Rare Congenital Bleeding Disorders – Challenges Remain

Rare congenital bleeding disorders, typically defined as rare coagulation factor deficiencies (except haemophilia A or B) or hereditary platelet disorders, may be overlooked due to the rarity of such conditions, resulting in delayed diagnosis and inadequate treatment. As commonly observed in rare diseases, extensive clinical trials are lacking to inform treatment decisions. The complexities in the management and treatment of these disorders include, for instance, the poor correlation between factor activity levels and the bleeding phenotype in certain deficiencies, thereby complicating the prediction of bleeding risks. Furthermore, knowledge and expertise tend to be confined to specialized centres.

In this theme issue of Haemostaseologie – Progress in Haemostasis-Diagnosis and Treatment of Rare Congenital Bleeding Disorders, experts from the DACH (Germany, Austria and Switzerland) region and Europe contribute to addressing these unmet clinical needs with four comprehensive reviews and two original research articles.

The first review by Holstein and coauthors [1] on behalf of the Haemophilia Board of the GTH (Gesellschaft für Thrombose und Hämostaseforschung, Society of Thrombosis and Haemostasis Research, in Germany, Austria, and Switzerland), focuses on the bleeding phenotype, thrombotic risk and therapeutic strategies of single-factor deficiencies. The authors summarize the recent literature alongside expert recommendations. They emphasize that a proper genetic evaluation and detailed bleeding history are instrumental for risk stratification and informed treatment decisions. Additionally, epidemiological insights derived from the German haemophilia registry and a survey conducted among GTH members shed light on estimated patient populations and treatment approaches within the GTH region.

The second review, authored by Casini and de Moerloose [2] as internationally recognized specialists for fibrinogen disorders, concentrates on young and ageing women with hypo- and afibrinogenaemia. This population warrants particular attention due to the unique challenges women affected by fibrinogen disorders face related to menstruation, pregnancy and childbirth, a high risk of miscarriage and gynaecological bleeding. Furthermore, the risk for thrombotic events needs to be considered. The authors highlight the necessity of a multidisciplinary team to ensure adequate care and genetic counselling to these women and their families. Practical recommendations for replacement strategies are proposed to enhance the management of women across all ages suffering from hypo- and afibrinogenaemia.

Another exceedingly rare disorder is autosomal recessive combined vitamin K-dependent coagulation factor deficiency (VKCFD). The review by Raharimanana et al [3] summarizes pathophysiology, clinical manifestations and therapeutic modalities associated with VKCFD. This condition is caused by various mutations within the vitamin K cycle, complicating genetic diagnosis. Clinical presentations can vary significantly, ranging from mild to severe bleeding complications. Additionally, non-haemostatic symptoms may arise due to impaired synthesis of vitamin K-dependent proteins that play crucial roles in bone health and cardiovascular integrity. The review underscores the critical importance of appropriate treatment, which can enable affected individuals to sustain a normal quality of life.

The significance of genetic diagnostics as an integral component of the evaluation process for patients with rare congenital bleeding disorders is demonstrated by Pezeshkpoor et al,[4] who elucidate the mutational spectrum observed in patients with factor XI deficiency. Their analysis examines the variant detection rate in relation to factor XI levels, and they report 48 novel mutations within the FXI gene. The implications of large deletions affecting adjacent genes are discussed, reinforcing the necessity for accurate genetic diagnosis. The authors propose that elucidating the genetic aetiology of a particular disease enhances the understanding of its clinical manifestations, such as the significant variability observed in bleeding symptoms associated with FXI deficiency.

For individuals presenting with a clinical bleeding disorder and for health care professionals, attaining an accurate diagnosis holds considerable significance. The publication by Böckelmann et al [5] shows that considering an inherited platelet disorder as the cause of a bleeding disorder is essential. Therefore, platelet function analyses and molecular genetic analyses are elementary to identify the correct diagnosis, which enables to initiate the accurate therapy.

Assessing the risk of bleeding in certain factor deficiencies presents challenges due to the weak correlation between factor levels and the clinical bleeding phenotype. Furthermore, in specific rare bleeding disorders, the potential for thrombotic events must also be considered. Diagnostic assays that examine the coagulation process beyond the initial clot formation duration seek to assess the quality and stability of the clot or the overall clotting capacity. In the review conducted by Dreier et al,[6] the potential advantages of global coagulation assays (such as thrombin generation, thrombelastometry and thrombodynamics) for the diagnosis and monitoring of rare bleeding disorders are examined, elucidating the underlying mechanisms, benefits and limitations associated with these diagnostic tools.

We express our gratitude to all contributors and reviewers for their significant input to this theme issue concerning rare congenital bleeding disorders, which provides valuable insights into the clinical and genetic diagnosis, management and monitoring of such rare haemostatic conditions.

Publication History

Received: 26 August 2025

Accepted: 27 August 2025

Article published online:
15 October 2025

• References

• 1 Holstein K, Gutensohn K, Alesci RS, Krause M, Scholz U, Wermes C, Halimeh S. Overview on rare congenital bleeding disorders and epidemiological data from the German Haemophilia Registry (DHR) and a survey in Germany, Austria and Switzerland. Hamostaseologie 2025; 45: 378-389
• 2 Casini A, de Moerloose P. Management of young and ageing women with afibrinogenemia and hypofibrinogenemia. Hamostaseologie 2025; 45: 390-395
• 3 Raharimanana A, Cunat S, Falaise C, Oudot C, Fournel A, Dargaud Y. Hereditary combined deficiency of the vitamin K-dependent coagulation factors. Hamostaseologie 2025; 45: 396-404
• 4 Pezeshkpoor B, Banchev A, Preisler B. et al. Understanding congenital FXI deficiency: Genetic diagnosis and factor XI activity correlations. Hamostaseologie 2025; 45: 405-413
• 5 Böckelmann D, Friman T, Glonegger H, Wartiovaara-Kautto U, Zieger B. Late diagnosis of NBEAL2-related gray platelet syndrome in Finnish siblings with lifelong thrombocytopenia. Hamostaseologie 2025; 45: 414-418
• 6 Dreier T, Mehic D, Gebhardt J. Usefulness of global coagulation tests, thrombin generation and viscoelastic tests for assessing the bleeding phenotype in rare coagulation factor deficiencies. Hamostaseologie 2025; 45: 419-430