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Biomedical subjects

A Girolami

Publications and source records attributed to A Girolami.

At least 55 records · Page 3Linked to original sources
PubMed2001

A dysfunctional factor X (factor X San Giovanni Rotondo) present at homozygous and double heterozygous level: identification of a novel microdeletion (delC556) and missense mutation (Lys(408)-->Asn) in the factor X gene. A study of an Italian family.

Low levels of factor X (F.X) were detected in a 4-year-old boy who experienced acute lymphoblastic leukemia and bleeding manifestations. Laboratory data suggested the presence of a dysfunctional F.X molecule. Two novel F.X gene mutations were identified in the proband that was double heterozygous for both: a microdeletion (delC556) in exon VI resulting in a frameshift leading to a termination codon at position 226. This deletion was found in six family members with reduced F.X antigen and activity levels. A second mutation characterised by a G(1344)-->C transversion in exon VIII was detected in the proband resulting in a Lys(408)-->Asn substitution. This latter mutation was present in several asymptomatic family members from the paternal and the maternal side. The proband's sister was homozygous for the Lys(408)-->Asn substitution and exhibited low F.X activity with a normal antigen level. The naturally occurring F.X Lys(408)-->Asn (F.X(K408N)) variant was isolated from plasma of either homozygous or double heterozygous individuals. NH(2)-terminal sequencing of the heavy chain of F.X(K408N) failed to show any sequence abnormality in patients who were also carriers of the delC556, suggesting that this latter lesion accounted for the lack of F.X synthesis. Purified F.X Lys(408)-->Asn had an identical behaviour to normal F.X as judged by SDS-PAGE and immunoblotting. Clotting assay using purified F.X(K408N) and F.X-deficient plasma resulted in a laboratory phenotype similar to that observed in a homozygous subject for F.X Lys(408)-->Asn substitution. This is the first characterisation of a naturally occurring F.X variant with a mutation at the COOH-terminal end of the molecule.

Amino Acid Sequence↗
PubMed2001

Von Willebrand factor collagen binding activity in the diagnosis of von Willebrand disease: an alternative to ristocetin co-factor activity?

The capability of von Willebrand factor (VWF) to bind platelet glycoprotein Ib (GPIb) and promote platelet plug formation is currently evaluated in vitro using the ristocetin co-factor activity (VWF:RCo) assay. The replacement of this cumbersome and not always reproducible test with the collagen binding activity of VWF (VWF:CBA) has been attempted with controversial results. To evaluate the capacity of VWF:CBA to identify classic and variant von Willebrand disease (VWD) compared with VWF:RCo, we studied 10 type 2A and 12 type 2B VWD patients, together with 30 type 1 VWD patients with reduced platelet VWF content. In both 2A and 2B VWD, VWF:CBA and VWF:RCo were decreased, but that of VWF:CBA was more consistent. The difference was more evident when values were expressed as a ratio, obtained by normalizing VWF:CBA and VWF:RCo with the VWF antigen value; the ratio for VWF:CBA was always below 0.2, while that for VWF:RCo was greater than 0.4, and in no patient was the VWF:CBA value higher than VWF:RCo. In contrast, in type 1 VWD, the decrease in VWF:CBA was similar to that seen in VWF:RCo with the ratios always within the normal range. To better investigate the relationship between VWF:CBA and VWF:RCo, and the representation of large/intermediate VWF multimers, to which both tests are sensitive, 1-deamino-cys-8-D-arginine-vasopressin (DDAVP) was infused in type 2A and 2B VWD patients. The differences between the two tests were even more evident after DDAVP, and in type 2A, even though large multimers were persistently decreased, VWF:RCo was normalized, while VWF:CBA remained defective. These findings clearly indicate that VWF:CBA detects the absence of large and intermediate VWF multimers better than VWF:RCo. Hence, we suggest adding VWF:CBA to the panel of tests employed in the diagnosis of VWD. Moreover, owing to the difficulty in performing VWF:RCo and its low reproducibility, we suggest that, when necessary, VWF:CBA may be substituted for VWF:RCo.

Blood Coagulation Tests↗
PubMed2001

Age as the major predictive factor of long-term response to splenectomy in immune thrombocytopenic purpura.

Sixty-one consecutive patients undergoing splenectomy for chronic immune thrombocytopenia were retrospectively evaluated. Platelet response was considered as complete (CR) when platelet count rose to > 100 x 109/l, partial (PR) when 30-100 x 109/l or absent (NR) if otherwise. Follow-up (mean time 7.6 years) was possible in 54 patients. Forty-eight patients (88%) had an immediate response to splenectomy (39 CR, 9 PR) whereas six (12%) were NR. Thirty-six responders (67%) had sustained remission (31 CR; 5 PR) without further treatment; thrombocytopenia recurred in 12 patients (33%). The probability curve of continued remission showed a constant relapse-rate during the first 36 months; a further step of relapse was observed beginning 70 months after surgery. The only positive predictive factor for the long-term response to splenectomy was age < 40 (P < 0.005). Neither duration of thrombocytopenia nor previous response to medical treatment (steroids and/or intravenous immunoglobulins) were related to splenectomy response.

Adolescent↗
PubMed2001

A highly polymorphic microsatellite in the factor V gene is an informative tool for the study of factor V-related disorders.

The role of factor V (FV) mutations in activated protein C (APC) resistance and FV deficiency is well established. We report on the identification of a highly polymorphic (AT)n microsatellite marker in the FV gene, which represents an informative tool for the investigation of the origin and evolution of pathologically relevant FV genetic components. A high number of different microsatellite alleles were found to be associated with FV R506Q and FV H1299R, two single-origin mutations. An example of the use of the microsatellite marker in family studies of thrombophilia and FV deficiency is also provided.

Factor V↗
PubMed2001

Early transfusion of factor VIII/von Willebrand factor concentrates seems to be effective in the treatment of gastrointestinal bleeding in patients with von Willebrand type III disease.

The association between gastrointestinal angiodysplasia and von Willebrand disease was reported 30 years ago. The clinical course of patients with von Willebrand disease and angiodysplasia is characterized by numerous admissions to hospital for gastrointestinal bleeding necessitating transfusion with packed red cells, factor VIII and plasma. The management of these patients is problematic. Numerous treatments for the gastrointestinal bleeding have been proposed: surgery, electrocoagulation, laser photocoagulation, sclerotherapy, arteriography with embolization, immunoglobulins, oestrogens, and octreotide, but no treatment modality has been successful in all cases. We report a 66-year-old-female with small bowel angiodysplasia and von Willebrand type III disease in whom prompt administration of factor VIII/vWF concentrates was effective. Education of patients to recognize minimal gastrointestinal bleeding manifestations, periodical clinical visits and early infusion of factor VIII/vWF seems to be fundamental for the success of this therapy. A longer follow-up and the study of other patients are needed to confirm our observation.

Aged↗
PubMed2001

Mild bleeding diathesis in a boy with combined severe haemophilia B (C(10400)-->T) and heterozygous factor V Leiden.

Haemophilia B patients with factor IX (FIX) activity < 1% are usually characterized by severe bleeding episodes early in life. We report a case of sporadic severe haemophilia B, clinically characterized by mild bleeding diathesis. The presence of anamnestic thrombophlebitis in the patient's mother prompted us to investigate a possible associated hypercoagulable condition. Resistance to activated protein C due to factor V R506Q mutation was present in the mother and in the propositus, in the homozygous and heterozygous form, respectively. Molecular analysis of the FIX gene led to the identification of a nonsense mutation resulting in a stop codon at position 50, previously described and usually responsible for a severe pattern of haemophilia B. The implications of this unusual association are discussed.

Activated Protein C Resistance↗
PubMed2001

Diagnosis of recurrent deep vein thrombosis.

Long-term follow-up studies demonstrated that venous thromboembolism is a chronic disease, as the rate of recurrent deep vein thrombosis (DVT) continuously increases after the primitive thrombotic episode. Objective testing is mandatory to confirm or refute the presence of recurrent DVT, as only 30% of patients with suspected recurrence have a new documented thrombotic episode. There is no consensus on the preferred diagnostic procedure; furthermore, both invasive and noninvasive methods are limited in this context. Venography, the established gold standard, is invasive, costly, inconvenient and requires high technical skills. Among noninvasive techniques, serial impedance plethysmography, alone or in combination with leg scanning and venography, and serial compression ultrasound (CUS), were adequately investigated. At present, the recommended approach is represented by a quantitative CUS method that possesses an excellent reproducibility and accuracy. The safety of withholding anticoagulants from patients with a normal quantitative CUS work-up has been recently demonstrated in a prospective management study.

Anticoagulants↗
PubMed2001

Type 2M von Willebrand disease variant characterized by abnormal von willebrand factor multimerization.

We describe a von Willebrand disease (VWD) variant characterized by low plasma and platelet von Willebrand factor (VWF), impaired ristocetin-induced VWF binding to platelet glycoprotein Ib (GPIb), and abnormal VWF multimer pattern not associated with the absence of large forms. A C-to-T transition at nucleotide 4120 in exon 28 of the VWF gene was found; this mutation introduces a cysteine at the codon for Arg 611 of mature VWF. In addition to the decreased factor VIII (FVIII) and VWF levels, ristocetin-induced platelet aggregation (RIPA) was almost absent, and VWF ristocetin cofactor activity (VWF:RCo) was significantly more decreased than VWF antigen. The patients (mother and son) also showed a defect in VWF collagen-binding activity. Plasma VWF multimers were decreased, with no limit in the size of large forms, and the normal discontinuous multimer organization was replaced by a diffuse smear, especially detectable in the large forms. This picture was emphasized by 1-deamino-8-D -arginine vasopressin (DDAVP) infusion, so that the abnormal VWF multimers appeared to have a molecular weight higher than those present in, or released by, human umbilical vein endothelial cells. DDAVP also increased FVIII and VWF levels but did not normalize the GPIb-dependent VWF functions expressed as RIPA and VWF:RCo. We include this variant in type 2M VWD, focusing on the abnormality in GPIb-dependent VWF function. We advance that this defect depends on the mutation in the GPIb binding domain of VWF rather than the abnormal VWF multimer pattern.

Adult↗
PubMed2001

Plasma and platelet von Willebrand factor abnormalities in patients with uremia: lack of correlation with uremic bleeding.

Chronic renal failure often is associated with abnormal bleeding that may represent an important complication of this disorder. The hemorrhagic tendency currently is attributed to altered primary hemostasis, mainly platelet dysfunction. However, von Willebrand factor (vWF) also seems to be involved, even though the nature of its abnormalities is still controversial. To gain insight into the role of vWF in determining uremic bleeding, we studied 11 patients with stable, chronic renal failure. We found a significant increase in plasma factor VIII (FVIII), vWF:antigen (Ag), and vWF:ristocetin cofactor (Rco) levels, associated with a mean decrease in platelet vWF:Ag. Plasma vWF multimer pattern was characterized by increased representation of all oligomers in all patients, but five patients also showed a slight decrease in large vWF multimers. In addition, platelet vWF multimer pattern displayed a decrease in all components, especially those with high molecular weight. Despite normal bleeding time, collagen-induced platelet aggregation was defective in almost all patients, whereas vWF collagen binding capacity was normal. The levels of glycocalicin, the circulating fragment of glycoprotein Ib-IX, the major platelet vWF receptor, were also normal. In six patients who also were studied after initiation of dialysis, collagen-induced platelet aggregation was impaired further. Moreover, plasma vWF, and especially FVIII levels, were increased additionally, in association with a normalized platelet vWF content and an improved vWF multimer pattern. The results suggest that vWF abnormalities are present in uremia. Moreover, thrombopathy caused by impaired collagen-induced platelet aggregation is constantly present and apparently not improved by dialytic treatment.

Adult↗
PubMed2001

Homozygous patients with the 20210 G to A prothrombin polymorphism remain often asymptomatic in spite of the presence of associated risk factors.

Patients who are homozygous for the G to A nontranslated prothrombin polymorphism only occasionally have venous thrombosis. An evaluation of all published papers on the subjects has disclosed that nine patients of the 35 so far reported remained asymptomatic in spite of the presence of associated congenital or acquired thrombotic risk factors. We saw an additional patient recently, bringing the total to 10 of 36 patients. Some of these patients remained asymptomatic in spite of multiple or repetitive risk factors (e.g., five pregnancies in the case of one patient). Twelve patients who were homozygous and who had this polymorphism developed symptoms only in the presence of the same risk factors. This may suggest that this abnormality played a small role, if any, in both groups of patients. The finding that several patients with this abnormality remained asymptomatic in spite of associated risk factors casts serious doubts about the prothrombotic significance of this polymorphism. Until this problem is clarified, the clinician must abstain from attributing a prothrombotic effect to this polymorphism.

Adolescent↗
PubMed2001

Hemophilia A, von Willebrand disease, and atherosclerosis of abdominal aorta and leg arteries: factor VIII and von Willebrand factor defects appear to protect abdominal aorta and leg arteries from atherosclerosis.

We hypothesized that patients with hemophilia or von Willebrand disease might be protected from atherosclerosis because of their coagulation defect. We studied 40 subjects affected by these two coagulation diseases using echocolor Doppler of the abdominal aorta and leg arteries, and compared the results with those obtained in 40 control patients who were homogenous with study patients in terms of sex, age, and risk factors for atherosclerosis. The probands presented a lower number of plaques than the 40 control subjects in the aorta and in the leg arteries. The most serious hemophilic patients had fewer plaques than controls or than patients with mild hemophilia. Both hemophilia and von Willebrand disease seem to protect against atherosclerosis.

Aorta, Abdominal↗
PubMed2001

Idiopathic deep vein thrombosis and subsequent cancer: suggestions for a patient-oriented and practical approach.

The relationship between an idiopathic deep vein thrombosis and a cancer is well established. It is not clear yet whether all patients with an idiopathic deep vein thrombosis should be thoroughly investigated for an occult cancer or only some. As a matter of fact, once a physician is faced with a patient who has an idiopathic deep vein thrombosis, three approaches are possible, mainly: 1) a wait and see approach; 2) a limited investigation: and 3) an extensive or invasive investigation. No sure criteria for the selection of the patients who should be extensively investigated are available. Suggestions have been made in this regard. Negative family or personal history for thrombosis, advanced age, deep vein thrombosis of upper limbs, existence of silent deep vein thrombosis in contralateral leg, tendency to relapse and/or to migrate, constitutional symptoms, or smoking may represent important clues that may justify an extensive study. This patient-oriented approach is mainly based on the experience of the caring physician.

Decision Trees↗
PubMed2001

ProC global: a new automated screening assay for the evaluation of total function of the protein C system.

Protein C (PC) pathway represents a major physiologic inhibitory mechanism regulating the coagulation cascade. A new automated functional screening assay (ProC Global) for the evaluation of the PC-system was tested to define its ability to identify patients with known inherited defects such as factor V (FV) Leiden mutation and PC and protein S (PS) deficiency. A total of 249 patients who were symptomatic or asymptomatic for previous venous thromboembolism (VTE) were evaluated, 50 of whom had FV Leiden mutation, 36 had PC deficiency, and 34 had PS deficiency. One hundred healthy subjects were also tested, as well as 40 blood donors of both sexes in whom coagulation abnormalities were not found. Results of ProC Global test were expressed as normalized ratio (NR) and values below an established cut-off level were consistent with a positive test. ProC Global was positive in all 50 patients with the FV Leiden mutation (mean NR = 0.59; range, 0.37 to 0.69). ProC Global correctly identified 32 of 36 (89%) PC defects (mean NR = 0.63; range, 0.34 to 1.21) and 25 of 34 (73.5%) PS defects (mean NR = 0.76; range, 0.5 to 1.23). Overall, 92.5% of hereditary defects of the PC system considered in this study were identified by ProC Global test. ProC Global exhibited NR above cut-off level in all 40 blood donors without coagulation defects. ProC Global is a new automated screening test with some diagnostic potential in identifying patients with defects of the PC system. However, ProC Global in its current form cannot substitute the assay of each single component of this inhibitory system in the daily screening for thrombophilia.

Adolescent↗
PubMed2001

The value of ultrasound screening for proximal vein thrombosis after total hip arthroplasty--a prospective cohort study.

The role of ultrasound screening for proximal deep-vein thrombosis (DVT) following major hip surgery is controversial. 202 consecutive patients, who had received warfarin prophylaxis after total hip arthroplasty underwent a bilateral ultrasound assessment of the proximal vein system (using the criterion of vein compressibility) before hospital discharge. In the 9 patients (4.5%; 95% CI, 2.1-8.3%) with positive test anticoagulant treatment was successfully continued for three months. In all the remaining 193 patients the warfarin treatment was withdrawn. A second ultrasound test was performed 15 days later, and showed a new (asymptomatic) abnormality compatible with proximal DVT in 2 patients (1.0%; 95% CI, 0.1-3.7%). All other 191 patients remained asymptomatic until the completion of a 3-month follow-up period (rate of symptomatic thromboembolism, 0/191, 0%; 95% CI, 0-1.9%). Because of the relatively high incidence of proximal DVT in patients undergoing major orthopaedic surgery under warfarin prophylaxis, screening for proximal DVT at hospital discharge in these patients is indicated. The negativity of this test has the potential of safely preventing the extension of anticoagulation beyond hospital stay. A larger controlled study in which the value of this strategy is tested against the prolongation of oral anticoagulation in patients with a negative ultrasound screening at discharge is indicated.

Aged↗