Semin Thromb Hemost
DOI: 10.1055/s-0043-1764470
Review Article

A Brief History of Hemostasis and Thrombosis at the Mayo Clinic[*]

Dong Chen
1   Division of Hematopathology, Mayo Clinic, Rochester, Minnesota
Rajiv Pruthi
1   Division of Hematopathology, Mayo Clinic, Rochester, Minnesota
› Author Affiliations


Coagulation is a crucial biological mechanism in human bodies to prevent blood loss. Abnormal coagulation can cause bleeding diathesis or thrombosis, common pathologic conditions in our clinical practice. Many individuals and organizations have dedicated their efforts in the past decades to understanding the biological and pathological mechanisms of coagulation and developing laboratory testing tools and treatment options to help patients with bleeding or thrombotic conditions. Since 1926, the Mayo Clinic coagulation group has made significant contributions to the clinical and laboratory practice, basic and translational research on various hemostatic and thrombotic disorders, and the education and collaboration to share and advance our knowledge in coagulation through a highly integrated team and practice model. We would like to use this review to share our history and inspire medical professionals and trainees to join the efforts to advance our understanding of coagulation pathophysiology and improve our care for patients with coagulation disorders.


We dedicate this manuscript to the pioneers of Mayo Clinic's coagulation group who laid the foundation for the advances in patient care, research, and education in the field of coagulation. They have given us a legacy of excellence and commitment to the highest standards that we strive to uphold. Their courage and dedication to explore the unknown and to make a difference in the lives of the patients they served is an example we aim to follow.

* Dedicated to the pioneers of Mayo Clinic's coagulation group who laid the foundation for the advances in patient care, research, and education in the field of coagulation.

Publication History

Article published online:
20 March 2023

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  • References

  • 1 Rowntree LG, Shionoya T. Experimental extracorporeal thrombosis in vivo. Mayo Clin Proc 1926; 1 (35) 196-197
  • 2 Rowntree LG, Shionoya T. Studies in experimental extracorporeal thrombosis: I. A method for the direct observation of extracorporeal thrombus formation. J Exp Med 1927; 46 (01) 7-12
  • 3 Johnson WR, Shionoya T, Rowntree LG. Studies in experimental extracorporeal thrombosis: Vii. Extracorporeal thrombosis in experimental obstructive jaundice and after the intravenous administration of bile acids. J Exp Med 1928; 48 (06) 871-884
  • 4 Dam H. The antihæmorrhagic vitamin of the chick.: Occurrence and chemical nature. Nature 1935; 135: 652-653
  • 5 Butt H, Snell A. . Vitamin K. Philadelphia: W. B. Saunders Company; 1941
  • 6 Butt HR, Magath TB, Seldon TH. Hypoprothrombinemia; effect of transfusions of blood fortified by administration of vitamin K to donors. Arch Intern Med (Chic) 1948; 81 (02) 131-136
  • 7 Butt H, Allen E, Bollman J. A preparation from spoiled sweet clover [3,3′-methylene-bis-(4-hydroxycoumarin)] which prolongs coagulation and prothrombin time of the blood: preliminary report of experimental and clinical studies. Proc Staff Meet Mayo Clin 1941; 16: 388-395
  • 8 Allen EV, Barker NW, Waugh JM. A PREPARATION FROM SPOILED SWEET CLOVER: [3,3′-Methylene-Bis-(4-Hydroxycoumarin)] Which Prolongs Coagulation and Prothrombin Time of the Blood: A Clinical Study. J Am Med Assoc 1942; 120 (13) 1009-1015
  • 9 Mertz E, Owen C. Imidazole buffer: its use in blood clotting studies. Proc Soc Exp Biol Med 1940; 43 (01) 204-205
  • 10 Owen CA, Bollman JL. Prothrombin conversion factor of dicumarol plasma. Proc Soc Exp Biol Med 1948; 67 (02) 231-234
  • 11 Magath T. Technic of the prothrombin time determination. Am J Clin Pathol Tech Suppl 1939; 3: 187-189
  • 12 Howell W. Condition of the blood in hemophilia, thrombosis and purpura. Arch Intern Med 1941; 13: 76
  • 13 Owen Jr CA. Historical account of tests of hemostasis. Am J Clin Pathol 1990; 93 (4, Suppl 1): S3-S8
  • 14 Owen C, Isaacson J. . Automatic Prothrombin Timer. Patent US. U.S.A.; 1969
  • 15 Hyun BH, Dawson EA, Butcher J, Custer RP. Studies on soybean phosphatide (inosithin) as a platelet substitute. Stability and effective concentrations in the thromboplastin generation test. Am J Clin Pathol 1960; 33: 209-213
  • 16 Frojmovic MM, Panjwani R. Blood cell structure-function studies: light transmission and attenuation coefficients of suspensions of blood cells and model particles at rest and with stirring. J Lab Clin Med 1975; 86 (02) 326-343
  • 17 Maldonado JE. Dysplastic platelets and circulating megakaryocytes in chronic myeloproliferative diseases. II. Ultrastructure of circulating megakaryocytes. Blood 1974; 43 (06) 811-820
  • 18 Maldonado JE. The ultrastructure of the platelets in refractory anemia (“preleukemia”) and myelomonocytic leukemia. Ser Haematol 1975; 8 (01) 101-125
  • 19 Maldonado JE, Gilchrist GS, Brigden LP, Bowie EJ. Ultrastructure of platelets in Bernard-Soulier syndrome. Mayo Clin Proc 1975; 50 (07) 402-406
  • 20 Maldonado JE, Pierre RV. The platelets in preleukemia and myelomonocytic leukemia. Ultrastructural cytochemistry and cytogenetics. Mayo Clin Proc 1975; 50 (10) 573-587
  • 21 Bowie EJ, Owen Jr CA. Some factors influencing platelet retention in glass bead columns including the influence of plastics. Am J Clin Pathol 1971; 56 (04) 479-483
  • 22 Olson JD, Brockway WJ, Fass DN, Magnuson MA, Bowie EJ. Evaluation of ristocetin-Willebrand factor assay and ristocetin-induced platelet aggregation. Am J Clin Pathol 1975; 63 (02) 210-218
  • 23 Heit JA, Minor TA, Andrews JC, Larson DR, Li H, Nichols WL. Determinants of plasma fibrin D-dimer sensitivity for acute pulmonary embolism as defined by pulmonary angiography. Arch Pathol Lab Med 1999; 123 (03) 235-240
  • 24 Gastineau DA, Kazmier FJ, Nichols WL, Bowie EJ. Lupus anticoagulant: an analysis of the clinical and laboratory features of 219 cases. Am J Hematol 1985; 19 (03) 265-275
  • 25 Proven A, Bartlett RP, Moder KG. et al. Clinical importance of positive test results for lupus anticoagulant and anticardiolipin antibodies. Mayo Clin Proc 2004; 79 (04) 467-475
  • 26 Bowie EJ, Thompson Jr JH, Pascuzzi CA, Owen Jr CA. Thrombosis in systemic lupus erythematosus despite circulating anticoagulants. J Lab Clin Med 1963; 62: 416-430
  • 27 Bowie EJ. Lipid-related clotting reactions of clinical significance. Arch Pathol Lab Med 1992; 116 (12) 1345-1349
  • 28 Didisheim P, Bowie EJ, Owen Jr CA. Intravascular coagulation-fibrinolysis (ICF) syndrome and malignancy: historical review and report of two cases with metastatic carcinoid and with acute myelomonocytic leukemia. Thromb Diath Haemorrh Suppl 1969; 36: 215-231
  • 29 Owen Jr CA, Bowie EJ. Intravascular coagulation-fibrinolysis (ICF) syndrome. Ann Clin Lab Sci 1972; 2 (01) 26-30
  • 30 Bowie EJ, Owen Jr CA. Symposium on the diagnosis and treatment of intravascular coagulation-fibrinolysis (ICF) syndrome, with special emphasis on this syndrome in patients with cancer. Introduction. Mayo Clin Proc 1974; 49 (09) 635
  • 31 Kazmier FJ, Bowie EJ, Hagedorn AB, Owen Jr CA. Treatment of intravascular coagulation and fibrinolysis (ICF) syndromes. Mayo Clin Proc 1974; 49 (09) 665-672
  • 32 Bowie EJ, Owen CA. The clinical pathology of intravascular coagulation. Bibl Haematol 1983; ; ( (49) 217-224
  • 33 Machovich R, Owen WG. A factor from endothelium facilitates activation of plasminogen by tissue plasminogen activator. Enzyme 1988; 40 (2-3): 109-112
  • 34 Machovich R, Owen WG. An elastase-dependent pathway of plasminogen activation. Biochemistry 1989; 28 (10) 4517-4522
  • 35 Denson KW, Lurie A, De Cataldo F, Mannucci PM. The factor-X defect: recognition of abnormal forms of factor X. Br J Haematol 1970; 18 (03) 317-327
  • 36 Bajaj SP, Mann KG. Simultaneous purification of bovine prothrombin and factor X. Activation of prothrombin by trypsin-activated factor X. J Biol Chem 1973; 248 (22) 7729-7741
  • 37 Heldebrant CM, Butkowski RJ, Bajaj SP, Mann KG. The activation of prothrombin. II. Partial reactions, physical and chemical characterization of the intermediates of activation. J Biol Chem 1973; 248 (20) 7149-7163
  • 38 Heldebrant CM, Mann KG. The activation of prothrombin. I. Isolation and preliminary characterization of intermediates. J Biol Chem 1973; 248 (10) 3642-3652
  • 39 Heldebrant CM, Noyes C, Kingdon HS, Mann KG. The activation of prothrombin. 3. The partial amino acid sequences at the amino terminal of prothrombin and the intermediates of activation. Biochem Biophys Res Commun 1973; 54 (01) 155-160
  • 40 Mann KG, Bajaj SP, Heldebrant CM, Butkowski RJ, Fass DN. Intermediates of prothrombin activation. Ser Haematol 1973; 6 (04) 479-493
  • 41 Bloom JW, Nesheim ME, Mann KG. A rapid technique for the preparation of factor V deficient plasma. Thromb Res 1979; 15 (5-6): 595-599
  • 42 Nesheim ME, Myrmel KH, Hibbard L, Mann KG. Isolation and characterization of single chain bovine factor V. J Biol Chem 1979; 254 (02) 508-517
  • 43 Mann KG, Nesheim ME, Hibbard LS, Tracy PB. The role of factor V in the assembly of the prothrombinase complex. Ann N Y Acad Sci 1981; 370: 378-388
  • 44 Olson JD, Brockway WJ, Fass DN, Bowie EJ, Mann KG. Purification of porcine and human ristocetin-Willebrand factor. J Lab Clin Med 1977; 89 (06) 1278-1294
  • 45 Fass DN, Knutson GJ, Bowie EJ. Porcine Willebrand factor: a population of multimers. J Lab Clin Med 1978; 91 (02) 307-320
  • 46 Brockway WJ, Fass DN. The nature of the interaction between ristocetin-Willebrand factor VIII coagulant activity molecule. J Lab Clin Med 1977; 89 (06) 1295-1305
  • 47 Fass DN, Knutson GJ, Katzmann JA. Monoclonal antibodies to porcine factor VIII coagulant and their use in the isolation of active coagulant protein. Blood 1982; 59 (03) 594-600
  • 48 Toole JJ, Knopf JL, Wozney JM. et al. Molecular cloning of a cDNA encoding human antihaemophilic factor. Nature 1984; 312 (5992): 342-347
  • 49 Pruthi RK, Daniels TM, Heit JA, Chen D, Owen WG, Nichols WL. Plasma von Willebrand factor multimer quantitative analysis by in-gel immunostaining and infrared fluorescent imaging. Thromb Res 2010; 126 (06) 543-549
  • 50 Blackshear JL, Wysokinska EM, Safford RE. et al. Indexes of von Willebrand factor as biomarkers of aortic stenosis severity (from the Biomarkers of Aortic Stenosis Severity [BASS] study). Am J Cardiol 2013; 111 (03) 374-381
  • 51 Blackshear JL, McRee CW, Safford RE. et al. von Willebrand factor abnormalities and Heyde syndrome in dysfunctional heart valve prostheses. JAMA Cardiol 2016; 1 (02) 198-204
  • 52 Sutor AH, Bowie EJ, Owen Jr CA. Effect of cold on bleeding: hippocrates vindicated. Lancet 1970; 2 (7682): 1084
  • 53 Sutor AH, Bowie EJ, Owen Jr CA. Quantitative bleeding time (hemorrhagometry). A review. Mayo Clin Proc 1977; 52 (04) 238-240
  • 54 Diez-Martin J, Sikkink RA, Gilchrist GS, Bowie EJ, Fass DN. Development of anti-bovine thrombin antibodies following neurosurgical procedures. Br J Haematol 1990; 74 (03) 369-370
  • 55 Gatt A, Chen D, Pruthi RK. et al. From vitamin K antagonists to liver international normalized ratio: a historical journey and critical perspective. Semin Thromb Hemost 2014; 40 (08) 845-851
  • 56 Stoflet ES, Koeberl DD, Sarkar G, Sommer SS. Genomic amplification with transcript sequencing. Science 1988; 239 (4839): 491-494
  • 57 Bottema CD, Ketterling RP, Ii S, Yoon HS, Phillips III JA, Sommer SS. Missense mutations and evolutionary conservation of amino acids: evidence that many of the amino acids in factor IX function as “spacer” elements. Am J Hum Genet 1991; 49 (04) 820-838
  • 58 Sommer SS, Bowie EJ, Ketterling RP, Bottema CD. Missense mutations and the magnitude of functional deficit: the example of factor IX. Hum Genet 1992; 89 (03) 295-297
  • 59 Gostout B, Vielhaber E, Ketterling RP. et al. Germline mutations in the factor IX gene: a comparison of the pattern in Caucasians and non-Caucasians. Hum Mol Genet 1993; 2 (03) 293-298
  • 60 Ketterling RP, Vielhaber EL, Lind TJ, Thorland EC, Sommer SS. The rates and patterns of deletions in the human factor IX gene. Am J Hum Genet 1994; 54 (02) 201-213
  • 61 Heit JA. Venous thromboembolism epidemiology: implications for prevention and management. Semin Thromb Hemost 2002; 28 (Suppl (Suppl. 02) 3-13
  • 62 Heit JA, Silverstein MD, Mohr DN, Petterson TM, O'Fallon WM, Melton III LJ. Predictors of survival after deep vein thrombosis and pulmonary embolism: a population-based, cohort study. Arch Intern Med 1999; 159 (05) 445-453
  • 63 Heit JA, Mohr DN, Silverstein MD, Petterson TM, O'Fallon WM, Melton III LJ. Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-based cohort study. Arch Intern Med 2000; 160 (06) 761-768
  • 64 Heit JA, Silverstein MD, Mohr DN, Petterson TM, O'Fallon WM, Melton III LJ. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med 2000; 160 (06) 809-815
  • 65 Heit JA, Melton III LJ, Lohse CM. et al. Incidence of venous thromboembolism in hospitalized patients vs community residents. Mayo Clin Proc 2001; 76 (11) 1102-1110
  • 66 Heit JA, Armasu SM, McCauley BM. et al. Identification of unique venous thromboembolism-susceptibility variants in African-Americans. Thromb Haemost 2017; 117 (04) 758-768
  • 67 Bick AG, Weinstock JS, Nandakumar SK. et al; NHLBI Trans-Omics for Precision Medicine Consortium. Inherited causes of clonal haematopoiesis in 97,691 whole genomes. Nature 2020; 586 (7831): 763-768
  • 68 Bick AG, Weinstock JS, Nandakumar SK. et al; NHLBI Trans-Omics for Precision Medicine Consortium. Author correction: inherited causes of clonal haematopoiesis in 97,691 whole genomes. Nature 2021; 591 (7851): E27
  • 69 Chen D, Uhl CB, Bryant SC. et al. Diagnostic laboratory standardization and validation of platelet transmission electron microscopy. Platelets 2018; 29 (06) 574-582
  • 70 Karon BS, Tolan NV, Koch CD. et al. Precision and reliability of 5 platelet function tests in healthy volunteers and donors on daily antiplatelet agent therapy. Clin Chem 2014; 60 (12) 1524-1531
  • 71 Markello T, Chen D, Kwan JY. et al. York platelet syndrome is a CRAC channelopathy due to gain-of-function mutations in STIM1. Mol Genet Metab 2015; 114 (03) 474-482
  • 72 Perez Botero J, Im R, Chen D, Patnaik MM. Grey platelet syndrome misdiagnosed as ITP. Br J Haematol 2016; 173 (05) 662
  • 73 DiFilippo EC, Coltro G, Carr RM. et al. Spectrum of abnormalities and clonal transformation in germline RUNX1 familial platelet disorder and a genomic comparative analysis with somatic RUNX1 mutations in MDS/MPN overlap neoplasms. Leukemia 2020; 34 (09) 2519-2524