Venous thromboembolism (VTE) is a phenomenon where there is a development of thrombus in a vein. When this stems from the lower extremities of the body (occurring in more than 90% of patients),1 it is classified as deep vein thrombosis (DVT). Pulmonary embolism (PE) occurs when a thrombus is removed from its originating point and subsequently transported to the lung. VTE is reported to cause a staggering 900,000 new cases and 300,000 casualties annually just in the USA2. However, reportedly VTE is significantly less frequent among Asian patients3,4. Since the onset and manifestation of the disease are often silent, it is imperative that thromboprophylaxis is implemented, particularly before major orthopaedic surgery5. The administration of thromboprophylaxis, however, is not as widespread among Asian patients who are at a greater risk of thrombotic events6. A recent cross-sectional study undertaken on more than 1600 pregnant women who had their delivery reported that only five out of 601 women at risk of a thrombotic event (based on The Royal College of Obstetricians and Gynaecologists guidelines) received thromboprophylaxis7. Low molecular weight heparin (LMWH) is the most ubiquitous prophylactic measure against VTE. Gervaso et al8 summarized that LMWH significantly decreases the risk of VTE in patients suffering from cancer who are undergoing chemotherapy - a risk reduction of 0.54. The authors also highlighted that in a randomized study on 672 cancer patients, those on LMWH treatment had a VTE recurrence rate of 8 per cent compared with 15.8 per cent in those administered vitamin K antagonists as prophylaxis. Recent studies on Asian patients have reported that the occurrence of VTE is greater than previously reported, especially in the aftermath of significant orthopaedic surgery9–13. Studies in the Indian context have reported an incidence of 22 per 10,000 hospital admissions14. However, not much has been documented about the efficiency and risk of using thromboprophylaxis in patients prone to VTE in India. A local understanding of the disease burden, risk factors, epidemiology, food and nutrition and environmental factors, particularly in the Indian context, is thus vital.
Search strategy
A literature search was carried out on PubMed and Google Scholar with the key words “Venous Thromboembolism”, “Venous Thromboembolism risk factors”, “Venous Thromeboembolism environmental factors”, and “Venous Thromboembolism association with COVID-19” or “in India” at the end of each search. All relevant articles were selected for further analysis, however, priority was first assigned to the articles with data on Indian population over Western populations. Table I summarizes the studies on the Indian demographics that have been included in this review.
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Table I: Studies assessing venous thromboembolism in the Indian demographic
Epidemiology
Although it has previously been reported that the incidence of DVT is lesser in Asian population than Caucasians [a relative risk of 0.2 (0.1-0.5, P=0.002) at 95 per cent confidence intervals]15,16, findings from studies conducted on orthopaedic17,18 patients in the Asian subcontinent suggest otherwise (22.6 and 48.6% of patients out of those who underwent total hip replacement and knee replacement developed DVT, respectively). Analysis of clinical studies on post-operative VTE from several Asian countries9 showed that the incidence of DVT following a general surgery was 13 per cent, 16 per cent following a total hip replacement, 50 per cent in the aftermath of a total knee replacement procedure and 18 per cent following a hip fracture surgery. The Surgical Multinational Asian Registry in Thrombosis (SMART) study prospectively analyzed 2420 symptomatic VTE patients for up to one month post-surgery in India10 and several other Asian countries. Symptomatic VTE following surgery was observed in 2.3 per cent of cases, while incidence of sudden death was reported in 1.2 per cent. The rate of VTE or mortality among these patients on one month follow up was 1.5 per cent. The SMART venography study revealed that the rate of VTE following othropaedic surgery in Asians was 36.5 per cent11. The Assessment of the Incidence of DVT in Asia study assessed the incidence of DVT following significant orthopaedic interventions in the absence of thromboprophylaxis among 407 subjects from Asian countries12. The study reported that the rate of total DVT (58.1%) and proximal DVT (17.1%) was greatest among patients who underwent a total knee replacement surgery. Among those who underwent a hip fracture surgery, total and proximal DVT was 42 and 7.2 per cent, respectively, while it was found that patients subjected to a hip replacement surgery had an incidence rate of 25.6 and 5.8 per cent, respectively. Another prospective epidemiological study13, which assessed the rate of VTE in a Japanese population in the aftermath of significant abdominal surgery in the absence of thromboprophylaxis reported that 20.8 per cent of the patients subsequently developed distal DVT, while 2.9 per cent developed proximal DVT and 0.6 per cent developed PE. The Epidemiologic International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting study reported a mean prevalence of VTE of 52 per cent among thousands of patients in 30 countries, including India, who were enrolled in hospitals for acute care with or without thromboprophylaxis6. The study reported that the risk of VTE among general ward patients ranged between 21 and 71 per cent, while it was found to be significantly higher among patients who underwent major surgery (44-80%). However, Bagaria et al19 reported a lower rate VTE among the Indian population in a study on 147 patients subjected to orthopaedic surgery without thromboprophylaxis. Bilgi et al20 reported that among 301 patients undergoing surgical intervention, VTE occurred in 7.3 per cent at 30 days post-surgery, with the risk of VTE being highest among those who had a higher Adapted Caprini score. In a recent prospective observational study on 156 patients with an acute manifestation of chronic obstructive pulmonary disorder Meitei et al21 reported a 10.3 per cent prevalence of VTE, which is higher than similar studies among other Asian communities but lower than Caucasian and Black demographics. Singh et al22 reviewed VTE in cancer patients and reported that a 20 per cent incidence of thrombotic events in cancer patients. A retrospective study on 1190 cancer patients attending the outpatient department of four tertiary care hospitals in India found that 29 patients developed a thrombotic episode (2.4% incidence)23. Aggarwal et al24 found that 64 out of 771 patients referred to the thrombosis clinic of a tertiary hospital in north India had cancer. Table II outlines the prevalence of VTE in the aforementioned studies.
Table II: Epidemiology of venous thromboembolism
Disease burden
Cardiovascular diseases (CVD) were the foremost cause of death in the 20th century, with up to 80 per cent of deaths due to CVD originating from low- and middle-income countries25. Reportedly annual incidence of thrombosis is 1-2 per 1000 individuals annually26–28. VTE entails the imperative requirement of administration of anticoagulants, as a consequence of which there is an increased risk29 of bleeding of approximately 7.22 per 100 patient-years30. Case fatality rate after 30 days has been estimated to be roughly six per cent26. Long-term consequences entail the inevitable risk of recurrence, which is estimated to affect 20-25 per cent of all patients within five years post the initial occurrence31. Research has also thrown light on post-thrombotic syndrome as a potential long-term consequence of DVT in 20-50 per cent of patients32. Another rare but potentially life-threatening long-term consequence is chronic thromboembolic pulmonary hypertension, a condition that affects about 0.6 per cent of patients with PE33. VTE has also been reported to be a major contributor to disability-adjusted life years (DALYs) lost (an estimated 7681 DALYs lost)34, and significant healthcare costs (up to $ 69.3 billion every year in the USA alone and up to € 13 billion annually in the EU)35. In context to obesity as a risk factor for CVD, while India currently has an estimated overweight population of 135 million, it has been suggested that the prevalence will double by 204036.
Risk factors
Genetic: Some of the genetic risk factors making individuals susceptible to developing VTE include mutations in factor V Arg506Gln [factor V Leiden (FVL)], prothrombin G20210A gene, deficiencies in protein C, protein S, antithrombin37 and dysfibrinogenemia38. Although studies have reported these genetic risk factors to account for up to 60 per cent of VTE cases, there remain a significant proportion of cases with unknown aetiology39. Studies have also established the association between VTE and elevated plasma coagulation factors namely factor VIII39–41 and von Willebrand factor (VWF)40,42. ABO blood groups, identified as risk factors for VTE, may also play a role in the development of the same43–45. Studies have shown that individuals not having O blood group have elevated plasma levels of factor VIII and VWF43,46,47. It has been reported by several studies that the prevalence of mutations in FVL and prothrombin G20210A gene is significantly less among Orientals48–50. Conversely, Asian populations with VTE have consistently presented with an increased rate of deficiencies in protein S, protein C and antithrombin compared to Caucasians51–53. Activated protein C (APC) resistance is another inheritable factor that predisposes the Western population to greater susceptibility to VTE54. Mutations in FVL, factor V Arg306Thr (factor V Cambridge)55 and factor V Ile359Thr (factor V Liverpool)56 are known triggers for APC resistance. There have not been any reports documenting the presence of the aforementioned mutations among Indian patients, until now. The aforementioned genetic risk factors and their prevalence, both among the general population and the thrombotic population, are presented in Table III.
Table III: Genetic risk factors which make individuals more susceptible to venous thromboembolism
Acquired: Studies have reported that cancer accounts for 16-40 per cent of VTE cases among Asian population51,57–59. Long drawn out surgeries, prolonged periods of immobilization, anti-phospholipid syndrome, pregnancy, obesity, hyperhomocysteinaemia and old age have also been identified as potential risk factors. In a retrospective observational study conducted on 330 VTE patients, it was found that among those with a known risk factor for VTE, surgery (56%) and cancer (16%) were the most prevalent causes60. Kamerkar et al61 reported that a history of the previous thrombotic event (34%), major surgical intervention (28%) and prolonged immobilization (13.8%) are some of the major acquired risk factors for VTE. It has been reported that the incidence of VTE is substantially higher in patients aged 80 yr or above62. However, in the Indian context, a multicentre retrospective study on 549 VTE patients reported that 44 per cent of the patients were in the 40-59 yr age group, while 34 per cent of patients were under 4061. Prabhakar et al63 found that exposure to high altitude hypoxia confers a greater risk to the onset of VTE than among those living in plain lands, especially among younger population. The authors reported elevated levels of several plasma coagulation factors such as VWF, factor VIII as well as other markers such as D-dimer, fibrinogen, haemoglobin and red blood cells among hypoxic population living at elevated altitudes of above 3000 m who developed VTE. Pelvic acetabular trauma is also reportedly a significant risk factor for VTE in Indians. Sen et al64 reported that in a study on 56 Indian patients undergoing surgery for pelvic acetabular fractures, 16 patients developed VTE. Six patients with proximal DVT were further seen to develop PE. Twelve cases were reported on proximal DVT, distal DVT was reported in two while, PE was seen in 10. The use of catheters in hospitalized patients was also a significant risk factor for the onset of VTE, as reported by Gupta et al65 in their prospective observational study of paediatric thrombotic patients. The authors reported that 38.7 per cent of all thrombotic events were caused by the use of central venous catheters, whereas infection accounted for roughly 20 per cent of the cases;
Environmental factors
Smoking is a well documented contributing factor for arterial thrombosis. Wolpin et al66 reported that smokers with any blood type apart from O blood group have a greater likelihood of the onset of PE as compared to subjects who do not smoke. Likewise, air pollution is also reported to be a risk factor for VTE67–69 owing to its positive association with the risk of CVD, hyper-coagulability and arterial thrombosis70. Other environmental risk factors for VTE include use of exogenous hormones and corticosteroids. Among women, additional risk factors for VTE include oral contraceptive use and hormone therapy71. However, there are very little data on the risk of the aforementioned environmental factors on VTE onset in Indians.
Food & nutrition
Some studies have suggested the potential role of dietary vegetables in preventing thrombosis72,73 owing to their constituent vitamin B and folate content, which help in the reduction of homocysteine levels and improve endothelial function. The consumption of fish rich in ω-3 fatty acid74 can potentially lower hyper coagulability among individuals. Certain nutritional elements present in fresh vegetables, such as capsaicin (found in fresh chillies), have been reported to enhance fibrinolysis and reduce platelet aggregation75,76. Research has shown that individuals who consume regular amounts of vegetables77, fish77,78, whole grains79 and alcohol79 have a lower risk of VTE onset in comparison with those who do not, while people who consume high amounts of red meat and processed meat are more prone to a thrombotic event77. Studies have reported that individuals consuming a healthy vegetarian diet with greater intake of fibre, phytochemicals and antioxidants are less likely to suffer from cardiovascular and thrombotic events80,81 and regular dietary consumption of marine fish provides cardioprotection82,83, potentially due to their high concentrations of long-chain N-3-polyunsaturated fatty acids, namely eicosapentaenoic acid and docosahexaenoic acid.
Several food items, which are an integral part of the Indian diet have been reported to be cardioprotective. Garlic and its extracts have been reported to exhibit several beneficial effects, namely lowered serum cholesterol levels and improved lipid profile84. The consumption of garlic is also associated with lowered fibrinogen, enhanced fibrinolysis and prothrombin time and inhibition of platelet aggregation - all of which help decrease blood coagulability85,86. Fruits and vegetables are rich in flavonoids, namely quercetin, myricetin and kaempferol. Studies have shown that a balanced diet should include a daily intake of up to 34 mg of flavonoids87, of which a significant chunk should be constituted by quercetin. It has been reported that in vitro quercetin can potentially inhibit platelet aggregation88,89. Certain other food items, namely grape juice, soy and cocoa, also possess cardioprotective properties. However, data on the potential effect of these food items on Indians are scarce as of now. Thus, future research should be aimed at evaluating the effects of both whole food and their individual phytochemical constituents on haemostasis and thrombosis, so as to throw light on the possible antagonistic/synergistic effects of certain nutritional elements in the Indian diet on VTE.
Association with coronavirus disease 2019 (COVID-19)
Patients with the COVID-19 and admitted to general ward or in intensive care unit, have a higher tendency to develop VTE90. Studies on SARS, MERS and H1N1 influenza had also demonstrated a similar surge in thromboembolic incidents90. With approximately 20 per cent of patients developing VTE, COVID-19 is therefore potentially identified as a risk factor for precipitating a thromboembolic incident91. A study conducted by Cui et al92 detected VTE among 20 (25%) of 81 patients showing signs of severe COVID-19 pneumonia, of which eight passed away. When the D-dimer titre/levels in patients with VTE were compared with those patients without VTE, the former showed a 6.5-fold increase (6.5 μg/ml vs. 0.8 μg/ml)92,93. The interplay between thrombosis and inflammation has been touted as a potential rationale for the same, as SARS-CoV-2, the causative pathogen behind COVID-19, has been shown to thrive in such hypercoagulable state.
Pathogenesis: SARS-CoV-2 infection in human triggers an inflammatory reaction due to the release of chemokines, cytokines and activation of mast cells. The subsequent interplay between the inflammatory and coagulator pathways along with the activation of the complement system creates a hypercoagulable environment. On reaching alveolar epithelium, the SARS-CoV-2 virus attaches itself to the angiotensin-converting enzyme 2 (ACE2) receptor, thereby eliciting the release and activation of several pro-inflammatory cytokines and chemokines, namely interleukin-6 (IL-6), IL-8, tumour necrosis factor-alpha, C-C motif chemokine ligand 2 (CCL2) and C-C motif chemokine ligand 3 (CCL3)91. This consequently activates the epithelial cells, monocytes and neutrophils. Furthermore, the virus can directly infect endothelial cells via the ACE2 receptors, resulting in endothelial activation and dysfunction, thus triggering a coagulation cascade, which eventually leads to the formation of a thrombin and fibrin clot. Platelet activation and protease-activated receptor signalling pathway lead to further inflammation, and the consequent interaction between thrombosis and inflammation results in an elevated state of inflammatory environment in the body, thus causing coagulation lesions91. Several studies have shown a significant increase in the release of IL-6 in COVID-19 patients, thereby demonstrating a potential association between IL-6 and fibrinogen levels, which augments inflammatory thrombosis94.
Risk factors: Old age, immobilization, obesity and smoking are the chief risk factors for VTE among those affected by COVID-19. Pre-existing comorbidities, including previous thromboembolic episodes, cardiac or pulmonary failure, malignancy and kidney disease also increase the risk of developing VTE95. Some other risk factors include hypoxia, postpartum infection, sepsis and pre-eclampsia96,97. The tendency of hypercoagulation has also been found to be considerably more in males, Whites and individuals from the African-American community suffering from COVID-1998; no such data have been generated from Indian settings. In brief, all factors that are directly or indirectly responsible for haemoconcentration play a role in the development of VTE in COVID-19.
Screening: The International Society on Thrombosis and Haemostasis has recommended assessing the D-dimer levels, prothrombin time, partial thromboplastin time and platelet count in COVID-19 patients requiring hospitalization99. According to recent studies, the abnormality in the coagulation pathways has been attributed to poor prognosis100 along with the increase in D-dimer and fibrinogen degradation products, evident in patients who died from COVID-19101. The elevation in D-dimer indicates activation of fibrinolysis and coagulation pathways and serves as an effective screening tool to identify individuals more prone to developing VTE102. This parameter can therefore be used as a test for detecting any active thrombotic process: a test that is highly sensitive, with low specificity103. Based on a study conducted on 81 severely infected COVID-19 patients, it was noted that for detection of VTE, D-dimer titre >1500 ng/ml had a sensitivity of 85 per cent, a specificity of 88.5 per cent and a negative predictive value of 94.7 per cent81. These findings were seconded by another study reporting similar results104.
Prophylaxis: Considering the high risk of developing VTE among COVID-19 patients, VTE prophylaxis should be an integral part of COVID-19 management protocol. Administration of anticoagulants in similar patients has shown promising results - Tang et al105 reported a decreased 28 day mortality in COVID-19 patients with sepsis-induced coagulopathy score ≥4 or D-dimer level >6 fold of the upper limit of normal. LMWH is ubiquitous as a prophylactic measure against VTE in COVID patients106. Several guidelines for VTE prophylaxis in COVID-19 have since been published, such as the Journal of the American College of Cardiology state of the art review107, Swiss consensus statement108 and NHS model109.
Vaccine-induced VTE: A large cohort study conducted on 281,264 participants from Denmark and Norway who received the ChAdOx1-S vaccine led to 59 VTE events among the trial cohort, which was higher than the expected incidence of VTE events (30) in the general population110. The authors reported an increased incidence of thrombotic episodes amounting to 11 excess VTE cases per 100000 vaccinations. They also reported an increase in the incidence of cerebral venous thrombosis amounting to seven observed events as opposed to 0.3 expected events among the vaccine recipients (excess of 2.5 per 100000 vaccinations, or 1 in 40000 vaccine recipients). The authors, however, concluded that the absolute risk of VTE is minimal in the greater context of the proven benefit of the ChAdOx1-S vaccine against COVID-19, especially from a public health perspective, and can be minimized by greater surveillance and follow ups post-vaccination in high-risk groups. A similar issue was also reported with the Ad26.COV2.S vaccine against COVID-19, wherein six cases of cerebral venous sinus thrombosis (CVST) were reported among >7 million recipients of the aforementioned vaccine, which led to a pause in the use of the Ad26.COV2.S vaccine by the FDA and CDC111. However, upon analysis of the safety data, the FDA and CDC lifted the ban, with the caveat of a warning added to the fact sheet of the vaccine. In the Indian context, Khan et al112 reviewed data pertaining to vaccine induced thrombotic thrombocytopenia and CVST, and reported no cases of CVST in India following the administration of AZD1222 (ChAdOx1) vaccine - the made in India variant of the ChAdOx1-S vaccine.
Conclusion
The existing data on VTE in the Indian demographic setting are inadequate, which necessitates the conduct of quality research on the same. This will help bridge the void, which persists with respect to existing screening modalities and prophylaxis protocols to reduce the impact of VTE, both in terms of cost of healthcare as well as mortality and morbidity. Asian countries make up more than 50 per cent of the global population, and while the data are relatively scarce, recent progress has shown that the contribution of Asian countries to the global VTE burden, although lower than their Caucasian counterparts, is still quite significant. Over the past few decades, there has been a significant rise in the incidence of VTE cases among Asians, which can be attributed to the improvements in rapid detection of VTE and subsequent implementation of thromboprophylaxis therapies to mitigate the same, resulting in a decrease in thromboembolic episodes even in high-risk patients. The next step should comprise devising further risk assessment strategies - developing, testing and implementing them, which would enable us to screen the patients prone to developing VTE, thus ensuring commencement of thromboprophylaxis at the earliest. Also research is required on the underlying inflammatory pathogenesis, associated with COVID-19 and VTE, so as to better predict potential VTE outcomes in COVID-19 patients and minimize the loss of lives.
Financial support & sponsorship: None.
Conflicts of Interest: None.
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