Phenotypes of Disseminated Intravascular Coagulation

Abstract

Two phenotypes of disseminated intravascular coagulation (DIC) are systematically reviewed. DIC is classified into thrombotic and fibrinolytic phenotypes characterized by thrombosis and hemorrhage, respectively. Major pathology of DIC with thrombotic phenotype is the activation of coagulation, insufficient anticoagulation with endothelial injury, and plasminogen activator inhibitor-1-mediated inhibition of fibrinolysis, leading to microvascular fibrin thrombosis and organ dysfunction. DIC with fibrinolytic phenotype is defined as massive thrombin generation commonly observed in any type of DIC, combined with systemic pathologic hyperfibrinogenolysis caused by underlying disorder that results in severe bleeding due to excessive plasmin formation. Three major pathomechanisms of systemic hyperfibrinogenolysis have been considered: (1) acceleration of tissue-type plasminogen activator (t-PA) release from hypoxic endothelial cells and t-PA-rich storage pools, (2) enhancement of the conversion of plasminogen to plasmin due to specific proteins and receptors that are expressed on cancer cells and endothelial cells, and (3) alternative pathways of fibrinolysis. DIC with fibrinolytic phenotype can be diagnosed by DIC diagnosis followed by the recognition of systemic pathologic hyperfibrin(ogen)olysis. Low fibrinogen levels, high fibrinogen and fibrin degradation products (FDPs), and the FDP/D-dimer ratio are important for the diagnosis of systemic pathologic hyperfibrin(ogen)olysis. Currently, evidence-based treatment strategies for DIC with fibrinolytic phenotypes are lacking. Tranexamic acid appears to be one of the few methods to be effective in the treatment of systemic pathologic hyperfibrin(ogen)olysis. International cooperation for the elucidation of pathomechanisms, establishment of diagnostic criteria, and treatment strategies for DIC with fibrinolytic phenotype are urgent issues in the field of thrombosis and hemostasis.

Keywords

disseminated intravascular coagulation (DIC) - fibrinolysis - phenotype - plasmin - thrombin

Authors' Contribution

T.W. and S.G. designed the review and wrote the drafts of the manuscript. All the authors have read and approved the final version of the manuscript.

Publikationsverlauf

Eingereicht: 30. Juli 2023

Angenommen: 30. August 2023

Accepted Manuscript online:
01. September 2023

Artikel online veröffentlicht:
03. Oktober 2023

• References

• 1 Marder VJ, Feinstein DI, Colman RW, Levi M. Consumptive thrombohemorrhagic disorders. In: Colman RW, Marder VJ, Clowes AW, George JN, Goldharber SZ. eds. Hemostasis and Thrombosis. Basic Principles and Clinical Practice. 5th ed.. Philadelphia, PA: Lippincott Wiliams & Wikins; 2006: 1571-1600
• 2 Taylor Jr FB, Toh CH, Hoots WK, Wada H, Levi M. Scientific Subcommittee on Disseminated Intravascular Coagulation (DIC) of the International Society on Thrombosis and Haemostasis (ISTH). Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost 2001; 86 (05) 1327-1330
• 3 Gando S, Levi M, Toh CH. Disseminated intravascular coagulation. Nat Rev Dis Primers 2016; 2: 16037
• 4 Suffredini AF, Harpel PC, Parrillo JE. Promotion and subsequent inhibition of plasminogen activation after administration of intravenous endotoxin to normal subjects. N Engl J Med 1989; 320 (18) 1165-1172
• 5 Levi M, ten Cate H, van der Poll T, van Deventer SJ. Pathogenesis of disseminated intravascular coagulation in sepsis. JAMA 1993; 270 (08) 975-979
• 6 Hack CE. Fibrinolysis in disseminated intravascular coagulation. Semin Thromb Hemost 2001; 27 (06) 633-638
• 7 Gando S. Role of fibrinolysis in sepsis. Semin Thromb Hemost 2013; 39 (04) 392-399
• 8 Gando S, Wada T. Disseminated intravascular coagulation in cardiac arrest and resuscitation. J Thromb Haemost 2019; 17 (08) 1205-1216
• 9 Gando S, Nakanishi Y, Tedo I. Cytokines and plasminogen activator inhibitor-1 in posttrauma disseminated intravascular coagulation: relationship to multiple organ dysfunction syndrome. Crit Care Med 1995; 23 (11) 1835-1842
• 10 Alhamdi Y, Toh CH. Recent advances in pathophysiology of disseminated intravascular coagulation: the role of circulating histones and neutrophil extracellular traps. F1000 Res 2017; 6: 2143
• 11 Popescu NI, Lupu C, Lupu F. Disseminated intravascular coagulation and its immune mechanisms. Blood 2022; 139 (13) 1973-1986
• 12 Huber D, Cramer EM, Kaufmann JE. et al. Tissue-type plasminogen activator (t-PA) is stored in Weibel-Palade bodies in human endothelial cells both in vitro and in vivo. Blood 2002; 99 (10) 3637-3645
• 13 Lowenstein CJ, Morrell CN, Yamakuchi M. Regulation of Weibel-Palade body exocytosis. Trends Cardiovasc Med 2005; 15 (08) 302-308
• 14 Kruithof EK, Dunoyer-Geindre S. Human tissue-type plasminogen activator. Thromb Haemost 2014; 112 (02) 243-254
• 15 Medcalf RL. Fibrinolysis: from blood to the brain. J Thromb Haemost 2017; 15 (11) 2089-2098
• 16 Mutch NJ. BN. Plasminogen activation and regulation of fibrinolysis. In: Marder VJ, Aird WC, Bennet JS, Schulman S, White GC. eds. Hemostasis and Thrombosis. Basic Principles and Clinical Practice. Philadelphia, PA: Lippincott Williams & Willkins; 2013: 314-333
• 17 Longstaff C. Measuring fibrinolysis: from research to routine diagnostic assays. J Thromb Haemost 2018; 16 (04) 652-662
• 18 Plug T, Meijers JC. Structure-function relationships in thrombin-activatable fibrinolysis inhibitor. J Thromb Haemost 2016; 14 (04) 633-644
• 19 Gando S, Wada T. Thromboplasminflammation in COVID-19 coagulopathy: three viewpoints for diagnostic and therapeutic strategies. Front Immunol 2021; 12: 649122
• 20 Kannemeier C, Shibamiya A, Nakazawa F. et al. Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation. Proc Natl Acad Sci U S A 2007; 104 (15) 6388-6393
• 21 Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol 2013; 13 (01) 34-45
• 22 Baker CJ, Smith SA, Morrissey JH. Polyphosphate in thrombosis, hemostasis, and inflammation. Res Pract Thromb Haemost 2018; 3 (01) 18-25
• 23 Plow EF. Leukocyte elastase release during blood coagulation. A potential mechanism for activation of the alternative fibrinolytic pathway. J Clin Invest 1982; 69 (03) 564-572
• 24 Wu K, Urano T, Ihara H. et al. The cleavage and inactivation of plasminogen activator inhibitor type 1 by neutrophil elastase: the evaluation of its physiologic relevance in fibrinolysis. Blood 1995; 86 (03) 1056-1061
• 25 Kohno I, Inuzuka K, Itoh Y. et al. A monoclonal antibody specific to the granulocyte-derived elastase-fragment D species of human fibrinogen and fibrin: its application to the measurement of granulocyte-derived elastase digests in plasma. Blood 2000; 95 (05) 1721-1728
• 26 Bach-Gansmo ET, Halvorsen S, Godal HC, Skjønsberg OH. Impaired clot lysis in the presence of human neutrophil elastase. Thromb Res 1995; 80 (02) 153-159
• 27 Cruz DBD, Helms J, Aquino LR. et al. DNA-bound elastase of neutrophil extracellular traps degrades plasminogen, reduces plasmin formation, and decreases fibrinolysis: proof of concept in septic shock plasma. FASEB J 2019; 33 (12) 14270-14280
• 28 Gando S, Otomo Y. Local hemostasis, immunothrombosis, and systemic disseminated intravascular coagulation in trauma and traumatic shock. Crit Care 2015; 19 (01) 72
• 29 Asakura H. Classifying types of disseminated intravascular coagulation: clinical and animal models. J Intensive Care 2014; 2 (01) 20
• 30 Wada T, Gando S, Ono Y. et al. Disseminated intravascular coagulation with the fibrinolytic phenotype predicts the outcome of patients with out-of-hospital cardiac arrest. Thromb J 2016; 14: 43
• 31 Sawamura A, Hayakawa M, Gando S. et al. Disseminated intravascular coagulation with a fibrinolytic phenotype at an early phase of trauma predicts mortality. Thromb Res 2009; 124 (05) 608-613
• 32 Sugawara J, Suenaga K, Hoshiai T. et al. Efficacy of recombinant human soluble thrombomodulin in severe postpartum hemorrhage with disseminated intravascular coagulation. Clin Appl Thromb Hemost 2013; 19 (05) 557-561
• 33 Okajima K, Koga S, Okabe H, Inoue M, Takatsuki K. Characterization of the fibrinolytic state by measuring stable cross-linked fibrin degradation products in disseminated intravascular coagulation associated with acute promyelocytic leukemia. Acta Haematol 1989; 81 (01) 15-18
• 34 Gando S, Sawamura A, Hayakawa M. Trauma, shock, and disseminated intravascular coagulation: lessons from the classical literature. Ann Surg 2011; 254 (01) 10-19
• 35 Winther-Larsen A, Sandfeld-Paulsen B, Hvas AM. Hyperfibrinolysis in patients with solid malignant neoplasms: a systematic review. Semin Thromb Hemost 2021; 47 (05) 581-588
• 36 Lemarchant S, Docagne F, Emery E, Vivien D, Ali C, Rubio M. tPA in the injured central nervous system: different scenarios starring the same actor?. Neuropharmacology 2012; 62 (02) 749-756
• 37 Kolev K, Longstaff C. Bleeding related to disturbed fibrinolysis. Br J Haematol 2016; 175 (01) 12-23
• 38 Pinsky DJ, Naka Y, Liao H. et al. Hypoxia-induced exocytosis of endothelial cell Weibel-Palade bodies. A mechanism for rapid neutrophil recruitment after cardiac preservation. J Clin Invest 1996; 97 (02) 493-500
• 39 Moore HB, Moore EE, Lawson PJ. et al. Fibrinolysis shutdown phenotype masks changes in rodent coagulation in tissue injury versus hemorrhagic shock. Surgery 2015; 158 (02) 386-392
• 40 Gertler JP, Perry L, L'Italien G. et al. Ambient oxygen tension modulates endothelial fibrinolysis. J Vasc Surg 1993; 18 (06) 939-945 , discussion 945–946
• 41 Pinsky DJ, Liao H, Lawson CA. et al. Coordinated induction of plasminogen activator inhibitor-1 (PAI-1) and inhibition of plasminogen activator gene expression by hypoxia promotes pulmonary vascular fibrin deposition. J Clin Invest 1998; 102 (05) 919-928
• 42 Liao H, Hyman MC, Lawrence DA, Pinsky DJ. Molecular regulation of the PAI-1 gene by hypoxia: contributions of Egr-1, HIF-1alpha, and C/EBPalpha. FASEB J 2007; 21 (03) 935-949
• 43 Gupta N, Zhao YY, Evans CE. The stimulation of thrombosis by hypoxia. Thromb Res 2019; 181: 77-83
• 44 de Lloyd L, Jenkins PV, Bell SF. et al. Acute obstetric coagulopathy during postpartum hemorrhage is caused by hyperfibrinolysis and dysfibrinogenemia: an observational cohort study. J Thromb Haemost 2023; 21 (04) 862-879
• 45 Kruithof EK, Tran-Thang C, Gudinchet A. et al. Fibrinolysis in pregnancy: a study of plasminogen activator inhibitors. Blood 1987; 69 (02) 460-466
• 46 Gando S, Kameue T, Nanzaki S, Nakanishi Y. Massive fibrin formation with consecutive impairment of fibrinolysis in patients with out-of-hospital cardiac arrest. Thromb Haemost 1997; 77 (02) 278-282
• 47 Matsunaga S, Masuko H, Takai Y, Kanayama N, Seki H. Fibrinogen may aid in the early differentiation between amniotic fluid embolism and postpartum haemorrhage: a retrospective chart review. Sci Rep 2021; 11 (01) 8379
• 48 Schwameis M, Schober A, Schörgenhofer C. et al. Asphyxia by drowning induces massive bleeding due to hyperfibrinolytic disseminated intravascular coagulation. Crit Care Med 2015; 43 (11) 2394-2402
• 49 al-Mashhadani SA, Gader AG, al Harthi SS, Kangav D, Shaheen FA, Bogus F. The coagulopathy of heat stroke: alterations in coagulation and fibrinolysis in heat stroke patients during the pilgrimage (Haj) to Makkah. Blood Coagul Fibrinolysis 1994; 5 (05) 731-736
• 50 Bouchama A, Al-Mohanna F, Assad L. et al. Tissue factor/factor VIIa pathway mediates coagulation activation in induced-heat stroke in the baboon. Crit Care Med 2012; 40 (04) 1229-1236
• 51 Matsumoto H, Takeba J, Umakoshi K. et al. Successful treatment for disseminated intravascular coagulation (DIC) corresponding to phenotype changes in a heat stroke patient. J Intensive Care 2019; 7: 2
• 52 Hijazi N, Abu Fanne R, Abramovitch R. et al. Endogenous plasminogen activators mediate progressive intracerebral hemorrhage after traumatic brain injury in mice. Blood 2015; 125 (16) 2558-2567
• 53 Hayakawa M, Maekawa K, Kushimoto S. et al. Hyperfibrinolysis in severe isolated traumatic brain injury may occur without tissue hypoperfusion: a retrospective observational multicentre study. Crit Care 2017; 21 (01) 222
• 54 Wada T, Shiraishi A, Gando S. et al. Pathophysiology of coagulopathy induced by traumatic brain injury is identical to that of disseminated intravascular coagulation with hyperfibrinolysis. Front Med (Lausanne) 2021; 8: 767637
• 55 Wada T, Gando S, Maekaw K. et al. Disseminated intravascular coagulation with increased fibrinolysis during the early phase of isolated traumatic brain injury. Crit Care 2017; 21 (01) 219
• 56 Kaufman HH, Hui KS, Mattson JC. et al. Clinicopathological correlations of disseminated intravascular coagulation in patients with head injury. Neurosurgery 1984; 15 (01) 34-42
• 57 Stein SC, Smith DH. Coagulopathy in traumatic brain injury. Neurocrit Care 2004; 1 (04) 479-488
• 58 Cardenas JC, Matijevic N, Baer LA, Holcomb JB, Cotton BA, Wade CE. Elevated tissue plasminogen activator and reduced plasminogen activator inhibitor promote hyperfibrinolysis in trauma patients. Shock 2014; 41 (06) 514-521
• 59 Mathur R, Suarez JI. Coagulopathy in isolated traumatic brain injury: myth or reality. Neurocrit Care 2023; 38 (02) 429-438
• 60 Nielsen VG, Matika RW, Ley ML. et al. Tissue-type plasminogen activator-induced fibrinolysis is enhanced in patients with breast, lung, pancreas and colon cancer. Blood Coagul Fibrinolysis 2014; 25 (03) 248-253
• 61 Bell WR. The fibrinolytic system in neoplasia. Semin Thromb Hemost 1996; 22 (06) 459-478
• 62 Kulić A, Cvetković Z, Libek V. Primary hyperfibrinolysis as the presenting sign of prostate cancer: a case report. Vojnosanit Pregl 2016; 73 (09) 877-880
• 63 Wada Y, Uchiba M, Kawano Y. et al. Severe bleeding tendency caused by a rare complication of excessive fibrinolysis with disseminated intravascular coagulation in a 51-year-old Japanese man with prostate cancer: a case report. J Med Case Rep 2012; 6: 378
• 64 D'Alessio S, Blasi F. The urokinase receptor as an entertainer of signal transduction. Front Biosci (Landmark Ed) 2009; 14 (12) 4575-4587
• 65 Kimura S, D'Andrea D, Iwata T. et al. Expression of urokinase-type plasminogen activator system in non-metastatic prostate cancer. World J Urol 2020; 38 (10) 2501-2511
• 66 Ellis V. Functional analysis of the cellular receptor for urokinase in plasminogen activation. Receptor binding has no influence on the zymogenic nature of pro-urokinase. J Biol Chem 1996; 271 (25) 14779-14784
• 67 Ikezoe T. Pathogenesis of disseminated intravascular coagulation in patients with acute promyelocytic leukemia, and its treatment using recombinant human soluble thrombomodulin. Int J Hematol 2014; 100 (01) 27-37
• 68 Luo M, Hajjar KA. Annexin A2 system in human biology: cell surface and beyond. Semin Thromb Hemost 2013; 39 (04) 338-346
• 69 Madureira PA, O'Connell PA, Surette AP, Miller VA, Waisman DM. The biochemistry and regulation of S100A10: a multifunctional plasminogen receptor involved in oncogenesis. J Biomed Biotechnol 2012; 2012: 353687
• 70 Peterson EA, Sutherland MR, Nesheim ME, Pryzdial EL. Thrombin induces endothelial cell-surface exposure of the plasminogen receptor annexin 2. J Cell Sci 2003; 116 (Pt 12): 2399-2408
• 71 Huang B, Deora AB, He KL. et al. Hypoxia-inducible factor-1 drives annexin A2 system-mediated perivascular fibrin clearance in oxygen-induced retinopathy in mice. Blood 2011; 118 (10) 2918-2929
• 72 Deora AB, Kreitzer G, Jacovina AT, Hajjar KA. An annexin 2 phosphorylation switch mediates p11-dependent translocation of annexin 2 to the cell surface. J Biol Chem 2004; 279 (42) 43411-43418
• 73 Fisher Jr DF, Yawn DH, Crawford ES. Preoperative disseminated intravascular coagulation associated with aortic aneurysms. A prospective study of 76 cases. Arch Surg 1983; 118 (11) 1252-1255
• 74 Tromholt N, Jørgensen SJ, Hesse B, Hansen MS. In vivo demonstration of focal fibrinolytic activity in abdominal aortic aneurysms. Eur J Vasc Surg 1993; 7 (06) 675-679
• 75 Shireman PK, McCarthy WJ, Pearce WH, Shively VP, Cipollone M, Kwaan HC. Elevations of tissue-type plasminogen activator and differential expression of urokinase-type plasminogen activator in diseased aorta. J Vasc Surg 1997; 25 (01) 157-164
• 76 Hayashi T, Morishita E, Ohtake H, Oda Y, Asakura H, Nakao S. Expression of annexin II in experimental abdominal aortic aneurysms. Int J Hematol 2009; 90 (03) 336-342
• 77 Hayakawa M, Sawamura A, Gando S. et al. Disseminated intravascular coagulation at an early phase of trauma is associated with consumption coagulopathy and excessive fibrinolysis both by plasmin and neutrophil elastase. Surgery 2011; 149 (02) 221-230
• 78 Oudijk EJ, Nieuwenhuis HK, Bos R, Fijnheer R. Elastase mediated fibrinolysis in acute promyelocytic leukemia. Thromb Haemost 2000; 83 (06) 906-908
• 79 Tamura N, Kimura S, Farhana M. et al. C1 esterase inhibitor activity in amniotic fluid embolism. Crit Care Med 2014; 42 (06) 1392-1396
• 80 Todo Y, Tamura N, Itoh H, Ikeda T, Kanayama N. Therapeutic application of C1 esterase inhibitor concentrate for clinical amniotic fluid embolism: a case report. Clin Case Rep 2015; 3 (07) 673-675
• 81 Wada T, Shiraishi A, Gando S. et al. Disseminated intravascular coagulation immediately after trauma predicts a poor prognosis in severely injured patients. Sci Rep 2021; 11 (01) 11031
• 82 Hifumi T, Kondo Y, Shimazaki J. et al. Prognostic significance of disseminated intravascular coagulation in patients with heat stroke in a nationwide registry. J Crit Care 2018; 44: 306-311
• 83 Barbui T, Finazzi G, Falanga A. The impact of all-trans-retinoic acid on the coagulopathy of acute promyelocytic leukemia. Blood 1998; 91 (09) 3093-3102
• 84 Wada H, Thachil J, Di Nisio M. et al; Guidance for diagnosis and treatment of DIC from harmonization of the recommendations from three guidelines. J Thromb Haemost 2013; 11 (04) 761-767
• 85 Roberts I, Shakur H, Afolabi A. et al. CRASH-2 collaborators. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet 2011; 377 (9771): 1096-1101 , 1101.e1–1101.e2
• 86 CRASH-3 trial collaborators. Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial. Lancet 2019; 394 (10210): 1713-1723
• 87 WOMAN Trial Collaborators. Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial. Lancet 2017; 389 (10084): 2105-2116
• 88 Medcalf RL. The traumatic side of fibrinolysis. Blood 2015; 125 (16) 2457-2458
• 89 Ageron FX, Shakur-Still H, Roberts I. Effects of tranexamic acid treatment in severely and non-severely injured trauma patients. Transfusion 2022; 62 (Suppl. 01) S151-S157
• 90 Moore EE, Moore HB, Gonzalez E, Sauaia A, Banerjee A, Silliman CC. Rationale for the selective administration of tranexamic acid to inhibit fibrinolysis in the severely injured patient. Transfusion 2016; 56 (Suppl. 02) S110-S114
• 91 Gando S, Shiraishi A, Wada T. et al; JAAM FORECAST TRAUMA Study Group. Effects of tranexamic acid on coagulofibrinolytic markers during the early stage of severe trauma: a propensity score-matched analysis. Medicine (Baltimore) 2022; 101 (32) e29711
• 92 Gando S, Shiraishi A, Wada T. et al. A multicenter prospective validation study on disseminated intravascular coagulation in trauma-induced coagulopathy. J Thromb Haemost 2020; 18 (09) 2232-2244
• 93 Morrow GB, Feller T, McQuilten Z. et al. Cryoprecipitate transfusion in trauma patients attenuates hyperfibrinolysis and restores normal clot structure and stability: results from a laboratory sub-study of the FEISTY trial. Crit Care 2022; 26 (01) 290
• 94 Olwill SA, McGlynn H, Gilmore WS, Alexander HD. All-trans retinoic acid-induced downregulation of annexin II expression in myeloid leukaemia cell lines is not confined to acute promyelocytic leukaemia. Br J Haematol 2005; 131 (02) 258-264
• 95 Holloway RW, Thomas ML, Cohen AM. et al. Regulation of cell surface protease receptor S100A10 by retinoic acid therapy in acute promyelocytic leukemia (APL)^☆ . Cell Death Dis 2018; 9 (09) 920
• 96 Hashimoto S, Koike T, Tatewaki W. et al. Fatal thromboembolism in acute promyelocytic leukemia during all-trans retinoic acid therapy combined with antifibrinolytic therapy for prophylaxis of hemorrhage. Leukemia 1994; 8 (07) 1113-1115
• 97 Grottke O, Honickel M, Braunschweig T, Reichel A, Schöchl H, Rossaint R. Prothrombin complex concentrate-induced disseminated intravascular coagulation can be prevented by coadministering antithrombin in a porcine trauma model. Anesthesiology 2019; 131 (03) 543-554
• 98 Wada T, Shiraishi A, Gando S. et al. Association of antithrombin with development of trauma-induced disseminated intravascular coagulation and outcomes. Front Immunol 2022; 13: 1026163