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Biomedical subjects

G Castaman

Publications and source records attributed to G Castaman.

At least 73 records · Page 4Linked to original sources
PubMed1996

Mutation pattern in clinically asymptomatic coagulation factor VII deficiency.

A total of 122 subjects, referred after presurgery screening or checkup for prolonged prothrombin time, were characterized for the presence of coagulation factor VII deficiency. Fourteen subjects carried a partial and asymptomatic deficiency, and in half of them dysfunctional molecules were detected in plasma. In nine subjects we found five missense mutations differing from those previously found in factor VII deficient patients. The others were homozygous for a common polymorphism (R353Q) that affects factor VII levels. A new codon dimorphism (A330) was also found in exon 8. Four mutations (R223W, M298I, R304Q, and R353Q) located at FVII-specific residues point out protein regions that are important for coagulation factor evolution, and two mutations (G342E and E265K) affect generic or partially generic residues. The newly reported mutations were combined with those we previously found, totalling 17 independent mutations responsible for FVII deficiency in 27 Italian pedigrees. We observed several similarities with the mutation pattern determined in factor IX, which include a high percentage of transitions at CpG doublets, the presence of hot spot sites affected by multiple substitutions, and of several topologically equivalent mutations.

Factor VII Deficiency↗
PubMed1996

Clinical usefulness of desmopressin for prevention of surgical bleeding in patients with symptomatic heterozygous factor XI deficiency.

Heterozygous factor XI (FXI) deficiency is sometimes associated with a significant bleeding tendency. Fresh frozen plasma of FXI concentrates are the mainstay of treatment in patients with a clear bleeding history, especially prior to surgery. However, these treatments are not completely free of risk. Furthermore, thrombosis has been reported in patients with FXI deficiency infused with FXI concentrate. No data are available on the possible efficacy of desmopressin in these patients. Two patients with a clear bleeding history associated with FXI deficiency and no additional haemostatic defects agreed to be treated with desmopressin before carpal tunnel surgery and dental extraction. The reduced basal FXI activity and antigen levels slightly increased after infusion, reaching borderline values. No bleeding was observed after surgical procedures. Desmopressin treatment seems a reasonable and useful choice in symptomatic, heterozygous FXI-deficient patients, thus reducing the cost of treatment, the risk of transmission of blood-borne viruses, and of thrombosis.

Blood Loss, Surgical↗
PubMed1996

Detection of new polymorphic markers in the factor V gene: association with factor V levels in plasma.

Three novel polymorphisms were found in the repeated region of the large exon 13 of factor V gene, one giving rise to a codon dimorphism (Ser1240) and two causing aminoacid substitutions (His1299Arg, Leu1257Ile). An increasing frequency of the Arg1299 (R2 allele) correlated with a decreasing mean plasma factor V activity in the groups of subjects under study, which included 26 unrelated subjects with partial factor V deficiency. Family studies supported the co-inheritance both of low factor V activity and of R2 allele. The reduction of factor V activity associated with the R2 allele was not clinically symptomatic even in the homozygous condition and was characterized by a parallel reduction of antigen in plasma, in which abnormal molecules were not detected. Data suggest that the R2 allele represents a marker in linkage with an unknown defect rather than a functional polymorphism. These studies provide the first evidence of a genetic component in determining factor V levels in plasma and of a genetic linkage between the factor V gene and factor V deficiency. They also define specific haplotypes which are associated with factor V deficiency or with APC resistance (Arg506Gln) and are valuable tools for the study of factor V defects.

Base Sequence↗
PubMed1996

Prospective multicenter study on subcutaneous concentrated desmopressin for home treatment of patients with von Willebrand disease and mild or moderate hemophilia A.

Desmopressin is the treatment of choice in most patients with von Willebrand disease (vWD) and mild hemophilia A (HA). Several studies have demonstrated that the intravenous and subcutaneous route of administration are equivalent in terms of pharmacokinetics and clinical efficacy. Home therapy of vWD and mild HA is desirable but so far there have been only a few case reports and no prospective studies. We report the results of a prospective study of home therapy in patients with vWD and mild-moderate HA using concentrated desmopressin self-administered subcutaneously. Clinical efficacy and safety were assessed by the patient using a questionnaire and direct interview. The patients were instructed on self-administration and dosage, reasons for treatment, recognition of side effects and recording clinical efficacy. The study lasted 12 months (range 6-17). During this time, 43/100 (43%) of the enrolled vWD patients (median basal VIII:C 24%, range 9-49) and 36/69 (52%) of HA patients (median basal VIII:C 10%, range 5-34) self-administered the drug. A total of 127 bleeding episodes requiring treatment occurred in patients with vWD and 92 in HA patients. There were 10 treatment failures of which 7 required in-hospital treatment. Overall, in 94% of treatments (excluding menorrhagia) the response was scored as excellent or good. In 86% of treated episodes of menorrhagia the response was scored as excellent or good. According to the patients, 81% of clinical situations would have required in-hospital treatment. Mild flushing, with or without headache, was the only consistent side-effect, reported in about 30% of treatments. In conclusion, home therapy with subcutaneous desmopressin for von Willebrand disease and hemophilia A was well accepted by the patients and proved feasible, efficacious and safe for the prevention or prompt treatment of bleeding.

Adolescent↗
PubMed1995

Characterization of two cases of acquired transitory von Willebrand syndrome with ciprofloxacin: evidence for heightened proteolysis of von Willebrand factor.

We characterized the cause of two cases of transitory acquired von Willebrand syndrome associated with the administration of ciprofloxacin. Purified Ig from the two patients did not inhibit Ristocetin Cofactor activity or binding to collagen of normal plasma, ruling out the possibility of an inhibitor. The analysis of multimeric pattern of plasma von Willebrand Factor (vWF) showed the lack of larger multimers in both patients, with a relative decrease of all the remaining forms in the first patient. The subunit composition of plasma vWF showed a marked reduction of the native 225 Kd subunit (31.9% and 32.9%; normal range 74-86%) and an increased proportion of the 189, 176, and 140 Kd fragments. These abnormalities disappeared during the follow-up, without any specific therapy. In conclusion, a common pathophysiological basis is demonstrated in both patients, with a heightened proteolysis of plasma vWF by an unknown mechanism.

Bleeding Time↗
PubMed1995

Platelet von Willebrand factor abnormalities in myeloproliferative syndromes.

Plasma and platelet von Willebrand factor (vWF) measurements, multimeric pattern and subunit composition of plasma vWF were obtained in 29 consecutive patients with chronic myeloproliferative syndromes. In the 8 patients with chronic myelogenous leukemia (CML), plasma vWF was significantly higher than in the 11 patients with essential thrombocythemia (ET) and in the 10 patients with polycythemia vera (PV). The RiCof/vWF:Ag ratio was low in all these groups of patients (mean 0.64 +/- 0.1, 0.66 +/- 0.2, and 0.61 +/- 0.2; normal 0.97 +/- 0.2). Bleeding time was prolonged (> 7.5 min) in 1/8 CML patients, 1/10 with PV, and 3/11 with ET. Plasma vWF multimers showed a minor loss of the largest multimers in 3/8 patients with CML, 4/10 with PV, and a more severe reduction in 9/11 ET patients. The latter pattern correlated with an abnormal proteolysis of vWF, expressed by a major increase of the 140-Kd fragment and decrease of the intact 225-Kd subunit in ET patients, whereas the 176-Kd fragment was significantly increased in all the subgroups of patients. Platelet vWF was significantly higher in CML patients in comparison to ET and normal controls. However, minor losses of the larger multimers were evident in all the subsets of patients. In ET patients also the intermediate forms were lacking in platelets, accompanied by a significant decrease of platelet RiCof. This abnormality was significantly correlated with the occurrence of bleeding symptoms in PV and ET patients (P = 0.007; Fisher's exact test). In conclusion, plasma and platelet vWF abnormalities are common findings in myeloproliferative syndromes and are more severe in ET. The more pronounced platelet vWF abnormalities in ET may reflect the more frequent bleeding symptoms observed in this disorder.

Adult↗
PubMed1995

Molecular bases of CRM+ factor X deficiency: a frequent mutation (Ser334Pro) in the catalytic domain and a substitution (Glu102Lys) in the second EGF-like domain.

The presence of gene lesions in coagulation factor X (FX, Stuart factor) was investigated in asymptomatic subjects with FX deficiency characterized by the presence of dysfunctional molecules in plasma, as demonstrated by the discrepancy between clotting activity and antigen level. A missense mutation (Ser334Pro) in the catalytic domain was found in three unrelated families in both the homozygous and the heterozygous conditions, and also in the compound heterozygous form with the substitution of Lys for 102 Glu. None of the mutations was detected in 40 unrelated subjects from the same geographic area. The Ser334Pro mutation affects a serine protease region characterized by extensive variation in the coagulation factors but conserved in mammalian factor X molecules. The Glu102Lys mutation affects a residue of the second EGF-like module also conserved in protein C. Both mutated residues are surface-exposed and found in protein regions suggested to be involved in macromolecular interactions which are impaired in the dysfunctional molecules.

Base Sequence↗
PubMed1995

A novel candidate mutation (Arg611-->His) in type I 'platelet discordant' von Willebrand's disease with desmopressin-induced thrombocytopenia.

In three affected members of a family with type I 'platelet discordant' von Willebrand's disease displaying desmopressin-induced thrombocytopenia, we have detected in exon 28 of the von Willebrand factor gene a heterozygous G(4121)-->A transition, which predicts an Arg611-->His substitution. The mutated allele was absent in 50 normal individuals. An unrelated patient with a similar phenotype was also found to be heterozygous for this mutation. The mutation is located in the A1 domain of von Willebrand factor, where most type 2B von Willebrand's disease mutations are found. Mutations in this domain result in von Willebrand factor multimers with enhanced affinity for platelet glycoprotein Ib, and this may explain the association of Arg611-->His with the moderate thrombocytopenia observed after desmopressin infusion.

Base Sequence↗
PubMed1995

Factor VIII:C increases after desmopressin in a subgroup of patients with autosomal recessive severe von Willebrand disease.

Patients with severe von Willebrand disease (vWD) usually show no increase of factor VIII/von Willebrand factor (VIII/vWF) after desmopressin (DDAVP) infusion and the bleeding time (BT) remains markedly prolonged. We have tested the biological responsiveness to DDAVP in six patients, belonging to six different families, with phenotypic evidence for severe vWD. Baseline VIII:C ranged from 12 to 32IU/dl, ristocetin cofactor activity (RiCof) was unmeasurable in all the patients, vWF antigen (vWF:Ag) ranged from 0.5 to 3.5 IU/dl, and in all patients the BT was longer than 30 min. No measurable vWF was present in patient's platelets, and plasma and platelet vWF multimers were virtually absent. An autosomal recessive pattern of inheritance was evident in all the propositi. After DDAVP infusion, there was no BT shortening. In four patients, VIII:C increased post-infusion and in three patients levels greater than 50 IU/dl were attained. RiCof reached a maximum of 11 IU/dl and vWF:Ag 9 IU/dl. In one of these four patients, DDAVP allowed a safe dental extraction, without resorting to blood products. In the remaining two patients no VIII/vWF changes were observed after DDAVP. In conclusion, a subgroup of patients with severe vWD shows an increase of VIII:C after DDAVP. A test infusion with this agent is advisable in patients with severe vWD before considering treatment with VIII/vWF concentrates.

Adolescent↗
PubMed1995

Current management of von Willebrand's disease.

von Willebrand's disease (vWD) is the most frequent inherited disorder and is the result of a deficiency and/or abnormality of von Willebrand factor (vWF). As a consequence, the level of factor VIII, the presence of which reflects the ability of vWF to stabilise it, is usually low. Bleeding time, which reflects the ability of vWF to promote platelet adhesion to subendothelium, is therefore prolonged. However, from a therapeutic point of view, it appears that the correction of factor VIII and bleeding time is sufficient to prevent or treat bleeding in these patients. There are 2 main therapeutic tools to improve or normalise these major determinants of the bleeding tendency in this disorder. The majority of patients, identified by a test infusion, can be successfully treated by giving desmopressin (DDAVP), a synthetic analogue of vasopressin. Desmopressin is able to induce the increase of autologous vWF released from endothelial cells, leading to the correction of factor VIII levels and of bleeding time. In the remaining cases, blood products, namely factor/vWF concentrates, are required to accomplish haemostasis. All these concentrates are able to correct factor VIII levels, whereas their effect on bleeding time may not be consistent. The modern virucidal techniques abolish the risk of transmission of blood-borne viruses (e.g. hepatitis viruses and HIV) and make these products safer than blood-bank cryoprecipitate.

Female↗