Venous thromboembolism in cancer patients: Still looking for answers (Review)

Iorga,Roua  Anamaria; Bratu,Ovidiu  Gabriel; Marcu,Radu  Dragos; Constantin,Traian; Mischianu,Dan  Liviu Dorel; Socea,Bogdan; Gaman,Mihnea‑Alexandru; Diaconu,Camelia  Cristina

doi:10.3892/etm.2019.8019

Venous thromboembolism in cancer patients: Still looking for answers (Review)

Authors:
- Roua Anamaria Iorga
- Ovidiu Gabriel Bratu
- Radu Dragos Marcu
- Traian Constantin
- Dan Liviu Dorel Mischianu
- Bogdan Socea
- Mihnea‑Alexandru Gaman
- Camelia Cristina Diaconu
View Affiliations

Affiliations: Internal Medicine Department, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania, Urology Department, Emergency University Central Military Hospital, 010825 Bucharest, Romania, University of Medicine and Pharmacy ‘Carol Davila’, Bucharest 050474, Romania
Published online on: September 18, 2019 https://doi.org/10.3892/etm.2019.8019
Pages: 5026-5032

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Patients with cancer‑associated venous thromboembolism (VTE) represent a real challenge in clinical practice. Patients with cancer have a greater risk both of VTE and bleeding. There are only a few studies regarding the therapeutic approach of VTE in patients with cancer, especially after cancer surgery, and on thromboprophylaxis during chemotherapy. Many of the anticoagulation therapy recommendations for cancer patients are extrapolated from trials that are not conducted in cancer cohorts. It is essential to assess the efficacy and safety of VTE prophylaxis in this particular subgroup, which bears higher risks both of VTE recurrence and major hemorrhagic events. The introduction of direct oral anticoagulants in everyday practice represented a major evolution of the anticoagulant treatment. Direct anticoagulants could represent a more appealing alternative to low‑molecular‑weight heparin in paraneoplastic venous thrombosis, due to the patient comfort, easy administration of the drug and emerging studies that prove similar efficacy and safety as the standard treatment. However, there is limited data on the treatment with direct oral anticoagulants in patients with paraneoplastic venous thromboembolism.

View Figures

View References

1	Levine M: Treatment of thrombotic disorders in cancer patients. Haemostasis. 27 (Suppl 1):38–43. 1997.PubMed/NCBI
2	Carrier M, Khorana AA, Moretto P, Le Gal G, Karp R and Zwicker JI: Lack of evidence to support thromboprophylaxis in hospitalized medical patients with cancer. Am J Med. 127:82–6.e1. 2014. View Article : Google Scholar : PubMed/NCBI
3	Moheimani F and Jackson DE: Venous thromboembolism: Classification, risk factors, diagnosis, and management. ISRN Hematol. 2011:1246102011. View Article : Google Scholar : PubMed/NCBI
4	Alikhan R, Cohen AT, Combe S, Samama MM, Desjardins L, Eldor A, Janbon C, Leizorovicz A, Olsson CG and Turpie AG; MEDENOX Study, : Risk factors for venous thromboembolism in hospitalized patients with acute medical illness: Analysis of the MEDENOX Study. Arch Intern Med. 164:963–968. 2004. View Article : Google Scholar : PubMed/NCBI
5	van Rooden CJ, Schippers EF, Barge RM, Rosendaal FR, Guiot HF, van der Meer FJ, Meinders AE and Huisman MV: Infectious complications of central venous catheters increase the risk of catheter-related thrombosis in hematology patients: A prospective study. J Clin Oncol. 23:2655–2660. 2005. View Article : Google Scholar : PubMed/NCBI
6	Kenneth AB: Drug-induced thrombosis in patients with malignancy. UpToDate. 2017, https://www.uptodate.comJanuary 7–2019
7	O'Connell CL, Boswell WD, Duddalwar V, Caton A, Mark LS, Vigen C and Liebman HA: Unsuspected pulmonary emboli in cancer patients: Clinical correlates and relevance. J Clin Oncol. 24:4928–4932. 2006. View Article : Google Scholar : PubMed/NCBI
8	Sørensen HT, Mellemkjaer L, Olsen JH and Baron JA: Prognosis of cancers associated with venous thromboembolism. N Engl J Med. 343:1846–1850. 2000. View Article : Google Scholar : PubMed/NCBI
9	Chew HK, Wun T, Harvey D, Zhou H and White RH: Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med. 166:458–464. 2006. View Article : Google Scholar : PubMed/NCBI
10	Gross CP, Galusha DH and Krumholz HM: The impact of venous thromboembolism on risk of death or hemorrhage in older cancer patients. J Gen Intern Med. 22:321–326. 2007. View Article : Google Scholar : PubMed/NCBI
11	Hultcrantz M, Björkholm M, Dickman PW, Landgren O, Derolf ÅR, Kristinsson SY and Andersson TML: Risk for arterial and venous thrombosis in patients with myeloproliferative neoplasms: A population-based cohort study. Ann Intern Med. 168:317–325. 2018. View Article : Google Scholar : PubMed/NCBI
12	Elting LS, Escalante CP, Cooksley C, Avritscher EB, Kurtin D, Hamblin L, Khosla SG and Rivera E: Outcomes and cost of deep venous thrombosis among patients with cancer. Arch Intern Med. 164:1653–1661. 2004. View Article : Google Scholar : PubMed/NCBI
13	Walker AJ, Card TR, West J, Crooks C and Grainge MJ: Incidence of venous thromboembolism in patients with cancer - a cohort study using linked United Kingdom databases. Eur J Cancer. 49:1404–1413. 2013. View Article : Google Scholar : PubMed/NCBI
14	Stein PD, Beemath A, Meyers FA, Skaf E, Sanchez J and Olson RE: Incidence of venous thromboembolism in patients hospitalized with cancer. Am J Med. 119:60–68. 2006. View Article : Google Scholar : PubMed/NCBI
15	Khorana AA, Francis CW, Culakova E, Kuderer NM and Lyman GH: Frequency, risk factors, and trends for venous thromboembolism among hospitalized cancer patients. Cancer. 110:2339–2346. 2007. View Article : Google Scholar : PubMed/NCBI
16	Cohen AT, Katholing A, Rietbrock S, Bamber L and Martinez C: Epidemiology of first and recurrent venous thromboembolism in patients with active cancer. A population-based cohort study. Thromb Haemost. 117:57–65. 2017. View Article : Google Scholar : PubMed/NCBI
17	Kenneth AB: Pathogenesis of the hypercoagulable state associated with malignancy. UpToDate. 2017, https://www.uptodate.comJanuary 9–2019
18	van Doormaal FF, Raskob GE, Davidson BL, Decousus H, Gallus A, Lensing AW, Piovella F, Prins MH and Büller HR: Treatment of venous thromboembolism in patients with cancer: Subgroup analysis of the Matisse clinical trials. Thromb Haemost. 101:762–769. 2009. View Article : Google Scholar : PubMed/NCBI
19	Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, Huisman M, King CS, Morris TA, Sood N, et al: Antithrombotic therapy for VTE disease. Chest. 149:315–352. 2016. View Article : Google Scholar : PubMed/NCBI
20	Lyman GH, Bohlke K, Khorana AA, Kuderer NM, Lee AY, Arcelus JI, Balaban EP, Clarke JM, Flowers CR, Francis CW, et al American Society of Clinical Oncology, : Venous thromboembolism prophylaxis and treatment in patients with cancer: American society of clinical oncology clinical practice guideline update 2014. J Clin Oncol. 33:654–656. 2015. View Article : Google Scholar : PubMed/NCBI
21	Francis CW, Kessler CM, Goldhaber SZ, Kovacs MJ, Monreal M, Huisman MV, Bergqvist D, Turpie AG, Ortel TL, Spyropoulos AC, et al: Treatment of venous thromboembolism in cancer patients with dalteparin for up to 12 months: The DALTECAN Study. J Thromb Haemost. 13:1028–1035. 2015. View Article : Google Scholar : PubMed/NCBI
22	Streiff MB, Holmstrom B, Angelini D, Ashrani A, Bockenstedt PL, Chesney C, Fanikos J, Fenninger RB, Fogerty AE, Gao S, et al: NCCN Guidelines insights: Cancer-associated venous thromboembolic disease, Version 2.2018. J Natl Compr Canc Netw. 16:1289–1303. 2018. View Article : Google Scholar : PubMed/NCBI
23	Kahale LA, Hakoum MB, Tsolakian IG, Matar CF, Terrenato I, Sperati F, Barba M, Yosuico VE, Schünemann H and Akl EA: Anticoagulation for the long-term treatment of venous thromboembolism in people with cancer. Cochrane Database Syst Rev. 6:CD0066502018.PubMed/NCBI
24	Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, et al Randomized comparison of low-molecular-weight heparin versus oral anticoagulant therapy for the prevention of recurrent venous thromboembolism in patients with cancer (CLOT) Investigators, : Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 349:146–153. 2003. View Article : Google Scholar : PubMed/NCBI
25	Meyer G, Marjanovic Z, Valcke J, Lorcerie B, Gruel Y, Solal-Celigny P, Le Maignan C, Extra JM, Cottu P and Farge D: Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: A randomized controlled study. Arch Intern Med. 162:1729–1735. 2002. View Article : Google Scholar : PubMed/NCBI
26	Deitcher SR, Kessler CM, Merli G, Rigas JR, Lyons RM and Fareed J; ONCENOX Investigators, : Secondary prevention of venous thromboembolic events in patients with active cancer: Enoxaparin alone versus initial enoxaparin followed by warfarin for a 180-day period. Clin Appl Thromb Hemost. 12:389–396. 2006. View Article : Google Scholar : PubMed/NCBI
27	Lee AYY, Kamphuisen PW, Meyer G, Bauersachs R, Janas MS, Jarner MF and Khorana AA; CATCH Investigators, : Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer. A randomized clinical trial. JAMA. 314:677–686. 2015. View Article : Google Scholar : PubMed/NCBI
28	Hull RD, Pineo GF, Brant RF, Mah AF, Burke N, Dear R, Wong T, Cook R, Solymoss S, Poon MC, et al LITE Trial Investigators, : Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med. 119:1062–1072. 2006. View Article : Google Scholar : PubMed/NCBI
29	Harrison L, McGinnis J, Crowther M, Ginsberg J and Hirsh J: Assessment of outpatient treatment of deep-vein thrombosis with low-molecular-weight heparin. Arch Intern Med. 158:2001–2003. 1998. View Article : Google Scholar : PubMed/NCBI
30	Rose AJ, Sharman JP, Ozonoff A, Henault LE and Hylek EM: Effectiveness of warfarin among patients with cancer. J Gen Intern Med. 22:997–1002. 2007. View Article : Google Scholar : PubMed/NCBI
31	Khorana AA, Noble S, Lee AYY, Soff G, Meyer G, O'Connell C and Carrier M: Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: Guidance from the SSC of the ISTH. J Thromb Haemost. 16:1891–1894. 2018. View Article : Google Scholar : PubMed/NCBI
32	Prins MH, Lensing AW, Bauersachs R, van Bellen B, Bounameaux H, Brighton TA, Cohen AT, Davidson BL, Decousus H, Raskob GE, et al EINSTEIN Investigators, : Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: A pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J. 11:212013. View Article : Google Scholar : PubMed/NCBI
33	Schulman S, Goldhaber SZ, Kearon C, Kakkar AK, Schellong S, Eriksson H, Hantel S, Feuring M and Kreuzer J: Treatment with dabigatran or warfarin in patients with venous thromboembolism and cancer. Thromb Haemost. 114:150–157. 2015. View Article : Google Scholar : PubMed/NCBI
34	Vedovati MC, Germini F, Agnelli G and Becattini C: Direct oral anticoagulants in patients with VTE and cancer: A systematic review and meta-analysis. Chest. 147:475–483. 2015. View Article : Google Scholar : PubMed/NCBI
35	Agnelli G, Buller HR, Cohen A, Gallus AS, Lee TC, Pak R, Raskob GE, Weitz JI and Yamabe T: Oral apixaban for the treatment of venous thromboembolism in cancer patients: Results from the AMPLIFY trial. J Thromb Haemost. 13:2187–2191. 2015. View Article : Google Scholar : PubMed/NCBI
36	Prisco D, Tufano A, Cenci C, Pignatelli P, Santilli F, Di Minno G and Perticone F: Position paper of the Italian Society of Internal Medicine (SIMI) on prophylaxis and treatment of venous thromboembolism in patients with cancer. Intern Emerg Med. 14:21–38. 2019. View Article : Google Scholar : PubMed/NCBI
37	https://clinicaltrials.gov/ct2/show/NCT02744092April 20–2016
38	https://clinicaltrials.gov/ct2/show/NCT03240120August 4–2017
39	https://clinicaltrials.gov/ct2/show/NCT03045406February 7–2017
40	https://clinicaltrials.gov/ct2/show/NCT02581176October 20–2015
41	Raskob GE, van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D, Grosso MA, Kakkar AK, Kovacs MJ, Mercuri MF, et al Hokusai VTE Cancer Investigators, : Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 378:615–624. 2018. View Article : Google Scholar : PubMed/NCBI
42	Young AM, Marshall A, Thirlwall J, Chapman O, Lokare A, Hill C, Hale D, Dunn JA, Lyman GH, Hutchinson C, et al: Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: Results of a randomized trial (SELECT-D). J Clin Oncol. 36:2017–2023. 2018. View Article : Google Scholar : PubMed/NCBI
43	https://clinicaltrials.gov/ct2/show/NCT03139487May 4–2017
44	https://clinicaltrials.gov/ct2/show/NCT02746185April 21–2016
45	https://clinicaltrials.gov/ct2/show/NCT02583191October 22–2015
46	Hakoum MB, Kahale LA, Tsolakian IG, Matar CF, Yosuico VE, Terrenato I, Sperati F, Barba M, Schünemann H and Akl EA: Anticoagulation for the initial treatment of venous thromboembolism in people with cancer. Cochrane Database Syst Rev. 1:CD0066492018.PubMed/NCBI
47	Cohen AT, Spiro TE, Büller HR, Haskell L, Hu D, Hull R, Mebazaa A, Merli G, Schellong S, Spyropoulos AC, et al MAGELLAN Investigators, : Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 368:513–523. 2013. View Article : Google Scholar : PubMed/NCBI
48	Akl EA, van Doormaal FF, Barba M, Kamath G, Kim SY, Kuipers S, Middeldorp S, Yosuico V, Dickinson HO and Schünemann HJ: Parenteral anticoagulation may prolong the survival of patients with limited small cell lung cancer: A Cochrane systematic review. J Exp Clin Cancer Res. 27:42008. View Article : Google Scholar : PubMed/NCBI
49	van Doormaal FF, Di Nisio M, Otten HM, Richel DJ, Prins M and Buller HR: Randomized trial of the effect of the low molecular weight heparin nadroparin on survival in patients with cancer. J Clin Oncol. 29:2071–2076. 2011. View Article : Google Scholar : PubMed/NCBI
50	Yhim HY, Choi WI, Kim SH, Nam SH, Kim KH, Mun YC, Oh D, Hwang HG, Lee KW, Song EK, et al: Long-term rivaroxaban for the treatment of acute venous thromboembolism in patients with active cancer in a prospective multicenter trial. Blood J. 130:37112017.
51	https://clinicaltrials.gov/ct2/show/NCT03214172July 11–2017
52	https://clinicaltrials.gov/ct2/show/NCT02742623April 19–2016
53	https://clinicaltrials.gov/ct2/show/NCT01989845November 21–2013
54	https://clinicaltrials.gov/ct2/show/NCT03692065October 2–2018
55	https://clinicaltrials.gov/ct2/show/NCT02585713October 23–2015
56	Trujillo-Santos J, Nieto JA, Tiberio G, Piccioli A, Di Micco P, Prandoni P, Monreal M and Registry RIETE; RIETE Registry, : Predicting recurrences or major bleeding in cancer patients with venous thromboembolism. Findings from the RIETE Registry. Thromb Haemost. 100:435–439. 2008. View Article : Google Scholar : PubMed/NCBI
57	Hutten BA, Prins MH, Gent M, Ginsberg J, Tijssen JG and Büller HR: Incidence of recurrent thromboembolic and bleeding complications among patients with venous thromboembolism in relation to both malignancy and achieved international normalized ratio: A retrospective analysis. J Clin Oncol. 18:3078–3083. 2000. View Article : Google Scholar : PubMed/NCBI
58	Lyman GH, Khorana AA, Kuderer NM, Lee AY, Arcelus JI, Balaban EP, Clarke JM, Flowers CR, Francis CW, Gates LE, et al American Society of Clinical Oncology Clinical Practice, : Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 31:2189–2204. 2013. View Article : Google Scholar : PubMed/NCBI
59	Agnelli G, George DJ, Kakkar AK, Fisher W, Lassen MR, Mismetti P, Mouret P, Chaudhari U, Lawson F and Turpie AG; SAVE-ONCO Investigators, : Semuloparin for thromboprophylaxis in patients receiving chemotherapy for cancer. N Engl J Med. 366:601–609. 2012. View Article : Google Scholar : PubMed/NCBI
60	Maraveyas A, Waters J, Roy R, Fyfe D, Propper D, Lofts F, Sgouros J, Gardiner E, Wedgwood K, Ettelaie C, et al: Gemcitabine versus gemcitabine plus dalteparin thromboprophylaxis in pancreatic cancer. Eur J Cancer. 48:1283–1292. 2012. View Article : Google Scholar : PubMed/NCBI
61	Agnelli G, Gussoni G, Bianchini C, Verso M, Mandalà M, Cavanna L, Barni S, Labianca R, Buzzi F, Scambia G, et al PROTECHT Investigators, : Nadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic or locally advanced solid cancer receiving chemotherapy: A randomised, placebo-controlled, double-blind study. Lancet Oncol. 10:943–949. 2009. View Article : Google Scholar : PubMed/NCBI
62	https://clinicaltrials.gov/ct2/show/NCT02048865January 29–2014
63	https://clinicaltrials.gov/ct2/show/NCT02555878September 22–2015
64	Walenga JM and Adiguzel C: Drug and dietary interactions of the new and emerging oral anticoagulants. Int J Clin Pract. 64:956–967. 2010. View Article : Google Scholar : PubMed/NCBI
65	Lohr LK: Drug interactions with newer oral chemotherapy agents. US Pharm. 34 (Oncology suppl):4–8. 2009.
66	Neagu M, Caruntu C, Constantin C, Boda D, Zurac S, Spandidos DA and Tsatsakis AM: Chemically induced skin carcinogenesis: Updates in experimental models (Review). Oncol Rep. 35:2516–2528. 2016. View Article : Google Scholar : PubMed/NCBI
67	Voiculescu VM, Caruntu C, Solomon I, Lupu M, Ilie MA, Boda D, et al: Squamous cell carcinoma: biomarkers and potential therapeutic targetsHuman Skin Cancers-Pathways, Mechanisms, Targets and Treatments. IntechOpen; London: pp. 135–159. 2018
68	Lupu M, Caruntu A, Caruntu C, Papagheorghe LML, Ilie MA, Voiculescu V, Boda D, Constantin C, Tanase C, Sifaki M, et al: Neuroendocrine factors: The missing link in non-melanoma skin cancer (Review). Oncol Rep. 38:1327–1340. 2017. View Article : Google Scholar : PubMed/NCBI
69	Boda D, Docea AO, Calina D, Ilie MA, Caruntu C, Zurac S, Neagu M, Constantin C, Branisteanu DE, Voiculescu V, et al: Human papilloma virus: Apprehending the link with carcinogenesis and unveiling new research avenues (Review). Int J Oncol. 52:637–655. 2018.PubMed/NCBI
70	Popescu R, Bratu O, Spinu D, Marcu D, Farcas C, Dinu M and Mischianu D: Neuroendocrine differentiation in prostate cancer – a review. Rom J Mil Med. 118:16–19. 2015.
71	Marcu D, Spinu D, Mischianu D, Socea B, Oprea I and Bratu O: Oncological follow-up after radical prostatectomy. Rom J Mil Med. 120:39–42. 2017.
72	Radulescu A, Madan V, Aungurenci A, Bratu O, Farcas C, Dinu M and Mischianu D: Antibiotic resistant urinary tract infections in an urology ward. Rom J Mil Med. 118:20–22. 2015.
73	Spinu D, Bratu O, Popescu R, Marcu D, Radulescu A and Mischianu D: Clostridium difficile-an emerging plague. Rom J Mil Med. 118:12–15. 2015.
74	Socea LI, Visan DC, Barbuceanu SF, Apostol TV, Bratu OG and Bogdan S: The antioxidant activity of some acylhydrazones with dibenzo[a,d][7]annulene moiety. Rev Chim Buchar. 69:795–797. 2018.
75	https://clinicaltrials.gov/ct2/show/NCT01444612October 3–2011
76	https://clinicaltrials.gov/ct2/show/NCT00219973September 22–2005
77	https://clinicaltrials.gov/ct2/show/NCT02366871February 19–2015
78	Perry JR, Julian JA, Laperriere NJ, Geerts W, Agnelli G, Rogers LR, Malkin MG, Sawaya R, Baker R, Falanga A, et al: PRODIGE: A randomized placebo-controlled trial of dalteparin low-molecular-weight heparin thromboprophylaxis in patients with newly diagnosed malignant glioma. J Thromb Haemost. 8:1959–1965. 2010. View Article : Google Scholar : PubMed/NCBI
79	Solomon I, Voiculescu VM, Caruntu C, Lupu M, Popa A, Ilie MA, Albulescu R, Caruntu A, Tanase C, Constantin C, et al: Neuroendocrine factors and head and neck squamous cell carcinoma: An affair to remember. Dis Markers. 2018:97878312018. View Article : Google Scholar : PubMed/NCBI
80	Boda D: Cellomics as integrative omics for cancer. Curr Proteomics. 10:237–245. 2013. View Article : Google Scholar
81	Marras LC, Geerts WH and Perry JR: The risk of venous thromboembolism is increased throughout the course of malignant glioma: An evidence-based review. Cancer. 89:640–646. 2000. View Article : Google Scholar : PubMed/NCBI
82	Neagu M, Constantin C, Tanase C and Boda D: Patented biomarker panels in early detection of cancer. Recent Pat Biomark. 1:10–24. 2011. View Article : Google Scholar
83	Lupu M, Caruntu A, Caruntu C, Boda D, Moraru L, Voiculescu V and Bastian A: Non-invasive imaging of actinic cheilitis and squamous cell carcinoma of the lip. Mol Clin Oncol. 8:640–646. 2018.PubMed/NCBI
84	Herishanu Y, Misgav M, Kirgner I, Ben-Tal O, Eldor A and Naparstek E: Enoxaparin can be used safely in patients with severe thrombocytopenia due to intensive chemotherapy regimens. Leuk Lymphoma. 45:1407–1411. 2004. View Article : Google Scholar : PubMed/NCBI
85	Ibrahim RB, Skewes MD and Kuriakose P: ‘Sailing in troubled waters’: A review of the use of anticoagulation in adult cancer patients with thrombocytopenia. Blood Coagul Fibrinolysis. 27:615–630. 2016. View Article : Google Scholar : PubMed/NCBI
86	Stopa JD, Neuberg D, Puligandla M, Furie B, Flaumenhaft R and Zwicker JI: Protein disulfide isomerase inhibition blocks thrombin generation in humans by interfering with platelet factor V activation. JCI Insight. 2:e893732017. View Article : Google Scholar : PubMed/NCBI
87	Zwicker JI, Schlechter BL, Stopa JD, Liebman HA, Aggarwal A, Puligandla M, Caughey T, Bauer KA, Kuemmerle N, Wong E, et al CATIQ Investigators 11, : Targeting protein disulfide isomerase with the flavonoid isoquercetin to improve hypercoagulability in advanced cancer. JCI Insight. 4(ii)2019.PubMed/NCBI
88	https://clinicaltrials.gov/ct2/show/NCT02195232July 21–2014
89	Tica OA, Tica O, Antal L, Hatos A, Popescu MI, Pantea Stoian A, Bratu OG, Gaman MA, Pituru SM and Diaconu CC: Modern oral anticoagulant treatment in patients with atrial fibrillation and heart failure: Insights from the clinical practice. Farmacia. 66:972–976. 2018. View Article : Google Scholar
90	https://clinicaltrials.gov/ct2/show/NCT01524653February 2–2012