Predicting Thrombotic Events in Rheumatoid Arthritis by Using Bleeding Time: Look at the Platelet
Main Article Content
Abstract
Background: Rheumatoid Arthritis (RA) is associated with an elevated risk of thrombosis, which contributes to increased major adverse cardiovascular events and mortality in individuals with RA aged over 50, as compared to the general population. This increased thrombotic risk is thought to be due to systemic inflammation leading to platelet dysfunction. Additionally, certain RA treatments have been associated with an increased risk of clot formation. We proposed the hypothesis that a shortened bleeding time measurement could serve as an identifying marker for individuals at risk of clotting events. The bleeding time assesses platelet function. Aspirin can reverse the short bleeding time and may prevent the incidence of thrombosis.
Methods: Sequential RA patients over age 50 (n=246) at one center had bleeding time testing at the initial visit and 2 weeks after beginning a medication known to affect coagulation. These were estrogen, rofecoxib, celecoxib, naproxen, ibuprofen, aspirin, tofacitinib, baricitinib, upadacitinib, filgotinib, and anti-coagulants.
Results: The RA control group had a bleeding time of 3.7 + 0.4 minutes. This is a shorter bleeding time than expected in the normal population, where bleeding time is 4 to 7 minutes. The RA patients who developed MACE or thrombotic events had shorter bleeding time at 2.3 + 0.4 minutes, significantly shorter than the RA control group, p<0.001. A shorter bleeding time was demonstrated with COX-2 agents, rofecoxib and celecoxib at less than 2.5 minutes, and JAK agents had short bleeding time from 1.5 to 2.3 minutes, all significantly lower than the control p<0.002. Adding daily 81 mg low dose aspirin to JAK reversed the bleeding time to the control values. A bleeding time measured at less than 3 minutes was associated with higher incident rates of thrombotic events and MACE.
Conclusion: These findings suggest that bleeding time less than 3 minutes may serve as a clinically relevant marker for assessing thrombotic risk in RA patients. Further research with larger cohorts is warranted to validate and expand upon these observations, potentially paving the way for the incorporation of bleeding time testing into the clinical management of RA patients to optimize thrombotic risk assessment and preventive strategies.
Article Details
How to Cite
GREENWALD, Maria; BALL, JoAnn; GARCIA, Denise.
Predicting Thrombotic Events in Rheumatoid Arthritis by Using Bleeding Time: Look at the Platelet.
Medical Research Archives, [S.l.], v. 12, n. 4, apr. 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/5282>. Date accessed: 15 may 2024.
doi: https://doi.org/10.18103/mra.v12i4.5282.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Avina-Zubieta J, Thomas J, Sudatsafavi M, et.al. Risk of incident cardiovascular events in patients with rheumatoid arthritis: a meta-analysis of observational studies. Ann Rheum Dis 2012;71:1524-9.
2. Choi E, Ganeshalingam K, Semb A, et.al. Cardiovascular risk in rheumatoid arthritis: recent advances in the understanding of the pivotal role of inflammation. Rheumatology 2014;53:2143-54.
3. Choi H, Rho Y, ZHU Y, ET.AL. The risk of pulmonary embolism and deep vein thrombosis in rheumatoid arthritis. Ann Rheum Dis 2013;72:1182-1187.
4. Chung W, Peng C, Lin C, et.al. Rheumatoid arthritis increases the risk of deep vein thrombosis and pulmonary thromboembolism. Ann Rheum Dis 2014; 73:1774-1780.
5. Ytterberg S, Bhatt D, Mikuls T, et.al. Cardiovasscular and cancer risk with tofacitinib in rheumatoid arthritis. N Engl J Med 2022;385:316-326. https://doi.org/10.1056/NEJMc2202778.
6. Undas A, Brummel-Ziedins K, Mann K. Antithrombotic properties of aspirin and resistance to aspirin: beyond strictly antiplatelet actions. Blood 2007;109:2285-92 doi:10.1182/blood-2006-01-010645.
7. Aslan J. Platelet proteomes, pathways, and phenotypes as informants of vascular wellness and disease. Arteriosclerosis Thrombosis Vasc Biol 2021;41:999-1011.
8. Awtry E, Loscalzo J. Aspirin. Circulation. 2000;101:1206-1218.
9. Antithrombotic Trialists Collaboration Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324:71-86.
10. Undas A, Undas R, Musiel J, et.al. A low dose of aspirin (75 mg daily) lowers thrombin generation. Blood Coagul Fibrinolysis 2000; 11: 231-234.
11. Grosser T, Fries S, FitzGerald GA. Biological basis for the cardiovascular consequences of COX-1 inhibition: therapeutic challenges and opportunities. J Clin Invest. 2006;116:4-15.
12. Greenberg H, Gottesdiener K, Huntington M, et.al. A new cyclooxyrgenase 2 inhibitor rofecoxib did not alter the anti platelet effects of low-dose aspirin in healthy volunteers. J Clinic Pharmacy 2000;40:1509-15.
13. Lorand L. Factor XIII: structure, activation, and interactions with fibrinogen and fibrin. Ann N Y Acad Sci. 2001;936:291-311.
14. Rayes J, Watson S, Nieswandt B. Functional significance of the platelet immune receptors GPVI and CLEC-2. J Clinic Invest. 2019; 129:12-23.
15. Nieswandt B, Varga-Szabo D, Elvers M. Integrins in platelet activation. J Thromb Haemost. 2009 Jul;7 Suppl 1:206-9. doi: 10.1111/j.1538-7836.2009.03370.x.
16. Karas SP, Rosse WF, Kurlander RJ. Characterization of the IgG-Fc receptor on human platelets. Blood 1982;60: 1277-1282.
17. Pons-Estel G, Guillermo J, Scanzi A et.al. The phospholipid syndrome.Journal of autoimmunity 2017;76: 10-20.
18. Eaton, N., Subramaniam, S., Schulte, M., Drew, C., Jakab, D., Haberichter, S., Weiler, H., & Falet, H. (2020). Bleeding diathesis in mice lacking JAK2 in platelets. Blood advances, 5 15, 2969-2981
https://doi.org/10.1182/blood-2020-138510.
19. Zheng T, Izquierdo I, Reitsma S, et.al. Platelets and tyrosine kinase inhibitors. Am J Physiology 2022.
doi.org/10.1152/ajpcell.00040.2022
20. Parra-Izquierdo I, Melrose A, Pang J, et.al. Janus kinase inhibitors ruxolitinib and baricitinib impair glycoprotein-VI medicated platelet function. Platelets 2021; 33:1-12.
21. Zaleskas, V., Krause, D., Lazarides, K., Patel, N., Hu, Y., Li, S., & Etten, R. (2006). Molecular Pathogenesis and Therapy of Polycythemia Induced in Mice by JAK2 V617F. PLoS ONE, 1.
https://doi.org/10.1371/journal.pone.0000018.
22. Brummett A, Navratil A, Bryan J, etal. Inhibition of JAK3 activity reduced the phosphorylation of cPLA and COX-2 protein levels. Infection and Immunity 2014;82: 970-982.
23. Muthian G, Rainwear H, Johnson C, et.al. Cox-2 inhibitors modulate IL-12 signaling through JAK-STAT pathway leading to TH1 response in experimental allergic encephalomyelitis. J Clinic Immune 2006;26: 73-85.
24. anovic M. Antiplatelet and antithrombotic drugs. In: Frishman WH, Sonnenblick EH, Sica DA, editors. Cardiovascular Pharmaceutics. New York, NY: McGraw Hill; 2003. pp. 259-299.
25. Demers LM, Budin RE, Shaikh BS. The effects of aspirin on megakaryocyte prostaglandin production.Proc Soc Exp Biol Med.1980;163:24-29.
26. Williams S, Fatah K, Hjemdahl P, Blomback M. Better increase in fibrin gel porosity by low-dose than intermediate dose acetylsalicylic acid. Eur Heart J. 1998;19:1666-1672.
27. McNeil JJ, Nelson MR, Woods RL, et al. Effect of aspirin on all-cause mortality in the healthy elderly. N Engl J Med 2018; 379:1519. https://doi.org/10.1056/NEJMoa1803955.
28. Iacoviello L, De Curtis A, D'Adamo MC, et al. Prostacyclin is required for tPA release after venous occlusion. Am J Physiol. 1994;266(2 pt 2):H429-434.
29. Campbell CL, Steinhubl SR. Variability in response to aspirin: do we understand the clinical relevance? J Thromb Haemost. 2005;3:665-669.
30. Mason PJ, Jacobs AK, Freedman JE. Aspirin resistance and atherothrombotic disease. J Am Coll Cardiol. 2005;46:986-993.
31. Sanderson S, Emery J, Baglin T, Kinmonth AL. Narrative review: aspirin resistance and its clinical implications. Ann Intern Med. 2005;142:370-380.
32. Grotemeyer K-H, Scharafinski HW, Husstedt IW. Two-year follow-up of aspirin responder and aspirin non-responder. A pilot study including 180 post-stroke patients. Thromb Res. 1993;71:397-403.
33. Mason P, Jacobs A, Freedman J. J American Coll Cardiology 2005;46:986-93.
34. Dufrost, V., Risse, J., Reshetnyak, T., Satybaldyeva, M., Du, Y., Yan, X., Salta, S., Gerotziafas, G., Jing, Z., Elalamy, I., Wahl, D., & Zuily, S. (2018). Increased risk of thrombosis in antiphospholipid syndrome patients treated with direct oral anticoagulants. Results from an international patient-level data meta-analysis. Autoimmunity reviews, 2018;17: 1011-1021. https://doi.org/10.1016/j.autrev.2018.04.009.
35. Harker L, Slichter S. The bleeding time as a screening test for evaluation of platelet function. NEJM 1972; 287:155-159.
36. Weiss JH, Lages B. Evidence for tissue factor-dependent activation of the classic extrinsic coagulation mechanism in blood obtained from bleeding-time wounds. Blood. 1989;71:629-635.
37. Rodgers, R., & Levin, J. (1990). A critical reappraisal of the bleeding time. Seminars in thrombosis and hemostasis, 16 1, 1-20. https://doi.org/10.1055/S-2007-1002658.
38. Quehennberger P, Handler S, MannhalterC, et.al. Evaluation of a highly specific functional test for the detection of factor V Leiden. International J Clinical Laboratory Research. 2000;30:113-117. https://doi.org/10.1007/S005990070009.
39. Kyrle PA, Westwick J, Scully MF, Kakkar VV, Levis GP. Investigation of the interaction of blood platelets with the coagulation system at the site of plug formation ex vivo in man: effect of low-dose aspirin. Thromb Haemost. 1987;57:62-69.
40. Szczeklik A, Krzanowski M, Gora P, Radwan J. Antiplatelet drugs and generation of thrombin in clotting blood. Blood. 1992;80:2006-2011.
41. Hemker HC, Giesen P, Al Dieri R, et al. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb. 2003;33:4-15.
42. Bender M, May F, Lorenz V, et.al. Combined in vivo depletion of glycoprotein VI and C-type LectinCompromises Hemostasis and abrogates arterial thrombosis in mice. Arteriosclerosis, Thrombosis, and Vascular Biology 2013;33: 926-934.
43. Jirouskova M, She A, Johnson G, et.al. a guide to murine platelet structure, function, assays, and genetics alteration. Journal of Thrombosis and Haemostasis. 2007;5:661-669.
44. De Caterina R, Lanza M, Marca G, et.al. Bleeding time and bleeding. Blood 1994;84: 3363-3370.
45. Mengle-Gaw L, Hubbard R, Karim A, et.al. Review of Cox2 inhibitors and bleeding time. Rheumatology1999; 38: 779-788.
46. Matheson A, Figgitt D. Drugs 2001;61: 833-865.
47. Gels. Update on clinical developments with celecoxib COX-2 inhibitor. Scan J Rheumatol 1999; 28:31-7.
48. Liu J, Li N, Yang J, et.al. The Proceedings of the National Academy of Sciences PNAS 2010;107:17017-22.
49. Mielke, C., Kaneshiro, M., Maher, I., Weiner, J., & Rapaport, S. The standardized normal Ivy bleeding time and its prolongation by aspirin. Blood 1969;34: 204-215. https://doi.org/10.1182/BLOOD.V34.2.204.204.
50. Aversa, L., Vázquez, A., Peñalver, J., Dascal, E., & Bustelo, P. Bleeding Time in Normal Children. Journal of Pediatric Hematology/ Oncology, 1995;17: 25-28. https://doi.org/10.1097/00043426-199502000-00004.
51. Schwartz, L., Brister, S., Bourassa, M., Peniston, C., & Buchanan, M. Interobserver Reproducibility and Biological Variability of the Surgicutt II Bleeding Time. Journal of Thrombosis and Thrombolysis, 1998;6:155-158. https://doi.org/10.1023/A:1008861924107.
52. Buchanan, G., & Holtkamp, C. A comparative study of variables affecting the bleeding time using two disposable devices. American journal of clinical pathology, 1989;91: 45-51. https://doi.org/10.1093/AJCP/91.1.45.
53. Khan F, Tritscjler T. Khan S, et.al. Venous thromboembolism. Lancet 2021;398:64-77.
54. Aksu K, Donmez A, Keser G. Inflammation induced thrombosis. Current Pharm Des 2012;18:1478-1493.
55. Mease, Philip, et al. "Incidence of venous and arterial thromboembolic events reported in the tofacitinib rheumatoid arthritis, psoriasis and psoriatic arthritis development programmes and from real-world data."Ann Rheum Dis 2020;79: 1400-1413. https://doi.org/10.1136/annrheumdis-2019-216761
56. Molander V, Bower H, Frisell T, Askling J. Risk of venous venous thromboembolism in rheumatoid arthritis and its association with disease activity. Ann Rheum Dis 2021;80:169-175.
57. Yoshimura M, Fujieda Y, Sugawara M, et.al. Disease activity as a risk factor for venous thromboembolism in rheumatoid arthritis. Rheumatol Int 2022; 42:1939-1946.
58. Smolen JS, Landewé RBM, Bijlsma JWJ, et al. EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis2020;79:685-699.
59. Charles-Schoeman, Christina, et al. "Risk of major adverse cardiovascular events with tofacitinib versus tumour necrosis factor inhibitors in patients with rheumatoid arthritis with or without a history of atherosclerotic cardiovascular disease: a post hoc analysis from ORAL Surveillance."Annals of the rheumatic diseases 2023;82: 119-129. Https://doi.org/10.1136/annrheumdis-2022-222259
60. Ridker P, Everett B, Thuren T, et.al. Anti-inflammatory therapy with canakinubab for atherosclerotic disease. N Engl J Med 2017;377:1119-31.
61. Anderson D, et/al. American Society of Hematology 2019 guidelines for management of venous thromboembolism. Blood 2019;3:3898.
62. Major Extremity Trauma Research Consortium. Aspirin or low-molecular-weight heparin for thromboprophylaxis after a fracture. N Engl J Med 2023;388:203-13.
63. Berry A, Finucane B, Myers S, et.al. Association of supernumerary sex chromosome aneuploidies with venous thromboembolism. JAMA 2023;329:235-243.
64. Castellano J,Pocock S, Bhatt D, et.al. Polypill Strategy in secondary cardiovascular prevention. N Engl J Med 2022; 387:967-977.
65. Viganò, G., Gaspari, F., Locatelli, M., Pusineri, F., Bonati, M., & Remuzzi, G. (1988). Dose-effect and pharmacokinetics of estrogens given to correct bleeding time in uremia. Kidney international, 34 6, 853-8. https://doi.org/10.1038/KI.1988.260.
66. Livio, M., Mannucci, P., Viganò, G., Mingardi, G., Lombardi, R., Mecca, G., & Remuzzi, G. (1986). Conjugated estrogens for the management of bleeding associated with renal failure. New Engl J Med, 1986:315: 731-5.
67. Bauer K, Lip G. Hereditary Thrombophilia Downloaded February 29, 2024.UpToDate
68. ESHRE Capri Workshop Group, S. Eichinger, J.L.H. Evers, A. Glasier, C. La Vecchia, I. Martinelli, S. Skouby, E. Somigliana, D.T. Baird, G. Benagiano, P.G. Crosignani, L. Gianaroli, E. Negri, A. Volpe, A. Glasier, P.G. Crosignani, Venous thromboembolism in women: a specific reproductive health risk, Human Reproduction Update, Volume 19, Issue 5, September/October 2013, Pages 471-482, https://doi.org/10.1093/humupd/dmt028
2. Choi E, Ganeshalingam K, Semb A, et.al. Cardiovascular risk in rheumatoid arthritis: recent advances in the understanding of the pivotal role of inflammation. Rheumatology 2014;53:2143-54.
3. Choi H, Rho Y, ZHU Y, ET.AL. The risk of pulmonary embolism and deep vein thrombosis in rheumatoid arthritis. Ann Rheum Dis 2013;72:1182-1187.
4. Chung W, Peng C, Lin C, et.al. Rheumatoid arthritis increases the risk of deep vein thrombosis and pulmonary thromboembolism. Ann Rheum Dis 2014; 73:1774-1780.
5. Ytterberg S, Bhatt D, Mikuls T, et.al. Cardiovasscular and cancer risk with tofacitinib in rheumatoid arthritis. N Engl J Med 2022;385:316-326. https://doi.org/10.1056/NEJMc2202778.
6. Undas A, Brummel-Ziedins K, Mann K. Antithrombotic properties of aspirin and resistance to aspirin: beyond strictly antiplatelet actions. Blood 2007;109:2285-92 doi:10.1182/blood-2006-01-010645.
7. Aslan J. Platelet proteomes, pathways, and phenotypes as informants of vascular wellness and disease. Arteriosclerosis Thrombosis Vasc Biol 2021;41:999-1011.
8. Awtry E, Loscalzo J. Aspirin. Circulation. 2000;101:1206-1218.
9. Antithrombotic Trialists Collaboration Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324:71-86.
10. Undas A, Undas R, Musiel J, et.al. A low dose of aspirin (75 mg daily) lowers thrombin generation. Blood Coagul Fibrinolysis 2000; 11: 231-234.
11. Grosser T, Fries S, FitzGerald GA. Biological basis for the cardiovascular consequences of COX-1 inhibition: therapeutic challenges and opportunities. J Clin Invest. 2006;116:4-15.
12. Greenberg H, Gottesdiener K, Huntington M, et.al. A new cyclooxyrgenase 2 inhibitor rofecoxib did not alter the anti platelet effects of low-dose aspirin in healthy volunteers. J Clinic Pharmacy 2000;40:1509-15.
13. Lorand L. Factor XIII: structure, activation, and interactions with fibrinogen and fibrin. Ann N Y Acad Sci. 2001;936:291-311.
14. Rayes J, Watson S, Nieswandt B. Functional significance of the platelet immune receptors GPVI and CLEC-2. J Clinic Invest. 2019; 129:12-23.
15. Nieswandt B, Varga-Szabo D, Elvers M. Integrins in platelet activation. J Thromb Haemost. 2009 Jul;7 Suppl 1:206-9. doi: 10.1111/j.1538-7836.2009.03370.x.
16. Karas SP, Rosse WF, Kurlander RJ. Characterization of the IgG-Fc receptor on human platelets. Blood 1982;60: 1277-1282.
17. Pons-Estel G, Guillermo J, Scanzi A et.al. The phospholipid syndrome.Journal of autoimmunity 2017;76: 10-20.
18. Eaton, N., Subramaniam, S., Schulte, M., Drew, C., Jakab, D., Haberichter, S., Weiler, H., & Falet, H. (2020). Bleeding diathesis in mice lacking JAK2 in platelets. Blood advances, 5 15, 2969-2981
https://doi.org/10.1182/blood-2020-138510.
19. Zheng T, Izquierdo I, Reitsma S, et.al. Platelets and tyrosine kinase inhibitors. Am J Physiology 2022.
doi.org/10.1152/ajpcell.00040.2022
20. Parra-Izquierdo I, Melrose A, Pang J, et.al. Janus kinase inhibitors ruxolitinib and baricitinib impair glycoprotein-VI medicated platelet function. Platelets 2021; 33:1-12.
21. Zaleskas, V., Krause, D., Lazarides, K., Patel, N., Hu, Y., Li, S., & Etten, R. (2006). Molecular Pathogenesis and Therapy of Polycythemia Induced in Mice by JAK2 V617F. PLoS ONE, 1.
https://doi.org/10.1371/journal.pone.0000018.
22. Brummett A, Navratil A, Bryan J, etal. Inhibition of JAK3 activity reduced the phosphorylation of cPLA and COX-2 protein levels. Infection and Immunity 2014;82: 970-982.
23. Muthian G, Rainwear H, Johnson C, et.al. Cox-2 inhibitors modulate IL-12 signaling through JAK-STAT pathway leading to TH1 response in experimental allergic encephalomyelitis. J Clinic Immune 2006;26: 73-85.
24. anovic M. Antiplatelet and antithrombotic drugs. In: Frishman WH, Sonnenblick EH, Sica DA, editors. Cardiovascular Pharmaceutics. New York, NY: McGraw Hill; 2003. pp. 259-299.
25. Demers LM, Budin RE, Shaikh BS. The effects of aspirin on megakaryocyte prostaglandin production.Proc Soc Exp Biol Med.1980;163:24-29.
26. Williams S, Fatah K, Hjemdahl P, Blomback M. Better increase in fibrin gel porosity by low-dose than intermediate dose acetylsalicylic acid. Eur Heart J. 1998;19:1666-1672.
27. McNeil JJ, Nelson MR, Woods RL, et al. Effect of aspirin on all-cause mortality in the healthy elderly. N Engl J Med 2018; 379:1519. https://doi.org/10.1056/NEJMoa1803955.
28. Iacoviello L, De Curtis A, D'Adamo MC, et al. Prostacyclin is required for tPA release after venous occlusion. Am J Physiol. 1994;266(2 pt 2):H429-434.
29. Campbell CL, Steinhubl SR. Variability in response to aspirin: do we understand the clinical relevance? J Thromb Haemost. 2005;3:665-669.
30. Mason PJ, Jacobs AK, Freedman JE. Aspirin resistance and atherothrombotic disease. J Am Coll Cardiol. 2005;46:986-993.
31. Sanderson S, Emery J, Baglin T, Kinmonth AL. Narrative review: aspirin resistance and its clinical implications. Ann Intern Med. 2005;142:370-380.
32. Grotemeyer K-H, Scharafinski HW, Husstedt IW. Two-year follow-up of aspirin responder and aspirin non-responder. A pilot study including 180 post-stroke patients. Thromb Res. 1993;71:397-403.
33. Mason P, Jacobs A, Freedman J. J American Coll Cardiology 2005;46:986-93.
34. Dufrost, V., Risse, J., Reshetnyak, T., Satybaldyeva, M., Du, Y., Yan, X., Salta, S., Gerotziafas, G., Jing, Z., Elalamy, I., Wahl, D., & Zuily, S. (2018). Increased risk of thrombosis in antiphospholipid syndrome patients treated with direct oral anticoagulants. Results from an international patient-level data meta-analysis. Autoimmunity reviews, 2018;17: 1011-1021. https://doi.org/10.1016/j.autrev.2018.04.009.
35. Harker L, Slichter S. The bleeding time as a screening test for evaluation of platelet function. NEJM 1972; 287:155-159.
36. Weiss JH, Lages B. Evidence for tissue factor-dependent activation of the classic extrinsic coagulation mechanism in blood obtained from bleeding-time wounds. Blood. 1989;71:629-635.
37. Rodgers, R., & Levin, J. (1990). A critical reappraisal of the bleeding time. Seminars in thrombosis and hemostasis, 16 1, 1-20. https://doi.org/10.1055/S-2007-1002658.
38. Quehennberger P, Handler S, MannhalterC, et.al. Evaluation of a highly specific functional test for the detection of factor V Leiden. International J Clinical Laboratory Research. 2000;30:113-117. https://doi.org/10.1007/S005990070009.
39. Kyrle PA, Westwick J, Scully MF, Kakkar VV, Levis GP. Investigation of the interaction of blood platelets with the coagulation system at the site of plug formation ex vivo in man: effect of low-dose aspirin. Thromb Haemost. 1987;57:62-69.
40. Szczeklik A, Krzanowski M, Gora P, Radwan J. Antiplatelet drugs and generation of thrombin in clotting blood. Blood. 1992;80:2006-2011.
41. Hemker HC, Giesen P, Al Dieri R, et al. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb. 2003;33:4-15.
42. Bender M, May F, Lorenz V, et.al. Combined in vivo depletion of glycoprotein VI and C-type LectinCompromises Hemostasis and abrogates arterial thrombosis in mice. Arteriosclerosis, Thrombosis, and Vascular Biology 2013;33: 926-934.
43. Jirouskova M, She A, Johnson G, et.al. a guide to murine platelet structure, function, assays, and genetics alteration. Journal of Thrombosis and Haemostasis. 2007;5:661-669.
44. De Caterina R, Lanza M, Marca G, et.al. Bleeding time and bleeding. Blood 1994;84: 3363-3370.
45. Mengle-Gaw L, Hubbard R, Karim A, et.al. Review of Cox2 inhibitors and bleeding time. Rheumatology1999; 38: 779-788.
46. Matheson A, Figgitt D. Drugs 2001;61: 833-865.
47. Gels. Update on clinical developments with celecoxib COX-2 inhibitor. Scan J Rheumatol 1999; 28:31-7.
48. Liu J, Li N, Yang J, et.al. The Proceedings of the National Academy of Sciences PNAS 2010;107:17017-22.
49. Mielke, C., Kaneshiro, M., Maher, I., Weiner, J., & Rapaport, S. The standardized normal Ivy bleeding time and its prolongation by aspirin. Blood 1969;34: 204-215. https://doi.org/10.1182/BLOOD.V34.2.204.204.
50. Aversa, L., Vázquez, A., Peñalver, J., Dascal, E., & Bustelo, P. Bleeding Time in Normal Children. Journal of Pediatric Hematology/ Oncology, 1995;17: 25-28. https://doi.org/10.1097/00043426-199502000-00004.
51. Schwartz, L., Brister, S., Bourassa, M., Peniston, C., & Buchanan, M. Interobserver Reproducibility and Biological Variability of the Surgicutt II Bleeding Time. Journal of Thrombosis and Thrombolysis, 1998;6:155-158. https://doi.org/10.1023/A:1008861924107.
52. Buchanan, G., & Holtkamp, C. A comparative study of variables affecting the bleeding time using two disposable devices. American journal of clinical pathology, 1989;91: 45-51. https://doi.org/10.1093/AJCP/91.1.45.
53. Khan F, Tritscjler T. Khan S, et.al. Venous thromboembolism. Lancet 2021;398:64-77.
54. Aksu K, Donmez A, Keser G. Inflammation induced thrombosis. Current Pharm Des 2012;18:1478-1493.
55. Mease, Philip, et al. "Incidence of venous and arterial thromboembolic events reported in the tofacitinib rheumatoid arthritis, psoriasis and psoriatic arthritis development programmes and from real-world data."Ann Rheum Dis 2020;79: 1400-1413. https://doi.org/10.1136/annrheumdis-2019-216761
56. Molander V, Bower H, Frisell T, Askling J. Risk of venous venous thromboembolism in rheumatoid arthritis and its association with disease activity. Ann Rheum Dis 2021;80:169-175.
57. Yoshimura M, Fujieda Y, Sugawara M, et.al. Disease activity as a risk factor for venous thromboembolism in rheumatoid arthritis. Rheumatol Int 2022; 42:1939-1946.
58. Smolen JS, Landewé RBM, Bijlsma JWJ, et al. EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis2020;79:685-699.
59. Charles-Schoeman, Christina, et al. "Risk of major adverse cardiovascular events with tofacitinib versus tumour necrosis factor inhibitors in patients with rheumatoid arthritis with or without a history of atherosclerotic cardiovascular disease: a post hoc analysis from ORAL Surveillance."Annals of the rheumatic diseases 2023;82: 119-129. Https://doi.org/10.1136/annrheumdis-2022-222259
60. Ridker P, Everett B, Thuren T, et.al. Anti-inflammatory therapy with canakinubab for atherosclerotic disease. N Engl J Med 2017;377:1119-31.
61. Anderson D, et/al. American Society of Hematology 2019 guidelines for management of venous thromboembolism. Blood 2019;3:3898.
62. Major Extremity Trauma Research Consortium. Aspirin or low-molecular-weight heparin for thromboprophylaxis after a fracture. N Engl J Med 2023;388:203-13.
63. Berry A, Finucane B, Myers S, et.al. Association of supernumerary sex chromosome aneuploidies with venous thromboembolism. JAMA 2023;329:235-243.
64. Castellano J,Pocock S, Bhatt D, et.al. Polypill Strategy in secondary cardiovascular prevention. N Engl J Med 2022; 387:967-977.
65. Viganò, G., Gaspari, F., Locatelli, M., Pusineri, F., Bonati, M., & Remuzzi, G. (1988). Dose-effect and pharmacokinetics of estrogens given to correct bleeding time in uremia. Kidney international, 34 6, 853-8. https://doi.org/10.1038/KI.1988.260.
66. Livio, M., Mannucci, P., Viganò, G., Mingardi, G., Lombardi, R., Mecca, G., & Remuzzi, G. (1986). Conjugated estrogens for the management of bleeding associated with renal failure. New Engl J Med, 1986:315: 731-5.
67. Bauer K, Lip G. Hereditary Thrombophilia Downloaded February 29, 2024.UpToDate
68. ESHRE Capri Workshop Group, S. Eichinger, J.L.H. Evers, A. Glasier, C. La Vecchia, I. Martinelli, S. Skouby, E. Somigliana, D.T. Baird, G. Benagiano, P.G. Crosignani, L. Gianaroli, E. Negri, A. Volpe, A. Glasier, P.G. Crosignani, Venous thromboembolism in women: a specific reproductive health risk, Human Reproduction Update, Volume 19, Issue 5, September/October 2013, Pages 471-482, https://doi.org/10.1093/humupd/dmt028