Investigations on the Hemostatic Potential of Physiological Body Fluids

Abstract

Current blood coagulation models consider the interactions between blood, the vessel wall, and other tissues that expose tissue factor (TF), the main initiator of coagulation. A potential role of body fluids other than blood is generally not considered. In this review, we summarize the evidence that body fluids such as mother's milk saliva, urine, semen, and amniotic fluid trigger coagulation. The ability of these body fluids to trigger coagulation is explained by the presence of extracellular vesicles (EVs). These EVs expose extrinsic tenase complexes (i.e., complexes of TF and activated factor VII) that can trigger coagulation. Why these body fluids share this activity, however, is unknown. Possible explanations are that these body fluids contribute to hemostatic protection and/or to the regulation of the epithelial barrier function. Further investigations may help understand the underlying cellular and biochemical pathways regulating or contributing to coagulation and innate immunity, which may be directly relevant to medical conditions such as gastrointestinal bleeding and chronic inflammatory bowel disease.

Keywords

tissue factor - factor VIIa - extracellular vesicles - physiological body fluids

Publikationsverlauf

Eingereicht: 11. Juli 2024

Angenommen: 05. August 2024

Artikel online veröffentlicht:
23. Oktober 2024

• References

• 1 Versteeg HH, Heemskerk JW, Levi M, Reitsma PH. New fundamentals in hemostasis. Physiol Rev 2013; 93 (01) 327-358
• 2 Spronk HM, Govers-Riemslag JW, ten Cate H. The blood coagulation system as a molecular machine. BioEssays 2003; 25 (12) 1220-1228
• 3 Furie B, Furie BC. The molecular basis of blood coagulation. Cell 1988; 53 (04) 505-518
• 4 Ikkala E, Helske T, Myllylä G, Nevanlinna HR, Pitkänen P, Rasi V. Changes in the life expectancy of patients with severe haemophilia A in Finland in 1930-79. Br J Haematol 1982; 52 (01) 7-12
• 5 Pool JG, Shannon AE. Production of high-potency concentrates of antihemophilic globulin in a closed-bag system. N Engl J Med 1965; 273 (27) 1443-1447
• 6 Solé A. Die Muttermilch als Blutstillungsmittel. Klin Wochenschr 1935; 38: 1354-1359
• 7 Kraszewski W, Lindenfeld L. Über Blutgerinnungsfördernde Eigenschaften von Muttermilch. Wien Klin Wochenschr 1936; 24: 863-864
• 8 Gonmori H, Takeda Y. Properties of human tissue thromboplastins from brain, lung, arteries, and placenta. Thromb Haemost 1976; 36 (01) 90-103
• 9 Smith SA, Comp PC, Morrissey JH. Phospholipid composition controls thromboplastin sensitivity to individual clotting factors. J Thromb Haemost 2006; 4 (04) 820-827
• 10 Glanzmann E. Einführung in die Kinderheilkunde. Springer Verlag Wien; 1934
• 11 Hess MW. Über die Gerinnungsaktivität der Frauenmilch. Blut 1961; 7: 211-213
• 12 Hu Y, Hell L, Kendlbacher RA. et al. Human milk triggers coagulation via tissue factor-exposing extracellular vesicles. Blood Adv 2020; 4 (24) 6274-6282
• 13 Hu Y, Repa A, Lisman T. et al. Extracellular vesicles from amniotic fluid, milk, saliva, and urine expose complexes of tissue factor and activated factor VII. J Thromb Haemost 2022; 20 (10) 2306-2312
• 14 Sutor AH. Vitamin K deficiency bleeding in infants and children. Semin Thromb Hemost 1995; 21 (03) 317-329
• 15 Humphrey SP, Williamson RT. A review of saliva: normal composition, flow, and function. J Prosthet Dent 2001; 85 (02) 162-169
• 16 Hunter JB. The action of saliva and gastric juice on the clotting of blood. Br J Surg 1928; 16 (62) 203-207
• 17 Bellis CJ, Birnbaum W, Scott FH. Effect of saliva on coagulation of the blood. Proc Soc Exp Biol Med 1932; 29 (09) 1107-1108
• 18 Bellis CJ, Scott FH. Saliva and coagulation of blood. Proc Soc Exp Biol Med 1933; 30 (09) 1373-1375
• 19 Glazko AJ, Greenberg DM. The mechanism of the action of saliva in blood coagulation. Am J Physiol 1939; 125 (01) 108-112
• 20 Nour-Eldin F, Wilkinson JF. The blood clotting factors in human saliva. J Physiol 1957; 136 (02) 324-332
• 21 Whitcomb DC, Lowe ME. Human pancreatic digestive enzymes. Dig Dis Sci 2007; 52 (01) 1-17
• 22 Douglas SR, Colebrook L. On the advantage of using a broth containing trypsin in making blood cultures. Lancet 1916; 188: 180-183
• 23 Eagle H, Harris TN. Studies in blood coagulation: V. The coagulation of blood by proteolytic enzymes (Trypsin, Papain). J Gen Physiol 1937; 20 (04) 543-560
• 24 Kisiel W, Hanahan DJ. The action of factor Xa, thrombin and trypsin on human factor II. Biochim Biophys Acta 1973; 329 (02) 221-232
• 25 Esteller A. Physiology of bile secretion. World J Gastroenterol 2008; 14 (37) 5641-5649
• 26 Chung SC, Kim YC, Hong SK, Lee PH. Effect of bile on the blood coagulation. Yonsei Med J 1964; 5: 24-28
• 27 Engel AM, Alexander B. The effects of bile salts on some coagulation components and related enzymes. Thromb Diath Haemorrh 1972; 27 (03) 594-609
• 28 Moore Jr JE, Bertram CD. Lymphatic system flows. Annu Rev Fluid Mech 2018; 50: 459-482
• 29 Miller GJ, Howarth DJ, Attfield JC. et al. Haemostatic factors in human peripheral afferent lymph. Thromb Haemost 2000; 83 (03) 427-432
• 30 Zhang W, Li J, Liang J, Qi X, Tian J, Liu J. Coagulation in lymphatic system. Front Cardiovasc Med 2021; 8: 762648
• 31 Sands JM, Layton HE. The physiology of urinary concentration: an update. Semin Nephrol 2009; 29 (03) 178-195
• 32 Grunke W. Studien über die Blutgerinnung mit besonderer Berücksichtigung der Hämophilie. Z Gesamte Exp Med 1935; 96: 512-516
• 33 Thaler J, Samadi N, Kraemmer D. et al. Saliva and urine from persons with hemophilia A trigger coagulation bypassing factor VIII. Hamostaseologie 2023; 43: 13-27
• 34 Tocantins LM, Lindquist JN. Thromboplastic activity of the urine. Proc Soc Exp Biol Med 1947; 65 (01) 44-49
• 35 Howell WH. The nature and action of the thromboplastic (zymoplastic) substance of the tissues. Am J Physiol 1912; 31 (01) 1-21
• 36 Vonkaulla KN, Vonkaulla E. Inactivation of pathological inhibitors of intrinsic thromboplastin by procoagulant from human urine. Acta Haematol 1963; 30: 25-34
• 37 Tiede A, Collins P, Knoebl P. et al. International recommendations on the diagnosis and treatment of acquired hemophilia A. Haematologica 2020; 105 (07) 1791-1801
• 38 Wiggins R, Glatfelter A, Kshirsagar B, Beals T. Lipid microvesicles and their association with procoagulant activity in urine and glomeruli of rabbits with nephrotoxic nephritis. Lab Invest 1987; 56 (03) 264-272
• 39 Théry C, Witwer KW, Aikawa E. et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles 2018; 7 (01) 1535750
• 40 Carty N, Taylor I, Roath OS, el-Baruni K, Francis JL. Urinary tissue factor activity in colorectal disease. Br J Surg 1990; 77 (10) 1091-1094
• 41 Carty N, Taylor I, Roath OS, el-Baruni K, Francis JL. Urinary tissue factor activity in malignancy. Thromb Res 1990; 57 (03) 473-478
• 42 Lwaleed BA, Bass PS, Francis JL, Chisholm M. Functional and structural properties of urinary tissue factor. Nephrol Dial Transplant 1999; 14 (03) 588-596
• 43 Lwaleed BA, Francis JL, Chisholm M. Urinary tissue factor levels in patients with bladder and prostate cancer. Eur J Surg Oncol 2000; 26 (01) 44-49
• 44 Definition of tear. Accessed May 9, 2024 at: www.merriam-webster.com
• 45 Liu H, Yuan W, Pang Q, Xue C, Yan X. Single-particle analysis of tear fluid reveals abundant presence of tissue factor-exposing extracellular vesicles with strong coagulation activity. Talanta 2022; 239: 123089
• 46 Wilkins RH, Smith W, Anlyan WG, Hetherington DC, Woodhall B. The effects of normal cerebrospinal fluid on blood clotting and fibroblast growth. J Surg Res 1961; 1: 260-266
• 47 Niewiarowski S, Hausmanowa-Petrusewicz I, Wegrzynowicz Z. Blood clotting factors in cerebrospinal fluid. J Clin Pathol 1962; 15 (06) 497-500
• 48 Tutuarima JA, Hische EA, van Trotsenburg L, van der Helm HJ. Thromboplastic activity of cerebrospinal fluid in neurological disease. Clin Chem 1985; 31 (01) 99-100
• 49 Owen DH, Katz DF. A review of the physical and chemical properties of human semen and the formulation of a semen simulant. J Androl 2005; 26 (04) 459-469
• 50 Huggins C, Neal W. Coagulation and liquefaction of semen: proteolytic enzymes and citrate in prostatic fluid. J Exp Med 1942; 76 (06) 527-541
• 51 Fernández JA, Heeb MJ, Radtke KP, Griffin JH. Potent blood coagulant activity of human semen due to prostasome-bound tissue factor. Biol Reprod 1997; 56 (03) 757-763
• 52 Brody I, Ronquist G, Gottfries A. Ultrastructural localization of the prostasome - an organelle in human seminal plasma. Ups J Med Sci 1983; 88 (02) 63-80
• 53 Carson SD, De Jonge CJ. Activation of coagulation factor X in human semen. J Androl 1998; 19 (03) 289-294
• 54 Lwaleed BA, Goyal A, Delves G, Gossai S, Greenfield RS, Cooper AJ. Seminal factor VII and factor VIIa: supporting evidence for the presence of an active tissue factor-dependent coagulation pathway in human semen. Int J Androl 2007; 30 (06) 543-549
• 55 Rodgers RJ, Irving-Rodgers HF. Formation of the ovarian follicular antrum and follicular fluid. Biol Reprod 2010; 82 (06) 1021-1029
• 56 Gentry PA, Plante L, Schroeder MO, LaMarre J, Young JE, Dodds WG. Human ovarian follicular fluid has functional systems for the generation and modulation of thrombin. Fertil Steril 2000; 73 (04) 848-854
• 57 Franz C, Böing AN, Montag M. et al. Extracellular vesicles in human follicular fluid do not promote coagulation. Reprod Biomed Online 2016; 33 (05) 652-655
• 58 Fitzsimmons ED, Bajaj T. Embryology, Amniotic Fluid. StatPearls; 2024
• 59 Meyer J. Embolia pulmonar amnio caseosa. Bras Med 1926; 40: 301-303
• 60 Oda T, Tamura N, Ide R. et al. Consumptive coagulopathy involving amniotic fluid embolism: the importance of earlier assessments for interventions in critical care. Crit Care Med 2020; 48 (12) e1251-e1259
• 61 Weiner AE, Reid DE, Roby CC. The hemostatic activity of amniotic fluid. Science 1949; 110 (2851): 190-191
• 62 Phillips LL, Davidson Jr EC. Procoagulant properties of amniotic fluid. Am J Obstet Gynecol 1972; 113 (07) 911-919
• 63 Lockwood CJ, Bach R, Guha A, Zhou XD, Miller WA, Nemerson Y. Amniotic fluid contains tissue factor, a potent initiator of coagulation. Am J Obstet Gynecol 1991; 165 (5, Pt 1): 1335-1341
• 64 Hell L, Wisgrill L, Ay C. et al. Procoagulant extracellular vesicles in amniotic fluid. Transl Res 2017; 184: 12-20.e1
• 65 Hu Y, Scharrer A, Hau C. et al. Coagulation signaling from amniotic fluid to fetal skin. Blood Adv 2022; 6 (19) 5538-5541
• 66 Diz-Küçükkaya R. Inherited platelet disorders including Glanzmann thrombasthenia and Bernard-Soulier syndrome. Hematology (Am Soc Hematol Educ Program) 2013; 2013: 268-275
• 67 Wiggins RC, Glatfelter A, Kshirsagar B, Brukman J. Procoagulant activity in normal human urine associated with subcellular particles. Kidney Int 1986; 29 (02) 591-597
• 68 Day BJ. The science of licking your wounds: function of oxidants in the innate immune system. Biochem Pharmacol 2019; 163: 451-457
• 69 Yiee JH, Baskin LS. Penile embryology and anatomy. ScientificWorldJournal 2010; 10: 1174-1179
• 70 Lwaleed BA, Goyal A, Delves GH, Cooper AJ. Seminal hemostatic factors: then and now. Semin Thromb Hemost 2007; 33 (01) 3-12
• 71 Anamthathmakula P, Winuthayanon W. Mechanism of semen liquefaction and its potential for a novel non-hormonal contraception. Biol Reprod 2020; 103 (02) 411-426
• 72 Le Gall SM, Szabo R, Lee M. et al. Matriptase activation connects tissue factor-dependent coagulation initiation to epithelial proteolysis and signaling. Blood 2016; 127 (25) 3260-3269
• 73 Kondreddy V, Wang J, Keshava S, Esmon CT, Rao LVM, Pendurthi UR. Factor VIIa induces anti-inflammatory signaling via EPCR and PAR1. Blood 2018; 131 (21) 2379-2392
• 74 Kondreddy V, Pendurthi UR, Xu X, Griffin JH, Rao LVM. FVIIa (Factor VIIa) induces biased cytoprotective signaling in mice through the cleavage of PAR (protease-activated receptor)-1 at canonical Arg41 (Arginine41) site. Arterioscler Thromb Vasc Biol 2020; 40 (05) 1275-1288
• 75 Fonseka P, Marzan AL, Mathivanan S. Introduction to the community of extracellular vesicles. Subcell Biochem 2021; 97: 3-18
• 76 van der Pol E, Böing AN, Gool EL, Nieuwland R. Recent developments in the nomenclature, presence, isolation, detection and clinical impact of extracellular vesicles. J Thromb Haemost 2016; 14 (01) 48-56
• 77 Yeshi K, Ruscher R, Hunter L, Daly NL, Loukas A, Wangchuk P. Revisiting inflammatory bowel disease: pathology, treatments, challenges and emerging therapeutics including drug leads from natural products. J Clin Med 2020; 9 (05) 1273
• 78 Telofski LS, Morello III AP, Mack Correa MC, Stamatas GN. The infant skin barrier: can we preserve, protect, and enhance the barrier?. Dermatol Res Pract 2012; 2012: 198789
• 79 Patchett SE, O'Donoghue DP. Pharmacological manipulation of gastric juice: thrombelastographic assessment and implications for treatment of gastrointestinal haemorrhage. Gut 1995; 36 (03) 358-362
• 80 Vandersteene J, Baert E, Planckaert GMJ. et al. The influence of cerebrospinal fluid on blood coagulation and the implications for ventriculovenous shunting. J Neurosurg 2018; 130 (04) 1244-1251