[The concomitant presence of prohemorrhagic and thrombophilic changes in coagulation factor V: a severe defect of coagulant activity and homozygote resistance to activated protein C]. / Presenza concomitante di alterazioni proemorragiche e trombofiliche del fattore V della coagulazione: difetto grave di attività coagulante e resistenza omozigote alla proteina C attivata.

We describe the peculiar and concomitant presence of a severe coagulation defect predisposing to bleeding and a mutation associated with inherited thrombophilia. A 6-year-old boy had a severe deficiency in factor V procoagulant activity and antigen and yet remained asymptomatic. This paradox might be explained by the hypothesis of the simultaneous presence of a thrombophilic disorder that might have restored hemostatic balance. The boy was a homozygous carrier of the Arg506Gln mutation of coagulation factor V, that renders this factor resistant to inactivation by its naturally occurring inhibitor, activated protein C. The family members, none of whom had bleeding or thrombotic symptoms, were heterozygotes for either the bleeding or the thrombophilic defect. Despite the severity of the bleeding defect, the absence of bleeding symptoms in the boy can be explained by the hypothesis that any residual amount of factor V present in his plasma is resistant to inactivation by activated protein C.

A type 2b von Willebrand disease mutation (Ile546-->Val) associated with an unusual phenotype.

Type 2B von Willebrand disease (vWD) is typically characterized by enhanced ristocetin-induced platelet aggregation (RIPA) caused by increased von Willebrand factor (vWF) affinity for platelets. Furthermore, absence of larger vWF multimers in plasma is characteristic of the originally described type IIB patients, now considered a subgroup of type 2B. We describe here three affected members of a family presenting with prolonged bleeding time, thrombocytopenia, markedly enhanced RIPA and spontaneous platelet aggregation, but normal plasma vWF antigen and ristocetin cofactor activity. Larger plasma vWF multimers, albeit decreased, were present in relatively greater proportion than in other type IIB patients. Genetic studies performed in two of these patients resulted in the identification of a previously unreported A-->G transition at nucleotide 4175 in the sequence of the pre-pro-vWF cDNA, corresponding to the substitution Ile546-->Val in the mature vWF subunit. This mutation appears to be responsible for an unusual type 2B phenotype, with greater enhancement of the vWF-platelet interaction than in typical cases but partial preservation of the larger vWF multimers in plasma.

Clinical manifestations in 28 Italian and Iranian patients with severe factor VII deficiency.

There has been wide variation in the reported haemorrhagic manifestations of factor VII deficiency. We examined type and frequency of clinical manifestations in 28 Iranian and Italian patients with severe deficiency (factor VII coagulant activity 2% or less). The most frequent symptoms were epistaxis and menorrhagia, whereas soft tissue bleeding such as haemarthrosis and muscle haematoma was less frequent. Only 5 of 9 patient who underwent surgery without factor VII replacement therapy had postoperative bleeding severe enough to require blood transfusion. No thrombotic manifestation occurred. A factor VII functional assay based on the use of human thromboplastin was a better predictor of the bleeding tendency of these patients than a rabbit thromboplastin-based functional assay or immunoassay. On the whole, this study shows that in severe factor VII deficiency bleeding in mucosal tracts is not uncommon. Surgery can sometimes be performed without replacement therapy and without haemorrhagic complications.

Proteolysis of von Willebrand factor is decreased in acute promyelocytic leukaemia by treatment with all-trans-retinoic acid.

Plasma von Willebrand factor (VWF) was investigated in five patients with acute promyelocytic leukaemia (APL) before and after administration of the differentiating agent all-trans-retinoic acid (ATRA). The purpose of this study was to see how the proteolytic state associated with APL affects VWF structure and function and whether ATRA reverses any abnormality. At the onset of APL, multimeric analysis of plasma VWF revealed a lack of the largest multimers. After ATRA, there was a progressive correction of the multimeric pattern in all cases, with transient appearance of ultralarge multimers in two cases. Proteolysis was investigated with immunopurified and reduced VWF from each patient's plasma. This was electrophoresed and probed with two monoclonal antibodies that identify the 225 kD native subunit and the three native fragments of 189, 176 and 140 kD and differentiate novel proteolytic fragments produced by different proteinases. At the onset of APL, the 225 kD native subunit was relatively decreased, with the appearance of an array of novel VWF proteolytic fragments, ranging in size from <140 to <225 kD. These novel fragments observed in patients were similar to those produced in vitro by digestion of purified VWF with plasmin or elastase. After ATRA therapy, proteolysis diminished progressively in parallel with the improvement of other haemostatic measurements, but persisted to some extent. We conclude that VWF proteolysis in APL is produced by plasmin and elastase. Changes of VWF structure and function might adversely affect haemostasis in APL. Therefore, improvement of VWF after ATRA administration might explain in part the effectiveness of this drug in reducing haemorrhagic complications.