Characterization of a novel mutation in the F8 promoter region associated with mild hemophilia A and resistance to DDAVP therapy

Riccardi, Federica; Rivolta, Gianna Franca; Franchini, Massimo; Pattacini, C.; Neri, Tauro Maria; Tagliaferri, Annarita

doi:10.1111/j.1538-7836.2009.03468.x

Cited by 11 publications

(15 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The DDAVP test was performed in the great majority of haemophilia A patients (69/75, 92%), with an overall response rate of 78% [54/69; 39 (57%) complete responders and 15 (22%) partial responders]. A lack of response to DDAVP was closely related to the type of mutation [9/15 (60%) non‐responders, belonging to three unrelated families, had a C‐257T>G mutation in the promoter region] [22] (Fig. 5).…”

Section: Resultsmentioning

confidence: 99%

The natural history of mild haemophilia: a 30‐year single centre experience

et al. 2011

Self Cite

View full text Add to dashboard Cite

Although up to 50% of all haemophilic patients followed at haemophilia treatment centres (HTCs) are affected by a mild factor VIII (FVIII) or factor IX (FIX) defect, published data regarding the natural history of these disorders are scarce. To fill this lack of information, a retrospective single centre study was conducted. All cases with mild haemophilia (75 A and 7 B) followed at the regional reference HTC of Parma were evaluated. The patients' median age at diagnosis was 11.5 years and their median age at first bleeding was 5.5 years; 95% of patients had a history of haemorrhagic problems during their life. Twenty-three percent of patients were infected by HCV, and none by HIV. Genetic analysis was performed in 80 patients (97% haemophilia A and 100% haemophilia B) and 21 different mutations were characterized. Eleven percent of patients had never received treatment, whereas 67% were treated with plasma-derived or recombinant FVIII/FIX concentrates (4% developed inhibitors). desmopressin (DDAVP) was used in 80% of the haemophilia A patients. The response to DDAVP was closely related to the patients' genetic profile, as 60% of non-responders had a mutation in the F8 promoter region. Patients with mild haemophilia may experience a variety of medical problems, sometimes challenging for the physicians, during their lifetime. The HTCs play an important role in the management of these patients, whose diagnosis is often delayed. The HTCs should improve patients' knowledge and consideration of their disease and encourage them to maintain regular contact with their haemophilia care provider.

show abstract

Section: Resultsmentioning

confidence: 99%

The natural history of mild haemophilia: a 30‐year single centre experience

et al. 2011

Self Cite

View full text Add to dashboard Cite

show abstract

“…Interestingly, eight out of nine patients without detectable causative F8 mutations did not respond to DDAVP. In addition, we have recently characterized a family group carrying a novel mutation in the F8 promoter region, resulting in mild HA associated with a lack of response to DDAVP [143]. Overall, these findings suggest that, similarly to type 1 VWD [144], the response to DDAVP of mild HA might be at least partially genetically determined.…”

Section: Treatmentmentioning

confidence: 96%

Mild hemophilia A

Franchini

Favaloro

Lippi

2010

Journal of Thrombosis and Haemostasis

Self Cite

View full text Add to dashboard Cite

Summary. Mild hemophilia A (HA), defined by clinical features and factor VIII coagulant activity (FVIII:C) between 0.05 and 0.40 IU mL−1, is characteristically distinct from severe HA. Indeed, although the molecular characterization of mild HA has permitted the identification of specific underlying mutations, its clinical phenotype is strikingly different from that of patients with a severe FVIII defect, where spontaneous hemorrhages or recurrent joint bleeding are usual manifestations. With aging, mild HA patients may develop complications (i.e. cancers and cardiovascular disorders), the management of which may prove challenging due to the concomitant bleeding tendency. Furthermore, the development of inhibitors provides an additional major complication in these patients, because it increases the severity of the bleeding phenotype and complicates their management. Standard management of mild HA includes the use of desmopressin and antifibrinolytic agents for minor bleeding episodes or surgical procedures, whilst major bleeding or surgery requires replacement therapy with FVIII concentrates. As regards treatment of patients with inhibitors, bypassing agents (i.e. activated prothrombin complex concentrates and recombinant activated FVII) have proven effective in the treatment of bleeding episodes, but as there are insufficient data to determine the optimal approach to immune tolerance induction in this group of patients, their optimal management remains controversial. Rituximab is a newer, promising therapeutic option for inhibitor eradication in such patients. Many aspects concerning mild HA remain to be clarified, including the molecular basis, the natural history and the optimal diagnostic and therapeutic strategies. Only large prospective studies will shed light on this condition.

show abstract

“…The effect of desmopressin varies between patients, and has been suggested to depend on the hemophilia-causing mutation [2][3][4].…”

mentioning

confidence: 99%

“…While both the plasma-and platelet-derived molecules can form a functional complex, several studies demonstrate that the two cofactor pools are physically and functionally distinct [2][3][4][5][6][7]. Despite these differences, the entire platelet-derived pool of the procofactor, FV, is endocytosed from the plasma by megakaryocytes [4,8] via a two-receptor system consisting of a specific, unknown FV receptor and low density lipoprotein (LDL) receptor-related protein-1 (LRP-1) [9], an endocytic receptor belonging to a superfamily of proteins related to the LDL receptor [10].…”

mentioning

confidence: 99%

“…This binding interaction facilitates binding of another FV molecule to LRP-1, which mediates endocytosis through Ca 2+ - [9] and clathrin-dependent [8] mechanisms. Endocytosed FV is modified intracellularly to form the unique platelet-derived cofactor molecule [2][3][4][5][6][7] and trafficked to a-granules. The platelet-derived cofactor molecule plays the predominant hemostatic role at sites of vascular injury [12]; therefore, elucidation of the mechanisms regulating its endocytosis, modification and storage in a-granules will provide insight into the events leading to formation of a fibrin clot.…”

mentioning

confidence: 99%

See 1 more Smart Citation