The coronavirus disease 2019 (COVID-19) pandemic has spread globally at an alarmingly rapid rate. Within a span of seven months, there were more than 12 million cases of infection and 550,000 deaths worldwide as of July 2020. Prolonged lockdown periods aimed at curtailing COVID-19 infection rates have challenged social norms and disrupted the lifestyles of many. The burden placed on healthcare systems and medical professionals worldwide has also been immense.[2-4]
COVID-19 primarily infects the respiratory system, resulting in a spectrum of disease ranging from mild upper respiratory tract infections to life-threatening acute respiratory distress syndrome (ARDS). The systemic complications of severe COVID-19 disease include widespread activation of the immune system and generation of a prothrombotic state. Studies evaluating thromboembolic events in COVID-19 have reported findings of an increased incidence of venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism (PE).[6-19] The development of VTE is significantly associated with severe disease and higher mortality rate in COVID-19. The association of COVID-19 with arterial thrombotic events such as coronary and cerebrovascular events is, however, less clear.[68-10131620] In addition, findings of widespread pulmonary microthrombi formation are increasingly reported in postmortem studies.[21-27] The aetiology of pulmonary microvascular thrombosis has been attributed to a pulmonary intravascular coagulopathy process specific to COVID-19.
In recognition of COVID-19 infection as a significant risk factor for the development of VTE, multiple interim European and American guidelines[29-36] on management of thrombotic risk in COVID-19 have been developed. It is unclear if these guidelines can be extrapolated directly to the Asian population, which has a significantly lower incidence of VTE and higher bleeding risk from anticoagulation use.[37-45] The role of anticoagulation in management of arterial and microvascular thrombosis in COVID-19 is also not well established. Thus, there is a need to ascertain the population incidence rate of arteriovenous thromboembolic events and microvascular thrombosis in COVID-19 to guide management.
This review article summarises the current understanding of arteriovenous thromboembolic complications and pulmonary microvascular thrombosis in COVID-19. We also propose a management strategy for prevention and treatment of thrombotic events in Asian COVID-19 patients based on current evidence in the literature and existing management guidelines.
The main clinical question addressed in this article is whether COVID-19 increases the risk of arteriovenous thromboembolic events. A better understanding of the thrombotic risks associated with COVID-19 would help physicians to improve clinical management of this patient group. Our review also aimed to discuss how clinical management in Asian COVID-19 patients might differ from those in Caucasian guidelines due to Asian predilections for reduced thrombotic tendencies and increased bleeding risk. We reviewed and summarised information from medical journals and major clinical guidelines reporting on pathophysiology, incidence and management of VTE, cerebrovascular and acute coronary vascular events in COVID-19.
Comprehensive searches of major medical databases were carried out, including MEDLINE via PubMed, Ovid, Embase and Cochrane Library. Search terms and keywords used were ‘COVID-19’, ‘thrombosis’, ‘deep vein thrombosis’, ‘pulmonary embolism’, ‘anticoagulation’, ‘coagulopathy’, ‘myocardial infarction’, ‘stroke’, ‘cerebrovascular events’ and ‘coronary events’. Our search did not yield any meta-analysis or randomised controlled trials on the topic of interest. The evidence that we obtained was from retrospective cohort studies and case series. As the COVID-19 cohorts that were studied were highly heterogenous due to selection bias, we decided against performing pooled analysis of the laboratory coagulation parameters and incidence of thrombotic events. Instead, we summarised the literature in a descriptive manner, stating the range of incidences of VTE, cerebrovascular and acute coronary vascular events across the different cohorts of COVID-19 patients.
COVID-19-RELATED ARTERIOVENOUS THROMBOEMBOLISM
We identified 18 cohort studies that described coagulation parameters of patients with COVID-19 [Table 1]. The patient population, methodology and description of laboratory results were highly heterogenous between these studies.
Median D-dimer values ranged from 0.16 mg/L to 0.66 mg/L in non-critically ill COVID-19 patients [6101416182446-56] but were consistently higher in critically ill COVID-19 patients, ranging from 0.39 mg/L to 2.4 mg/L across the studies. Elevated D-dimer levels were also found to be associated with increased risk of thrombosis and mortality. Median activated partial thromboplastin time (APTT) values were abnormal in a single study by Tang et al, with six other studies reporting normal median values. The incidence of disseminated intravascular coagulopathy (DIC) was reported by two studies; Al-Samkari et al and Tang et al reported the incidence of DIC to be 0.75% (3/400) and 8%, respectively.
The clinical significance of lupus anticoagulant and its possible association with thrombotic complications in COVID-19 is yet unclear. Studies that evaluated levels of lupus anticoagulant have found increased incidence of positive lupus anticoagulant in COVID-19 patients. Harzallah et al  found that 25 (45%) out of 56 patients in a COVID-19 cohort tested positive for lupus anticoagulant, while Helms et al found that 50 (87.7%) out of 57 critically ill patients with clinical suspicion for coagulopathy tested positive for lupus anticoagulant. Bowles et al performed lupus anticoagulant assays in a subset of 34 patients with abnormal APTT results and found that 31 (90%) of them tested positive for it.
The diagnostic criteria for antiphospholipid syndrome involve positive titres of immunoglobulin G and immunoglobulin M isotypes of anticardiolipin and anti-B2 glycoproteins antibodies. The published case series performed limited evaluation of these antiphospholipid antibodies. This limits their utility in the evaluation of antiphospholipid syndrome as a plausible mechanism of thrombosis in COVID-19.
We included 14 observational cohort studies that had reported on the incidence of VTE in COVID-19 patients [Table 2]. The majority of patients in the cohort studies were critically ill Caucasian COVID-19 patients. Four studies[61417-19] included non-critically ill COVID-19 patients and two studies included Asian critically ill COVID-19 patients.
The baseline characteristics of the COVID-19 cohorts studied, criteria for admission to the intensive care unit (ICU) and definition of severe COVID-19 infection differed between studies. The threshold to perform diagnostic imaging, such as computed tomography pulmonary angiography and venous ultrasonography of the extremities, was also not standardised across studies.
The incidence of VTE in non-critically ill COVID-19 cohorts ranged from 0% to 4.8% across five studies,[61317-19] while incidence rates in the critically ill COVID-19 cohort was markedly higher, ranging from 7.6% to 60% across 13 studies. Notably, the majority of the patients in these studies received at least prophylactic doses of anticoagulation. A cohort study  in Asians in which patients did not receive chemical thromboprophylaxis reported a VTE incidence rate of 25%.
Two studies compared the incidence rates of VTE in COVID-19 patients to matched cohorts of non-COVID-19 patients. Helms et al compared 150 COVID-19 ARDS cases with a matched cohort of non-COVID-19 ARDS patients. VTE complications and PE incidence were 2.6 times and 6.2 times more likely in patients with COVID-19, respectively, despite 70% of cases receiving prophylactic anticoagulation and 30% receiving therapeutic doses of heparin. Poissy et al compared VTE incidence in a COVID-19 cohort to historic matched controls from the same intensive care unit and to matched controls with severe influenza infection. The VTE incidence in COVID-19 was 3.3 times higher compared to matched ICU controls and 2.74 times greater compared to patients with severe influenza infection.
The results from these cohort studies suggest that COVID-19 is an independent risk factor for VTE. However, more studies in an Asian population are needed to further determine VTE risk in Asian COVID-19 patients.
The incidence of arterial thrombosis in COVID-19 is much lower than that of VTE. Acute coronary syndrome [Table 3] and strokes [Table 4] in COVID-19 patient cohorts ranged from 0% to 3.6%[68-101316] and 0.9% to 2.7%, respectively.
None of the studies compared the incidence of acute coronary syndrome and myocardial infarction between COVID-19 and non-COVID-19 controls. A study done in two academic teaching hospitals in New York, comprising 1,916 COVID-19 patients, reported that the incidence of ischaemic stroke in COVID-19 was greater than that of patients admitted to the same centre with influenza (odds ratio 7.6, 95% confidence interval [CI] 2.3–25.2). However, the COVID-19 cohort was not matched with the influenza cohort in terms of disease severity, with 25% of the COVID-19 being critically ill as compared to 6% in the influenza cohort. Multivariate analysis of stroke risk did not take into account critical illness status, thus limiting any strong conclusion regarding direct risk of ischaemic stroke in COVID-19.
Another large cohort study reviewing the characteristics of stroke patients with COVID-19 was performed by Yaghi et al  on 3,556 patients admitted to the Langone health system in New York. The authors compared the clinical characteristics of COVID-19 patients with stroke to those of concurrent stroke without COVID-19 (contemporary control) and historical cohort of stroke patients admitted to the same health system (historical control). The overall incidence of stroke was very low, with only 0.9% of COVID-19 patients experiencing an ischaemic stroke. As compared to contemporary stroke controls, COVID-19 patients had higher mortality, higher median peak D-dimer levels and were more likely to have a cryptogenic stroke subtype (65.6% vs. 30.4%, p = 0.003). Cryptogenic stroke was defined by the authors as a ischaemic stroke that is not caused by atherosclerotic disease or cardioembolic phenomenon, the two commonest subtype of ischaemic stroke. The finding of reduced primary atherosclerotic disease as a cause of ischaemic stroke in COVID-19 cohorts was also observed in the cohort study by Merkler et al.
These findings suggest that atherosclerotic disease and arterial thrombosis are not the predominant cause of ischaemic strokes in COVID-19 cohorts. Instead, mechanisms related to severe illness or sepsis might account for the increase in incidence of cryptogenic strokes in COVID-19. They include: (a) hypotension and inadequate cerebral perfusion; (b) relative hypertension leading to posterior reversible encephalopathy syndrome; (c) septic embolisation; (d) stress cardiomyopathy; and (e) paroxysmal atrial fibrillation. Another large study on 700 COVID-19 patients similarly concluded that the risk of cardiac arrests and arrhythmias was related to critical illness status rather than COVID-19 disease state.
Autopsy findings of pulmonary embolism and pulmonary microvascular thrombosis
Histopathologic findings in postmortem COVID-19 cohorts [Table 5] frequently demonstrate histopathological features similar to that in ARDS, namely diffuse alveolar damage, Type 2 pneumocyte hyperplasia, hyaline membrane thickening with fibrin deposition and infiltration of alveolar spaces with inflammatory exudate. In addition, a high frequency (46%–100%) of PE and microthrombi formation within pulmonary arterioles and alveolar capillaries were noted in the postmortem studies.
Anticoagulation use in COVID-19
Two recently published retrospective cohort studies have described an association between anticoagulation use and reduced mortality rates among patients with severe COVID-19 disease.
Tang et al  reported that the use of prophylactic doses of heparin, the majority being low-molecular-weight heparin (LMWH) at 40–60 mg/day, was associated with a significant reduction in 28-day mortality for a subset of patients with severe COVID-19 disease. Further analysis on the same cohort showed that in patients with severe COVID-19 with an International Society on Thrombosis and Haemostasis (ISTH) sepsis-induced coagulopathy (SIC) score of ≥4, the use of heparin was associated with significantly reduced 28-day mortality (40.0% vs. 64.2%, P = 0.029) as compared to patients without anticoagulation therapy. The components of the ISTH SIC score include platelet count <100 × 109 platelet cells/L, prothrombin time/international normalised ratio >1.4 and sequential organ failure assessment score >2. Tang et al. also stratified the mortality risk of patients based on D-dimer results and demonstrated that the use of heparin in severe COVID-19 was associated with a 20% reduction in 28-day mortality (32.8% vs. 52.4%, P = 0.017).
Another large cohort study evaluating anticoagulation therapy in COVID-19 was performed on COVID-19 patients admitted to the Mount Sinai Health System in New York City, United States. The study reported that the use of treatment doses of anticoagulation was associated with a significant reduction in hospital mortality rates (29.1% vs. 62.7%) and a longer median survival (21 days vs. nine days) among COVID-19 patients who required mechanical ventilation. In the study, the use of treatment doses of anticoagulation in critically ill COVID-19 patients was associated with a low overall incidence of major bleeding events (<3%).
Pathological processes behind thrombotic complications
The progression of acute disease in COVID-19 can be divided into three phases: an early phase that comprises viral infiltration and replication resulting in lymphocytopenia, a second phase comprising of respiratory compromise and abnormal chest imaging, and a third phase consisting of an exaggerated inflammatory response driven by host immunity with elevated inflammatory biomarkers and secondary organ damage.
Severe COVID-19 can cause a prothrombotic state that rarely progresses to overt DIC. The processes leading to thrombotic complications in severe COVID-19 can be postulated to arise from mechanisms that stem from Virchow’s triad: endothelial injury, stasis and hypercoagulability.
Direct and indirect endothelial injury in severe COVID-19 infection
Direct endothelial cell injury can occur due to invasion of endothelial cells by the COVID-19 virus or central venous and vascular catheters in severely ill COVID-19 patients. Direct vascular injury causes a release of prothrombotic factors, including von Willebrand factor (vWF) and activation of the clotting cascade.
The systemic release of inflammatory cytokines from severe COVID-19 infections can cause dysfunction of endothelial cells lining the pulmonary vasculature, allowing increased macrophage and neutrophil migration and presentation of activated tissue factor. The pulmonary microvasculature is particularly susceptible to injury by COVID-19 due to its close anatomical juxtaposition with Type II pneumocytes. Proximal airway epithelial cells and Type II pneumocytes ubiquitously express angiotensin-converting enzyme (ACE-2) receptor, a receptor that the Coronavirus family shows great tropism for. However, smaller airway epithelium does not express ACE-2 well and is less susceptible to coronaviruses. The inflammatory cytokines responsible for vascular injury in severe COVID-19 infections include interleukin-6 (IL-6), tumour necrosis factor-alpha and interferon gamma. Notably, non-survivors of severe COVID-19 infections have consistently exhibited higher levels of inflammatory markers, including IL-6, ferritin and C-reactive protein.
Stasis potentiating prothrombotic state in severe COVID-19 infections
Long-term immobilisation of severe COVID-19 infection patients from protracted illness and hospitalisation may increase the risk of VTE. Intentional fluid restriction as part of a lung-protective ventilation strategy in severe COVID-19 ARDS can cause inadvertent haemoconcentration and predispose patients to venous stasis. In addition, patients with severe hypoxaemia from ARDS also develop hypoxic vasoconstriction of pulmonary capillaries with further reduction of pulmonary blood flow. The combination of aforementioned factors may lead to the formation of pulmonary microvascular thrombi. Of note, pulmonary vasculature microthrombi and vascular endothelial dysfunction may be the primary cause of hypoxaemia in COVID-19 rather than parenchymal lung disease. This is supported by observations that the marked hypoxaemia associated with severe COVID-19 disease was often not characterised by dense consolidation and low lung compliance seen in severe ARDS.
Hypercoagulability in severe COVID-19 infections
The widespread activation of the immune system and ensuing cytokine storm drive an inflammatory cascade and resultant hypercoagulable state. This results in widespread damage and activation of vascular endothelial cells, an increased activity of antigen-presenting cells and activation of platelets and coagulation pathways. Patients with severe COVID-19 respiratory illness were found to have increased levels of serum fibrinogen, vWF, factor VIII, fibrin-degradation products such as D-dimer, and lupus anticoagulant. Pulmonary vascular endothelial injury, release of prothrombotic factors, activation of clotting cascade, and migration of microphages and neutrophils leads to microvascular thrombosis. This thrombotic tendency of the pulmonary microvascular has been described as pulmonary intravascular coagulopathy.
Thrombosis in severe COVID-19 infections a different entity from disseminated intravascular coagulopathy
Overt DIC is rare in COVID-19 patients, and platelets and fibrinogen levels are often not markedly reduced. Mild thrombocytopenia (platelets <150 × 109 platelet cells/L), mildly prolonged prothrombin time and fibrinogen levels at the upper limits of normal can be occasionally seen in severe COVID-19 infections. The coagulation derangements that are occasionally seen in severe COVID-19 more closely represent SIC or a DIC subtype with suppressed fibrinolysis activity.
Current guidelines for management of thrombotic complications in COVID-19
Interim guidelines [29-36] on anticoagulation use in COVID-19 have been proposed by major medical societies and hospitals from North America and Europe. These guidelines recognise COVID-19 as an independent risk factor for the development of VTE. The CHEST guidelines from America  consider all hospitalised patients with COVID-19 to be at increased risk of VTE. This is because the incidence of VTE in non-critically ill patients with COVID-19 is above 1% despite the use of VTE thromboprophylaxis. As such, current VTE guidelines for COVID-19 are consistent in their recommendation of starting standard prophylactic anticoagulation for all hospitalised COVID-19 patients.
However, there is no consensus regarding the role of therapeutic anticoagulation in management of thrombotic complications associated with COVID-19. Guidelines from the European Society of Cardiology and Mount Sinai Health System recommend the use of therapeutic anticoagulation for patients with severe COVID-19 infection who are mechanically ventilated and/or demonstrate markedly elevated biomarkers for venous thrombosis.
VTE, cerebrovascular, coronary vascular disease incidence and bleeding risk in Asian population
The VTE incidence in Asians may be up to 80% lower when compared to Caucasian counterparts, based on data from population studies. A large cohort study by Nicole Tran et al  evaluated the incidence of VTE among different Asian ethnic groups and Caucasian. This study reported a hazard ratio of 0.4–0.6 for VTE in Chinese, Japanese and Filipino as compared to Caucasians, with the risk of South Asians developing VTE being similar to that in Caucasians.
The lower incidence of VTE in the Asian population has been attributed predominantly to a lower prevalence of genetic mutations that predispose patients to a prothrombotic state, including Factor V Leiden and Prothrombin G20210A mutation. Decreased awareness of VTE risk among physicians in Asian hospitals and a lower tendency for performing imaging tests have also been proposed as an explanation for the lower reported incidence of VTE in studies performed on Asians. The genetic pool of South Asians may be closer to Middle Easterners and Europeans, thus accounting for the increased risk for VTE as compared to other Asian ethnicities.
The reduced risk of VTE in Asians is also apparent in ICU cohorts, wherein critical illness is a recognised acquired risk factor for the development of VTE. The incidence of VTE in Caucasian population in intensive care unit settings is as high as 31% without the use of thromboprophylaxis. VTE thromboprophylaxis significantly reduces the incidence of asymptomatic VTE to as low as 11%. The reported incidence of radiologically diagnosed VTE in Asian ICU patients without the use of VTE prophylaxis was lower at 19%, with a further reduction to 9.5% following routine use of VTE thromboprophylaxis.
VTE incidence rates in many Asian countries are increasing and approaching rates that are reported in developed Caucasian countries. This is attributed to improved clinician awareness and screening for VTE as well as an overall increase in risk factors for VTE. Significant risk factors for VTE in many Asian countries include longer life expectancies and higher incidences of malignancy. It is crucial for clinicians managing Asian patients to actively screen for risk factors for VTE in spite of the reduced ethnic risk for VTE among Asians.
The incidence of ischaemic stroke differs significantly between ethnicities. In a large population study, the age- and gender-adjusted ischaemic stroke incidence was 43% lower in Chinese and 63% lower in South Asians as compared to Caucasian patients. The proportions of ischaemic stroke subtypes also differ greatly between Asians and Caucasians, suggesting a racial predisposition to different pathophysiological processes. While the commonest cause of stroke among Caucasians is cardioembolic in nature (up to 30%), primary atherosclerosis in small vessels causing lacunar strokes is the most common (up to 50%) reason for stroke among Asians.[71-73]
Coronary vascular disease, of which the predominant pathophysiogy process is atherosclerosis, is highest among South Asians as compared to Caucasians (hazard ratio 1.35, 95% CI 1.3–1.4) and Chinese. Significant differences in the incidence of coronary artery disease also exists among different Asian ethnic groups.
A large study evaluating the risk of intracranial haemorrhage (ICH) in patients on warfarin reported a hazard ratio of 4.06 in the Asian group as compared to Caucasians.[42-44] Asian patients on novel oral anticoagulants (NOACs) had a significantly increased risk of developing ICH (2.11% vs. 0.97%, P <0.001) as compared to Caucasian patients. Several authors have reported NOACs to be associated with a lower bleeding risk when compared to Vitamin K antagonists among Asian cohorts, suggesting that NOACs should be the oral anticoagulation of choice in the Asian population.[79-81]
Venous thromboembolism prophylaxis in Asian COVID-19 patients
The Asian venous thromboembolism guidelines, recently updated in 2017, emphasise the assessment of risk factors for VTE to guide the use of VTE prophylaxis in Asians. The major risk factors for development of VTE remain consistent across all ethnicities. Significant VTE risk factors include advanced age, obesity, pregnancy, malignancy, major abdominal surgery, critical illness, prolonged immobility, stroke and trauma.
Asians are considered less prothrombotic and have an increased risk of bleeding from anticoagulation. However, there is growing evidence that COVID-19 itself is a strong independent risk factor for thrombosis. Furthermore, as clot formation is facilitated in COVID-19, the risk of bleeding is concurrently reduced. This leads to an inherent risk of thrombosis and a lower risk of bleeding in COVID-19, independent of ethnicity. Thrombotic risk in COVID-19 is proportional to the severity of the disease.
Criteria for hospitalisation vary between countries; some choose to admit all patients diagnosed with COVID-19, while others only admit those who are at high risk of deterioration. Asian COVID-19 patients who require hospital admission due to risk of further deterioration should be considered for VTE prophylaxis. Patients who are well enough to be managed in the community are at lower risk for developing thrombosis. These patients likely do not require VTE prophylaxis in the absence of other known VTE risk factors.
Patients categorised as having severe COVID-19 or critically ill (requiring ICU admission) should be prescribed at least a prophylactic anticoagulation dosage of LMWH or unfractionated heparin. Predictors of progression to severe COVID-19 may include the need for oxygen supplementation (suggesting early respiratory failure), high risk scores for VTE such as the Padua score, and elevated serum biochemical markers for thrombosis such as D-dimer levels. The Padua score and D-dimer levels have been demonstrated in studies to correlate with increased mortality, critical illness status and poor prognosis in COVID-19.
Venous thromboembolism treatment in Asian COVID-19 patients
As the bleeding risk from anticoagulation use is higher in Asians, it is ideal to establish a definitive diagnosis of VTE with imaging tests before starting a patient on therapeutic anticoagulation. In patients with COVID-19, clinicians should be aware of the increased risk of thrombotic complications and reduce their threshold to perform relevant imaging tests for the diagnosis of arteriovenous thromboembolic events. All diagnostic imaging tests should be carried out safely with appropriate infection control measures in place. VTE that is confirmed on imaging should then be managed with standard treatment doses of anticoagulation.
A subgroup of critically ill and severely hypoxaemic patients may not be able to undergo diagnostic imaging tests for PE due to their unstable clinical condition or kidney failure limiting the use of radiocontrast agents. Point-of-care ultrasonography in this group of patients may help to further determine the likelihood of PE.
A multidisciplinary team, comprising a minimum of an intensivist and a haematologist, should weigh the risk of clinical deterioration from untreated VTE against the bleeding risk from empirical therapeutic anticoagulation. Global haemostatic tests, such as thromboelastography and rotational thromboelastometry, may be performed to define bleeding risks and guide risk stratification in patients who are being considered for empirical therapeutic anticoagulation.
Arterial thromboembolic events, ischaemic strokes and myocardial infarctions in COVID-19
Our review of the literature shows that the overall incidence of arterial thromboembolic events is low in COVID-19. The majority of the ischaemic strokes in COVID-19 cohorts were due to cardioembolic or cryptogenic causes, both of which are uncommon subtypes of ischaemic strokes in Asians. The risk of ischaemic stroke and myocardial infarction in Asians with COVID-19 may not be specifically elevated beyond baseline atherosclerotic risk factors and critical illness status. There is insufficient evidence to recommend antiplatelets or anticoagulation therapy for the prevention of arterial-thromboembolic events in Asian COVID-19 patients.
Pulmonary microvascular thrombus and COVID-19
Our literature review did not provide sufficient data to clearly define the underlying incidence and risk factors of pulmonary microvascular thrombus formation in COVID-19.
Pulmonary microthrombi may be suspected in patients with severe hypoxaemia, disproportionately low degree of radiological infiltrates within the lung parenchyma and a normal to low-normal lung compliance. A major differential is PE, for which therapeutic anticoagulation is proven to be effective in reducing morbidity and mortality. No studies to date have evaluated the role of anticoagulation in the prevention or treatment of pulmonary microvascular thrombosis. There should be a reduced threshold to perform diagnostic imaging when PE or pulmonary microthrombi is suspected. Computed tomography pulmonary angiography can confirm the diagnosis of a pulmonary embolus, allowing clinicians to distinguish between PE and pulmonary microthrombi as the predominant cause of respiratory failure. This is clinically important as the role of therapeutic anticoagulation in the latter is not well established.
AREAS FOR FURTHER RESEARCH
Further definition of the indication and role of anticoagulation in COVID-19
At least 27 clinical trials focused on the role of anticoagulation in the management of arteriovenous thromboembolic events in COVID-19 have been registered on the ClinicalTrials.gov database. As of date, 12 randomised controlled trials evaluating the role of anticoagulation in COVID-19 have started recruiting patients. The results of these trials will provide more guidance on the clinical indications for therapeutic anticoagulation in COVID-19.
Utility of D-dimer as a risk stratification tool in COVID-19
Elevated D-dimer levels were found to positively correlate with the likelihood of critical illness, increase in VTE and mortality in COVID-19 [Table 1]. COVID-19 patients with raised D-dimer levels may potentially benefit from closer monitoring in high dependency units or ICUs. There should be a heightened clinical suspicion for arteriovenous thromboembolic complications and lowered threshold to perform diagnostic imaging scans in patients with raised D-dimer levels.
Further studies are needed to determine if D-dimer levels can be utilised clinically as a risk stratification tool for VTE and to predict likelihood of progression from mild to severe COVID-19.
Specific arteriovenous thromboembolic risk within the Asian population
The incidence and risk of coronary artery disease, ischaemic strokes and VTE in different population and ethnicity groups with COVID-19 need to be established. Knowledge of this data would aid clinicians in improving management of thromboembolic complications in COVID-19 patients.
COVID-19 is a significant risk factor for the development of VTE. Despite the lower incidence of VTE and higher bleeding risk from anticoagulation use in Asians, VTE prophylaxis should be considered for all hospitalised Asian COVID-19 patients. Asian COVID-19 patients who are at high risk of clinical deterioration or critically ill should be managed with at least prophylactic anticoagulation in the absence of contraindications. There should be increased awareness of VTE and a reduced threshold to perform diagnostic imaging for VTE in Asian COVID-19 patients. Adequate infection control measures should be maintained throughout. Confirmation of a diagnosis of VTE before starting therapeutic anticoagulation is recommended due to the higher bleeding risk from anticoagulation use in Asians.
The overall incidence of myocardial infarction and ischaemic strokes in COVID-19 is low. The risk of these arterial thrombotic events in COVID-19 is likely related to severe illness and systemic sepsis, rather than COVID-19-specific mechanisms.
The results of ongoing randomised control trials will further elucidate the role of anticoagulation in the management of arteriovenous thromboembolic complications in COVID-19.
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Conflicts of interest
There are no conflicts of interest.
1. World Health Organization WHO Coronavirus Disease (COVID-19) Dashboard Available at:https://covid19.who.int
Accessed August 10, 2020
2. Wong J, Ng SY, Goh MH, et al. Anaesthesia and intensive care medicine in a COVID-19 pandemic Singapore Med J 2020 Jun 26 https://doi.org/10.11622/smedj. 2020094. [Epub ahead of print]
3. Tay KJD, Lee YHD Trauma and orthopaedics in the COVID-19 pandemic:breaking every wave Singapore Med J 2020 61 396 8
4. Wong J, Goh QY, Tan Z, et al. Preparing for a COVID-19 pandemic:a review of operating room outbreak response measures in a large tertiary hospital in Singapore Can J Anaesth 2020 67 732 45
5. Rothan HA, Byrareddy SN The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak J Autoimmun 2020 109 102433
6. Al-Samkari H, Karp Leaf RS, Dzik WH, et al. COVID and coagulation:bleeding and thrombotic manifestations of SARS-CoV2 infection Blood 2020 136 489 500
7. Cui S, Chen S, Li X, Liu S, Wang F Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia J Thromb Haemost 2020 18 1421 4
8. Fraissé M, Logre E, Pajot O, et al. Thrombotic and hemorrhagic events in critically ill COVID-19 patients:a French monocenter retrospective study Crit Care 2020 24 275
9. Goyal P, Choi JJ, Pinheiro LC, et al. Clinical characteristics of Covid-19 in New York City N Engl J Med 2020 382 2372 4
10. Helms J, Tacquard C, Severac F, et al. High risk of thrombosis in patients with severe SARS-CoV-2 infection:a multicenter prospective cohort study Intensive Care Med 2020 46 1089 98
11. Klok FA, Kruip MJHA, van der Meer NJM, et al. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19:an updated analysis Thromb Res 2020 191 148 50
12. Llitjos JF, Leclerc M, Chochois C, et al. High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients J Thromb Haemost 2020 18 1743 6
13. Lodigiani C, Iapichino G, Carenzo L, et al. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy Thromb Res 2020 191 9 14
14. Middeldorp S, Coppens M, van Haaps TF, et al. Incidence of venous thromboembolism in hospitalized patients with COVID-19 J Thromb Haemost 2020 18 1995 2002
15. Poissy J, Goutay J, Caplan M, et al. Pulmonary embolism in patients with COVID-19:awareness of an increased prevalence Circulation 2020 142 184 6
16. Thomas W, Varley J, Johnston A, et al. Thrombotic complications of patients admitted to intensive care with COVID-19 at a teaching hospital in the United Kingdom Thromb Res 2020 191 76 7
17. Xu JF, Wang L, Zhao L, et al. Risk assessment of venous thromboembolism and bleeding in COVID-19 patients Pulmonology 2020 Mar 24 https://doi.org/10.21203/rs0.3.rs-18340/v1. Preprint
18. Moll M, Zon RL, Sylvester KW, et al. VTE in ICU patients with COVID-19 Chest 2020 Jul 22 https://doi.org/10.1016/j.chest. 20200.07.031. [In press]
19. Bilaloglu S, Aphinyanaphongs Y, Jones S, et al. Thrombosis in hospitalized patients with COVID-19 in a New York City health system JAMA 2020 324 799 801
20. Yaghi S, Ishida K, Torres J, et al. SARS-CoV-2 and stroke in a New York healthcare system Stroke 2020 51 2002 11
21. Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19 N Engl J Med 2020 383 120 8
22. Dolhnikoff M, Duarte-Neto AN, de Almeida Monteiro RA, et al. Pathological evidence of pulmonary thrombotic phenomena in severe COVID-19 J Thromb Haemost 2020 18 1517 9
23. Carsana L, Sonzogni A, Nasr A, et al. Pulmonary post-mortem findings in a large series of COVID-19 cases from Northern Italy medRxiv 2020 Apr 22 https://doi.org/10.1101/2020.04.19.20054262. Preprint
24. Magro C, Mulvey JJ, Berlin D, et al. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection:a report of five cases Transl Res 2020 220 1 13
25. Menter T, Haslbauer JD, Nienhold R, et al. Postmortem examination of COVID-19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings in lungs and other organs suggesting vascular dysfunction Histopathology 2020 May 4 https://doi.org/10.1111/his. 14134. [Epub ahead of print]
26. Schaller T, Hirschbühl K, Burkhardt K, et al. Postmortem examination of patients with COVID-19 JAMA 2020 323 2518 20
27. Wichmann D, Sperhake JP, Lütgehetmann M, et al. Autopsy findings and venous thromboembolism in patients with COVID-19:a prospective cohort study Ann Intern Med 2020 173 268 77
28. McGonagle D, O'Donnell JS, Sharif K, Emery P, Bridgewood C Immune mechanisms of pulmonary intraceascular coagulopathy in COVID-19 pneumonia Lancet Rheumatol 2020 2 e437 45
29. World Health Organization Clinical management of COVID-19 interim guidance Available at:https://www.who.int/publications/i/item/clinical-management-of-covid-19
Accessed August 10, 2020
30. Atallah B, Mallah SI, AlMahmeed W Anticoagulation in COVID-19 Eur Heart J Cardiovasc Pharmacother 2020 6 260 1
31. Bikdeli B, Madhavan MV, Jimenez D, et al. COVID-19 and thrombotic or thromboembolic disease:implications for prevention, antithrombotic therapy, and follow-up:JACC state-of-the-art review J Am Coll Cardiol 2020 75 2950 73
32. Casini A, Alberio L, Angelillo-Scherrer A, et al. Thromboprophylaxis and laboratory monitoring for in-hospital patients with COVID-19-a Swiss consensus statement by the Working Party Hemostasis Swiss Med Wkly 2020 150 w20247
33. Moores LK, Tritschler T, Brosnahan S, et al. Prevention, diagnosis, and treatment of VTE in patients with coronavirus disease 2019:CHEST guideline and expert panel report Chest 2020 158 1143 63
34. Thachil J, Tang N, Gando S, et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19 J Thromb Haemost 2020 18 1023 6
35. Zhai Z, Li C, Chen Y, et al. Prevention and treatment of venous thromboembolism associated with coronavirus disease 2019 infection:a consensus statement before guidelines Thromb Haemost 2020 120 937 48
36. Marietta M, Ageno W, Artoni A, et al. COVID-19 and haemostasis:a position paper from Italian Society on Thrombosis and Haemostasis (SISET) Blood Transfus 2020 18 167 9
37. Lee LH, Gallus A, Jindal R, Wang C, Wu CC Incidence of venous thromboembolism in Asian populations:a systematic review Thromb Haemost 2017 117 2243 60
38. Liao S, Woulfe T, Hyder S, et al. Incidence of venous thromboembolism in different ethnic groups:a regional direct comparison study J Thromb Haemost 2014 12 214 9
39. Liew NC, Alemany GV, Angchaisuksiri P, et al. Asian venous thromboembolism guidelines:updated recommendations for the prevention of venous thromboembolism Int Angiol 2017 36 1 20
40. Mehta RH, Cox M, Smith EE, et al. Race/ethnic differences in the risk of hemorrhagic complications among patients with ischemic stroke receiving thrombolytic therapy Stroke 2014 45 2263 9
41. Raskob GE, Angchaisuksiri P, Blanco AN, et al. Thrombosis:a major contributor to global disease burden Arterioscler Thromb Vasc Biol 2014 34 2363 71
42. Shen AY, Yao JF, Brar SS, Jorgensen MB, Chen W Racial/ethnic differences in the risk of intracranial hemorrhage among patients with atrial fibrillation J Am Coll Cardiol 2007 50 309 15
43. van Asch CJ, Luitse MJ, Rinkel GJ, et al. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin:a systematic review and meta-analysis Lancet Neurol 2010 9 167 76
44. Yap LB, Eng DT, Sivalingam L, et al. A comparison of dabigatran with warfarin for stroke prevention in atrial fibrillation in an Asian population Clin Appl Thromb Hemost 2016 22 792 7
45. Zhang C, Zhang Z, Mi J, et al. The cumulative venous thromboembolism incidence and risk factors in intensive care patients receiving the guideline-recommended thromboprophylaxis Medicine (Baltimore) 2019 98 e15833
46. Fogarty H, Townsend L, Ni Cheallaigh C, et al. COVID19 coagulopathy in Caucasian patients Br J Haematol 2020 189 1044 9
47. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China N Engl J Med 2020 382 1708 20
48. Guo T, Fan Y, Chen M, et al. Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19) JAMA Cardiol 2020 5 1 8
49. Han H, Yang L, Liu R, et al. Prominent changes in blood coagulation of patients with SARS-CoV-2 infection Clin Chem Lab Med 2020 58 1116 20
50. Mao L, Jin H, Wang M, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China JAMA Neurol 2020 77 683 90
51. Tang N, Bai H, Chen X, et al. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy J Thromb Haemost 2020 18 1094 9
52. Tang N, Li D, Wang X, Sun Z Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia J Thromb Haemost 2020 18 844 7
53. Wang D, Hu B, Hu C, et al. clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China JAMA 2020 323 1061 9
54. Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China JAMA Intern Med 2020 180 934 43
55. Zhang L, Yan X, Fan Q, et al. D-dimer levels on admission to predict in-hospital mortality in patients with Covid-19 J Thromb Haemost 2020 18 1324 9
56. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China:a retrospective cohort study Lancet 2020 395 1054 62
57. Harzallah I, Debliquis A, Drénou B Frequency of lupus anticoagulant in Covid-19 patients J Thromb Haemost 2020 May 9 https://doi.org/10.111/jth.14937. [Epub ahead of print]
58. Bowles L, Platton S, Yartey N, et al. Lupus anticoagulant and abnormal coagulation tests in patients with Covid-19 N Engl J Med 2020 383 288 90
59. Merkler AE, Parikh NS, Mir S, et al. Risk of ischemic stroke in patients with coronavirus disease 2019 (COVID-19) vs patients with influenza JAMA Neurol 2020 Jul 2 https://doi.org/10.1001/jamaneurol. 20200.2730. [Epub ahead of print]
60. Bhatla A, Mayer MM, Adusumalli S, et al. COVID-19 and cardiac arrhythmias Heart Rhythm 2020 17 1439 44
61. Paranjpe I, Fuster V, Lala A, et al. Association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with COVID-19 J Am Coll Cardiol 2020 76 122 4
62. Akhmerov A, Marbán E COVID-19 and the heart Circ Res 2020 126 1443 55
63. Zhang H, Rostami MR, Leopold PL, et al. Expression of the SARS-CoV-2 ACE2 receptor in the human airway epithelium Am J Respir Crit Care Med 2020 202 219 29
64. Ruan Q, Yang K, Wang W, Jiang L, Song J Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China Intensive Care Med 2020 46 846 8
65. Gattinoni L, Coppola S, Cressoni M, et al. COVID-19 does not lead to a “typical”acute respiratory distress syndrome Am J Respir Crit Care Med 2020 201 1299 300
66. Levi M, Thachil J, Iba T, Levy JH Coagulation abnormalities and thrombosis in patients with COVID-19 Lancet Haematol 2020 7 e438 40
67. Nicole Tran H, Klatsky AL Lower risk of venous thromboembolism in multiple Asian ethnic groups Prev Med Rep 2019 13 268 9
68. Geerts W, Cook D, Selby R, Etchells E Venous thromboembolism and its prevention in critical care J Crit Care 2002 17 95 104
69. Joynt GM, Li TS, Griffith JF, et al. The incidence of deep venous thrombosis in Chinese medical intensive care unit patients Hong Kong Med J 2009 15 24 30
70. Khan NA, McAlister FA, Pilote L, et al. Temporal trends in stroke incidence in South Asian, Chinese and white patients:a population based analysis PLoS One 2017 12 e0175556
71. Kim BJ, Kim JS Ischemic stroke subtype classification:an asian viewpoint J Stroke 2014 16 8 17
72. Mehndiratta MM, Khan M, Mehndiratta P, Wasay M Stroke in Asia:geographical variations and temporal trends J Neurol Neurosurg Psychiatry 2014 85 1308 12
73. Bang OY Considerations when subtyping ischemic stroke in Asian patients J Clin Neurol 2016 12 129 36
74. Zaman MJ, Philipson P, Chen R, et al. South Asians and coronary disease:is there discordance between effects on incidence and prognosis? Heart 2013 99 729 36
75. Nijjar AP, Wang H, Quan H, Khan NA Ethnic and sex differences in the incidence of hospitalized acute myocardial infarction:British Columbia, Canada 1995-2002 BMC Cardiovasc Disord 2010 10 38
76. Anand SS, Yusuf S, Vuksan V, et al. Differences in risk factors, atherosclerosis, and cardiovascular disease between ethnic groups in Canada:the Study of Health Assessment and Risk in Ethnic groups (SHARE) Lancet 2000 356 279 84
77. Mak KH, Chia KS, Kark JD, et al. Ethnic differences in acute myocardial infarction in Singapore Eur Heart J 2003 24 151 60
78. Guo YT, Zhang Y, Shi XM, et al. Assessing bleeding risk in 4824 Asian patients with atrial fibrillation:The Beijing PLA Hospital Atrial Fibrillation Project Sci Rep 2016 6 31755
79. Bang OY, Hong KS, Heo JH Asian patients with stroke plus atrial fibrillation and the dose of non-vitamin K oral anticoagulants J Stroke 2016 18 169 78
80. Wang KL, Yap ES, Goto S, et al. The diagnosis and treatment of venous thromboembolism in Asian patients Thromb J 2018 16 4
81. Xue Z, Zhou Y, Wu C, et al. Non-vitamin K antagonist oral anticoagulants in Asian patients with atrial fibrillation:evidences from the real-world data Heart Fail Rev 2019 Oct 26 https://doi.org/10.1007/s10741-019-09878-y. [Epub ahead of print]
82. Zeng DX, Xu JL, Mao QX, et al. Association of Padua prediction score with in-hospital prognosis in COVID-19 patients QJM 2020 Jul 11 https://doi.org/10.1093/qjmed/hcaa224. [Epub ahead of print]