key: cord-0818656-ss5gcils
authors: Ahuja, Natasha; Binder, Jasmine; Nguyen, Jessica; Langan Jr, Tom; O'Brien-Irr, Monica; Montross, Brittany; Khan, Sikhandar; Sharma, Aditya M; Harris, Linda M
title: Venous Thromboembolism in Patients with COVID-19 Infection: Risk Factors, Prevention, and Management
date: 2021-08-04
journal: Semin Vasc Surg
DOI: 10.1053/j.semvascsurg.2021.06.002
sha: f34b14f862c755598a82fe4624f573b3209eabad
doc_id: 818656
cord_uid: ss5gcils

Venous thromboembolic complications have emerged as serious sequelae in COVID-19 infections. This article summarizes the most current information regarding pathophysiology, risk factors and hematologic markers, incidence and timing of events, atypical venous thromboembolic complications, prophylaxis recommendations, and therapeutic recommendations. Data will likely to continue to rapidly evolve as more knowledge is gained regarding venous events in COVID-19 patients.

availability of the enzyme and disrupts the cycle by which it degrades ANGII. Effectively, increased levels of ANGII become available to bind with AT1R which stimulates interleukin-6 (IL-6) release causing inflammation and lung injury. 11, 12 Hypercoagulability may ensue since ANGII/AT1R also induces tissue factor and plasminogen activator inhibitor. 13, 14 Patients with increased ANGII levels are at higher risk for severe disease; a direct correlation between viral load, lung injury and ANGII levels has been reported. 10 High levels of other thrombotic and inflammatory markers such as D-Dimer, C-reactive protein (CRP), lactate dehydrogenase, ferritin, and IL-6 have been documented as well. 15 Multiple inflammatory pathways have been implicated in the development of thrombo-inflammation including cytokines, acute phase reactants and inflammatory cell mediated cellular injury. Elevated levels of IL-6, IL-7, tissue necrosis factor (TNF), and chemokines have been reported which create a prothrombotic environments through activation of monocytes, neutrophils, and the endothelium. 16, 17 Mononuclear phagocytes (MNP) have been found to be more prominent in bronchial alveolar fluid of patients with more severe disease and may play a role in the development of thrombotic complications. 18 Activated monocytes stimulate tissue factor expression, which triggers the clotting cascade to produce thrombin, which subsequently leads to thrombus formation, platelet activation and further augmentation of inflammatory pathways. 12, 19 Elevated levels of neutrophil extracellular traps (NETS) have been reported with COVID-19, occurring more commonly in hospitalized patients, particularly those requiring mechanical ventilation. 20 It is postulated that abnormal activation of neutrophils and production of NET may contribute to cytokine storm and adverse sequala of severe disease: organ damage, widespread thrombosis and death. 21, 22 Alternatively, Gan et al. has proposed that ANGII rather than "cytokine storm" may be responsible for the widespread vascular injury which results from endothelial damage, thrombosis, and vasoconstriction. They further suggest that this may better explain the early hypoxia but sustained lung compliance experienced by patients with COVID. 23 Infection also produces rigorous activation of the complement system which plays a vital role in severe COVID; potentially as a principle antecedent to cytokine storm. 24, 25 The proinflammatory effects of anaphylatoxins can occur within hours of infection 25 and may contribute to thrombotic microangiopathy (TMA) and organ dysfunction. 17, 24 Ramlall et al. also resounded the critical impact of complement on regulation of overall outcome from infection and was able to identify genetic variants within complement and coagulation regulators which could serve as potential markers of susceptibility. 26 A number of post-mortem COVID-19 studies have reported endothelial dysfunction in multiple vascular beds, including endothelial lining of the lungs, and pervasive thrombosis and microangiopathy. 27 Contributing factors include increased production of pulmonary interstitial cytokines, activation of complement components, and direct infection of the endothelium through ACE2 receptors. 28 Elevated levels of von Willebrand Factor (vWF) and Factor VII have also been reported in patients with COVID-19 further substantiating endothelial activation. 29, 30 Resulting endothelitis (inflammation of the endothelium in blood vessels) is a major precursor for thrombosis. 21 Early studies have indicated that a large number of patients with COVID-19 meet International Society of Thrombosis and Hemostasis (ISTH) criteria for disseminated intravascular coagulation (DIC) 31 but lack the clinically associated profile. 32, 33 They suggested that abnormal laboratory findings may reflect a more localized coagulopathy which resulted from extensive alveolar inflammation, but which remained limited to the pulmonary vasculature. 32, 33 Ciceri et al. hypothesized that in subgroups predisposed to severe outcomes, the process then Risks associated with severe COVID disease, development of complications and increased mortality have been well documented. Zhou et al in a meta-analysis of 34 studies identified a number of comorbidities including chronic respiratory disease, hypertension, cardiovascular disease, kidney disease, cerebral vascular disease, malignancy, diabetes and obesity which carried increased odds for severe/fatal VTE. 52 Racial disparity in COVID-19 outcomes has also been documented with African Americans having poorer outcomes than Caucasians or Asians. The etiology is not entirely clear and multiple factors such as socioeconomic status, underlying pathophysiology, differences in hemostasis factors, coagulation status and genetics may be at play. 53, 54 Severe COVID is associated with increased risk of VTE; with odds ratios approximating a 6 fold increase for severe disease as opposed to 3 fold with non-severe disease. 40 Notably, however, the risk factors of VTE and COVID-19 have indicated that hematologic biomarkers; particularly elevated admission D-dimer, >1.5 fold incremental increase in d-dimer, low admission level fibrinogen and CRP are more predictive of VTE than co-morbid states associated with severe COVID-19 and poorer prognosis. 40, 42 A number of studies have reported no significant difference in the incidence of venous thrombosis among patients with cardiovascular disease, kidney disease, cerebral vascular disease, diabetes or obesity compared to counterparts without disease. 38, 40, 51, 55, 56 Interestingly, Xiong reported a trend towards lower incidence of VTE among diabetics: OR .73 (.47-1.35). 55 These findings are perplexing given the interconnection between COVID-19 pathophysiology and the underlying pathology of these chronic illnesses. Similarly, racial disparity in the prevalence of COVID-19 has been reported, yet the incidence of VTE across racial groups is comparable. 1,56 Bilaloglu et al. in a study of 3334 consecutive COVID-19 hospitalizations reported a significantly higher incidence of VTE among Hispanics compared to Non-Hispanic White when "any type" of thrombosis was considered; HR:1.19 (1.15-3.18); P= .01. However, significance was lost when evaluation was limited to venous thrombosis (DVT/PE): HR: 2.01 (0.81-5.00); P= .13. Moreover, they found no significant difference in any type VTE or venous thrombosis between African Americans and Non-Hispanic Whites: Any VTE: HR: 0.93 (0.71-1.23); P=.62, venous thrombosis: HR: 0.97 (0.60-1.55); P= .89. 1 Once again, these findings are puzzling since pre-COVID-19 racial disparity in risk of VTE has been documented with African Americans carrying the highest rate, followed by Caucasians then Asians/Pacific Islanders. 53, 57 A compilation of VTE specific risks is presented in table 2. Male gender 50, 51, 55, 58 and ICU admission/need for mechanical ventilation 38, 42, 58, 59, 60 have emerged as prominent factors throughout multiple studies. Increased thrombotic events among ICU patients is not surprising; since critically ill patients are prone to hypercoagulability because of immobilization, mechanical ventilation, nutritional insufficiencies in addition to indwelling venous and arterial catheters. 2 Age has been frequently reported as well, but results have been inconsistent. A number of studies have documented increased incidence among older patients, 40 55 Baseline alterations in the RAS may possibly explain the pathogenesis in males and the elderly. Cancer has been identified by Li et al as an independent predictor of VTE presumably due to a pre-existing hypercoagulability. They also found that increased interval from symptom onset until hospital admission was independently associated as well. 40 Increased incidence of VTE among patients with Human Immune Deficiency Virus (HIV), 38 has also been reported.

Findings of own our study of 334 consecutive admissions with COVID-19 echoed results reported in the literature. We found that positive D-Dimer on admission LR: 3.21 (1.005-10.25); p= .049 and current smoker LR: 3.75 (1.005-10.23); p= .018 were independent risks for development of venous and/ arterial thrombosis while female gender portended lower risk; LR: .20 (.06-.72); p= .014. Race was not independently associated with development of venous/arterial thrombosis in COVID-19 admissions. Table 2 compiles the known, suspected risk factors for VTE in COVID-19.

According to Zhang et al. in a meta-analysis of 40 studies which included 7966 patients hospitalized with COVID-19, the pooled VTE prevalence was 13%; 7% in non-ICU patients, and 31% in ICU patients. Screening led to a threefold increase in VTE detection. Both PE and DVT were found to occur significantly more often among ICU than non-ICU patients: PE (37% vs. 10%; P < .0001); DVT (40% vs 12%; P = .0065). 60 The temporal relationship between COVID-19 diagnosis, development of associated coagulopathy, and subsequent occurrence of VTE has been explored but not fully elucidated. Li et al reported an independent association between VTE and a longer interval from symptom onset to hospital admission. 40 Likewise, a number of studies on hospitalized COVID-19 patients have reported progressive increases in the cumulative incidence of VTE from days 7-21. 36, 48, 59 Middledorp et al noted the incidence of symptomatic VTE was 10% at 7 days, increasing to 21% at 14 days and 25% at 21 days. On further subgroup analysis of ICU patients, they found the 20day cumulative incidence of VTE was 60%. 59 Collectively, these data suggest that VTE are less likely to occur as early sequelae of COVID-19 and patients particularly those with severe disease, may remain at risk for an extended period.

Classification systems have been proposed to stratify severity of COVID-19 disease and risk for adverse sequelae. ISTH developed the sepsis-induced coagulopathy score (SIC) to quantify severity of COVID-19 illness. 61 The scoring system evaluates three criteria; SOFA (sequential organ failure assessment) which reflects the physiologic status of multiple organ systems with scores from 1 for normal to 24 for to most deranged, platelet count and PT/INR. A SIC score of 1 is assigned for results that fall within normal range and 2 for deranged values: platelet count (x10 9 /L): <100; PT/INR: <1.4 and SOFA: > 2. Total SIC scores > 4 have been used to define severe COVID-19. 62 Other designations using alternative criteria to identify severe disease have been established. According to the National Health Commission of China, after confirmation of infection by identifying SARS-CoV-2 RNA, patients meeting any of the following criteria were diagnosed as having severe COVID-19: respiratory rate ≥ 30 breaths/minute, arterial oxygen saturation ≤ 93% while at rest, or PaO2/FiO2 ≤ 300 mmHg. 43, 62 In the United States, the National Institutes of Health (NIH) has defined severe COVID-19 as those individuals who have been diagnosed with COVID-19 via virologic testing (nucleic acid amplification or antigen test) and meet any of the following criteria: oxygen saturation < 94% on room air at sea level, PaO2/FiO2 ≤ 300 mmHg, respiratory rate > 30 breaths/minute, or lung infiltrates > 50%. 63 Most recently, a large NIH multiplatform, adaptive-design trial that incorporates three global studies/networks (REMAP-CAP, ATTACC, and ACTIV-4A) which evaluated the use of anticoagulation for COVID-19 defined severe state patients as those admitted to an ICU and receiving organ support (i.e. high flow nasal oxygen, receiving non-invasive or invasive mechanical ventilation, or are requiring vasopressor/inotrope). 64

Multiple studies have documented atypical VTE events with variable presentations. As such, patients presenting with unusual symptoms and found to have thrombosis should be assessed for COVID-19, even in the absence of respiratory symptoms.

Cerebral venous sinus thrombosis (CVST) has been documented multiple times in patients with COVID-19. CVST is an uncommon etiology of strokes with an increased incidence among women and younger patients (compared to ischemic strokes). Presenting symptoms range from headache to neurological deficits and seizures. 65, 66 Patients may also present with intracranial hemorrhage as a result of the sinus thrombosis. 67 Presence of CVST does not appear to be related to the severity of the COVID-19 infection, having been described in patients with mild to severe disease. The timeline is also varied with some patients having cerebral symptoms as their presenting symptoms for COVID-19 and others developing neurologic symptoms up to 2 weeks after onset of other COVID symptoms.

Colicky abdominal pain in COVID-19 patients may suggest VTE. Splanchnic vein thrombosis (SVT) has also been described in COVID-19 positive patients. 6 Most patients diagnosed with SVT presented with colicky abdominal pain which improved with anticoagulation, although presentation with gastrointestinal bleeding has also been described 66, 69 Most commonly, the portal vein 70 is involved, but involvement of other splanchnic veins have been reported. 71, 72 Ovarian and renal vein thrombosis has also been described with patients presenting with abdominal pain. [55] [56] [57] [73] [74] [75] 

Heightened clinical awareness of risk for VTE in COVID-19 patients in conjunction with serial laboratory monitoring of coagulation and inflammatory factors may lead to timely identification. The threshold to obtain definitive diagnostic studies such as ultrasonography for DVT and computed tomography angiography (CTPA), or ventilation/perfusion (V/Q) scan for PE should be low. However, routine screening of all patients with the COVID-19 diagnosis has not recommended 76 since prevalence of asymptomatic DVT in those with COVID-19 is low. Rather, clinical suspicion should be used to guide imaging decisions. 77 , Imaging studies may not be feasible in all cases, particularly those with severe COVID disease. Treatment should not be delayed if there is high clinical suspicion, as this may lead to poorer outcomes. Lippi et al suggested a direct association between COVID-19 associated coagulopathy and poor outcomes. 78 Moreover, the association between VTE and mortality has been well documented 59, 79 with rates reaching 39.1% in those patients with any VTE compared to 26% in those without. 79 In our own study, we found that patients with venous and/or arterial thrombotic events were more likely to require ICU admission (91% vs. 42%; p< .001), mechanical ventilation (68% vs.23%; p <.001), had longer hospital stays (30 vs. 12 days; p < .001), had higher incidence of sepsis (55% vs. 34%; p=.048), more multisystem failure (46% vs. 15%; p < .001) and higher mortality (55% vs.23%; p=.001).

The optimal VTE prophylaxis and treatment strategy for COVID-19 patients remains unclear due to lack of high-quality evidence. Issues yet to be addressed include the optimal agent for prophylaxis, level of intensify of prophylactic medication dosing, and time interval for treatment to continue.Aggressive prophylactic and treatment approaches, especially in critically ill patients have been advocated , yet data to support strategies beyond standard VTE management is still under investigation. Current reccomendations suggest that chemical prophylaxis is unnecessary forCOVID-19 patients who are not hospitalized . 63, 77, 80, 81 In contrast, all hospitalized COVID-19 patients should at minimum be treated with prophylactic dose of either low molecular weight heparin (LMWH) or unfractionated heparin (UFH) in the absence of any contraindications (i.e. bleeding, platelets < 25, etc.). 61, 62 A potential benefit of Heparin medications is their anti-inflammatory properties 82. Low molecular weight heparin has been advocated over UFH because of decreasing patient interaction with medical staff, and hence decreased risk of exposure. 81, 83 Prophylaxis recommendations for specific subgroups have also been addressed. Low molecular weight or UFH can be used for pregnant COVID-19 patients. 64, 77 When treating obese patients, dose adjustment based on body mass index will be necessary. 63 Mechanical thromboprophylaxis should be considered if anticoagulation is contraindicated,. 81, 83 Alternative agents such as fondaparinux may be used in patients with history of heparin induced thrombocytopenia (HIT),. 62, 63, 84, 85 The role of direct oral anticoagulants (DOACs) such as pixaban, rivaroxaban, edoxaban and dabigatran in treatment of VTE in COVID-19 is unclear. Moreover, the potential for significant drug interactions between DOACs and other medications used to treat COVID-19 such as dexamethasone, sarilumab, and tocilizumab is concerning. 64, 86 Moores et al suggested that DOACs may be beneficial in treating outpatient COVID-19 patients who have developed VTE. 81 Use of antiplatelet agents for VTE prevention is also being studied. 87 Determination for standard prophylaxis versus intermediate level prophylaxis or full therapeutic anticoagulation is unclear. Many strategies have been evaluated. Cuker et al has provided a detailed review of the various agents along with dosing recommendations 87 Standard prophylactic dosing levels include Enoxaparin 30-40 mg daily or BID dependent on BMI and Creatinine Clearance, or UFH ranges from 5000 U BID/TID to 7500U BID based on BMI. Intermediate dosing includes Enoxaparin 0.5 mg/kg BID or 30-60 mg BID dependent on Creatinine Clearance and BMI, or UFH 7500 U TID. Therapeutic dosing includes Enoxaparin 1 mg/kg BID or 1.5 mg/kg daily, or UFH dosed to a target aPTT or anti-Xa levels. 87 r. A summary of prophylaxis recommendations from multiple current studies is provided in table 3. 31, 48, 61, 63, 76, 77, 81, 83, [87] [88] [89] [90] [91] [92] Many institutional protocols have incorporated therapeutic-dose anticoagulation with weight based dosing. in critically ill patients., based on an early observational study by Lemos et al showing decreased ventilatory requirement and improved survival as compared to prophylactic dose anticoagulation. 93 However, other studies have shown no difference in outcomes. 37 Importantly, there has been recent concern of increased mortality with therapeutic anticoagulation. 64 Preliminary data from a multiplatform trial (REMAP-CAP, ATTACC, and ACTIV-4A) has suggested that for patients with severe COVID-19 infections (requiring high flow nasal oxygen, invasive or noninvasive mechanical ventilation, vasopressor therapy, or extracorporeal membrane oxygenation (ECMO) support), empiric therapeutic anticoagulation in the absence of VTE was associated with poorer outcomes including higher mortality. 64 In contrast, moderately ill patients, i.e. those requiring hospitalization but not ICU level of care, were found to have better outcomes with therapeutic as compared to prophylactic dose anticoagulation. Final results of these trials are still pending, and the interim data should be interpreted cautiously. 64 Hospitalized COVID -19 patients remain at increased risk after discharge, especially if non-ambulatory, and several studies suggest continued prophylaxis up to 4 weeks for those with additional risk factors with prophylactic doses of LMWH. 64 Outpatient management of VTE in COVID-19 patients should include anticoagulation for 3 months, similar to other provoked events. 46, 85 Anticoagulants typically include LMWH or DOAC medications.

Currently, there are over 100 ongoing clinical studies which assess various VTE issues in COVID-19, including best medications for prophylaxis, dosing levels for prophylaxis, extended therapy as well as other issues. A summary of current prospective, randomized studies is provided in Appendix 1. Details can be found at clinicaltrials.gov. Talesaz et al has provided a thorough review as well. 94

Interventions such as venous thrombectomy and thrombolysis for severely symptomatic DVT should be weighed against the risk of bleeding, and generally reserved for limb salvage purposes. In the absence of severe limb threatening VTE, invasive interventions should be avoided during the acute phase of the disease.

There is paucity of data on the use of advanced therapies such as systemic thrombolysis, catheter-directed therapies, surgical embolectomy, and ECMO in these patients to treat VTE. The CHEST guidelines recommend systemic thrombolysis only in patients with massive or highrisk PE especially if confirmed with imaging for routine VTE in non-COVID-19 patients. Thrombolytic therapy can also be considered in select patients without imaging should they have strong predilection to develop hypotension or cardiorespiratory compromise due to PE, i.e. progressive worsening tachycardia, decreased systolic blood pressure, worsening hypoxemia, severe right ventricular dysfunction, or signs of shock. 81, 95 The risk of bleeding needs to be strongly weighed in when considering thrombolytic therapy in these patients. Bleeding risk may be increased in patients with critically-ill COVID-19 due to high incidence of DIC, alveolar damage and hemorrhage, and renal dysfunction. 96, 97 Studies have shown variable rates of bleeding ranging from 2.7% to 21%, the majority being in the group of patients on anticoagulation. 20,98 A meta-analysis including 48 studies reported a pooled incidence of 7.8% (95% CI, 2.6-15.3) for bleeding and 3.9% (95% CI, 1.2-7.9) for major bleeding in COVID-19 patients. 99 Given these patients' complexity, a multidisciplinary team approach in treating them, particularly when advanced therapies are considered, is ideal. Such teams exist in many institutions as the pulmonary embolism response team (PERT). Kwok B et al. reported their experience with PERT in New York hospitals during the first phase of COVID-19 and noted increases in PE and PERT activations (26.8% vs. 64.4%, p < 0.001). 100 Management of these patients where similar to the historical control, with the majority treated with anticoagulation alone (89.5% vs. 86.4%, p = 0.70). Figure 2 describes an algorithm to diagnose and treatment of PE in COVID-19 patients. 101

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. 

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Center 2779 OR for VTE (95%CI) Non-Severe

Retro Single Center Meta-Analysis:12 Studies

P= .048 +DVT: Male vs FM 68% vs

092-1.33) Trend VTE: Male vs

VTE: ICU vs. Non-ICU 90%

000 VTE: with Mechan Vent vs. No VTE: with Mechan Vent 100% vs. 83.8%

VTE with Mechan Vent vs. NoVTE with Mechan Vent 60% vs. 37.5%

Cumulative VTE @ 21 days: ICU vs non-ICU 59% vs

VTE vs. No VTE (66y vs 60.5y

Mean difference (Years): VTE: 1.91(1.58 -5.40) older: Trend

No DVT 59 y vs. 64 y; P= .06 Trend VTE vs. No VTE 59

Center 312 Intrvl Days: Symp → Hosp. VTE vs. Non VTE 10 days vs

 Yu 38 142 COVID >2000 OR 10.9 DVT Trigonis, RA 39