Jeremiah Taylor, William Jiranek, Jerzy Bialecki, Ronald Navarro.

Response/Recommendation: Certain patient populations have been identified to be at greater risk for venous thromboembolism (VTE).

Strength of Recommendation: Limited.

Rationale: Multiple studies have been published to better identify patient populations with an elevated VTE risk. Current literature states those with hypoalbuminemia, inflammatory disease, non-optimal body mass index (BMI), active adenocarcinoma and hematologic malignancies, blood dyscrasias, chronic kidney disease (CKD) and/or human immunodeficiency virus (HIV) are at an increased risk for VTE. In addition, ethnicity has been investigated for association with VTE.

Several studies have investigated the association of hypoalbuminemia and VTE. A 2019 study of 188 patients with advanced gastric cancer reported a significantly lower mean serum albumin concentration in individuals that experienced VTE compared to controls as an independent variable in multivariate analysis (3.38 mg/dL vs 3.65 mg/dL, respectively)¹. A multivariate analysis indicated hypoalbuminemia was significantly correlated with VTE providing further evidence of the association. A separate study focused on identifying risk factors for VTE in total shoulder arthroplasty (TSA) patients found those with VTE were more likely to have a preoperative albumin level lower than 3.5 g/dL². Lastly, a study based in China with the aim of identifying the incidence and appropriate risk factors for VTE in lung cancer patients found patients with hypoalbuminemia (albumin < 3.5 g/dL) to have significantly more VTE events, as an independent risk factor³.

Current literature suggests inflammation is a risk factor for VTE. The activation of platelets and leukocytes can trigger the coagulation system through tissue factor induction⁴. A 2018 European Heart Journal article shows that patients with rheumatoid arthritis (RA) and mild psoriasis have significantly elevated risks of VTE following traditional risk factor adjustment⁵. Meanwhile, severe psoriasis and psoriatic arthritis patients with an anti-rheumatic drug prescription were found to have an elevated but non-statistically significant risk for VTE. A separate research project performed in Sweden indicated an increased VTE risk with increasing RA disease activity⁶. Those with inflammatory bowel disease (IBD), including ulcerative colitis and Crohn’s disease, have an increased risk of VTE as well^7,8. Research published by the Canadian association of gastroenterology approximates this risk in IBD to be 3-fold higher⁹. Lastly, patients with cystic fibrosis can have an increased VTE risk through thrombophilia secondary to inflammation, the use of central venous catheters, and the decrease of anticoagulant proteins¹⁰.

Having an optimal BMI is one way to mitigate the risk of experiencing VTE. A 2020 study by Pahlkotter et al., showed that morbidly obese (BMI > 40 Kg/m²) patients undergoing emergency surgical procedures were 1.7 times more likely to be diagnosed with pulmonary embolism (PE) compared with normal BMI patients. Increased BMI was also associated with the co-diagnosis of PE and deep venous thrombosis (DVT). In addition to this, patients with BMI less than 18.5 40 Kg/m² were 1.4 times more likely to experience a VTE compared with normal BMI patients¹¹.

All forms of cancer, most commonly active adenocarcinoma, have been shown to increase VTE rate by increasing levels of leukocytes, platelets, and tissue factor-positive (TF+) microvesicles. Current literature suggests cancer types can be broadly divided into 3 groups according to VTE risk. High-risk cancer types include pancreatic, ovarian, brain, stomach, gynecologic, and hematologic. Intermediate VTE risk cancers include colon and lung. While the low-risk VTE category consists of breast and prostate cancer¹². Hematologic malignancies are also associated with a higher risk of VTE^13–15. This subgroup represents a unique entity that undergoes therapy that can be thrombogenic¹³. The overall risk of VTE in patients with leukemia depends on the use of L-asparaginase treatment, older age, comorbidities, and central venous catheters¹³. Patients with acute promyelocytic leukemia are at particularly high-risk of VTE but also have an increased risk of bleeding¹³. Patients with aggressive lymphomas have a high incidence of VTE, roughly 10%¹³. Patients with multiple myeloma at highest risk of VTE are those receiving immunomodulatory agents such as thalidomide or lenalidomide¹³. Allogeneic stem cell transplantation carries a risk of thrombosis, particularly in patients developing graft versus host disease¹³.

Certain populations with blood dyscrasias have been identified to be at greater risk for VTE. Sickle cell anemia is seen to be associated with VTE and is more common in African and African American populations¹⁶. Kujovich, showed that Factor V Leiden thrombophilia is characterized by a poor anticoagulant response to activated protein C (APC) and an increased risk for VTE. Evidence suggests that heterozygosity for the Leiden variant has at most a modest effect on risk for recurrent thrombosis after initial treatment of a first VTE. A short course of prophylactic anticoagulation when circumstantial risk factors are present may prevent initial thrombosis in Leiden variant heterozygotes¹⁷. In a prospective cohort study, Tormene et al., described how antithrombin, protein C, and protein S defects are well-recognized inherited risk factors for VTE in adults. Screening for thrombophilia in children who belong to families with these defects seems justified to identify those who may benefit from thromboprophylaxis during risk periods for thrombosis¹⁸.

CKD is associated with an approximately two-fold increase in VTE risk and a higher VTE mortality rate than the population¹⁹. The increased risk of VTE is graded by a declining estimated glomerular filtration rate (eGFR) and albuminuria. eGFR is also inversely correlated with Factor VIII, an essential cofactor in the coagulation cascade. The lower eGFR seen in CKD patients effectively raises Factor VIII levels and increases the coagulability of blood to raise the risk of VTE.

HIV-positive patients are inherently hypercoagulable. HIV viral proteins effectively attack the function of the endothelium via pathways that reduce the synthesis of nitric oxide and upregulate monocyte chemoattractant protein-1 and adhesion. This results in increased leukocyte and platelet activation/adhesion to the endothelium²⁰. Clinically, in a recent multicenter study of 110 HIV-positive and 240 HIV-negative patients showcased increased rates of symptomatic VTE in the HIV-positive cohort after total hip or total knee arthroplasty. A multivariable logistic regression adjusting for sex, smoking, history of VTE, and joint replaced, identified HIV as an independent predictor of VTE²¹. With respect to viral load, one group of authors concluded that a higher viral load, and lower CD4⁺ cell count, was associated with a higher risk of thrombosis²², conversely, others have found no correlations²³.

Ethnicity has been studied but has yielded largely variable results. Several studies propose African Americans as having higher VTE incidence than Hispanics and Asian-Pacific Islanders^2,24. In contrast, a study conducted within an integrated healthcare system found no significant difference in postoperative VTE amongst white, African American, and Hispanic populations. However, the model of universal insurance in the study does not mirror the current United States system^25,26. In communities where health access is not as robust, it is unclear if these results are applicable.

In conclusion, certain patients can be identified to be at a greater risk for VTE. Current literature reveals an association between VTE with the following comorbidities: hypoalbuminemia, inflammatory disease, non-optimal BMI, active adenocarcinoma, and hematologic malignancies, blood dyscrasias, CKD, and/or the presence of HIV. In addition to this, ethnicity has been investigated with no clear association with VTE risk. In the case of all the proposed risk elevators, additional research is needed to develop appropriate risk mitigation therapies likely for the specific disease process.

References:

1.         Takayoshi K, Kusaba H, Aikawa T, et al. Hypoalbuminemia for the prediction of venous thromboembolism and treatment of direct oral anticoagulants in metastatic gastric cancer patients. Gastric Cancer. 2019;22(5):988-998. doi:10.1007/s10120-019-00930-2

2.         Lung BE, Kanjiya S, Bisogno M, Komatsu DE, Wang ED. Risk factors for venous thromboembolism in total shoulder arthroplasty. JSES Open Access. 2019;3(3):183-188. doi:10.1016/j.jses.2019.07.003

3.         Liu Y, Gu Y, Yi F, Cao B. [Retrospective Analysis of Risk Factors for Venous Thromboembolism in 283 Patients with Lung Cancer during Systemic Therapy]. Zhongguo Fei Ai Za Zhi. 2019;22(7):419-426. doi:10.3779/j.issn.1009-3419.2019.07.03

4.         Branchford BR, Carpenter SL. The Role of Inflammation in Venous Thromboembolism. Front Pediatr. 2018;6:142. doi:10.3389/fped.2018.00142

5.         Ogdie A, Kay McGill N, Shin DB, et al. Risk of venous thromboembolism in patients with psoriatic arthritis, psoriasis and rheumatoid arthritis: a general population-based cohort study. Eur Heart J. 2018;39(39):3608-3614. doi:10.1093/eurheartj/ehx145

6.         Molander V, Bower H, Frisell T, Askling J. Risk of venous thromboembolism in rheumatoid arthritis, and its association with disease activity: a nationwide cohort study from Sweden. Ann Rheum Dis. 2021;80(2):169-175. doi:10.1136/annrheumdis-2020-218419

7.         Cheng K, Faye AS. Venous thromboembolism in inflammatory bowel disease. World J Gastroenterol. 2020;26(12):1231-1241. doi:10.3748/wjg.v26.i12.1231

8.         Murthy SK, Robertson McCurdy AB, Carrier M, McCurdy JD. Venous thromboembolic events in inflammatory bowel diseases: A review of current evidence and guidance on risk in the post-hospitalization setting. Thromb Res. 2020;194:26-32. doi:10.1016/j.thromres.2020.06.005

9.         Nguyen GC, Bernstein CN, Bitton A, et al. Consensus statements on the risk, prevention, and treatment of venous thromboembolism in inflammatory bowel disease: Canadian Association of Gastroenterology. Gastroenterology. 2014;146(3):835-848.e6. doi:10.1053/j.gastro.2014.01.042

10.       Takemoto CM. Venous thromboembolism in cystic fibrosis. Pediatr Pulmonol. 2012;47(2):105-112. doi:10.1002/ppul.21566

11.       Pahlkotter MK, Mohidul S, Moen MR, et al. BMI and VTE Risk in Emergency General Surgery, Does Size Matter? : An ACS-NSQIP Database Analysis. Am Surg. 2020;86(12):1660-1665. doi:10.1177/0003134820940272

12.       Hisada Y, Mackman N. Cancer-associated pathways and biomarkers of venous thrombosis. Blood. 2017;130(13):1499-1506. doi:10.1182/blood-2017-03-743211

13.       Kekre N, Connors JM. Venous thromboembolism incidence in hematologic malignancies. Blood Rev. 2019;33:24-32. doi:10.1016/j.blre.2018.06.002

14.       Elice F, Rodeghiero F. Hematologic malignancies and thrombosis. Thromb Res. 2012;129(3):360-366. doi:10.1016/j.thromres.2011.11.034

15.       Falanga A, Marchetti M, Russo L. Venous thromboembolism in the hematologic malignancies. Curr Opin Oncol. 2012;24(6):702-710. doi:10.1097/CCO.0b013e3283592331

16.       Lizarralde-Iragorri MA, Shet AS. Sickle Cell Disease: A Paradigm for Venous Thrombosis Pathophysiology. Int J Mol Sci. 2020;21(15):E5279. doi:10.3390/ijms21155279

17.       Kujovich JL. Factor V Leiden thrombophilia. Genet Med. 2011;13(1):1-16. doi:10.1097/GIM.0b013e3181faa0f2

18.       Tormene D, Campello E, Simion C, et al. Incidence of VTE in asymptomatic children with deficiencies of antithrombin, protein C, and protein S: a prospective cohort study. Blood Adv. 2020;4(21):5442-5448. doi:10.1182/bloodadvances.2020002781

19.       Cheung KL, Bouchard BA, Cushman M. Venous thromboembolism, factor VIII and chronic kidney disease. Thromb Res. 2018;170:10-19. doi:10.1016/j.thromres.2018.07.029

20.       Agrati C, Mazzotta V, Pinnetti C, Biava G, Bibas M. Venous thromboembolism in people living with HIV infection (PWH). Transl Res. 2021;227:89-99. doi:10.1016/j.trsl.2020.07.007

21.       Olson JJ, Schwab P-E, Jackson J, Lange JK, Bedair HS, Abdeen A. HIV-Positive Patients Are at Increased Risk of Venous Thromboembolism After Total Joint Replacement. J Am Acad Orthop Surg. 2021;29(11):479-485. doi:10.5435/JAAOS-D-20-00737

22.       Crum-Cianflone NF, Weekes J, Bavaro M. Review: thromboses among HIV-infected patients during the highly active antiretroviral therapy era. AIDS Patient Care STDS. 2008;22(10):771-778. doi:10.1089/apc.2008.0010

23.       Saif MW, Bona R, Greenberg B. AIDS and thrombosis: retrospective study of 131 HIV-infected patients. AIDS Patient Care STDS. 2001;15(6):311-320. doi:10.1089/108729101750279687

24.       White RH. The epidemiology of venous thromboembolism. Circulation. 2003;107(23 Suppl 1):I4-8. doi:10.1161/01.CIR.0000078468.11849.66

25.       Hinman AD, Chan PH, Prentice HA, Paxton EW, Okike KM, Navarro RA. The Association of Race/Ethnicity and Total Knee Arthroplasty Outcomes in a Universally Insured Population. J Arthroplasty. 2020;35(6):1474-1479. doi:10.1016/j.arth.2020.02.002

26.       Okike K, Chan PH, Prentice HA, Navarro RA, Hinman AD, Paxton EW. Association of Race and Ethnicity with Total Hip Arthroplasty Outcomes in a Universally Insured Population. J Bone Joint Surg Am. 2019;101(13):1160-1167. doi:10.2106/JBJS.18.01316