Treatment of Coagulopathy in COVID-19 Patients: A scoping review

Background: Coagulopathy, including disseminated intravascular coagulation, is frequently noted in patients with coronavirus infection disease 2019 (COVID-19). Recently, a number of articles on this topic have been reported. Objective: The aim of this study is to identify existing gaps where further research on anticoagulants in COVID-19 patients with coagulopathy needs to be done. Methods: We used the PRISMA Extension for Scoping Reviews. The protocol was registered on May 21, 2020, before conducting this review. MEDLINE, CENTRAL, WHO-ICTRP, ClinicalTrial.gov and PROSPERO were used. Result: Eight studies were included; six studies were already published and two are ongoing. The reported results for three publications were from case series, three were from retrospective cohorts and two were from randomized controlled trials. Eight studies examined the effectiveness of low molecular weight heparin (LMWH), of which seven studies used a prophylactic dose and four studies used a therapeutic dose of LMWH. A prophylactic or therapeutic dose of unfractionated heparin was investigated in four and three studies, respectively. No recombinant human soluble thrombomodulin was investigated. Conclusion: The anticoagulants are limited to heparinoids, and the study designs were of low quality. Further studies with an improved design are needed to compare other available anticoagulants. ABSTRACT Provide a structured summary that includes (as applicable): background, objectives, eligibility criteria, sources of evidence, charting methods, results, and conclusions that relate to the review questions and objectives. Abstract Describe the rationale for the review in the context of what is already known. Explain why the review questions/objectives lend themselves to a scoping review approach.


Background
One of the major clinical manifestations noted in coronavirus disease 2019 (COVID-19) patients is coagulopathy, including disseminated intravascular coagulation (DIC) and thrombosis that is triggered, at least in part, by cytokines produced by in ammatory cells [1]. In addition, the endothelial cell derangement caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen that causes COVID-19, may contribute to the development of coagulopathy; SARS-CoV-2 exploits the angiotensinconverting enzyme 2 (ACE2) receptor expressed on the cell surface of vascular endothelial cells and induces diffuse endothelial in ammation, so-called endotheliitis [2], resulting in thrombotic microangiopathies [3]. This complex process plays a role in the development of the coagulopathy induced by SARS-CoV-2. A previous observational study found that the presence of coagulopathy, as evidenced by an increase in plasma levels of D-dimer, is associated with poor prognosis in COVID-19 patients [4]. Currently, many papers are focusing on the treatment of COVID-19-associated coagulopathy; however, there is no scoping review on this topic. The scoping review is a useful method to review evidence in rapidly emerging topics. The identi cation and analysis of knowledge gaps are valuable indications for conducting a scoping review [5]. The objective of this review is to conduct a scoping review to systematically map the anticoagulants used in this area and to identify the existing gaps where further research needs to be performed.

Protocol and Registration
We conducted this scoping review after the a priori protocol was registered in Protocols.io. Link: https://dx.doi.org/10.17504/protocols.io.bgrpjv5n in which the inclusion and exclusion criteria were described. The methodology to conduct scoping reviews by the Joanna Briggs Institute was followed [6], and the results are presented using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Extension for Scoping Reviews (PRISMA-ScR) [7].

Results
The results of the checklist [7] are described in Table 1. regarding the treatment of coagulopathy in COVID-19 patients were identi ed, and 38 studies were selected according to the title and abstract for further full-text review after the removal of duplicates ( Fig.   1). Among them, seven articles ful lled the inclusion criteria, and one article was assessed after reviewing the references of another study. Thus, eight studies were analyzed in the scoping review [8][9][10][11][12][13][14][15]. The results of the literature search strategy are described in Table 2. There is no previous scoping review on this topic.

Characteristics of the sources of evidence
The author, status, publication or registration data, location, study design, patient conditions, interventions, and outcomes of all the included studies are summarized in Map 1.

Results of the individual sources of evidence
Tang et al [8] Data and location: In March 2020 from China Study design: a retrospective cohort study Patients: 449 severe COVID-19 patients Coagulopathy and severity condition: Ninety-seven out of 449 patients (21.6%) met the SIC criteria (total score ≥ 4). Plasma levels of D-dimer exceeding 3.0 µg/mL were noted in 161 patients (32.2%).
Comparisons: 350 patients did not receive any anticoagulant.
Note: The number of heparin users and nonusers with SIC scores ≥4 and D-dimer values >3.0 µg/mL, respectively, were not reported. Neither therapy-related side effects nor the study design was reported.
Fogarty et al [9] Data and location: April 2020 from Ireland Study design: case series Patients: 83 hospitalized COVID-19 patients Coagulopathy and severity condition: The median and quantile D-dimer levels were 732 ng/ml (200 -10,000 ng/ml), and none of the patients met the diagnostic criteria of DIC as de ned according to the ISTH DIC score on admission.
Interventions: The dose of LMWH was based on a prophylactic dose and adjusted according to body weight and renal function (enoxaparin 20 mg OD if < 50 kg; enoxaparin 40 mg OD if 50-100 kg; 40 mg BD if 101-150 kg; 60 mg BD if >150 kg). Eight patients had renal impairment on admission and were therefore treated with enoxaparin 20 mg OD. Four patients were on therapeutic anticoagulation (2 patients on apixaban, 1 on edoxaban and 1 on warfarin).
Outcome: 50 patients (60.2%) had fully recovered and were discharged from the hospital without requiring ICU admission, while 20 remained in the hospital and 13 had died. Among the patients, 23 were transferred to the ICU during treatment.
Note: The study design was reported as a cohort, but this study did not compare the clinical outcomes among anticoagulants. Side effects were not reported.
Klok et al [10] Data and location: April 2020 from the Netherlands Interventions: The standard dose of nadroparin differed between hospitals: 2850 IU subcutaneous injection (sc) per day or 5700 IU per day if bodyweight > 100 kg; 5700 IU per day; 5700 IU sc twice daily; 2850 IU sc per day or 5700 IU per day if bodyweight > 100 kg; and 5700 IU sc per day.
Outcome: Twenty-two patients were discharged alive (12%), 139 (76%) were still in the ICU, and 23 died (13%). The number of patients with the composite outcome was 31, and ultrasonography con rmed DVT in 3 patients and arterial thrombotic events in 3 patients. Pulmonary embolism (n = 25) was the most frequent thrombotic complication. Coagulopathy de ned as above was an independent predictor of thrombotic complications (adjusted HR 4.1, 95% CI 1.9 -9.1).
Note: Neither therapy-related side effects nor the study design was reported.
Llitjos et al [11] Data and location: April 2020 from France Outcome: The overall rate of VTE at day 7 after ICU admission was 69%. The proportion of VTE was signi cantly higher in patients treated with prophylactic anticoagulation than in the therapeutic group (100% vs. 56%, respectively, p=0.03). The numbers of patients who developed ARDS, pulmonary embolism, acute kidney injury, and liver dysfunction or who died were 7, 0, 2, 1, and 1, respectively, in the prophylactic group and 14, 6, 7, 3, and 2 in the therapeutic group.
Note: Neither therapy-related side effects nor the study design was reported.
Yin et al [12] Data and location: April 2020 from China Study design: retrospective cohort study Patients: hospitalized COVID-19 patients Coagulopathy and severity condition: patients with D-dimer levels ≧ 3.0 µg/mL.
Note: Side effects were not reported.
Helms et al [13] Data and location: May 2020 from France study design: a case series Patients: 150 COVID-19 ARDS patients admitted to the ICU Coagulopathy and severity condition: The median quantile levels of D-dimer and brinogen were 2.27 mg/L (1.16 -20) and 6.99 g/L (6.08 -7.73), respectively. A total of 144 patients (96%) were diagnosed with non-JAAM-DIC (< 4 points), none of the patients were diagnosed with DIC by the ISTH criterion (< 5 points), and 22 patients (14.7%) had a positive SIC score. The median SAPS II score was 49 (37 -64) points.
Interventions: The prophylactic dose was 4000 UI/day for LMWH or 5-8 U/kg/h for UFH. The therapeutic dose was not described.
Outcome: Sixty-four clinically relevant thrombotic complications were diagnosed, with pulmonary embolisms being the most frequent event (16.7%). The reported side effects included hematoma in 4 patients (2.7%).
Note: The study design was reported as a cohort; however, the outcomes were not reported based on anticoagulants, and the study was judged as a case series. Usha et al [14] Data and location: in April 2020 from the U.S.A. Coagulopathy and severity condition: D-dimer (≥ 2-fold of the upper limit of normal) Interventions: therapeutic anticoagulation including the LMWH used in this study includes tinzaparin 175 U/kg once per day, enoxaparin 1.5 mg/kg once per day or 1 mg/kg twice per day or dalteparin 200 U/kg once per day or 100 U/kg twice per day. UFH will be administered using a bodyweight-based nomogram according to the center-speci c institutional protocol.
Comparison: the standard care Outcome: The primary outcome is the composite outcome of ICU admission, noninvasive positive pressure ventilation, invasive mechanical ventilation, or all-cause death up to 28 days.

Note: ongoing
Protocol versus overview Our planned search strategy registered in protocol.io was compared with the nal reported review methods. There was a difference between the study designs reported by original articles and those judged by our reviews. We chose to report the study design based on our judgment.

Discussion
This study is the rst scoping review that summarizes the available evidence on the treatment of coagulopathy in COVID-19 patients. Our results provide insights into the gap that exists among anticoagulants recommended by current therapeutic strategies. Some patterns were found after the scoping review. Most reviewed studies were related to heparin, especially the prophylactic dose and therapeutic dose of LMWH, and no published research evaluating the e cacy of recombinant human soluble thrombomodulin (rTM) was identi ed. A prophylactic dose of UFH or LMWH is not one of the therapeutic strategies to treat DIC or coagulopathy caused by severe underlying diseases [22]. However, the prophylactic dose of those anticoagulants was used in seven studies including for severe patients. A randomized control trial to compare the prophylactic dose to the therapeutic dose of LMWH is ongoing [14]. Compared with UFH, the use of rTM improved the DIC resolution rate in patients with DIC caused by hematological malignancies or infectious diseases [23], and rTM is approved only in Japan for use in daily clinical practice, which could explain why, currently, no study has reported the rTM treatment of COVID-19-induced coagulopathy. However, an international randomized trial to assess the effect of rTM on sepsis-associated coagulopathy was conducted [24], and it is the rationale to register a clinical trial comparing rTM with other anticoagulants.
The ISTH DIC score as well as D-dimer levels were utilized to assess coagulopathy in most studies. Given that COVID-19 patients showed a high level of interleukin-6 [25], which promotes the production of brinogen [26], the criteria released from JAAM or JSTH may be more suitable to evaluate the coagulopathy induced by COVID-19, as these criteria do not evaluate serum levels of brinogen. The serum levels of brinogen were higher in COVID-19 patients than in non-COVID-related acute respiratory distress syndrome patients [13] [27]. In addition to coagulopathy, the severity of the underlying disease is related to morbidity and mortality. Therefore, it is necessary to precisely evaluate the severity of COVID-19. Only one study [13] assessed the severity of the general condition of patients using SAPS II, and the others used clinical factors such as admission to the ICU.
There is also a gap in the study design. Most of the reviewed studies were observational, starting with low-quality evidence, according to the GRADE system for grading the quality of evidence [28], which likely limits the validity and reproducibility of the results. In addition to this gap, three studies did not report the study design, and one reported the design incorrectly and was judged by our reviewers to be a case series because of not comparing the results of anticoagulant use. Therefore, future studies that could apply to clinical practice should focus on improving study quality.

Strengths and limitations
Our review was conducted systematically according to the methodology after registration of a prior protocol. Performance was based on the recommendations from the PRISMA Extension for Scoping Reviews. We believe that this review followed a robust method. However, due to the urgent need for evidence on this topic and limited time, we did not contact authors to clarify the details of primary data when necessary. We did not search as many databases as possible. Because studies on this topic are rapidly being conducted, there may be other studies that were not examined in this review when the results are published.

Conclusion
Evidence on the treatment of coagulopathy in COVID-19 patients is accumulating but is still mainly focused on the use of heparinoids, observational study designs, and the assessment of coagulopathy by the ISTH DIC score. Further clinical trials are needed to compare other anticoagulants and may provide more accurate results by improving their study design.
Recently, ISTH has released the interim guidance on recognition and management of coagulopathy in COVID-19; it recommends the physicians to measure D-dimer, PT, and the platelet count to determine the patients requiring admission. Based on the reports by Tang et al [8], the prophylactic dose of LMWH is recommended for all admitted patients [29]. This guidance should be modi ed after the accumulation of more solid evidences.

Declarations
Contributions HM conceived this study and designed the protocol. HM and HO developed and conducted the literature search strategy. HM, HO, RT, MR, YS and TI drafted and revised the manuscript.

Con ict of interest
All of authors declare that they have no con icts of interests.

Objectives 4
Provide an explicit statement of the questions and objectives being addressed with reference to their key elements (e.g., population or participants, concepts, and context) or other relevant key elements used to conceptualize the review questions and/or objectives. Give numbers of sources of evidence screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally using a ow diagram.