Platelets with a W127X mutation in GPIX express sufficient residual amounts of GPIbα to support adhesion to von Willebrand factor and collagen.

Bernard-Soulier syndrome (BSS) is an inherited bleeding disorder caused by a defect in the platelet glycoprotein (GP) Ib/IX complex. The GPIX W127X mutation is the most common genetic defect in Japanese patients with BSS, which is often misdiagnosed as immune thrombocytopenic purpura, presumably due to residual expression of GPIbα. Neither the mechanism by which this mutation leads to a mild bleeding diathesis, nor whether functional GPIbα is expressed on platelet surfaces is known. We investigated GPIbα expression and function in platelets with a GPIX W127X mutation (GPIXW127X). GPIbα complexed with GPIbß by disulfide bonding was expressed on GPIXW127X platelets and stable CHO-K1 cells lacking GPIX but expressing GPIbα and GPIbß. Expression of GPIbα/ß on GPIXW127X platelets was sufficient to support adhesion to immobilized von Willebrand factor and type III collagen and ristocetin-induced platelet agglutination. A residual amount of functional GPIbα/ß heteromer expressed on GPIXW127X platelets partially compensates for the absence of the GPIb/IX complex. This may account for the mild bleeding phenotype of the BSS variant characterized by a non-sense mutation in GPIX.

Identification of four novel mutations in F5 associated with congenital factor V deficiency.

Coagulation factor V (FV) deficiency is a rare bleeding disorder characterized by low coagulant and antigen levels of FV with bleeding symptoms ranging from mild to severe. Only a limited number of mutations have been reported because of the large size of the factor V gene (F5) as well as the low prevalence. In this study, we have identified four novel mutations in F5 in five unrelated patients with congenital FV deficiency. All the patients, including two with undetectable FV activity, were asymptomatic and were found to have prolonged prothrombin time and activated partial thromboplastin time during preoperative screening or routine examinations. All four mutations found in this study are either missense or in-frame deletion. This is in contrast with previous reports of a high frequency of mutations introducing premature termination codons in inherited FV deficiency. Missense mutations of F5 might produce a mild phenotype and are not frequently diagnosed. Although FV deficiency is a very rare disorder with a predicted incidence of one in 1 million, this study suggests that the numbers of F5 mutations, especially missense mutations, are higher than estimated.

Increased IL-1beta production from dsRNA-stimulated leukocytes in febrile seizures.

This study examined the possibility that children with and without a history of febrile seizures might mount different immune responses to double-stranded ribonucleic acid, which is a common viral factor that induces host cell immune responses, and is recognized by Toll-like receptor 3. The production of interleukin-1beta and interferon-alpha from double-stranded ribonucleic acid-stimulated leukocytes was examined in 27 children (age 3.6+/-0.3 years) with a history of febrile seizures and in 18 children (age 3.4+/-0.2 years) without a history of febrile seizures. Significantly (P=0.0007) increased interleukin-1beta production was observed in children with a history of febrile seizures, compared with control subjects. When patients with a single prior episode of febrile seizures (n=9) and those with multiple prior episodes of febrile seizures (n=18) were compared, a significant difference in interleukin-1beta production was not observed. Genotyping of interleukin-1beta(-511), Toll-like receptor 3, Toll-IL-1 receptor domain-containing adapter inducing interferon-beta, and interleukin-1 receptor antagonist polymorphisms revealed no significant differences in allelic distribution among febrile seizure patients and control subjects. Interleukin-1beta production was not significantly influenced by genotype. Viral infection results in increased interleukin-1beta production in febrile seizure patients, and this may play a role in febrile seizures.

[Fatal opportunistic infection following disappearance of antibodies by immunosuppressive therapy in a patient with acquired factor VIII inhibitor].

An 83-year-old man without history of the hemorrhagic diathesis was admitted to our hospital with a 4-months history of purpura and subcutaneous hematoma. He had an extraordinarily prolonged activated partial thromboplastin time, and his factor VIII (F VIII) activity level was 0.2%. A study revealed the existence of an IgG type anti-F VIII inhibitor at a titer of 1004 Bethesda units/ml. He received recombinant factor VIIa and immunosuppressive therapy with cyclophosphamide, prednisolone and cyclosporin, but despite this the titer of F VIII inhibitor remained high. Although the inhibitor disappeared after methylprednisolone mini-pulse therapy, the patient died of opportunistic infections with cytomegalovirus and pneumocystis carinii. The majority of patients with acquired F VIII inhibitor belong to the elderly population, and the standard therapeutic strategy to eliminate the acquired F VIII inhibitor has not been established. Those patients with high titers of F VIII inhibitor require particularly long term immunosuppressive therapy. Therefore, it is important to bear in mind treatment-related opportunistic infections in a case with a high titer of acquired F VIII inhibitor.