9). At present, there is no official guidance about anticoagulation in COVID-19, except for previously promulgated guidelines (26–28, 34). There are reports indicating some benefit of anticoagulation particularly in critically ill patients with COVID-19 infection (18, 19), but the anticoagulation type is variable, and timing of onset is not reported, so comparisons are difficult. Of note, Paranjpe et al. (19) reported a similar mortality benefit for anticoagulation in intubated patients (29 vs. 62% mortality), though no further details about these subgroups are available in their manuscript. The report of Nadkarni and colleagues which did not identify a significant difference between therapeutic and prophylactic anticoagulation made no effort to propensity match or establish that the groups receiving prophylactic and/or therapeutic anticoagulation were similar. Thus, their data should not be over-interpreted to claim there is no benefit to therapeutic anticoagulation. By contrast, our data, while not conclusive, support the view that escalated anticoagulation may be appropriate when the D-dimer level rises. We designed our protocol to escalate the intensity of anticoagulation based on D-dimer levels because of the reported association of higher D-dimer levels to increased mortality (15, 35). We believed that early thromboprophylaxis would control the prothrombotic effect of severe COVID-19 infection, prevent early death from thrombotic complications, and limit the extent of microthrombi, thus preventing patient progression to multi-system organ failure (MSOF). This notion is supported by our analysis which indicates that ON-protocol anticoagulation controls the D-dimer level, prevents the occurrence of thromboembolic complications, preserves organ perfusion (as measured by preserved renal function), and is the only independent predictor of patient survival, and was accomplished without an increased risk of the need for transfusion. Our data underscore the importance of the timing of the anticoagulation. This early D-dimer driven escalation could also explain why the ON-protocol mortality we observed is lower than what has been reported in the literature for intubated ICU patients, whether they received anticoagulation or not (15, 33).

This study has several limitations, inherent to the single-institution, retrospective design with a small sample size and the fact that it is subject to residual confounding. Since the two groups of patients were treated in different ICUs, we cannot eliminate with certainty the possibility that other aspects of patient's care might explain the difference in the outcome. When these patients were becoming critically ill, our institution was in the rapidly escalating pandemic curve. In this phase bed availability and the patient assignment were a random event. COVID-19 treatment protocols have been otherwise consistent in our hospital for critically ill patients throughout the pandemic. The anticoagulation protocol was addressed and implemented institution-wide later allowing for this difference in care. However, we did not observe any major differences in the management other than the protocol for anticoagulation, and the propensity-matched analysis was similar. Nevertheless, propensity-matched analysis has its limitations, including the fact that in developing the propensity scores, important variables that could have affected the outcome may have been inadvertently omitted. Moreover, only two-thirds of the patients were able to be matched. Thus, while the use of anticoagulation was associated with improved outcomes, causality cannot be proved. Furthermore, creatinine was slightly more elevated in the OFF-protocol group, although the mean SOFA scores at protocol initiation were not significantly different. We do think comparisons between the two groups should be made with caution, but the outcomes of the OFF-protocol group are similar to those described in the literature (15, 19, 33). Additionally, our study did not include any comparison with patients not receiving anticoagulation, and we did not do further analysis to compare the two types of anticoagulation regimens that were used; low-molecular-weight heparin and unfractionated heparin. Our cohort was relatively overweight (mean BMI of 30); it is possible that a thinner cohort would have fewer thromboembolic complications. However, obesity is now a well-established risk factor for severe COVID-19 disease (36–38), and at least one report describes the mean BMI in their cohort as 29 (39). Thus our cohort's BMI is probably fairly representative of other critically-ill patients. Finally, although the differences in outcomes in the groups studied herein are impressive, the fact that pulmonary embolism/thrombosis symptoms frequently overlap those of severe COVID-19 infection, and that imaging was underutilized to prevent unnecessary staff exposure, might have led to underdiagnosis of thromboembolic complications. This fact might explain the higher D-dimer levels and higher mortality rate that was observed in the OFF-protocol group. And while recent commentaries call for controlled trials of anticoagulation in patients with COVID-19 (40), we believe the dramatic difference in outcomes revealed by these data should be carefully considered in designing and awaiting results of a double-blinded, controlled trial. These findings and the success of this protocol that has the longest follow-up among all published studies, provide a window toward understanding the mechanisms driving excessive thrombosis and its treatment in this disease.

Protocol-driven anticoagulation was safe and effective in the treatment of a cohort of COVID-19 patients and associated with significantly lower mortality and improved kidney function. Our findings should be validated in a larger randomized, controlled trial.

The data supporting the conclusions of this article will be made available by the authors upon reasonable request.

The studies involving human participants were reviewed and approved by Stony Brook University Committee on Research in Human Subjects. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

AT, SM, CM, NL, MB, DR, JR, PD, PV, JV, MT, and KK: study conception and design. AT, JR, MB, DR, MT, and JV: designed the clinical protocol. SM, WH, and MB: data analysis and making figures. AT, SM, CM, NL, MB, DR, JR, PD, PV, NC, LA, AS, AO, WH, JV, MT, and KK: planning the data analysis and data interpretation. PD, PV, NC, LA, AS, AO, SM, JR, CM, and AA: data acquisition. AT, CM, SM, NL, MT, and KK: drafting the manuscript. All authors: critically revising the manuscripts. All the authors gave the final approval of the version to be published.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.