Overview on Rare Congenital Bleeding Disorders and Epidemiological Data from the German Haemophilia Registry (DHR) and a Survey in Germany, Austria, and Switzerland

Abstract

Introduction

Rare bleeding disorders (RBDs), defined as hereditary coagulation factor deficits other than haemophilia, are characterized by a heterogenous clinical phenotype ranging from life-threatening bleeding to thrombosis. There are uncertainties concerning treatment intensity and levels needed to achieve haemostasis, and epidemiological data from Germany, Austria, and Switzerland (GTH region) are scarce.

Methods

We performed a narrative literature review, focusing on bleeding phenotype and thrombotic risk. Epidemiologic data, including adults and children, and general treatment approaches have been collected via an online survey among GTH haemophilia centres (all categories) and the general information service of the German national registry (Deutsches Hämophilieregister, DHR).

Results

We provided an overview on RBDs, revealing that especially in FV, FVII, and FXI deficiencies, the correlation between factor levels and bleeding phenotype is poor. A thrombotic risk needs to be considered in FVII deficiency and afibrinogenaemia or dysfibrinogenaemia. The survey was completed by 34 centres from Germany, Austria, and Switzerland, and compared with 137 centres reporting data to the DHR. FVII deficiency was confirmed to be the most frequent, and FII deficiency was the rarest RBD in this region. For treatment, single factor concentrates were preferred over multifactor concentrates or plasma, and tranexamic acid was often part of the treatment. Approximately 30, 40, and <10% of patients with severe FV, FVII, and FXI deficiency (defined as factor level <10%), respectively, were receiving prophylactic treatment, suggesting an overall milder bleeding phenotype.

Conclusion

More detailed registry data could give insights into the treatment landscape of RBDs, considering the challenge of clinical trials in rare diseases.

Keywords

rare bleeding disorders - bleeding phenotype - thrombosis - treatment

Introduction

Rare bleeding disorders (RBDs) are traditionally defined as inherited coagulation factor deficiencies except haemophilia A or B.[1] RBDs are characterized by a heterogenous clinical phenotype ranging from life-threatening bleeding to thrombosis, dependent on the coagulation factor affected and severity of the deficiency.[2] [3] Due to the autosomal recessive inheritance in most cases, mainly homozygous or compound heterozygous affected persons (exhibiting bi-allelic genetic variants) may experience major spontaneous bleeding, with prevalences ranging from 1:500,000 for FVII deficiency to 1:2,000,000 for FII or FXIII deficiency.[2] [4] However, in certain factor deficiencies, also milder forms—often associated with mono-allelic genetic variants—may manifest with bleeding symptoms in particular clinical situations, such as invasive procedures, childbirth, or trauma.[5] [6] The prevalence of mild RBDs remains largely unknown and is likely underestimated.

In haemophilia A and B (factor VIII and factor IX deficiency) decisions on treatment and its intensity are primarily influenced by the residual factor levels, as these levels correlate with the risk of bleeding.[7] For the RBDs, particularly those involving factor V, VII, and XI deficiency, this correlation is poor, resulting in less clearly defined treatment indications.[2] [3] [5] Moreover, certain RBDs, notably afibrinogenaemia and factor VII deficiency, have been associated with thrombotic events,[8] thereby complicating the selection of an appropriate therapeutic approach.

We aimed to briefly review the recent literature to present an overview, focusing on bleeding phenotype, thrombotic risk, and treatment of the different coagulation factor deficiencies. Given the limited epidemiological data available for the ‘DACH’ region (Germany, Austria, Switzerland), the GTH haemophilia board obtained data from the German Haemophilia Registry via a general information service and conducted a survey among members of the GTH (Gesellschaft für Thrombose- und Hämostaseforschung, Society of Thrombosis and Haemostasis Research, in Germany, Austria, Switzerland).

Methods

Narrative Literature Review

A literature search was performed in December 2024 using the following key words: rare bleeding disorders, fibrinogen deficiency, hypofibrinogenaemia, dysfibrinogenaemia, afibrinogenaemia, factor V, factor VII, factor X, factor XI, factor XIII deficiency. Literature was included if it contained critical findings or recent data published within the last decade.

Survey

An online survey was administered to collect data on centres and approximate patient populations (categorized as: 0, 1–10, 11–40, >40, or in very rare conditions 0, 1–5, 6–10, >10) followed with the respective RBDs, including pediatric and adult patients, and general treatment approach. Approximate numbers were collected for all patients with the respective deficiency and for patients with fibrinogen levels <1 g/L or factor activity <10% (FII, V, VII, X, XI, XIII) to simplify the survey, although this definition of ‘severe’ deficiencies differs from the European Network of Rare Bleeding Disorders and ISTH-SSC proposed definition for severe deficiencies (undetectable levels of fibrinogen, FII, FV, FXIII; and levels of FVII and FX <10%).[5] [9] The survey was distributed to all members of the GTH haemophilia board and in a second wave to all GTH members (health care professionals, HCPs) via the monthly newsletter. HCPs from all categories of haemophilia centres were invited to participate. The results of the survey were aggregated and presented anonymously; no individual patient data were collected; therefore, no ethics approval was necessary. Patient numbers were derived from the categories, resulting in the presentation of patient population ranges.

The German Haemophilia Registry (Deutsches Hämophilieregister, DHR) is a nationwide database, located at the Paul-Ehrlich-Institut and incorporated in the German Transfusion Act (Transfusionsgesetz, TFG). For HCP managing individuals with bleeding disorders, it is obligatory to submit summarized data or—as soon as the patient has given informed consent—single patient data. Data on rare coagulation factor deficiencies other than haemophilia can be reported as single patient data beginning 2019 when the registry was updated.[10] For the annual report,[11] a data extraction has been conducted in September 2024. Cumulative data in accordance with section 21 of the TFG, derived from the summary data collection of 2022, will be reported here.

Results

Literature Review

This narrative review focuses on rare single coagulation factor deficiencies apart from haemophilia A and B. The combined deficiencies of factor V/VIII and of the vitamin K dependent factors or fibrinolytic disorders are beyond the scope of this review. Key results are summarized in [Table 1].

Table 1 Key findings from the narrative literature review

Affected coagulation factor	Prevalence of severe, bi-allelic deficiency[14]	Correlation of factor level with bleeding phenotype	Thrombotic risk	Treatment	Factor levels associated with low bleeding risk	Factor trough levels needed to be maintained for major surgery
Fibrinogen - Afibrinogenaemia 1A - Afibrinogenaemia 1B - Hypofibrinogenaemia 2 - Dysfibrinogenaemia 3A - Dysfibrinogenaemia 3B	1:1,000,000[12] [13]	Strong in hypofibrinogenaemia (2)	High in afibrinogenaemia and dysfibrinogenaemia (1B and 3B)	Fibrinogen concentrate	>0.7–1 g/L[2] [16] >1–1.5 g/L[24] >0.5 g/L[4] [38]	>1.5 g/L2 >1.5–2 g/L[20] >1 g/L[24] >1–1.5[38]
Factor II (prothrombin)	1:2,000,000	Strong	In dysprothrombinaemia with thrombotic phenotype[23]	PCC	>20%[24] >30%[38]	>20%[2] [24] [38]
Factor V	1:1,000,000	Weak	With certain mutations, e.g., FV Besacon	Plasma	>12–15%[2] [5] >15–20%[4] [24] >20%[38]	>15–20%[2] [24] >25%[38]
Factor VII	1:500,000	Weak	Possibly with overtreatment in certain mutations (e.g., FVII Padua)	rFVIIa or pd FVII concentrates	>8–25%[2] [5] >10–20%[24] >20%[38] >15–20%[4]	>20%[2]
Factor X	1:1,000,000	Strong	With repeated PCC?	Pd FX, pd FIX/X concentrates (or PCC)	>10–56%[2] [5] >40%[39] >20%[24] [38] >15–20%[4]	>20–30%[2] >20%[24] [38]
Factor XI	1:1,000,000 1:30,000	Very weak	With FXI concentrate?	Plasma or pd FXI concentrates	>25%[2] [5] >20%[24] >15–30%[38] >15–20%[4]	Unknown[2] >30%[38]
Factor XIII	1:2,000,000	Strong		Pd or rFXIII concentrates	>3–15%[2] [5] >10–20%[24] >20%[38] >3–5%[4] > 30%[55]	>20%[2] [38] >50%[56]

Abbreviation: PCC, prothrombin complex concentrates.

Fibrinogen Disorders

Fibrinogen plays a crucial role in haemostasis and thrombosis, in interaction between coagulation factors and blood cells[12] as well as in wound healing and inflammation.[13] Congenital fibrinogen disorders are caused by mutations in the FGA, FGB, or FGG genes on chromosome 4 and are classified as afibrinogenaemia, hypofibrinogenaemia, dysfibrinogenaemia, or hypodysfibrinogenaemia based on the levels of functional and antigenic fibrinogen. Quantitative disorders are afibrinogenaemia, characterized by a complete absence of fibrinogen, and hypofibrinogenaemia, a concomitant reduction of functional and antigenic fibrinogen. Qualitative disorders include dysfibrinogenaemia characterized by reduced functional fibrinogen with normal antigenic levels and hypo-dysfibrinogenaemia defined by a discordant decrease of functional and antigenic fibrinogen ([Table 2]).[14] Prevalence of afibrinogenaemia has been estimated to be 1:1,000,000, while the prevalences of hypofibinogenaemias and dysfibinogenaemias remain largely unknown due to the possibility of many cases being asymptomatic.[13] [14] In afibrinogenaemia, undetectable levels of fibrinogen activity and antigen may result in a severe bleeding phenotype with spontaneous intracranial, intramuscular, and joint bleeds. However, thrombotic events may also occur in afibrinogenaemia with thrombotic phenotype (type 1B, [Table 2]).[13] [14] In hypofibrinogenaemia, bleeding risk correlates with fibrinogen levels.[15] [16] A fibrinogen activity of >0.7 g/L seems to be sufficient to protect from spontaneous bleeds with most patients with fibrinogen levels >1 g/L being asymptomatic,[5] which could only be partly confirmed in a large prospective multicentre study (PRO-RBDD).[16] In dysfibrinogenaemia and hypo-dysfibrinogenaemia, clinical phenotype may manifest as bleeding and/or thrombotic events, depending on the underlying mutation.[14] [16] [17] [18] In the event of a thrombotic episode, anticoagulation is recommended despite low functional fibrinogen; in type 3B patients even long-term anticoagulation should be considered.[18] The qualitative fibrinogen defects follow an autosomal dominant inheritance in contrast to the quantitative defects with autosomal recessive inheritance, with the bi-allelic variants resulting in severe phenotype.[16] [19]

Table 2 Definition of fibrinogen disorders according to ISTH/SSC laboratory and clinical criteria[13]

Quantitative
1 Afibrinogenaemia  1A. Afibrinogenaemia (bleeding phenotype or asymptomatic)  1B. Afibrinogenaemia with thrombotic phenotype
2 Hypofibrinogenaemia  2A. Severe hypofibrinogenaemia (functional fibrinogen level <0.5 g/L)  2B. Moderate hypofibrinogenaemia (functional fibrinogen level 0.5–0.9 g/L)  2C. Mild hypofibrinogenaemia (functional fibrinogen level 1 g/L—lower limit of normal value)  2D. Hypofibrinogenaemia with fibrinogen storage disease
Qualitative
3 Dysfibrinogenaemia  3A. Dysfibrinogenaemia with bleeding phenotype, asymptomatic or thrombotic events not fulfilling criteria for 3B  3B. Thrombosis-related dysfibrinogenaemia—carriers of a thrombotic fibrinogen mutationa or suffering from thrombotic events with a first-degree familial thrombotic history (relatives with the same genotype) without any other thrombophilia
4 Hypodysfibrinogenaemia  4A. Severe hypodysfibrinogenaemia (antigenic fibrinogen level <0.5 g/L)  4B. Moderate hypodysfibrinogenaemia (antigenic fibrinogen level between 0.5 and 0.9 g/L)  4C. Mild hypodysfibrinogenaemia (antigenic fibrinogen level between 1 g/L and lower limit of normal value)

Note: ^aFibrinogen Dusart, Fibrinogen Caracas V, Fibrinogen Ijmuiden, Fibrinogen New York I, Fibrinogen Nijmegen, Fibrinogen Naples at homozygous state, Fibrinogen Melun.

Bleeding is the most frequent symptom of fibrinogen disorders and bleeding treatment is largely based on replacement of fibrinogen. Several plasma-derived fibrinogen concentrates are available offering safe and effective bleeding treatment, superior over plasma infusions or cryoprecipitate.[20] Pharmacokinetic studies suggested a dose of approximately 70 mg/kg body weight in afibrinogenaemia to achieve a fibrinogen level of approximately 1.3 g/dL with a half-life of 74 hours, but with remarkable individual variability.[20] These studies confirmed that targeting a pre-operative peak level of 1 g/L for minor and 1.5 to 2.0[21] g/L for major surgeries was sufficient to achieve haemostasis. As thrombotic risk is a major concern in fibrinogen disorders, it appears to be not primarily linked to fibrinogen replacement. In contrast, biomarkers for coagulation activation decreased after fibrinogen replacement in afibrinogenaemia with thrombotic phenotype.[20] This finding, together with the high prevalence of cerebral haemorrhage observed in an international multicentre cross-sectional study, may support the use of prophylactic treatment in afibrinogenaemia with a severe bleeding phenotype.[22]

Factor II Deficiency

Congenital factor II (FII) or prothrombin deficiency is extremely rare, and prevalence is estimated to be 1:2,000,000 for the severe forms. FII levels correlate with bleeding phenotype. Patients with FII with levels <5% typically experience early and severe symptoms; however, complete absence of FII is incompatible with survival.[19] [23] FII deficiencies are classified as type 1, quantitative disorders, and type 2, qualitative disorders or dysprothrombinaemias (characterized by a reduced prothrombin activity with normal antigen; some authors proposed an FII activity/antigen ratio of <0.7 for diagnosis[24]), which may show milder bleeding phenotypes.[25] [26] A thrombotic phenotype also is observed in dysprothrombinaemias, associated with certain mutations that affect the pro- and anticoagulant activities of thrombin.[25]

Due to the rarity of the disease, no single factor concentrate has been developed and prothrombin complex concentrates (PCC) are commonly used to treat or prevent bleeds.[23] For major surgeries, it is recommended to maintain a level of >20%, which can be achieved by 20 to 40 IU/kg PCC before surgery and subsequently 10 to 20 IU/kg every 48 hours.[2]

Factor V Deficiency

Factor V (FV) functions as a cofactor in the prothrombinase complex of FXa and FVa on the platelet membrane, together with calcium and phospholipids, to accelerate the activation of prothrombin to thrombin, promoting haemostasis. The majority of FV circulates in plasma, but approximately 20% of FV is stored in α granules of platelets. Synthesis occurs primarily in liver cells, but megakaryocytes also contribute to platelet FV storage.[27] [28] Correlation between plasma FV activity and bleeding phenotype is poor, partly explained through platelet FV activity or modulating effect of tissue factor pathway inhibitor (TFPI).[28] Severe bleeding episodes such as intracranial bleeds may occur, resulting in a need for prophylaxis.

FV also plays a role in the inactivation process of coagulation as substrate and cofactor for activated protein C (APC) for inactivating FVa and FVIIIa. Apart from the thrombophilic FV Leiden mutation (APC resistance), there are mutations in the F5 gene, leading to FV deficiency and a thrombophilic state, e.g., FV Besançon.[29] FV also exerts anticoagulant properties through its interaction with TFPIα. It appears that FV is essential for stabilization of TFPIα in circulation and acts together with the TFPIα cofactor protein S. A splicing isoform of FV, FV short, serves as carrier and cofactor for TFPIα and its overexpression, like in East Texas bleeding disorder, can result in bleeding and prolongation of coagulation tests despite normal FV activity.[30]

Current therapeutic options for FV deficiency are the transfusion of plasma or platelets as there is currently no single factor concentrate available. Virus-inactivated plasma is the preferred option for planned and long-term treatment.[28] To achieve FV levels of >15 to 20% during surgery, 15 to 25 mL/kg plasma needs to be infused before surgery followed by 10 mL/kg every 12 hours. Mucosal bleeding may also be effectively managed with tranexamic acid.[2] Few cases have been documented demonstrating the successful off-label use of rFVIIa.[31] In the event of severe intracranial haemorrhage, orthotopic liver transplantation has been reported as curative intervention for severe FV deficiency.[2] [32]

Factor VII Deficiency

Activated factor VII (FVII) in complex with tissue factor (TF) plays a critical role in the initiation of haemostasis and only small amounts are needed for this process.[33]

With a prevalence of 1:500,000 for the severe form, inherited factor VII (FVII) deficiency is the most prevalent RBD. The correlation between FVII activity and bleeding symptoms is rather weak and conflicting associations have been reported in the literature. Recent real-world data from the Netherlands have, for the first time, observed a moderate correlation (r = − 0.515, p < 0.01) between FVII activity and bleeding phenotype. The previously established threshold of 30% FVII activity for being more likely asymptomatic[5] was found to be inaccurate in 57% of patients in this cohort.[34] In women with hereditary FVII deficiency no correlation of FVII levels with bleeding events was observed.[35] Therefore, clinically relevant thresholds of FVII activity are still debated. As bleeding tendency remains stable during life, the time of onset of first symptoms seems to be a robust predictor of the subsequent bleeding phenotype.[33]

A correlation between genetic variants and FVII levels has been observed in several studies indicating that heterozygous pathogenic variants are associated with lower FVII levels than common variants,[36] [37] however, without an association to the bleeding phenotype.

In some cases, thrombotic events have been documented in association with FVII deficiency. Thrombotic events were more prevalent with certain F7 variations such as FVII Padua (Arg304Gln mutation),[38] possibly due to underestimation of FVII activity and overtreatment. In these cases, usually a type 2 deficiency is found with normal antigen levels and activity levels dependent on the tissue thromboplastin reagent. Patients usually exhibit a mild bleeding phenotype. Therefore, the use of recombinant human TF preparations and highly sensitive clotting assays are recommended for diagnosis,[39] while the bleeding history is essential for treatment decisions as well as careful evaluation of thrombotic risk. Genetic testing is helpful for identifying mutations associated with thrombotic risk as well as evaluation of other clinical and molecular thrombotic risk factors.

For treatment and prevention of bleeds, several therapeutic options exist, including recombinant activated FVII (rFVIIa) or plasma-derived FVII concentrates.[2] Plasma or PCC may be considered if FVII concentrates are not available. rFVIIa should be administered in doses of 15 to 30 µg/kg before surgery and every 4 to 6 hours in the first 24 hours and then every 8 to 12 hours; pdFVII at 10 to 40 IU/kg in the same intervals[2] to maintain FVII levels of >20%. These recommendations pertain primarily to major surgery and should be reserved for patients at high risk of bleeding; other surgical procedures may be managed with tranexamic acid. The necessity for repeated administration should be carefully considered.[40] Despite the short plasma half-life of FVII of 4 to 6 hours, prophylactic treatment with two to three infusions per week seems to be effective, suggesting that FVII might be retained in the extravascular space or bind to TF.[33]

Factor X Deficiency

Factor X (FX) plays a central role in the coagulation process, activating thrombin within the tenase complex. Consequently, the complete absence of FX is incompatible with survival. FX deficiency is an autosomal recessive bleeding disorder; a good correlation between factor levels and bleeding severity has been observed.[5] [6] Prevalence is estimated to be 1:1,000,000. Patients with severe, bi-allelic deficiency (FX <10%) are at risk of intracranial bleeds, sometimes being the presenting symptom at birth. Other bleeding symptoms include joint, gastrointestinal, and muscular bleeds, as well as menorrhagia. Patients with an FX activity of >40% are more likely asymptomatic.[41] The diagnosis and treatment of FX deficiency will benefit from a more complete understanding of the correlation between the F10 genotype and the bleeding severity.[42] To facilitate this understanding, an interactive database for FX variants has been established.[43]

Current treatment options include plasma, PCC, a dual factor concentrate (FIX/X), available in Switzerland, or a single plasma derived FX concentrate (pdFX). Half-life of FX is approximately 30 hours. Efficacy and safety have been proven in several prospective and retrospective studies revealing no cases of thrombosis or inhibitors with treatment.[44] For bleeding, treatment doses of 25 IU/kg are suggested; in the context of surgery, doses of 30 to 50 IU/kg have been used. Prophylaxis has been shown to be effective with doses of 40 IU/kg twice weekly in children <12 years and 25 IU/kg twice weekly in patients >12 years of age, followed by tailored dosing to achieve FX trough levels of >5%.[44]

In case pdFX is not available, PCC in an initial dose of 20 to 30 IU/kg prior to surgery is recommended with subsequent doses of 10 to 20 IU/kg/24 hours if required.[2] Caution is needed with repetitive doses of PCC as factors with longer half-life (e.g., FII) might accumulate and contribute to thrombotic risk.

Factor XI Deficiency

Factor XI (FXI) is part of the intrinsic pathway and involved in thrombin generation, prevention of premature fibrinolysis, and the proinflammatory kallikrein-kinin system. Activation occurs by FXIIa, thrombin, or through auto-activation by FXIa in the presence of polyanions.[45] FXIa activates FIX to FIXa, contributing to thrombin generation. FIX activation is not exclusively dependent on FXIa, but is also catalyzed by the FVIIa/TF pathway, which may help to explain why FXI does not seem to play a pivotal role in thrombin generation.[45]

Prevalence of severe FXI deficiency is estimated to be 1 to 55:1,000,000, but it is more prevalent in the Ashkenazi and Iraqi Jewish population, where individuals with homozygosity or compound heterozygosity may be seen in 1:450 (0.2%).[45] [46] Bleeding severity does not correlate with FXI levels. Bleeding is more prevalent in tissues with high fibrinolytic activity (e.g., urogenital tract, oral cavity, or tonsils) and antifibrinolytics such as tranexamic acid have been shown to be effective.[2] [47]

Treatment is based on antifibrinolytic medications, plasma, and a single plasma derived FXI concentrate.

As some thrombotic events have been reported in association to FXI replacement,[48] [49] precautions with replacement therapy are recommended: indication for replacement should be carefully weighed against thrombotic risk factors, considering the individual bleeding history of the patient and the surgical site's fibrinolytic activity. The initial dose of FXI concentrate should not exceed 10 to 15 IU/kg and should be monitored for safety and efficacy. Thromboprophylaxis should be considered according to local guidelines.[49] For minor surgery, tranexamic acid alone may be sufficient. However, the combination of tranexamic acid and FXI concentrates should be avoided to mitigate the thrombotic risk.[26] The recommended dose for plasma is 15 to 25 mL/kg².

Patients with severe FXI deficiency seem to be protected against venous thrombosis, as shown in a cohort of 219 patients with FXI deficiency compared with the general population,[50] as well as stroke,[51] but not against myocardial infarction.[47] [52]

Factor XIII Deficiency

Factor XIII as fibrin stabilizing factor has multiple functions in the coagulation system as well as in inflammation and angiogenesis. It circulates in plasma in tetrameric form (FXIII-A₂B₂) with two potentially active A subunits (FXIII-A) and two carrier/inhibitory B subunits (FXIII-B).[53] FXIII-A is primarily synthesized in cells of bone marrow origin, e.g., megakaryocytes, monocytes, macrophages, and osteoblasts, and stored in platelets, whereas FXIII-B is synthesized in the liver. In plasma, FXIII is bound to fibrinogen and upon formation of fibrin and activation by thrombin and calcium, the B subunit is released and the active A subunit can act for fibrin cross-linking and incorporating antifibrinolytic proteins in the clot, making the clot resistant to fibrinolysis.[53]

Prevalence of severe FXIII deficiency is estimated to be 1:1–2,000,000. In more than 95% of cases, severe FXIII deficiency is caused by absence of the XIII-A subunit in plasma, platelets, monocytes, and placenta.[54] Typical clinical symptoms are umbilical cord bleeds in the neonatal period, pregnancy complications, and intracranial haemorrhage (ICH) with an incidence of up to 30%.[54] [55] Also, heterozygous carriers, especially women, may experience bleeding with haemostatic challenges during menstruation or childbirth.[56] In severe FXIII deficiencies, risk of abortion is high if FXIII levels are not maintained above 10%.[54] Laboratory diagnosis of FXIII deficiency is achieved by measuring FXIII activity and antigen. It is important to mention that FXIII deficiency it is not detectable via prothrombin time (PT) and activated partial thromboplastin time (aPTT).

For treatment and prevention of bleeds, a plasma-derived FXIII concentrate is available and, in some regions, also a recombinant FXIII-A₂ concentrate. In case FXIII concentrates are not available, cryoprecipitate or plasma may be used. In severe FXIII deficiency usually prophylaxis is recommended because of the high risk for ICH.[2] It has been demonstrated that an FXIII activity of >15% is protective against major bleeds; however, whether this trough level needs to be achieved during prophylaxis is not clear.[57] Patients with FXIII activity >30% are more likely to remain asymptomatic.[57] Due to the long half-life of FXIII (5–11 days), prophylactic replacement (e.g., 10–35 IU/kg) needs to be infused every 4 to 6 weeks, with potentially shorter intervals during pregnancy.[54] For surgery, after an initial dose of 10 to 40 IU/kg, levels of >20% should be maintained.[2] Others propose to aim for levels >50% during and after surgery to prevent bleeding and promote wound healing.[58]

Survey Results: Overview on Patient Populations and Treatment Approaches for RBDs in Germany, Switzerland, and Austria

The survey was completed by 34 HCPs representing 34 haemophilia centres in Germany, Switzerland, and Austria. Of these, 17 centres (50%) were classified as large (managing >40 patients with severe haemophilia), 12 (32%) as medium-sized (10–40 patients), 4 as small (<10 patients), and 1 did not report patient numbers. Regarding the type of institution, 20 centres were affiliated with university hospitals, 6 with tertiary community hospitals, and 8 operated as specialized private practices. In 12 centres adults were treated exclusively, 10 focused solely on children, and 12 provided care for adults and children. Most of the responding centres report their data annually to national registries, 97% of the German centres to the DHR.

The estimated patient populations (all severities and with a factor level of <10% or fibrinogen <1 g/L) treated across the 34 centres, and the estimated numbers of patients on prophylaxis are summarized in [Table 3]. The numbers are presented as ranges due to their collection in categories (e.g., 0, 1–10, 11–40, > 40). The most commonly deficient coagulation factor was factor VII, followed by fibrinogen, FX, FXI, and FXIII. Factor II (prothrombin) deficiency was identified as exceedingly rare.

Table 3 Estimated numbers of patients with RBDs registered across 34 centres in Germany, Austria, and Switzerland and estimated number of patients on prophylaxis

Type of coagulation factor deficiency	Number of patients, all severities, range	Number of patients with fibrinogen <1 g/L or factor level <10%, range	Number of patients on prophylaxis, range
Fibrinogen	209–563[a]	44–136b	17–65
Factor II	23–131b	5–25	2–10
Factor V	130–422c	27–71	4–20
Factor VII	589–991d	61–161b	21–85
Factor X	181–582c	23–95	20–80
Factor XI	217–573[a]	27–100	1–5
Factor XIII	247–574e	31–95	23–75

Abbreviation: RBDs, rare bleeding disorders.

Notes: Of the 34 centres, 2, 1, 2, 4, 0, 1, and 1 centres could not report patient numbers for fibrinogen, FII, FV, FVII, FX, FXI, and FXIII deficiency, respectively.

^a Three centres reported >40 patients; ^bOne center reported >10 patients; cTwo centres reported >40 patients; ^d11 centres reported >40 patients; ^eFour centres reported >40 patients.

The number of patients receiving regular prophylaxis was notably lower than the total number of patients with severe factor deficiencies, most accentuated with approximately 30, 40, and <10% of patients with severe FV, FVII, and FXI deficiency (factor level <10%), respectively, receiving prophylactic treatment ([Table 3]). However, information regarding bleeding phenotypes was not collected.

The general approaches to prophylaxis and bleeding treatment across centres are summarized in [Fig. 1]. Centres treating patients with the respective factor deficiencies reported the use of various haemostatic agents. Tranexamic acid was frequently used for the management of bleeding episodes and, in some cases, for prophylaxis. Whether it was administered as monotherapy or in combination with other treatments was not specified. When available, specific factor concentrates were preferred over multi-factor concentrates or plasma for management of these conditions. For severe FV deficiency, liver transplantation has been mentioned as an option in case of recurrent intracranial haemorrhage; also activated prothrombin complex concentrate (aPCC) and rFVIIa have been suggested for bleeding treatment in severe FV deficiency. For bleeding treatment in severe FXI deficiency, two HCPs suggested rFVIIa. Two HCPs suggested prophylactic anticoagulation in addition to replacement with fibrinogen concentrate in afibrinogenaemia.

Fig. 1 Haemostatic agents used for treatment of factor deficiencies. Displayed are numbers of centres using the different medications for each factor deficiency for prophylaxis and on-demand treatment. DDAVP, desmopressin; PCC, prothrombin complex concentrate; pd FVII, plasma-derived FVII concentrate; rFVIIa, recombinant activated FVII concentrate.

Epidemiological and Treatment Data from the German Haemophilia Registry (DHR)

In 2022, the DHR received data from 137 German centres on 17,516 patients, including 4,234 patients with RBDs. The majority of patients had haemophilia A (5,409) or B (1,018) or von Willebrand disease (6,855). Of all patients, 81% were reported in collective, 19% in individual reports.

[Table 4] presents the number of registered and treated patients, along with the total amount of haemostatic agents used. Severity of RBDs was not captured in the collective report, and low patient numbers in certain entities limited the feasibility of data extraction for research purposes.

Table 4 Number of patients registered in the DHR and amount of haemostatic agents used in 2022

Factor deficiency	Number of patients registered N, all (individual report)	Number of patients treated	Amount of medication used in treated patients
Fibrinogen (FI)  • Children  • Adults	512 (17) 173 339	13 102	Fibrinogen concentrate (g) 594 3,922
Prothrombin (FII)  • Children  • Adults	111 (2) 20 91	0 65	PCC (IU) 0 205,800
Factor V  • Children  • Adults	400 (3) 119 281	0 9	FFP (TU) 0 60
Factor VII  • Children  • Adults	2,070 (110) 508 1,562	38 136	PCC (IU) 0 2,000	pdFVII (IU) 610,800 2,848,000	rFVIIa (mg) 2,209 3,916
Factor X  • Children  • Adults	211 (19) 67 144	10 25	PCC (IU) 0 47,900	pdFX 301,350 161,200
Factor XI  • Children  • Adults	202 (3) 51 151	0 13	FFP (TU) 0 48	FEIBA (IU) 0 0
Factor XIII  • Children  • Adults	728 (58) 247 481	26 102	pdFXIII 399,000 1,611,250

Abbreviations: DHR, German Haemophilia Registry; FFP, fresh frozen plasma; IU, international units; pd plasma derived; PCC, prothrombin complex concentrate; rFVIIa recombinant activated FVII concentrate; TU, transfusion unit.

FVII deficiency is the most prevalent RBD. Yet only 8.4% of registered patients received treatment, with FXI deficiency similarly showing a 6.4% treatment rate. In contrast, treatment rates were higher for fibrinogen (22.5%), FII (58.6%), FX (16.6%), and FXIII (17.6%) deficiencies.

Discussion

The survey among haemophilia centres in Germany, Austria, and Switzerland and data from the DHR provided insights into the prevalence and management strategies of RBDs. As nearly all German centres contribute to the DHR, the epidemiologic data obtained through our survey are also reflected in the DHR. In our survey, 34 centres reported data, compared with 137 centres in the DHR, but with more granularity in our survey. Additionally, centres from Austria and Switzerland are represented in our survey.

The survey data from the DHR and the literature[1] support that FVII deficiency is the most common RBD. Only a low proportion (8.4%) of patients with FVII deficiency were treated in the DHR. Severity is not reported in the summary data of the DHR, but the surveyed centres (n = 34) reported that approximately 30% of patients with FVII deficiency had a severe form. Consistent with this, our survey revealed that only 13% of all patients were on prophylaxis. A similar picture is seen with FV and FXI deficiency. This might be attributed to the poor correlation of factor activity with bleeding phenotype in FV, FVII, and FXI deficiency and a generally milder bleeding phenotype. Therefore, no clear recommendation for prophylaxis has been provided for severe FVII deficiency in international guidelines. A UK guideline recommends considering prophylaxis in patients with a personal or family history of severe bleeding or with FVII activity of <1%,[26] while no specific recommendations exist for prophylaxis in FV or FXI deficiency.[26] The low treatment rate may in part reflect the restricted availability of specific factor concentrates, their pharmacokinetic limitations (such as short half-life), or concerns regarding thrombotic risk. A low proportion of patients receiving prophylaxis has also been described in a review by A. Shapiro for FV, FVII, and FXI deficiencies. The author postulated that infrequent severe bleeding episodes and a poor correlation between bleeding risk and factor levels may account for this observation, and emphasized the importance of considering the bleeding phenotype.[59] For FXI deficiency, even the indication for prophylaxis has been questioned due to a very low rate of spontaneous bleeds.[59] However, for severe FXIII deficiency, prophylaxis is standard of care due to the high risk for life-threatening bleeds, e.g., ICH,[59] which is also reflected in our survey, in which estimated numbers of patients with severe deficiency and number of patients on prophylaxis are consistent.

Our survey as well as data from the DHR confirm that severe FII deficiency is an ultra-rare RBD with 6 to 30 severe patients followed in surveyed centres and 111 patients of all severities in the DHR. If diagnosed, bleeding phenotype appears to be more severe with 58% of patients treated.

Treatment approaches in our survey are consistent with recommendations in the literature.[2] [26] In our survey, HCPs also prefer single factor concentrates over PCC or plasma if available. Due to the absence of data on administered doses and intended factor levels, a detailed comparison with guideline recommendations could not be performed. Successful liver transplantation as definite treatment for severe FV deficiency with ICH has been reported as single cases in the literature,[32] which has been also suggested by one centre in our survey. APCC does not contain FV, but whether a higher amount of preactivated coagulation factors may mitigate bleeding risk in severe FV deficiency remains unclear. There have been also some cases reported with successful use of off-label rFVIIa for bleeding treatment in severe FV deficiency.[31] The use of off-label rFVIIa for surgery in severe FXI deficiency has been reported in a small cohort of 10 patients; low doses of 15 to 20 µg/kg have been shown to be effective in combination with tranexamic acid, and no thrombotic events occurred.[60] This might also be an option in the case of FXI inhibitors or allergic reactions to plasma.

Future perspectives for RBDs with severe bleeding needing prophylaxis might be the use of rebalancing non-factor therapies like anti-TFPI antibodies, antithrombin-siRNA, or protein S lowering agents.[61] Although theoretical considerations and in vitro studies suggest a potential effect,[62] the safety and efficacy of this approach require evaluation in clinical trials.

Limitations of our survey include the reporting of only approximate data in categories and general treatment approaches; and a low proportion of haemophilia centres took part in the survey which might be not representative for the German-speaking countries. Patient numbers were self-reported and estimated by centres; therefore, real numbers might be higher or lower. To better characterize the treatment landscape of RBDs, comprehensive registry data are essential to advance the field. The DHR is a registry implemented in the German Transfusion Act with existing infrastructure. If most of the centres report their data to the DHR as individual patient data report, it could be analyzed in detail with sufficient numbers of patients for a research data export without violating data protection laws. With analysis of bleeding rates, it would be possible to evaluate whether low rates of prophylactic treatment, e.g., in FVII deficiency, reflect more likely undertreatment or a less severe bleeding phenotype. Real-world data from the Netherlands indicate that over 50% of patients with RBD not receiving haemostatic treatment—and still 28 and 19% of those receiving treatment for dental or surgical procedures, respectively—experience bleeding episodes, supporting the possibility of undertreatment.[63]

Additionally, it would be worth collecting data on management of surgeries to better define necessary levels of the different coagulation factors to achieve perioperative haemostasis.

In conclusion, we provide an overview on RBDs with focus on bleeding phenotype and thrombotic risk. Our findings highlight that, particularly in FV, FVII, and FXI deficiencies, the correlation between factor levels and bleeding phenotype is poor, and a thrombotic risk needs to be considered especially in FVII deficiency and afibrinogenaemia or dysfibrinogenaemia. Genetic testing might contribute to risk stratification.[64] ICH is a common complication of severe FXIII deficiency with prophylaxis needed in a high proportion of patients. The reasons for the low rate of treatment and prophylaxis in certain RBDs need to be further explored and might be answered by registry data, e.g., the DHR. Additional data are necessary to improve understanding and inform treatment strategies for patients with RBDs.

Conflict of Interest

K.H. received grants for research and clinical studies from Sobi, Bayer, NovoNordisk, Roche, GWT, CSL Behring, and Sanofi (to institution) and honoraria for lectures or advisory boards from Bayer, Biomarin, Biotest, CSL Behring, LFB, NovoNordisk, Pfizer, Roche/Chugai, Sobi, and Takeda (to person).

K.G. received honoraria for lectures from Werfen GmbH, CSL Behring, MD Horizonte, and Universitätsklinik Hamburg-Eppendorf; travel and congress support from Biomarin, Biotest, Chugai/Roche, Delab, INSTAND e.V., Novo Nordisk, MD Horizonte, SOBI, and Takeda; and research grants from Bayer, Novartis, Octapharma, Roche, SOBI, and Takeda.

R.S.A. received grants for research and clinical studies from NovoNordisk, Novartis, CSL Behring, Takeda, Grifols, and Bayer (to institution) and honoraria for lectures or advisory boards from Bayer, CSL Behring, LFB, Pfizer, Octapharma, Sobi, Takeda, Kedrion, Sanofi, and Novartis (to person).

M.K. received honoraria for lectures and advisory boards from Bayer Vital, BMS/Pfizer, CSL Behring, Daiichi-Sankyo, Novo Nordisk, Pfizer, Roche, and SOBI.

U.S. received honoraria for lectures from Pfizer Pharma, Takeda Pharma, SOBi Pharma, and Bayer Vital, advisory boards from Chugai Pharma, and SOBI Pharma, and congress support from Takeda.

C.W. received honoraria for lectures from NovoNordisk, Octaphama, Takeda, CSL Behring, Bayer, Biotest, LFB, and Roche, for advisory boards from Sobi, NovoNordisk, Octaphama, Takeda, CSL Behring, Roche, and Pfizer, and support for attending meetings or travel from Sobi, NovoNordisk, Octaphama, Takeda, CSL Behring, Bayer, Biotest, LFB, and Roche.

S.H. received research grants from Bayer, Baxalta Innovations (Now Shire), Biotest, CSL Behring, Novo Nordisk Pharma, Octapharma, and Pfizer Pharma; speakers honoraria from Bayer, Baxalta Innovations (Now Shire), Biotest, CSL Behring, Novartis, Novo Nordisk, Octapharma, Pfizer, and Roche; Swedish Orphan Biovitrum; honoraria for advisory boards from Bayer, Biotest, CSL Behring, Novo Nordisk, Octapharma, Chugai, and Swedish Orphan Biovitrum.

Authors' Contribution

All authors contributed to designing the survey. K.H. extracted and analyzed data and wrote the first draft of the manuscript. All authors contributed to manuscript writing and approved the final version.

• References

• 1 Peyvandi F, Palla R, Menegatti M, Mannucci PM. Introduction. Rare bleeding disorders: general aspects of clinical features, diagnosis, and management. Semin Thromb Hemost 2009; 35 (04) 349-355
• 2 Menegatti M, Peyvandi F. Treatment of rare factor deficiencies other than hemophilia. Blood 2019; 133 (05) 415-424
• 3 Tavasoli B, Zangooie A, Safdari SM. et al. Correlation between phenotype and coagulation factor activity level in rare bleeding disorders: a systematic review. Semin Thromb Hemost 2025; 51 (02) 180-195
• 4 Mannucci PM, Duga S, Peyvandi F. Recessively inherited coagulation disorders. Blood 2004; 104 (05) 1243-1252
• 5 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
• 6 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
• 7 Srivastava A, Santagostino E, Dougall A. et al. WFH Guidelines for the Management of Hemophilia, 3rd edition. Haemophilia 2020; 26 (S6): 1-158
• 8 Girolami A, Ruzzon E, Tezza F, Scandellari R, Vettore S, Girolami B. Arterial and venous thrombosis in rare congenital bleeding disorders: a critical review. Haemophilia 2006; 12 (04) 345-351
• 9 Peyvandi F, Di Michele D, Bolton-Maggs PHB, Lee CA, Tripodi A, Srivastava A. Project on Consensus Definitions in Rare Bleeeding Disorders of the Factor VIII/Factor IX Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. Classification of rare bleeding disorders (RBDs) based on the association between coagulant factor activity and clinical bleeding severity. J Thromb Haemost 2012; 10 (09) 1938-1943
• 10 Duda H, Hesse J, Haschberger B, Hilger A, Keipert C. The German Hemophilia Registry: growing with its tasks. J Clin Med 2020; 9 (11) 3408
• 11 Paul-Ehrlich-Institute. dhr-annual report 2022–2023. Accessed January 29, 2025 at: https://www.pei.de/DE/regulation/melden/dhr/dhr-node.html
• 12 Kattula S, Byrnes JR, Wolberg AS. Fibrinogen and fibrin in hemostasis and thrombosis. Arterioscler Thromb Vasc Biol 2017; 37 (03) e13-e21
• 13 de Moerloose P, Casini A, Neerman-Arbez M. Congenital fibrinogen disorders: an update. Semin Thromb Hemost 2013; 39 (06) 585-595
• 14 Casini A, Undas A, Palla R, Thachil J, de Moerloose P. Subcommittee on Factor XIII and Fibrinogen. Diagnosis and classification of congenital fibrinogen disorders: communication from the SSC of the ISTH. J Thromb Haemost 2018; 16 (09) 1887-1890
• 15 Casini A, Al-Samkari H, Hayward C, Peyvandi F. Rare bleeding disorders: advances in management [in Dutch]. Haemophilia 2024; 30 (Suppl. 03) 60-69
• 16 Mohsenian S, Palla R, Menegatti M. et al. Congenital fibrinogen disorders: a retrospective clinical and genetic analysis of the Prospective Rare Bleeding Disorders Database. Blood Adv 2024; 8 (06) 1392-1404
• 17 Castaman G, Giacomelli SH, Biasoli C, Contino L, Radossi P. Risk of bleeding and thrombosis in inherited qualitative fibrinogen disorders. Eur J Haematol 2019; 103 (04) 379-384
• 18 Casini A, de Moerloose P. How I treat dysfibrinogenemia. Blood 2021; 138 (21) 2021-2030
• 19 Palla R, Peyvandi F, Shapiro AD. Rare bleeding disorders: diagnosis and treatment. Blood 2015; 125 (13) 2052-2061
• 20 Casini A, de Moerloose P. Fibrinogen concentrates in hereditary fibrinogen disorders: past, present and future. Haemophilia 2020; 26 (01) 25-32
• 21 Mohsenian S, Mannucci PM, Menegatti M, Peyvandi F. Rare inherited coagulation disorders: no longer orphan and neglected. Res Pract Thromb Haemost 2024; 8 (04) 102460
• 22 Casini A, von Mackensen S, Santoro C. et al; QualyAfib Study Group. Clinical phenotype, fibrinogen supplementation, and health-related quality of life in patients with afibrinogenemia. Blood 2021; 137 (22) 3127-3136
• 23 Bollineni P, Suman FR, Jayaraman D, Subramani N, Gaddam S. Isolated prothrombin deficiency: a case report of a rare coagulation disorder and review of literature. Cureus 2024; 16 (03) e55940
• 24 Laffan MA, Manning MA. Investigation of hemostasis. In: Dacie and Lewis Practical Hematology (Twelth Edition). Elsevier; 2017
• 25 Girolami A, Ferrari S, Cosi E, Girolami B, Lombardi AM. Congenital prothrombin defects: they are not only associated with bleeding but also with thrombosis: a new classification is needed. Hematology 2018; 23 (02) 105-110
• 26 Mumford AD, Ackroyd S, Alikhan R. et al; BCSH Committee. Guideline for the diagnosis and management of the rare coagulation disorders: a United Kingdom Haemophilia Centre Doctors' Organization guideline on behalf of the British Committee for Standards in Haematology. Br J Haematol 2014; 167 (03) 304-326
• 27 Mann KG, Kalafatis M. Factor V: a combination of Dr Jekyll and Mr Hyde. Blood 2003; 101 (01) 20-30
• 28 Bernal S, Pelaez I, Alias L. et al. High mutational heterogeneity, and new mutations in the human coagulation factor V gene. Future perspectives for factor V deficiency using recombinant and advanced therapies. Int J Mol Sci 2021; 22 (18) 9705
• 29 Castoldi E, Hézard N, Mourey G. et al. Severe thrombophilia in a factor V-deficient patient homozygous for the Ala2086Asp mutation (FV Besançon). J Thromb Haemost 2021; 19 (05) 1186-1199
• 30 Mohapatra AK, Todaro AM, Castoldi E. Factor V variants in bleeding and thrombosis. Res Pract Thromb Haemost 2024; 8 (01) 102330
• 31 Kaya Z. Recombinant FVIIa therapy for heavy menstrual bleeding in patients with severe FV deficiency. Haemophilia 2018; 24 (04) e269-e270
• 32 DesPain AW, Kshetrapal A, Kousa YA. et al. Management of intracranial hemorrhage in severe factor V deficiency and definitive treatment with liver transplantation. Pediatr Transplant 2018; 22 (01) e13102
• 33 Bernardi F, Mariani G. Biochemical, molecular and clinical aspects of coagulation factor VII and its role in hemostasis and thrombosis. Haematologica 2021; 106 (02) 351-362
• 34 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
• 35 Halimeh S, Koch L, Kenet G. et al. Genotype-phenotype relationship among 785 unrelated white women with inherited congenital factor VII deficiency: a three-center database study. J Clin Med 2023; 13 (01) 49
• 36 Fraser C, Watson HG, Khan MM. Mild FVII deficiency—correlation between genotype and phenotype. Haemophilia 2023; 29 (04) 1160-1162
• 37 Quintavalle G, Riccardi F, Rivolta GF. et al; Ad-Hoc Study Group. F7 gene variants modulate protein levels in a large cohort of patients with factor VII deficiency. Results from a genotype-phenotype study. Thromb Haemost 2017; 117 (08) 1455-1464
• 38 Girolami A, de Marinis GB, Vettore S, Girolami B. Congenital FVII deficiency and pulmonary embolism: a critical appraisal of all reported cases. Clin Appl Thromb Hemost 2013; 19 (01) 55-59
• 39 Giansily-Blaizot M, Marty S, Chen SWW, Pellequer JL, Schved JF. Is the coexistence of thromboembolic events and Factor VII deficiency fortuitous?. Thromb Res 2012; 130 (Suppl. 01) S47-S49
• 40 Trossaert M, Chamouard V, Biron-Andreani C. et al. Management of rare inherited bleeding disorders: proposals of the French Reference Centre on Haemophilia and Rare Coagulation Disorders. Eur J Haematol 2023; 110 (06) 584-601
• 41 Peyvandi F, Auerswald G, Austin SK. et al. Diagnosis, therapeutic advances, and key recommendations for the management of factor X deficiency. Blood Rev 2021; 50: 100833
• 42 Herrmann FH, Auerswald G, Ruiz-Saez A. et al; Greifswald Factor X Deficiency Study Group. Factor X deficiency: clinical manifestation of 102 subjects from Europe and Latin America with mutations in the factor 10 gene. Haemophilia 2006; 12 (05) 479-489
• 43 Harris VA, Lin W, Perkins SJ. Analysis of 180 genetic variants in a new interactive FX variant database reveals novel insights into FX deficiency. TH Open 2021; 5 (04) e557-e569
• 44 Escobar MA, Kavakli K. Plasma-derived human factor X concentrate for the treatment of patients with hereditary factor X deficiency. Haemophilia 2024; 30 (01) 59-67
• 45 Lewandowska MD, Connors JM. Factor XI deficiency. Hematol Oncol Clin North Am 2021; 35 (06) 1157-1169
• 46 Zhang X, Lewandowska M, Aldridge M, Iglay K, Wolford E, Shapiro A. Global epidemiology of factor XI deficiency: a targeted review of the literature and foundation reports. Haemophilia 2023; 29 (02) 423-434
• 47 Wu SJ, Cacciola-Price NJ, Goldberg I, DeSancho MT. Real world management of individuals with severe FXI deficiency and its impact on clinical outcomes: experience from a haemophilia treatment centre. Haemophilia 2024; 30 (05) 1164-1169
• 48 Pike GN, Bolton-Maggs PHB. Factor XI-related thrombosis and the role of concentrate treatment in factor XI deficiency. Haemophilia 2015; 21 (04) 477-480
• 49 Bolton-Maggs P, Goudemand J, Hermans C, Makris M, de Moerloose P. FXI concentrate use and risk of thrombosis. Haemophilia 2014; 20 (04) e349-e351
• 50 Salomon O, Steinberg DM, Zucker M, Varon D, Zivelin A, Seligsohn U. Patients with severe factor XI deficiency have a reduced incidence of deep-vein thrombosis. Thromb Haemost 2011; 105 (02) 269-273
• 51 Salomon O, Steinberg DM, Koren-Morag N, Tanne D, Seligsohn U. Reduced incidence of ischemic stroke in patients with severe factor XI deficiency. Blood 2008; 111 (08) 4113-4117
• 52 Salomon O, Steinberg DM, Dardik R. et al. Inherited factor XI deficiency confers no protection against acute myocardial infarction. J Thromb Haemost 2003; 1 (04) 658-661
• 53 Muszbek L, Bereczky Z, Bagoly Z, Komáromi I, Katona É. Factor XIII: a coagulation factor with multiple plasmatic and cellular functions. Physiol Rev 2011; 91 (03) 931-972
• 54 Hsieh L, Nugent D. Factor XIII deficiency. Haemophilia 2008; 14 (06) 1190-1200
• 55 Alavi SER, Jalalvand M, Assadollahi V, Tabibian S, Dorgalaleh A. Intracranial hemorrhage: a devastating outcome of congenital bleeding disorders—prevalence, diagnosis, and management, with a special focus on congenital factor XIII deficiency. Semin Thromb Hemost 2018; 44 (03) 267-275
• 56 Naderi M, Mirzaei I, Yaghoubi S, Milani I, Cohan N. Postpartum hemorrhage in heterozygote factor XIII deficient women compared with healthy women. A cross-sectional experience from Iran. Clin Appl Thromb Hemost 2021 27. :10760296211051714
• 57 Menegatti M, Palla R, Boscarino M. et al; PRO-RBDD study group. Minimal factor XIII activity level to prevent major spontaneous bleeds. J Thromb Haemost 2017; 15 (09) 1728-1736
• 58 Žunić M, Vreča N, Bevc S. The role of factor XIII in patient blood management. Blood Coagul Fibrinolysis 2024; 35 (07) 325-333
• 59 Shapiro A. The use of prophylaxis in the treatment of rare bleeding disorders. Thromb Res 2020; 196: 590-602
• 60 Salomon O, Budnik I, Avishai E. et al. Single low dose of rFVIIa combined with antifibrinolytic agent is a simple and safe treatment for factor XI-deficient patients undergoing surgery. Thromb Haemost 2019; 119 (12) 1927-1932
• 61 Peyvandi F, Seidizadeh O, Mohsenian S, Garagiola I. Exploring nonreplacement therapies' impact on hemophilia and other rare bleeding disorders. Res Pract Thromb Haemost 2024; 8 (04) 102434
• 62 Barg AA, Brutman-Barazani T, Avishai E. et al. Anti-TFPI for hemostasis induction in patients with rare bleeding disorders, an ex vivo thrombin generation (TG) guided pilot study. Blood Cells Mol Dis 2022; 95: 102663
• 63 Maas DPMSM, Saes JL, Blijlevens NMA. et al; RBiN study group. Treatment of patients with rare bleeding disorders in the Netherlands: real-life data from the RBiN study. J Thromb Haemost 2022; 20 (04) 833-844
• 64 Simurda T, Asselta R, Zolkova J. et al. Congenital afibrinogenemia and hypofibrinogenemia: laboratory and genetic testing in rare bleeding disorders with life-threatening clinical manifestations and challenging management. Diagnostics (Basel) 2021; 11 (11) 2140

Publication History

Received: 17 February 2025

Accepted: 11 August 2025

Article published online:
15 October 2025