Reviews
Vol. 5 No. 2 (2026)
Bleeding complications of oral anticoagulant therapy: from ISCOAT to the START Register
A memory of Gualtiero Palareti
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Published: 10 April 2026
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On December 12, 2025, I had the honor of delivering a special lecture titled Bleeding Complications of Oral Anticoagulant Therapy: From ISCOAT to the START Register at the 20th Meeting on Bleeding and Thrombosis Care in Castellammare di Stabia, Naples (Italy). This lecture was dedicated to Gualtiero Palareti from Bologna, who sadly passed away on August 8 of the same year. Speaking at this event was a privilege, as Gualtiero was a remarkable figure in hemostasis and thrombosis, both in Italy and internationally. He was also an invaluable teacher to many of us. I took this opportunity to honor his legacy and reflect on his contributions over the past 36 years. In my lecture, I provided a brief history of anticoagulants that underpinned Gualtiero’s work, along with a general overview of the field. Additionally, I shared my personal observations on the Italian Federation of Anticoagulation Clinic and discussed studies conducted by ISCOAT (Italian Study on the Complications of Oral Anticoagulant Therapy) and the START Register, in which Gualtiero Palareti played a pivotal role.
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1. Schofield FW. Hemorrhagic sweet clover disease in cattle. Can Vet Rec 1922;3:74-5.
2. Roderick LM. The pathology of sweet clover disease in cattle. J Am Vet Med Assoc 1929;74:314-25.
3. Campbell HA, Roberts WL, Smith WK, et al. Studies on the hemorrhagic sweet clover disease. I. The preparation of hemorrhagic concentrates. J Biol Chem 1940;136:47-55. DOI: https://doi.org/10.1016/S0021-9258(18)73076-7
4. Bingham JB, Meyer OO, Pohile FJ. Studies on the hemorrhagic agent 3,3’-methylene-bis(4-hydroxycoumarin). I. Its effect on the prothrombin and coagulation time of the blood of dogs and humans. Am J Med Sci 1941;202:563-78. DOI: https://doi.org/10.1097/00000441-194110000-00009
5. Stenflo J, Fernlund P, Egan W, et al. Vitamin K-dependent modifications of glutamic acid residues in prothrombin. Proc Natl Acad Sci U S A 1974;71:2730-3. DOI: https://doi.org/10.1073/pnas.71.7.2730
6. Zweifler AJ, Coon WW, Willis PW 3rd. Bleeding during oral anticoagulant therapy. Am Heart J 1966;71:118-23. DOI: https://doi.org/10.1016/0002-8703(66)90665-X
7. Jacques LB. Spontaneous hemorrhage with anticoagulants. Circulation 1962;25:130-9. DOI: https://doi.org/10.1161/01.CIR.25.1.130
8. Zucker HD. Clinical experiences with dicumarol. Report of eighteen cases. JAMA 1944;124:217-20. DOI: https://doi.org/10.1001/jama.1944.02850040017004
9. Allen EV. The clinical use of anticoagulants. JAMA 1947;134:323-9. DOI: https://doi.org/10.1001/jama.1947.02880210001001
10. Reyers I, de Gaetano G, Donati MB. Prolongation by warfarin of “template” bleeding time in rats: a vitamin K-dependent effect. Proc Soc Exp Biol Med 1986;181:275-6. DOI: https://doi.org/10.3181/00379727-181-42253
11. Marongiu F, Biondi G, Sorano GG, et al. Bleeding time is prolonged during oral anticoagulant therapy. Thromb Res 1990;59:905-12. DOI: https://doi.org/10.1016/0049-3848(90)90114-R
12. Vermeer C, Hendrix H, Daemen M. Vitamin K-dependent carboxylases from non-hepatic tissues. FEBS Lett 1982;148:317-20. DOI: https://doi.org/10.1016/0014-5793(82)80832-6
13. Forfar JC. A 7-year analysis of haemorrhage in patients on long-term anticoagulant treatment. Br Heart J 1979;43:128-32. DOI: https://doi.org/10.1136/hrt.42.2.128
14. Verstraete M, Clark PA, Wright IS. Use of different tissue thromboplastins in the control of anticoagulant therapy. Circulation 1957;16:213-26. DOI: https://doi.org/10.1161/01.CIR.16.2.213
15. Rodman T, Pastor BH, Hoxter BL. A comparison of laboratory methods for the control of anticoagulant therapy with prothrombinopenic agents. II. Problems encountered in the laboratory control of anticoagulant therapy with one-stage determination of prothrombin complex activity. Am J Med 1961;31:555-63. DOI: https://doi.org/10.1016/0002-9343(61)90139-5
16. Poller L. The British comparative thromboplastin: the use of the national thromboplastin reagent for uniformity of laboratory control of oral anticoagulants and expression of results. Assoc Clin Pathol Broadsheet 1970;(No. ?).
17. Poller L. Oral anticoagulants reassessed. Br Med J (Clin Res Ed) 1982;284:1425-6. DOI: https://doi.org/10.1136/bmj.284.6327.1425
18. Kirkwood TB. Calibration of reference thromboplastins and standardisation of the prothrombin time ratio. Thromb Haemost 1983;49:238-44. DOI: https://doi.org/10.1055/s-0038-1657371
19. Poller L. Therapeutic ranges in anticoagulant administration. Br Med J (Clin Res Ed) 1985;290:1683-6. DOI: https://doi.org/10.1136/bmj.290.6483.1683
20. Petitti DB, Strom BL, Melmon KL. Duration of warfarin anticoagulant therapy and the probabilities of recurrent thromboembolism and hemorrhage. Am J Med 1986;81:255-9. DOI: https://doi.org/10.1016/0002-9343(86)90260-3
21. Gurwitz JH, Goldberg RJ, Holden A, et al. Age-related risks of long-term oral anticoagulant therapy. Arch Intern Med 1988;148:1733-6. DOI: https://doi.org/10.1001/archinte.1988.00380080037012
22. Petty GW, Lennihan L, Mohr JP, et al. Complications of long-term anticoagulation. Ann Neurol 1988;23:570-4. DOI: https://doi.org/10.1002/ana.410230607
23. Bussey HI, Rospond RM, Quandt CM, et al. The safety and effectiveness of long-term warfarin therapy in an anticoagulation clinic. Pharmacotherapy 1989;9:214-9. DOI: https://doi.org/10.1002/j.1875-9114.1989.tb04128.x
24. Landefeld CS, Goldman L. Major bleeding in outpatients treated with warfarin: incidence and prediction by factors known at the start of outpatient therapy. Am J Med 1989;87:144-52. DOI: https://doi.org/10.1016/S0002-9343(89)80689-8
25. Launbjerg J, Egeblad H, Heaf J, et al. Bleeding complications to oral anticoagulant therapy: multivariate analysis of 1010 treatment years in 551 outpatients. J Intern Med 1991;229:351-5. DOI: https://doi.org/10.1111/j.1365-2796.1991.tb00358.x
26. Fihn SD, McDonell M, Martin D, et al. Risk factors for complications of chronic anticoagulation. A multicenter study. Warfarin Optimized Outpatient Follow-up Study Group. Ann Intern Med 1993;118:511-20. DOI: https://doi.org/10.7326/0003-4819-118-7-199304010-00005
27. Palareti G, Leali N, Coccheri S, et al. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Italian Study on Complications of Oral Anticoagulant Therapy. Lancet 1996;348:423-8. DOI: https://doi.org/10.1016/S0140-6736(96)01109-9
28. Mariani G, Manotti C, Dettori AG. A computerized regulation of dosage in oral anticoagulant therapy. Res Clin Lab 1990;20:119-25. DOI: https://doi.org/10.1007/BF02877558
29. Palareti G, Coccheri S, Poggi M, et al. Oral anticoagulant therapy control: evidence that INR expression improves the inter-laboratory comparability of results: the Bologna oral anticoagulant control exercise. Thromb Haemost 1987;58:905-10. DOI: https://doi.org/10.1055/s-0038-1646013
30. Palareti G, Hirsh J, Legnani C, et al. Oral anticoagulation treatment in the elderly: a nested, prospective, case-control study. Arch Intern Med 2000;160:470-8. DOI: https://doi.org/10.1001/archinte.160.4.470
31. Poli D, Antonucci E, Testa S, et al. Bleeding risk in very old patients on vitamin K antagonist treatment: results of a prospective collaborative study on elderly patients followed by Italian Centres for Anticoagulation. Circulation 2011;124:824-9. DOI: https://doi.org/10.1161/CIRCULATIONAHA.110.007864
32. Ansell J. Bleeding in very old patients on vitamin K antagonist therapy. Circulation 2011;124:769-71. DOI: https://doi.org/10.1161/CIRCULATIONAHA.111.043935
33. Williams PL, Williams JP, Williams BR. The fine line of defensive medicine. J Forensic Leg Med 2021;80:102170. DOI: https://doi.org/10.1016/j.jflm.2021.102170
34. Poli D, Antonucci E, Dentali F, et al; Italian Federation of Anticoagulation Clinics (FCSA). Recurrence of ICH after resumption of anticoagulation with VK antagonists: CHIRONE study. Neurology 2014;82:1020-6. DOI: https://doi.org/10.1212/WNL.0000000000000245
35. Marongiu F, Barcellona D. The future of anticoagulation clinics: a journey to thrombosis centers? Haematologica 2005;90:298-301.
36. Eriksson UG, Bredberg U, Hoffmann KJ, et al. Absorption, distribution, metabolism, and excretion of ximelagatran, an oral direct thrombin inhibitor, in rats, dogs, and humans. Drug Metab Dispos 2003;31:294-305. DOI: https://doi.org/10.1124/dmd.31.3.294
37. Albers GW; SPORTIF Investigators. Stroke prevention in atrial fibrillation: pooled analysis of SPORTIF III and V trials. Am J Manag Care 2004;10(14 Suppl):S462-9.
38. Keisu M, Andersson TB. Drug-induced liver injury in humans: the case of ximelagatran. Handb Exp Pharmacol 2010;196:407-18. DOI: https://doi.org/10.1007/978-3-642-00663-0_13
39. Pengo V, Crippa L, Falanga A, et al. Phase III studies on novel oral anticoagulants for stroke prevention in atrial fibrillation: a look beyond the excellent results. J Thromb Haemost 2012;10:1979-87. DOI: https://doi.org/10.1111/j.1538-7836.2012.04866.x
40. Dogliotti A, Paolasso E, Giugliano RP. Novel oral anticoagulants in atrial fibrillation: a meta-analysis of large, randomized, controlled trials vs warfarin. Clin Cardiol 2013;36:61-7. DOI: https://doi.org/10.1002/clc.22081
41. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomized trials. Lancet 2014;383:955-62. DOI: https://doi.org/10.1016/S0140-6736(13)62343-0
42. Palareti G, Antonucci E, Migliaccio L, et al; Centers participating in the FCSA-START-Register (The ISCOAT 2016 study: Italian Study on Complications of Oral Anticoagulant Therapy-2016). Vitamin K antagonist therapy: changes in the treated populations and in management results in Italian anticoagulation clinics compared with those recorded 20 years ago. Intern Emerg Med 2017;12:1109-19. DOI: https://doi.org/10.1007/s11739-017-1678-9
43. Schafer A, Flierl U, Berliner D, et al. Anticoagulants for stroke prevention in atrial fibrillation in elderly patients. Cardiovasc Drugs Ther 2020;34:555-68. DOI: https://doi.org/10.1007/s10557-020-06981-3
44. Wallentin L, Yusuf S, Ezekowitz MD, et al. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalized ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet 2010;376:975-83. DOI: https://doi.org/10.1016/S0140-6736(10)61194-4
45. Antonucci E, Poli D, Tosetto A, et al; START-Register. Survey on anTicoagulated pAtients RegisTer. The Italian START-Register on anticoagulation with focus on atrial fibrillation. PLoS One 2015;10:e0124719. DOI: https://doi.org/10.1371/journal.pone.0124719
46. Testa S, Ageno W, Antonucci E, et al. Management of major bleeding and outcomes in patients treated with direct oral anticoagulants: results from the START-Event registry. Intern Emerg Med 2018;13:1051-8. DOI: https://doi.org/10.1007/s11739-018-1877-z
47. Poli D, Antonucci E, Ageno W, et al. Oral anticoagulation in very elderly patients with atrial fibrillation: results from the prospective multicenter START2-REGISTER study. PLoS One 2019;14:e0216831. DOI: https://doi.org/10.1371/journal.pone.0216831
48. Snyder Sulmasy L, Weinberger SE. Better care is the best defense: high-value clinical practice vs defensive medicine. Cleve Clin J Med 2014;81:464-7. DOI: https://doi.org/10.3949/ccjm.81a.14037
49. Palareti G, Antonucci E, Legnani C, et al. Bleeding and thrombotic complications during treatment with direct oral anticoagulants or vitamin K antagonists in venous thromboembolic patients included in the prospective, observational START2-register. BMJ Open 2020;10:e040449. DOI: https://doi.org/10.1136/bmjopen-2020-040449
50. Palareti G, Legnani C, Antonucci E, et al. Do women with venous thromboembolism bleed more than men during anticoagulation? Data from the real-life, prospective START-Register. Ther Adv Drug Saf 2021;12:20420986211062965. DOI: https://doi.org/10.1177/20420986211062965
51. Grandone E, Mastroianno M, Pacilli G, et al. Blood loss in women of childbearing potential taking oral anticoagulants for venous thromboembolism (the BLEED Study). Thromb Haemost 2025;125:523-32. DOI: https://doi.org/10.1055/a-2461-6822
52. Thompson LE, Maddox TM, Lei L, et al. Sex differences in the use of oral anticoagulants for atrial fibrillation: a report from the National Cardiovascular Data Registry (NCDR) PINNACLE Registry. J Am Heart Assoc 2017;6:e005801. DOI: https://doi.org/10.1161/JAHA.117.005801
53. Marongiu F, Grandone E, Marongiu S, et al. Stroke in women: anticoagulation in a complicated puzzle. Bleeding Thromb Vasc Biol 2024;3:137. DOI: https://doi.org/10.4081/btvb.2024.137
54. Palareti G, Testa S, Legnani C, et al. More early bleeds associated with high baseline direct oral anticoagulant levels in atrial fibrillation: the MAS study. Blood Adv 2024;8:4913-23. DOI: https://doi.org/10.1182/bloodadvances.2024013126
55. Tripodi A. Direct oral anticoagulants: does one dose fit all? Why, when and how testing. Bleeding Thromb Vasc Biol 2026;5:418. DOI: https://doi.org/10.4081/btvb.2026.418
56. Cohen AT, Goto S, Schreiber K, et al. Why do we need observational studies of everyday patients in the real-life setting? Eur Heart J Suppl 2015;17:D2-8. DOI: https://doi.org/10.1093/eurheartj/suv035
57. Marongiu F, Mameli A, Marongiu S, et al. Anticoagulants: evidence-based medicine, not always ethical. Semin Thromb Hemost 2025 Oct 23. doi:10.1055/a-2716-5675. Epub ahead of print. DOI: https://doi.org/10.1055/a-2716-5675
58. Piazza G, Grandone E. Thrombophilia, antithrombotic therapy, and recurrent pregnancy loss: a call for pragmatism in the face of unknowns. Semin Reprod Med 2021;39:167-76. DOI: https://doi.org/10.1055/s-0041-1735628
59. Concato J, Shah N, Horwitz RI. Randomized, controlled trials, observational studies, and the hierarchy of research designs. N Engl J Med 2000;342:1887-92. DOI: https://doi.org/10.1056/NEJM200006223422507
60. Benson K, Hartz AJ. A comparison of observational studies and randomized, controlled trials. N Engl J Med 2000;342:1878-86. DOI: https://doi.org/10.1056/NEJM200006223422506
How to Cite
1.
Marongiu F. Bleeding complications of oral anticoagulant therapy: from ISCOAT to the START Register: A memory of Gualtiero Palareti. Bleeding Thromb Vasc Biol [Internet]. 2026 Apr. 10 [cited 2026 May 6];5(2). Available from: https://www.btvb.org/btvb/article/view/457
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