Precision Medicine in Rare Bleeding Disorders

Rare bleeding disorders (RBDs) are also referred to by other names, including recessively inherited bleeding disorders, rare coagulation factor deficiencies, and rare congenital bleeding disorders.[1] Traditionally, these disorders include all coagulation factor deficiencies with bleeding tendency, except for hemophilia A and hemophilia B.[1] The estimated incidence of these disorders ranges widely, from 1 per 2 million for factor XIII (FXIII) and prothrombin (FII) deficiency to 1 per 500,000 for FVII deficiency in the general population.[1] [2] Over the last two decades, with rapid progress in laboratory diagnosis, molecular studies, and clinical characterization of bleeding disorders, there have been significant improvements in both case identification and treatment modalities. Additionally, other less common bleeding disorders, characterized by both bleeding tendency and rare incidence, have been included in this category.[1]

Today, inherited platelet function disorders, disorders of the fibrinolytic system, and other rare hemorrhagic disorders such as rare forms of von Willebrand disease (VWD) and platelet-type VWD (PT-VWD) can be included in this category. A large number of studies have been conducted on these rare disorders, and a wide range of disease variants have been identified in the underlying genes, illuminating their molecular basis.[3] This progress has advanced significantly from the discovery of the underlying genes for each disorder to the in vitro application of advanced gene editing systems like CRISPR/Cas (clustered regularly interspaced short palindromic repeats/CRISPR-associated).[4]

Growth has also occurred in therapeutic options, which have evolved from traditional choices such as whole blood transfusion, platelet concentrate, fresh frozen plasma (FFP), and cryoprecipitate to more advanced options: plasma-derived and recombinant or nanoengineered products that are now available for a considerable number of RBDs.[1] Despite all the advances, the shift in therapeutic intervention from traditional general recommendations to more specific personalized therapeutic recommendations (precision medicine) represents a significant improvement that can enhance the quality of life for these patients, as increasingly observed in hemophilia A and B.[5] The advent of next-generation sequencing (NGS) and genome-wide association studies (GWAS), along with the rapid growth of artificial intelligence (AI), may have a significant impact on this field. The identification of genetic modifiers that can directly affect disease phenotype can further accelerate this progress. Due to the importance of this field and its potential impact, this issue of Seminars in Thrombosis and Hemostasis (STH) aims to cover various aspects of RBDs, including laboratory, clinical, and molecular findings, which can potentially influence personalized patient management.

With regard to this, in the first paper of this issue, Cassini et al review the clinical, laboratory, and molecular aspects of congenital fibrinogen disorders (CFDs).[6] The authors report that patients with the same fibrinogen variant may have completely different clinical phenotypes. Additionally, they note some established genotype-phenotype correlations in CFDs, such as thrombotic-related dysfibrinogenemia and fibrinogen storage disease, while suggesting that other potential genetic modifiers may be identified through NGS.[6]

Due to the important role of genetics, Franchini and Focosi report that among different types of F5 gene mutations, splice site mutations and those associated with premature codon terminations are associated with severe FV deficiency, while the Met2120Thr polymorphism and the HR2 haplotype are associated with a milder phenotype.[7] There is a poor correlation between FV activity levels and severity of clinical presentations. The optimal treatment of the disorder depends on the clinical severity, with antifibrinolytics for management of mild FV deficiency and replacement therapy with FFP for severe deficiency to increase the FV levels to 20 to 25%.[7]

Although concomitant reduction of FV and FVIII would be expected to cause a more severe phenotype than separate single deficiencies of each coagulation factor, this is not the case, as patients with combined FV and FVIII deficiency (CF5F8D) experience a milder phenotype, as pointed out by Yakovleva and Zhang in their review.[8] There is a strong correlation between residual levels of FV and FVIII and the severity of clinical presentations in CF5F8D. However, although patients with MCFD2 mutations have lower plasma FV and FVIII activities, factor activity in CF5F8D cannot be used as a predictor of genotype. The mainstay of treatment in CF5F8D is on-demand therapy, and treatment is based on the severity of clinical presentations. When the FV level is above 10% in CF5F8D, bleeding rarely occurs due to FV deficiency, and FV replacement therapy is usually not required at this threshold. According to this review, the main challenge is to determine if and to what extent FV contributes to bleeding in CF5F8D.[8]

In the next review, Bernardi and Mariani outline the clinical, laboratory, and molecular aspects of FVII deficiency, one of the most common RBDs.[9] This review highlights that FVII deficiency is one of the most severe RBDs, with a clinical picture that may be even more severe than hemophilia A and B due to a high rate of intracranial hemorrhage (ICH), reported to be around 12% in one study. Despite several discrepancies, there is a modest correlation between FVII activity and severity of clinical presentations, though the same gene variant may be accompanied by heterogeneous clinical manifestations. Patients with FVII activity levels higher than 26% rarely experience spontaneous bleeding episodes. More than 1,000 patients diagnosed with FVII deficiency have been reported, and identified variants can be used for genetic counseling and diagnosis, including prenatal testing. The authors conclude that despite all advancements in the field, several questions remain open regarding the clinically relevant thresholds of plasma FVII levels, the correlation between FVII activity levels and FVII/FVIIa concentrations, and how these relate to both the generally mild clinical picture and the not-so-rare severe hemorrhages that can cause disability or may be life-threatening.[9]

Menegatti and Peyvandi, in their paper on FX deficiency, another one of the most severe RBDs, highlight the strong correlation between FX activity levels and bleeding severity, with life-threatening bleeding occurring in those with severe FX deficiency.[10] A total of 180 mutations have been reported in the F10 gene, with more than 50% concentrated in the FX serine protease domain. Complete absence of FX protein likely occurs with large F10 gene deletions; however, there is no clear link between phenotype and genotype or mutation location in the F10 gene. Small case series with the same genotype and phenotype in a specific geographical area do not strongly indicate genotype-phenotype correlation, but rather suggest a founder effect.[10]

In the next review,[11] Davidson and Gomez report a very high prevalence of 1 per 10 to 20,000 for FXI deficiency, much higher than the expected incidence of the disorder, based on the U.K. National Haemophilia Database. The authors report that as there is no correlation between FXI levels and severity of clinical presentations, genotype may be a more accurate predictor of bleeding risk and therefore aid in clinical management. One reason presented by the authors for the poor correlation between factor activity levels and bleeding severity is that FXI is not critical for hemostasis, and other factors may ameliorate the phenotype of FXI deficiency. Another reason is the presence of FXI in platelets that may rescue some patients with severe deficiency. Although rare, bleeding has been observed in individuals with heterozygous FXI deficiency, even with FXI activity within the normal range, and molecular study is the only way to detect such cases. The authors conclude that although the underlying gene variant does not predict bleeding risk, it can indicate the risk of inhibitor formation.[11]

Similar to FXI deficiency, a high prevalence of both severe and heterozygous FXIII-A deficiencies is reported in the next review by Dorgalaleh et al,[12] based on two large-scale molecular studies from Iran and Germany and the World Federation of Hemophilia annual report. There is no genotype-phenotype correlation in heterozygous and homozygous FXIII-A deficiencies. Different factors such as residual factor levels, clinical presentations, age, weight, and even gender can affect therapeutic efficacy and should be considered in personalized management strategies. The authors report that personalized pharmacokinetic-based replacement therapy represents the optimal approach that can optimize intervention efficacy in patients with FXIII deficiency, an approach that is best for all RBDs.[12]

Vitamin K-dependent coagulation factors deficiency (VKCFD), a part of familial multiple coagulation factor deficiencies, presents with heterogeneous manifestations ranging from mild to potentially life-threatening bleeding, as covered by Perrone et al in the next review.[13] The precise incidence of the disorder remains unclear, though 272 individuals with pathogenic variants have been reported worldwide. Available data are based on case reports and small case series, demonstrating variable clinical presentations among affected patients. In severe cases, clinical manifestations such as ICH may appear at birth, while those with mild deficiency may present later in life. The authors report two paradigmatic cases of VKCFD. The first is a 34-year-old woman incidentally found to have impaired routine coagulation tests. Following mixing studies and genetic testing, an underlying variant in the γ-glutamyl-carboxylase (GGCX) gene was detected. The second case involved a 45-year-old man who presented with recent onset of extensive bruising and widespread subcutaneous hematomas without personal or family history of bleeding, ultimately diagnosed with VKCFD secondary to Crohn's disease. To date, only 40 mutations have been detected in the GGCX gene. Among 47 patients identified with GGCX mutations, 33 had VKCFD1, of whom 25 demonstrated deficiency of all vitamin K-dependent coagulation factors. FX deficiency was observed in all patients, while decreased FIX activity was present only in patients with deficiency of all other coagulation factors. Molecular studies have revealed few mutations occurring in unrelated patients. Due to the risk of life-threatening bleeding, prophylaxis is strongly recommended from the time of diagnosis. Oral administration of vitamin K1 can correct low levels of vitamin K-dependent coagulation factors but may not prevent major bleeding. For patients with inadequate therapeutic response or intolerance to oral treatment, intravenous administration of vitamin K1 is appropriate. Patients with VKCFD1 and VKCFD2 show different therapeutic responses to vitamin K. According to in vitro studies, not all GGCX gene mutations are corrected by vitamin K administration. Mutations affecting structural or catalytically important sites, particularly the glutamate binding site, may respond better to prothrombin complex concentrate.[13]

The next paper by Tavasoli et al, using a systematic literature review methodology, attempts to address an important but unclear issue among all the above RBDs that has a direct impact on patient management: the correlation between coagulation factor activity and bleeding severity. As expected, despite all discrepancies, a moderate to strong correlation was found for FX deficiency and, to a lesser extent, FXIII and fibrinogen (FI) deficiencies, where decreased factor activity increased bleeding severity. This review also reported a weak or no association for FXI, FV, and even FVII deficiencies and bleeding risk. Although this systematic review helps to shed light on some ambiguities of this question in RBDs, further studies with larger patient populations are required to better illuminate this important matter in RBDs.[14]

This issue then transitions from rare coagulation factor deficiencies to rare platelet function disorders, beginning with Alan T. Nurden and Paquita Nurden's review of Glanzmann thrombasthenia (GT), the most common inherited platelet disorder characterized by life-long mucocutaneous bleeding.[15] A few GWAS have been performed to identify genomic modifiers of bleeding risk in inherited platelet function disorders, including GT. Generally, heterozygous individuals with approximately 50% expression of αIIbβ3 are asymptomatic, but single-allele mutations that affect αIIb or β3 and impact αIIbβ3 expression and function can explain bleeding in heterozygotes. The standard treatments for patients with GT include replacement and nonreplacement therapies, with platelet transfusion remaining the gold standard for severe bleeding. HMP-001, a bispecific antibody, is a new therapeutic agent.[15]

According to the next review by Kaya, Bernard–Soulier syndrome is a rare inherited platelet function disorder that can be classified into autosomal recessive biallelic and autosomal dominant monoallelic forms.[16] Generally, the biallelic form is diagnosed at young ages with mucocutaneous bleeding, while the monoallelic form is diagnosed later in life and is commonly misdiagnosed as immune thrombocytopenic purpura. Each type has its own laboratory features, and molecular diagnosis is recommended to properly identify the monoallelic form. The first-line treatment in patients with Bernard–Soulier syndrome is platelet transfusion. Alloimmunization is the main treatment complication in patients receiving long-term platelet transfusions, but the use of leukocyte-reduced products can decrease this risk. Alloimmunization against platelet surface antigens should be checked 3 months after the first platelet transfusion. Recombinant FVIIa can be used in patients with platelet refractoriness. More advanced options for platelet-refractory patients include GPIbα peptide-coated nanoparticles and artificial platelets produced from pluripotent stem cells.[16]

PT-VWD is a rare platelet function disorder characterized by mild to moderate bleeding tendencies, as described by Fu et al.[17] PT-VWD is frequently misdiagnosed as type 2B VWD, which can be considered its phenotypic twin. Differential diagnosis is mandatory for proper management, as the treatment approaches differ significantly between these conditions. Platelet transfusion is the primary treatment option for PT-VWD. Administration of von Willebrand factor (VWF)/FVIII concentrate, which is the main treatment for type 2B VWD, may worsen clinical presentations in PT-VWD. However, low doses that do not significantly affect platelet count may have therapeutic value. Desmopressin and other agents that increase the release of endogenous VWF should generally be avoided in PT-VWD patients. Recombinant FVIIIa is another potential therapeutic agent, though current evidence supporting its use is limited.[17] Recent advances have indicated the potential for antibodies disrupting the association of GPIbα and VWF as an alternative therapy. While 6B4 antibody showed questionable efficacy, AI-generated synthetic peptide showed preliminary promise as a therapy based on in vitro experiments. Such peptides could serve as an effective diagnostic technology for discriminating between 2B-VWD and PT-VWD.

Al-Ghafry et al then cover disorders of the fibrinolytic system, including plasminogen activator inhibitor-1 deficiency, α2-antiplasmin deficiency, and Quebec platelet disorder (which present with bleeding tendencies), as well as plasminogen deficiency (which presents with a thrombotic phenotype).[18] The diagnosis of these disorders involves a complex process, and molecular testing is recommended for patients strongly suspected of having fibrinolytic system disorders. Polymorphisms in fibrinolytic system genes can alter factor levels and may be associated with cardiovascular and cerebrovascular diseases. Antifibrinolytic agents are the primary treatment for patients with hemorrhagic manifestations; however, these drugs should be avoided in cases of hematuria. Further studies are required to establish optimal management protocols.[18]

The last paper in this issue is a historical review of RBDs, covering all rare coagulation factor deficiencies and two rare, combined coagulation factor deficiencies.[1] Fibrinogen (FI) and prothrombin (FII) were the first coagulation factors in this group to be identified, while FX was the last. The first patient diagnosed with an RBD presented with afibrinogenemia, while combined VKCFD was the most recent RBD in this group to be identified in a patient. FFP was initially the primary therapeutic choice for almost all RBDs, while plasma-derived products are now available for FI, FVII, FX, FXI, and FXIII deficiencies. Recombinant coagulation factors have also been developed for FVII and FXIII deficiencies. This historical review highlights the rapid progress in the field of RBDs, which have emerged from their orphan status, leading to current discussions about personalized treatment approaches.[1]

In total, this issue of STH provides a foundation for managing patients with RBDs in a more specific, personalized manner, aiming to improve their quality of life by decreasing bleeding frequency and tailoring treatment to their individual and genetic characteristics. Although there have been many advancements in this area, the advent of NGS, GWAS, and potentially AI can accelerate this progress, and we may observe significant changes in this field in the near future. Our only major omission in this issue is an update on prothrombin (FII) deficiency, due to the inability of invited authors to progress the submission. We hope this will be available in a future issue of STH, and for the interim we can point the reader to a previous STH paper on the topic.[19]

Publication History

Article published online:
05 December 2024

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