Hemostatic Manifestations of Invasive Fungal Infections: A Comprehensive Review of Pathophysiological Mechanisms in Sepsis-Induced Hemostatic Disturbances, with a Focus on the Neonatal Population

Abstract

Sepsis is a life-threatening condition that has challenged many clinicians over the years. The immune and hemostatic systems are the primary pillars of sepsis pathogenesis. Dysregulation of these intricate mechanisms significantly worsens the prognosis. Coagulopathy is a critical aspect of sepsis, with the degree of hemostatic impairment being a key determinant of poor outcomes. Although the concept of sepsis caused by bacteria has been well investigated, the fungal impact in the complexity of sepsis-related hemostatic derangement is not yet fully unraveled. In addition, sepsis occurs in patients across all age groups, with a particular concern for neonates, whose immature and vulnerable systems amplify the challenges. Notably, despite the high incidence of fungal septicemia in neonatal intensive care units (NICUs), along with its significant morbidity, mortality, and adverse neonatal outcomes, the impact of fungal sepsis on the neonatal hemostatic system—an essential determinant of prognosis—remains largely unexplored. The present review delves into the pathophysiologic mechanisms of sepsis-induced coagulopathy attributed to fungal infection, the mechanisms of fungal involvement in the hemostatic derangement, and attempts to contextualize this knowledge within the unique neonatal population. Finally, it aims to raise awareness of the critical need for a deep understanding of this hazardous condition to guide the development of optimal therapeutic strategies.

Keywords

hemostasis - fungal infections - platelets - sepsis-induced coagulopathy - neonates

Publikationsverlauf

Eingereicht: 29. Dezember 2024

Angenommen: 21. März 2025

Accepted Manuscript online:
24. März 2025

Artikel online veröffentlicht:
17. April 2025

• References

• 1 Singer M, Deutschman CS, Seymour CW. et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315 (08) 801-810
• 2 Maneta E, Aivalioti E, Tual-Chalot S. et al. Endothelial dysfunction and immunothrombosis in sepsis. Front Immunol 2023; 14: 1144229
• 3 Denning DW. Global incidence and mortality of severe fungal disease. Lancet Infect Dis 2024; 24 (07) e428-e438
• 4 Cecconi M, Evans L, Levy M, Rhodes A. Sepsis and septic shock. Lancet 2018; 392 (10141): 75-87
• 5 Kaufman D, Fairchild KD. Clinical microbiology of bacterial and fungal sepsis in very-low-birth-weight infants. Clin Microbiol Rev 2004; 17 (03) 638-680 table of contents
• 6 Tsantes AG, Parastatidou S, Tsantes EA. et al. Sepsis-induced coagulopathy: an update on pathophysiology, biomarkers, and current guidelines. Life (Basel) 2023; 13 (02) 350
• 7 Iba T, Helms J, Levy JH. Sepsis-induced coagulopathy (SIC) in the management of sepsis. Ann Intensive Care 2024; 14 (01) 148
• 8 Strausbaugh LJ. Hematologic manifestations of bacterial and fungal infections. Hematol Oncol Clin North Am 1987; 1 (02) 185-206
• 9 Sokou R, Palioura AE, Kopanou Taliaka P. et al. Candida auris infection, a rapidly emerging threat in the neonatal intensive care units: a systematic review. J Clin Med 2024; 13 (06) 1586
• 10 Sokou RPalioura AE. , Konstantinidi A, et al. The role of rotational thromboelastometry in early detection of the hemostatic derangements in neonates with systemic Candida infection. J Fungi (Basel) 2024; 11 (01) 17
• 11 Gao C, Bao B, Bao C, Wu W. Fungi fibrinolytic compound 1 plays a core role in modulating fibrinolysis, altering plasma clot structure, and promoting susceptibility to lysis. Pharmaceutics 2023; 15 (09) 2320
• 12 Giustozzi M, Ehrlinder H, Bongiovanni D. et al. Coagulopathy and sepsis: pathophysiology, clinical manifestations and treatment. Blood Rev 2021; 50: 100864
• 13 Schultz CM, Goel A, Dunn A. et al. Stepping up to the plate(let) against Candida albicans. Infect Immun 2020; 88 (04) e00784-19
• 14 Tang YQ, Yeaman MR, Selsted ME. Antimicrobial peptides from human platelets. Infect Immun 2002; 70 (12) 6524-6533
• 15 Portier I, Campbell RA. Role of platelets in detection and regulation of infection. Arterioscler Thromb Vasc Biol 2021; 41 (01) 70-78
• 16 Levi M. Platelets at a crossroad of pathogenic pathways in sepsis. J Thromb Haemost 2004; 2 (12) 2094-2095
• 17 Williams B, Zou L, Pittet JF, Chao W. Sepsis-induced coagulopathy: a comprehensive narrative review of pathophysiology, clinical presentation, diagnosis, and management strategies. Anesth Analg 2024; 138 (04) 696-711
• 18 Assinger A, Schrottmaier WC, Salzmann M, Rayes J. Platelets in sepsis: an update on experimental models and clinical data. Front Immunol 2019; 10: 1687
• 19 Stockschlaeder M, Schneppenheim R, Budde U. Update on von Willebrand factor multimers: focus on high-molecular-weight multimers and their role in hemostasis. Blood Coagul Fibrinolysis 2014; 25 (03) 206-216
• 20 Vardon-Bounes F, Ruiz S, Gratacap MP, Garcia C, Payrastre B, Minville V. Platelets are critical key players in sepsis. Int J Mol Sci 2019; 20 (14) 3494
• 21 Launder D, Dillon JT, Wuescher LM. et al. Immunity to pathogenic mucosal C. albicans infections mediated by oral megakaryocytes activated by IL-17 and candidalysin. Mucosal Immunol 2024; 17 (02) 182-200
• 22 Eberl C, Speth C, Jacobsen ID. et al. Candida: platelet interaction and platelet activity in vitro. J Innate Immun 2019; 11 (01) 52-62
• 23 Speth C, Hagleitner M, Ott HW, Würzner R, Lass-Flörl C, Rambach G. Aspergillus fumigatus activates thrombocytes by secretion of soluble compounds. J Infect Dis 2013; 207 (05) 823-833
• 24 Liang C, Lian N, Li M. The emerging role of neutrophil extracellular traps in fungal infection. Front Cell Infect Microbiol 2022; 12: 900895
• 25 Zhong H, Lu RY, Wang Y. Neutrophil extracellular traps in fungal infections: a seesaw battle in hosts. Front Immunol 2022; 13: 977493
• 26 Jawhara S. How fungal glycans modulate platelet activation via Toll-like receptors contributing to the escape of Candida albicans from the immune response. Antibiotics (Basel) 2020; 9 (07) 385
• 27 Valone FH, Epstein LB. Biphasic platelet-activating factor synthesis by human monocytes stimulated with IL-1-beta, tumor necrosis factor, or IFN-gamma. J Immunol 1988; 141 (11) 3945-3950
• 28 Jeremias J, Kalo-Klein A, Witkin SS. Individual differences in tumour necrosis factor and interleukin-1 production induced by viable and heat-killed Candida albicans. J Med Vet Mycol 1991; 29 (03) 157-163
• 29 Im SY, Choi JH, Ko HM. et al. A protective role of platelet-activating factor in murine candidiasis. Infect Immun 1997; 65 (04) 1321-1326
• 30 Vancraeyneste H, Charlet R, Guerardel Y. et al. Short fungal fractions of β-1,3 glucans affect platelet activation. Am J Physiol Heart Circ Physiol 2016; 311 (03) H725-H734
• 31 Saluk-Juszczak J, Krolewska K, Wachowicz B. beta-glucan from Saccharomyces cerevisiae as a blood platelet antioxidant. Platelets 2010; 21 (06) 451-459
• 32 Perkhofer S, Kehrel BE, Dierich MP. et al. Human platelets attenuate Aspergillus species via granule-dependent mechanisms. J Infect Dis 2008; 198 (08) 1243-1246
• 33 Rødland EK, Ueland T, Pedersen TM. et al. Activation of platelets by Aspergillus fumigatus and potential role of platelets in the immunopathogenesis of aspergillosis. Infect Immun 2010; 78 (03) 1269-1275
• 34 Zhao L, Bi Y, Kou J, Shi J, Piao D. Phosphatidylserine exposing-platelets and microparticles promote procoagulant activity in colon cancer patients. J Exp Clin Cancer Res 2016; 35: 54
• 35 Song L, Zhao Y, Wang G, Zou W, Sai L. Investigation of predictors for invasive pulmonary aspergillosis in patients with severe fever with thrombocytopenia syndrome. Sci Rep 2023; 13 (01) 1538
• 36 Coughlin SR. Protease-activated receptors in hemostasis, thrombosis and vascular biology. J Thromb Haemost 2005; 3 (08) 1800-1814
• 37 Deshmukh H, Rambach G, Sheppard DC. et al. Galactosaminogalactan secreted from Aspergillus fumigatus and Aspergillus flavus induces platelet activation. Microbes Infect 2020; 22 (08) 331-339
• 38 Deshmukh H, Speth C, Sheppard DC. et al. Aspergillus-derived galactosaminogalactan triggers complement activation on human platelets. Front Immunol 2020; 11: 550827
• 39 Tischler BY, Tosini NL, Cramer RA, Hohl TM. Platelets are critical for survival and tissue integrity during murine pulmonary Aspergillus fumigatus infection. PLoS Pathog 2020; 16 (05) e1008544
• 40 Perkhofer S, Kainzner B, Kehrel BE, Dierich MP, Nussbaumer W, Lass-Flörl C. Potential antifungal effects of human platelets against zygomycetes in vitro. J Infect Dis 2009; 200 (07) 1176-1179
• 41 Weyrich AS, Elstad MR, McEver RP. et al. Activated platelets signal chemokine synthesis by human monocytes. J Clin Invest 1996; 97 (06) 1525-1534
• 42 Nasillo V, Lagreca I, Vallerini D. et al. BTK inhibitors impair platelet-mediated antifungal activity. Cells 2022; 11 (06) 1003
• 43 Sola-Visner M. Platelets in the neonatal period: developmental differences in platelet production, function, and hemostasis and the potential impact of therapies. Hematology (Am Soc Hematol Educ Program) 2012; 2012: 506-511
• 44 Strauss T, Sidlik-Muskatel R, Kenet G. Developmental hemostasis: primary hemostasis and evaluation of platelet function in neonates. Semin Fetal Neonatal Med 2011; 16 (06) 301-304
• 45 Sallmon H, Weimann A, Bührer C, Metze B, Dame C, Cremer M. Immature platelet counts and thrombopoietin plasma concentrations in thrombocytopenic and non-thrombocytopenic preterm infants. Front Pediatr 2021; 9: 685643
• 46 Davenport P, Liu ZJ, Sola-Visner M. Fetal vs adult megakaryopoiesis. Blood 2022; 139 (22) 3233-3244
• 47 Davenport P, Sola-Visner M. Hemostatic challenges in neonates. Front Pediatr 2021; 9: 627715
• 48 Gunnink SF, Vlug R, Fijnvandraat K, van der Bom JG, Stanworth SJ, Lopriore E. Neonatal thrombocytopenia: etiology, management and outcome. Expert Rev Hematol 2014; 7 (03) 387-395
• 49 Burrows RF, Kelton JG. Fetal thrombocytopenia and its relation to maternal thrombocytopenia. N Engl J Med 1993; 329 (20) 1463-1466
• 50 Wiedmeier SE, Henry E, Sola-Visner MC, Christensen RD. Platelet reference ranges for neonates, defined using data from over 47,000 patients in a multihospital healthcare system. J Perinatol 2009; 29 (02) 130-136
• 51 Goel R, Josephson CD. Recent advances in transfusions in neonates/infants. F1000 Res 2018; 7: 7
• 52 Sokou R, Giallouros G, Konstantinidi A. et al. Thromboelastometry for diagnosis of neonatal sepsis-associated coagulopathy: an observational study. Eur J Pediatr 2018; 177 (03) 355-362
• 53 Hammoud MS, Al-Taiar A, Fouad M, Raina A, Khan Z. Persistent candidemia in neonatal care units: risk factors and clinical significance. Int J Infect Dis 2013; 17 (08) e624-e628
• 54 King J, Pana ZD, Lehrnbecher T, Steinbach WJ, Warris A. Recognition and clinical presentation of invasive fungal disease in neonates and children. J Pediatric Infect Dis Soc 2017; 6 (Suppl. 01) S12-S21
• 55 Kilpatrick R, Scarrow E, Hornik C, Greenberg RG. Neonatal invasive candidiasis: updates on clinical management and prevention. Lancet Child Adolesc Health 2022; 6 (01) 60-70
• 56 Oguz SS, Sipahi E, Dilmen U. C-reactive protein and interleukin-6 responses for differentiating fungal and bacterial aetiology in late-onset neonatal sepsis. Mycoses 2011; 54 (03) 212-216
• 57 Barton M, Shen A, O'Brien K. et al; Paediatric Investigators Collaborative Network on Infections in Canada (PICNIC). Early-onset invasive candidiasis in extremely low birth weight infants: perinatal acquisition predicts poor outcome. Clin Infect Dis 2017; 64 (07) 921-927
• 58 Guida JD, Kunig AM, Leef KH, McKenzie SE, Paul DA. Platelet count and sepsis in very low birth weight neonates: is there an organism-specific response?. Pediatrics 2003; 111 (6 Pt 1): 1411-1415
• 59 Tasneem F, Hossain M, Mahmud S, Ahmed SS. Clinical profile of fungal sepsis in new born: a tertiary centre experience from Bangladesh. J Pediatr Neonatal Care 2020; 10 (06) 170-173
• 60 Yang YC, Mao J. Value of platelet count in the early diagnosis of nosocomial invasive fungal infections in premature infants. Platelets 2018; 29 (01) 65-70
• 61 Manzoni P, Mostert M, Galletto P. et al. Is thrombocytopenia suggestive of organism-specific response in neonatal sepsis?. Pediatr Int 2009; 51 (02) 206-210
• 62 Lin HC, Lin HY, Su BH. et al. Reporting an outbreak of Candida pelliculosa fungemia in a neonatal intensive care unit. J Microbiol Immunol Infect 2013; 46 (06) 456-462
• 63 Zhao D, Qiu G, Luo Z, Zhang Y. Platelet parameters and (1, 3)-β-D-glucan as a diagnostic and prognostic marker of invasive fungal disease in preterm infants. PLoS One 2015; 10 (04) e0123907
• 64 Guo J, Wu Y, Lai W, Lu W, Mu X. The diagnostic value of (1,3)-β-D-glucan alone or combined with traditional inflammatory markers in neonatal invasive candidiasis. BMC Infect Dis 2019; 19 (01) 716
• 65 Goudjil S, Kongolo G, Dusol L. et al. (1-3)-β-D-glucan levels in candidiasis infections in the critically ill neonate. J Matern Fetal Neonatal Med 2013; 26 (01) 44-48
• 66 Amara U, Rittirsch D, Flierl M. et al. Interaction between the coagulation and complement system. Adv Exp Med Biol 2008; 632: 71-79
• 67 Low C, Syed D, Khan D. et al. Modulation of interleukins in sepsis-associated clotting disorders: interplay with hemostatic derangement. Clin Appl Thromb Hemost 2017; 23 (01) 34-39
• 68 Levi M, van der Poll T. Inflammation and coagulation. Crit Care Med 2010; 38 (2, Suppl): S26-S34
• 69 Levy JH, Sniecinski RM, Welsby IJ, Levi M. Antithrombin: anti-inflammatory properties and clinical applications. Thromb Haemost 2016; 115 (04) 712-728
• 70 Eliwan H, Omer M, McKenna E. et al. Protein C pathway in paediatric and neonatal sepsis. Front Pediatr 2022; 9: 562495
• 71 Curtiaud A, Iba T, Angles-Cano E, Meziani F, Helms J. Biomarkers of sepsis-induced coagulopathy: diagnostic insights and potential therapeutic implications. Ann Intensive Care 2025; 15 (01) 12
• 72 Sungurlu S, Kuppy J, Balk RA. Role of antithrombin III and tissue factor pathway in the pathogenesis of sepsis. Crit Care Clin 2020; 36 (02) 255-265
• 73 Mendes-Giannini MJS, Soares CP, da Silva JLM, Andreotti PF. Interaction of pathogenic fungi with host cells: molecular and cellular approaches. FEMS Immunol Med Microbiol 2005; 45 (03) 383-394
• 74 Kinasewitz GT, Yan SB, Basson B. et al; PROWESS Sepsis Study Group. Universal changes in biomarkers of coagulation and inflammation occur in patients with severe sepsis, regardless of causative micro-organism [ISRCTN74215569]. Crit Care 2004; 8 (02) R82-R90
• 75 Bras G, Satala D, Juszczak M. et al. Secreted aspartic proteinases: key factors in Candida infections and host-pathogen interactions. Int J Mol Sci 2024; 25 (09) 4775
• 76 Kaminishi H, Hamatake H, Cho T. et al. Activation of blood clotting factors by microbial proteinases. FEMS Microbiol Lett 1994; 121 (03) 327-332
• 77 Rüchel R. On the renin-like activity of Candida proteinases and activation of blood coagulation in vitro. Zentralbl Bakteriol Mikrobiol Hyg A 1983; 255 (2-3): 368-379
• 78 Rapala-Kozik M, Bochenska O, Zajac D. et al. Extracellular proteinases of Candida species pathogenic yeasts. Mol Oral Microbiol 2018; 33 (02) 113-124
• 79 Rapala-Kozik M, Karkowska J, Jacher A. et al. Kininogen adsorption to the cell surface of Candida spp. Int Immunopharmacol 2008; 8 (02) 237-241
• 80 He Q, Wei Y, Qian Y, Zhong M. Pathophysiological dynamics in the contact, coagulation, and complement systems during sepsis: potential targets for nafamostat mesilate. J Intensive Med 2024; 4 (04) 453-467
• 81 Harpf V, Rambach G, Würzner R, Lass-Flörl C, Speth C. Candida and complement: new aspects in an old battle. Front Immunol 2020; 11: 1471
• 82 Singh DK, Tóth R, Gácser A. Mechanisms of pathogenic Candida species to evade the host complement attack. Front Cell Infect Microbiol 2020; 10: 94
• 83 Crowe JD, Sievwright IK, Auld GC, Moore NR, Gow NA, Booth NA. Candida albicans binds human plasminogen: identification of eight plasminogen-binding proteins. Mol Microbiol 2003; 47 (06) 1637-1651
• 84 Napolitano F, Giudice V, Selleri C, Montuori N. Plasminogen system in the pathophysiology of sepsis: upcoming biomarkers. Int J Mol Sci 2023; 24 (15) 12376
• 85 Chen SM, Zou Z, Guo SY. et al. Preventing Candida albicans from subverting host plasminogen for invasive infection treatment. Emerg Microbes Infect 2020; 9 (01) 2417-2432
• 86 Matzaraki V, Gresnigt MS, Jaeger M. et al. An integrative genomics approach identifies novel pathways that influence candidaemia susceptibility. PLoS One 2017; 12 (07) e0180824
• 87 Tamayo D, Hernández O, Muñoz-Cadavid C, Cano LE, González A. Interaction between Paracoccidioides brasiliensis conidia and the coagulation system: involvement of fibrinogen. Mem Inst Oswaldo Cruz 2013; 108 (04) 488-493
• 88 McMichael MA, O'Brien M, Smith SA. Hypercoagulability in dogs with blastomycosis. J Vet Intern Med 2015; 29 (02) 499-504
• 89 Pal S, Curley A, Stanworth SJ. Interpretation of clotting tests in the neonate. Arch Dis Child Fetal Neonatal Ed 2015; 100 (03) F270-F274
• 90 Moiseiwitsch N, Brown AC. Neonatal coagulopathies: a review of established and emerging treatments. Exp Biol Med (Maywood) 2021; 246 (12) 1447-1457
• 91 Sokou R, Parastatidou S, Konstantinidi A. et al. Contemporary tools for evaluation of hemostasis in neonates. Where are we and where are we headed?. Blood Rev 2024; 64: 101157
• 92 Pichler E, Pichler L. The neonatal coagulation system and the vitamin K deficiency bleeding—a mini review. Wien Med Wochenschr 2008; 158 (13-14): 385-395
• 93 Harrington R, Kindermann SL, Hou Q, Taylor RJ, Azie N, Horn DL. Candidemia and invasive candidiasis among hospitalized neonates and pediatric patients. Curr Med Res Opin 2017; 33 (10) 1803-1812
• 94 Kopanou Taliaka P, Tsantes AG, Konstantinidi A. et al. Risk factors, diagnosis, and treatment of neonatal fungal liver abscess: a systematic review of the literature. Life (Basel) 2023; 13 (01) 167
• 95 Papadogeorgou P, Boutsikou T, Boutsikou M. et al. A global assessment of coagulation profile and a novel insight into ADAMTS-13 implication in neonatal sepsis. Biology (Basel) 2023; 12 (10) 1281
• 96 Sokou R, Tsantes AG, Lampridou M. et al. Thromboelastometry and prediction of in-hospital mortality in neonates with sepsis. Int J Lab Hematol 2024; 46 (01) 113-119
• 97 Grant HW, Hadley GP. Prediction of neonatal sepsis by thromboelastography. Pediatr Surg Int 1997; 12 (04) 289-292
• 98 Adalarasan N, Stalin S, Venkatasamy S, Sridevi S, Padmanaban S, Chinnaiyan P. Association and outcome of intracranial haemorrhage in newborn with fungal sepsis—a prospective cohort study. Indian J Neonatal Med Res 2022; 10: PO27-PO31
• 99 Saxonhouse MA, Manco-Johnson MJ. The evaluation and management of neonatal coagulation disorders. Semin Perinatol 2009; 33 (01) 52-65
• 100 Yang J, Wu Z, Long Q. et al. Insights into immunothrombosis: the interplay among neutrophil extracellular trap, von Willebrand factor, and ADAMTS13. Front Immunol 2020; 11: 610696
• 101 Chen J, Chung DW. Inflammation, von Willebrand factor, and ADAMTS13. Blood 2018; 132 (02) 141-147
• 102 Knoebl P. Blood coagulation disorders in septic patients. Wien Med Wochenschr 2010; 160 (5-6): 129-138
• 103 Lampridou M, Sokou R, Tsantes AG. et al. ROTEM diagnostic capacity for measuring fibrinolysis in neonatal sepsis. Thromb Res 2020; 192: 103-108
• 104 Yang YL, Xiang ZJ, Yang JH, Wang WJ, Xu ZC, Xiang RL. Adverse effects associated with currently commonly used antifungal agents: a network meta-analysis and systematic review. Front Pharmacol 2021; 12: 697330
• 105 Cheng Q, Wu Y, Yao Z. et al. Coagulation dysfunction events associated with echinocandins: a real-world study from FDA adverse event reporting system (FAERS) database. Thromb J 2024; 22 (01) 78
• 106 Nazzal M, Safi F, Arma F, Nazzal M, Muzaffar M, Assaly R. Micafungin-induced thrombotic thrombocytopenic purpura: a case report and review of the literature. Am J Ther 2011; 18 (06) e258-e260
• 107 Lang E, Lang F. Mechanisms and pathophysiological significance of eryptosis, the suicidal erythrocyte death. Semin Cell Dev Biol 2015; 39: 35-42
• 108 Lynch J, Wong-Beringer A. Caspofungin: a potential cause of reversible severe thrombocytopenia. Pharmacotherapy 2004; 24 (10) 1408-1411
• 109 Yuan SD, Wen KL, Cao YX, Huang WQ, Zhang A. Safety and efficacy of non-reduced use of caspofungin in patients with Child-Pugh B or C cirrhosis: a real-world study. Infection 2024; 52 (03) 1063-1072
• 110 Zhang Q, Zhou S, Zhou J. Tigecycline treatment causes a decrease in fibrinogen levels. Antimicrob Agents Chemother 2015; 59 (03) 1650-1655