Correlation between Phenotype and Coagulation Factor Activity Level in Rare Bleeding Disorders: A Systematic Review

Behnaz Tavasoli; Alireza Zangooie; Seyed Mehrab Safdari; Taraneh Hoseinnezhad; Ashkan Shabannezhad; Amirreza Alikhani; Zahra Salehi; Akbar Dorgalaleh

doi:10.1055/s-0044-1800832

Seminars in Thrombosis and Hemostasis, Table of Contents

Semin Thromb Hemost 2025; 51(02): 180-195
DOI: 10.1055/s-0044-1800832

Review Article

Correlation between Phenotype and Coagulation Factor Activity Level in Rare Bleeding Disorders: A Systematic Review

Behnaz Tavasoli^*

¹Department of Hematology and Blood Transfusion, School of Allied Medicine, Bushehr University of Medical Sciences, Bushehr, Iran

,

Alireza Zangooie^*

²Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran

³Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran

,

Seyed Mehrab Safdari

⁴Department of Hematology and Blood Banking, School of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran

,

Taraneh Hoseinnezhad

¹Department of Hematology and Blood Transfusion, School of Allied Medicine, Bushehr University of Medical Sciences, Bushehr, Iran

,

Ashkan Shabannezhad

⁴Department of Hematology and Blood Banking, School of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran

,

Amirreza Alikhani

⁴Department of Hematology and Blood Banking, School of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran

,

Zahra Salehi

⁵Hematology, Oncology and Stem Cell Transplantation Research Center, Research Institute for Oncology, Hematology and Cell Therapy, Tehran University of Medical Sciences, Tehran, Iran

,

Akbar Dorgalaleh

⁶Hamin Pazhuhan Tis Institute, Tehran, Iran

› Author Affiliations

Abstract

Rare bleeding disorders (RBDs) represent 3 to 5% of congenital bleeding disorders and are primarily inherited in an autosomal recessive manner, with increased prevalence in consanguineous populations. Clinically, RBDs can be accompanied by mild to severe bleeding episodes, often assessed using bleeding assessment tools (BATs) such as the International Society on Thrombosis and Hemostasis (ISTH)-BAT. However, the correlation between bleeding severity and coagulation factor activity levels remains inconsistent. This systematic review investigates this relationship to enhance understanding and improve management strategies for patients with RBD. This review adhered to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was registered with the International Prospective Register for Systematic Reviews (PROSPERO) (CRD42024504537). Using the PICO (Population, Intervention, Comparator, and Outcomes) framework, the study focused on RBD patients to explore the correlation between coagulation factor activity levels and bleeding severity. A comprehensive search was conducted across PubMed, Scopus, and Web of Science until April 1, 2024, with data extracted on bleeding severity, phenotype, and coagulation factor activity levels. The analysis highlights complex and often inconsistent relationships between coagulation factor levels and the severity of bleeding. In cases of fibrinogen deficiency, three out of four studies (n = 73 of 111 cases, 66%) demonstrated a moderate to strong correlation between fibrinogen levels and bleeding severity. In prothrombin deficiency, one of two studies (n = 16 of 29 cases, 55%) found a strong correlation between FII levels and bleeding severity. Four of six studies (n = 106 of 139 cases, 76%) in FV deficiency found a weak or no correlation between factor activity and bleeding severity. In combined FV and FVIII deficiency, two of three studies (n = 26 of 60 cases, 43%) found a significant correlation between factor activity and bleeding severity. In FVII deficiency, four (of nine) studies with a study population of 325 patients (65%) found a weak correlation between factor activity and severity of bleeding. Almost all studies (five of six studies, n = 114 of 118 patients, 97%) in FX deficiency revealed a strong correlation between FX levels and bleeding severity. In FXI deficiency, most studies (five of seven studies, n = 254 patients, 93%) found a weak or no correlation between factor activity and bleeding severity or symptoms. For FXIII deficiency, there was a moderate to strong correlation between FXIII activity and bleeding severity in all three studies (n = 61 patients). In conclusion, despite current controversies, this review highlights a moderate or strong correlation between factor activity and bleeding severity in fibrinogen, FX, and FXIII deficiencies, but no correlation or weak correlation for FV, FVII, and FXI deficiencies. Further prospective studies with standardized BATs on a large number of patients are needed to better understand these relationships and optimize patient management.

Keywords

rare bleeding disorders - coagulation factor deficiencies - congenital bleeding disorders - bleeding severity - bleeding phenotype

Full Text

References

References
1 Dorgalaleh A, Bahraini M, Shams M. et al. Molecular basis of rare congenital bleeding disorders. Blood Rev 2023; 59: 101029
2 Dorgalaleh A, Tabibian S, Hosseini MS, Shams M. Pharmacological management of rare coagulation factor deficiencies besides hemophilia. Expert Rev Hematol 2020; 13 (08) 811-834
3 Safarpour MM, Haghpanah S, Meshksar A, Karimi M. Phenotype report on patients with congenital Factor V deficiency in Southern Iran: recent ten years' experience. Turk J Haematol 2017; 34 (03) 250-253
4 Sang Y, Roest M, de Laat B, de Groot PG, Huskens D. Interplay between platelets and coagulation. Blood Rev 2021; 46: 100733
5 Saes JL, Verhagen MJA, Meijer K. et al. Bleeding severity in patients with rare bleeding disorders: real-life data from the RBiN study. Blood Adv 2020; 4 (20) 5025-5034
6 Adelaja A, Stanek JR, Flood VH, James P, Vesely S, O'Brien S. Assessment of ISTH-BAT Scores in a primary care clinic population of menstruating adolescents. Blood 2023; 142: 1243
7 Palla R, Siboni SM, Menegatti M, Musallam KM, Peyvandi F. European Network of Rare Bleeding Disorders (EN-RBD) group. Establishment of a bleeding score as a diagnostic tool for patients with rare bleeding disorders. Thromb Res 2016; 148: 128-134
8 de Wee EM, Sanders YV, Mauser-Bunschoten EP. et al; WiN study group. Determinants of bleeding phenotype in adult patients with moderate or severe von Willebrand disease. Thromb Haemost 2012; 108 (04) 683-692
9 Peyvandi F, Palla R, Menegatti M. et al; European Network of Rare Bleeding Disorders Group. Coagulation factor activity and clinical bleeding severity in rare bleeding disorders: results from the European Network of Rare Bleeding Disorders. J Thromb Haemost 2012; 10 (04) 615-621
10 Viswabandya A, Baidya S, Nair SC. et al. Correlating clinical manifestations with factor levels in rare bleeding disorders: a report from Southern India. Haemophilia 2012; 18 (03) e195-e200
11 Tavasoli B, Safa M, Dorgalaleh A. et al. Molecular and clinical profile of congenital fibrinogen disorders in Iran, identification of two novel mutations. Int J Lab Hematol 2020; 42 (05) 619-627
12 Page MJ, McKenzie JE, Bossuyt PM. et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021; 372: n71
13 Casini A, de Moerloose P, Neerman-Arbez M. Clinical features and management of congenital fibrinogen deficiencies. Semin Thromb Hemost 2016; 42: 366-374
14 Zekavat OR, Haghpanah S, Dehghani J, Afrasiabi A, Peyvandi F, Karimi M. Comparison of thrombin generation assay with conventional coagulation tests in evaluation of bleeding risk in patients with rare bleeding disorders. Clin Appl Thromb Hemost 2014; 20 (06) 637-644
15 Lancellotti S, Basso M, De Cristofaro R. Congenital prothrombin deficiency: an update. Semin Thromb Hemost 2013; 39 (06) 596-606
16 Girolami A, Santarossa C, Cosi E, Ferrari S, Lombardi AM, Girolami B. Bleeding manifestations in heterozygotes with prothrombin deficiency or abnormalities vs. unaffected family members as observed during a long follow-up study. Blood Coagul Fibrinolysis 2017; 28 (08) 623-626
17 Batsuli G, Kouides P. Rare coagulation factor deficiencies (factors VII, X, V, and II). Hematol Oncol Clin North Am 2021; 35 (06) 1181-1196
18 Duckers C, Simioni P, Rosing J, Castoldi E. Advances in understanding the bleeding diathesis in factor V deficiency. Br J Haematol 2009; 146 (01) 17-26
19 Duckers C, Simioni P, Spiezia L. et al. Residual platelet factor V ensures thrombin generation in patients with severe congenital factor V deficiency and mild bleeding symptoms. Blood 2010; 115 (04) 879-886
20 Park YH, Lim JH, Yi HG, Lee MH, Kim CS, Factor V. Factor V deficiency in Korean patients: clinical and laboratory features, treatment, and outcome. J Korean Med Sci 2016; 31 (02) 208-213
21 Zheng C, Zhang B. Combined deficiency of coagulation factors V and VIII: an update. Semin Thromb Hemost 2013; 39: 613-620
22 Shams M. Congenital factor VII deficiency, diagnosis, and management. In: Congenital Bleeding Disorders. Springer; 2023: 259-285
23 Mashayekhi A, Ghasemi E. Coagulation factor VII: genetic, molecular, and clinical characteristics. Trends Med Sci 2022; 2 (01) e128397
24 Greene LA, Goldenberg NA, Simpson ML. et al. Use of global assays to understand clinical phenotype in congenital factor VII deficiency. Haemophilia 2013; 19 (05) 765-772
25 Tiscia G, Favuzzi G, Chinni E. et al. Factor VII deficiency: a novel missense variant and genotype-phenotype correlation in patients from Southern Italy. Hum Genome Var 2017; 4: 17048
26 Rousseau F, Guillet B, Mura T. et al. Surgery in rare bleeding disorders: the prospective MARACHI study. Res Pract Thromb Haemost 2023; 7 (07) 102199
27 Toret E, Ay Y, Karapinar TH, Oymak Y, Kavakli K, Vergin RC. Evaluation of bleeding phenotype of inherited factor VII deficiency in children with a bleeding assessment tool and global assays. J Pediatr Hematol Oncol 2020; 42 (06) e527-e530
28 Tripathi P, Mishra P, Ranjan R, Tyagi S, Seth T, Saxena R. Factor VII deficiency - an enigma; clinicohematological profile in 12 cases. Hematology 2019; 24 (01) 97-102
29 Menegatti M, Peyvandi F. Factor X deficiency. Semin Thromb Hemost 2009; 35: 407-415
30 Peyvandi F, Mannucci PM, Lak M. et al. Congenital factor X deficiency: spectrum of bleeding symptoms in 32 Iranian patients. Br J Haematol 1998; 102 (02) 626-628
31 Lewandowska MD, Connors JM. Factor XI deficiency. Hematol Oncol Clin North Am 2021; 35 (06) 1157-1169
32 Borud LJ, Matarasso A, Spaccavento CM, Hanzlik RM. Factor XI deficiency: implications for management of patients undergoing aesthetic surgery. Plast Reconstr Surg 1999; 104 (06) 1907-1913
33 Kadir RA, Economides DL, Sabin CA, Pollard D, Lee CA. Assessment of menstrual blood loss and gynaecological problems in patients with inherited bleeding disorders. Haemophilia 1999; 5 (01) 40-48
34 Ko JKY, Lao TT, Cheung VYT. Pictorial Blood Loss Assessment Chart for evaluating heavy menstrual bleeding in Asian women. Hong Kong Med J 2021; 27 (06) 399-404
35 Hsieh L, Nugent D. Factor XIII deficiency. Haemophilia 2008; 14 (06) 1190-1200
36 De Cristofaro R. Congenital prothrombin deficiency: diagnosis and management. In: Congenital Bleeding Disorders. Springer; 2023: 191-209
37 Napolitano M, Siragusa S, Mariani G. Factor VII deficiency: clinical phenotype, genotype and therapy. J Clin Med 2017; 6 (04) 38
38 Lapecorella M, Mariani G. International Registry on Congenital Factor VII Deficiency. Factor VII deficiency: defining the clinical picture and optimizing therapeutic options. Haemophilia 2008; 14 (06) 1170-1175

Supplementary Material

Supplementary Material