key: cord-0864326-q5obtqxo
authors: Kow, Chia Siang; Zaihan, Abdullah Faiz; Hasan, Syed Shahzad
title: Anticoagulant approach in COVID-19 patients with cerebral venous thrombosis
date: 2020-08-03
journal: J Stroke Cerebrovasc Dis
DOI: 10.1016/j.jstrokecerebrovasdis.2020.105222
sha: da1465f9ac8c9f27b48e4243ab826391128ecf39
doc_id: 864326
cord_uid: q5obtqxo

nan

The authors declared no conflict of interest. No funding was received for the writing of this manuscript.

We appreciate Klein et al. [1] for reporting the case of cerebral venous thrombosis accompanied by hemorrhagic infarct in a young patient with novel coronavirus disease 2019 (COVID-19). The reporting of such a case would raise the awareness of the possibility of the occurrence of cerebral venous thrombosis in the course of COVID-19, especially among the young adults present with COVID-19 and neurological symptoms.

However, we would like to complement the discussion by Klein et al. regarding the anticoagulant approach in COVID-19 patients with cerebral venous thrombosis. Though we agree with authors that both unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) can be used in patients with COVID-19 associated venous thromboembolism during the acute period, the evidence appears to be stronger with low molecular weight heparins. To illustrate, in a 2017 Cochrane systematic review and meta-analysis [2] of 29 studies that compared LMWH with intravenous or subcutaneous unfractionated heparin in patients with acute venous thromboembolism (deep vein thrombosis and/or pulmonary embolism) in over 10,000 patients, it was reported that LMWH at three months was associated with significantly fewer thrombotic complications (odds ratio [OR] = 0.70, 95% confidence interval CI 0.56-0.90), significantly improved thrombus regression (OR = 0.71, 95% CI 0.61-0.82), significantly reduced rates of major hemorrhage (OR = 0.69, 95% CI 0.5-0.95), and a non-significant reduction in mortality (4.8 versus 5.7 percent; OR = 0.84, 95% CI 0.70-1.01).

Specifically, in patients present with acute cerebral venous thrombosis, though with limited data available, the evidence thus far shows that LMWH may be more effective than unfractionated heparin. In an open-label randomized controlled trial, 66 adults with cerebral venous thrombosis were randomly assigned to treatment with either UFH or LMWH [3] . It was reported that in-hospital mortality was significantly lower in the group randomized to LMWH compared to the group randomized to UFH (0% versus 19%). In addition, the proportion of patients with complete recovery at three months was greater for the group receiving LMWH (88% versus 63%), though the difference in the group receiving UFH was not statistically significant. Yet, in a case-control study, it was observed that significantly higher proportion of adult patients with cerebral venous thrombosis who received LMWH (n = 119) compared with UFH (n = 302) were independent at six months (adjusted odds ratio = 2.4, 95% CI 1.0-5.7), after adjustment of confounders [4] . Besides, treatment with LMWH was also associated with slightly lower rates of mortality (6% versus 8%) and new intracranial hemorrhage (10% versus 16%), though these outcomes were not significantly different between both treatment groups.

The efficacy of LMWH relative to UFH among patients with acute cerebral venous thrombosis accompanied by hemorrhagic stroke has been addressed in a subgroup analysis of a network metaanalysis which reported that LMWH demonstrated significantly lesser odds of intracranial and extracranial bleeding as compared to UFH (odds ratio = 0.4, 95% CI 0.16-0.97). Although not statistically significant, this network meta-analysis also suggested that patients treated with LMWH were more likely to obtain good recovery and lower mortality rate as compared to UFH after CVT [5] .

It is also worth mentioning that the 2017 European Stroke Organization guidelines for the diagnosis and treatment of cerebral venous thrombosis [6] , endorsed by the European Academy of Neurology, recommended LMWHs instead of UFH at therapeutic dosage for the treatment of adult patients with acute cerebral venous thrombosis.

In conclusion, we believe, based on currently available evidence, that LMWH may worth a consideration before UFH due to better safety and efficacy as well as more predictable pharmacokinetic profile as compared to dose-adjusted (in fact, the subject reported by Klein et al. received treatment with LMWH) [7] , though large trials may be needed to confirm its efficacy in COVID-19 patients with cerebral venous thrombosis relative to unfractionated heparin.

Nevertheless, we recognized that unfractionated heparin may be better suited for the critically ill patients who may need immediate surgery or other invasive operations (for example repeated lumbar puncture or planned surgery) as the activated partial thromboplastin time could return to normal within 1 hour upon stopping UFH infusion and that LMWH can only partially be reversed by protamine sulfate compared to a full reversion of UFH [8] . It should also be noted that UFH is particularly the only parenteral anticoagulant that is safe to be used in patients with renal failure which makes UFH indispensable despite the superior efficacy and safety of LMWHs. Other circumstances where intravenous UFH is preferred include possible poor subcutaneous absorption in patients with obesity.

Cerebral venous thrombosis: A typical presentation of COVID-19 in the young

Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for the initial treatment of venous thromboembolism

Low molecular weight heparin versus unfractionated heparin in cerebral venous sinus thrombosis: a randomized controlled trial

Unfractionated or low-molecular weight heparin for the treatment of cerebral venous thrombosis

Efficacy and risks of anticoagulation for cerebral venous thrombosis

European Stroke Organization guideline for the diagnosis and treatment of cerebral venous thrombosis -endorsed by the European Academy of Neurology

Pharmacological and clinical differences between low-molecular-weight heparins: implications for prescribing practice and therapeutic interchange

Treatment of cerebral venous and sinus thrombus