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Biomedical subjects

F Rodeghiero

Publications and source records attributed to F Rodeghiero.

At least 127 records · Page 7Linked to original sources
PubMed1994

The pathophysiology and treatment of hemorrhagic syndrome of acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) has been historically characterized by a high rate of early hemorrhagic death, particularly from intracranial bleeding. The hemorrhagic complications have been attributed to a combination of intravascular thrombin generation, excessive fibrinolysis and/or proteolytic activities released from blast cells. Before the era of all-trans retinoic acid (ATRA), the incidence of early fatal bleeding in recent series has ranged from 8 to 46%, and no anti-hemorrhagic treatment clearly appeared superior in abating this complication. This uncertainty is due to remain because of the lack of prospective studies. The increasing awareness of the need for prompt diagnosis and treatment of APL and the larger availability of supportive therapy has largely contributed to lessen the incidence of fatal bleeding, which can be reliably estimated around 10% in major centers. Groups pioneering the use of ATRA have reported a rapid improvement of the coagulopathy of APL, usually starting 48 h from the beginning of the treatment. However, the hemostatic changes during ATRA have been monitored only in a few patients and recent results suggest that hyperfibrinolysis/proteolysis is rapidly corrected by ATRA, whereas thrombin generation may persist longer. Moreover, although significantly less frequent, fatal bleeding may occur during ATRA and thrombotic events have also been reported so that hemostatic death rate is also approximately 10% in patients treated with ATRA. The combination of chemotherapy plus ATRA administration during induction has been suggested as a useful means of controlling hyperleukocytosis, and this could contribute in abating this unacceptably high rate of early death. On the other side, chemotherapy can dramatically exacerbate clotting abnormalities leading to catastrophic clinical outcomes. Thus, more detailed studies of the coagulopathy of APL and its changes during treatment with ATRA, or ATRA combined with chemotherapy, are required in order to offer the most appropriate treatment to these patients still at risk of severe bleeding and thrombotic complications.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

Clinical manifestations and management of inherited thrombophilia: retrospective analysis and follow-up after diagnosis of 238 patients with congenital deficiency of antithrombin III, protein C, protein S.

The clinical history of 238 patients with inherited thrombophilia (AT III = 94, PC = 103, PS = 41) was analyzed retrospectively at diagnosis and in the follow-up period after diagnosis. At diagnosis 129 patients (54%) had suffered from thrombosis, with a recurrence rate of 48%. The most frequent onset manifestation was deep vein thrombosis of lower limbs (58%). Thrombotic history started before 40 in 80% of the cases. Forty-nine percent of the venous thromboses were preceded by a triggering event, in most cases pregnancy (17%) and surgery (12%). After diagnosis, follow-up lasted a total of 1,113 pt-years. A policy of short-term prophylaxis during risk situations for all patients and long-term prophylaxis in symptomatic patients failed to prevent venous thrombotic episodes (diagnosed by objective methods) in 4 previously asymptomatic subjects and recurrence in 7 previously symptomatic subjects. After knowledge of the patients' diagnosis the incidence of venous thrombosis/100 pt-years was reduced as compared before diagnosis as total episodes (onset+recurrencies) (1.0 vs 1.9), onset episodes (0.7 vs 1.3) and recurrent episodes (1.3 vs 4.8), even though the differences were not statistically significant. However most of the venous thromboses occurred at a more advanced age (67% after 40 years) and without any apparent cause (83%), at significant variance with the period preceding the diagnosis; in particular the incidence of venous thrombotic onset in patients younger than 40 passed from 1.3/100 pt-years to 0.2/100 pt-years. In 6 recurrences after diagnosis a poor compliance for antithrombotic treatment was recognized.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Microheterogeneity of antithrombin III: effect of single amino acid substitutions and relationship with functional abnormalities.

Microheterogeneity of antithrombin III (AT-III) was investigated by crossed immunoelectrofocusing (CIEF) on eleven molecular variants. A normal pattern was found in five variants while two different abnormal CIEF patterns were found in the other four and two variants, respectively. Point mutations causing a major pI change (exceeding 4.0) of the amino acid substituted lead to alterations in the overall microheterogeneity. The variants thus substituted share a first type of abnormal CIEF pattern with alterations throughout the pH range, regardless of the location of the mutation (reactive site and adjacent regions or heparin binding region). Minor amino acid pI changes in these regions do not alter the AT-III overall microheterogeneity, whatever the resulting functional defect. However, if the mutation is placed in the region around positions 404 or 429, then even minor changes of the amino acid pI seem able to alter the overall charge, leading to a second type of abnormal CIEF pattern with the main alteration at pH 4.8-4.6. Neuraminidase treatment leads to disappearance of microheterogeneity except for the variants with the Arg393 to Cys substitution. Addition of thrombin induces CIEF modifications specifically related to the functional defect. A normal formation of thrombin-antithrombin complexes induces a shift towards the more acid pH range, whereas in the variants substituted at the reactive site the CIEF pattern is substantially unaffected by thrombin; variants substituted at positions 382-384 show a maximal thrombin-induced increase of the isoforms at pI 4.8-4.6. Therefore mutant antithrombins with different functional abnormalities but sharing a common CIEF pattern were well distinguished.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine↗
PubMed1993

Pharmacokinetics of monoclonally-purified and recombinant factor VIII in patients with severe von Willebrand disease.

A monoclonally-purified factor VIII (FVIII) concentrate, containing little von Willebrand factor (vWF), was infused to 11 patients with severe von Willebrand disease and unmeasurable levels of plasma vWF. In comparison with the historical data obtained infusing hemophiliacs in the same conditions, monoclonally-purified FVIII had a significantly shorter half-life and faster clearance from plasma but similar in vivo recovery and volume of distribution. Two additional patients with severe von Willebrand disease were also infused with recombinant FVIII totally devoid of vWF. Half-life was very short and in vivo recovery low, with a larger volume of distribution than for monoclonally-purified FVIII. We conclude that in patients with severe von Willebrand disease the small amounts of vWF contained in the monoclonally-purified FVIII concentrate are not sufficient to stabilize infused FVIII, nor to support the normal circulation of endogenous FVIII that these patients produce at a normal rate.

Adolescent↗
PubMed1993

Supranormal antithrombin III levels induced by concentrate administration are ineffective in quenching thrombin generation in acute promyelocytic leukemia.

Coagulation abnormalities occurring in patients with acute promyelocytic leukemia (APL) are partially corrected by heparin administration. This study was undertaken to verify if "supra-normal" levels of antithrombin III (AT-III) are similarly able to quench intravascular thrombin generation triggered by APL cells. Eight patients with APL were randomly assigned to receive either 50 U/kg (Group A) or 100 U/kg (Group B) of an AT-III concentrate, starting on the first day of chemotherapy and continuing for 7 days thereafter. Fibrinopeptide A (FPA), prothrombin fragment F1+2 and thrombin-AT III complexes, measured before and 15 minutes after each AT-III infusion, decreased significantly after each infusion, but the effect was minimal and short-lived, despite the achievement of post-infusion levels of AT-III activity well above 150% (Group A) or 200% (Group B). Small amounts of heparin were consistently detected in AT-III concentrates and post-infusion plasma samples. The short-lived quenching of thrombin generation after AT-III concentrate could be partially explained by the infusion of heparin, rather than by supranormal AT-III levels.

Adult↗
PubMed1993

High levels of histidine-rich glycoprotein and thrombotic diathesis. Report of two unrelated families.

Two new families with history of thrombosis and high levels of histidine-rich glycoprotein (HRG) are described. The propositus of family 1 died of massive pulmonary embolism at age 34. Among his relatives, the mother and the maternal grandmother had suffered from deep and superficial vein thrombosis in their youth. A maternal aunt had several episodes of superficial vein thrombosis (SVT). High levels of HRG were found in the mother, three siblings and two nephews. In the second family, the proposita suffered from spontaneous deep vein thrombosis (DVT) at age 24. The paternal grandmother and a paternal aunt had several episodes of SVT and DVT. Also in this family, high levels of HRG cosegregated with thrombotic symptoms. These new families confirm that genetically transmitted high levels of HRG could be associated to familial and juvenile thrombophilia.

Adolescent↗
PubMed1993

The genetic defect of type I von Willebrand disease "Vicenza" is linked to the von Willebrand factor gene.

Type I von Willebrand disease (vWD) Vicenza is a rare variant with autosomal dominant transmission, characterized by the presence of supranormal von Willebrand factor (vWF) multimers in plasma, similar to those normally found in endothelial cells and megakaryocytes. The patients have very low levels of plasma vWF contrasting with a mild bleeding tendency. The pathophysiology of this subtype is still unknown. The presence of supranormal multimers in the patients' plasma could be due to a mutation in the vWF molecule which affects post-translational processing, or to a defect in the cells' processing machinery, independent of the vWF molecule. In order to determine if type I vWD Vicenza is linked to the vWF gene, we studied six polymorphic systems identified within the vWF gene in two apparently unrelated families with type I vWD Vicenza. The results of this study indicate a linkage between vWF gene and the type I vWD Vicenza trait. This strongly suggests that type I vWD Vicenza is due to a mutation in one of the vWF alleles, which results in an abnormal vWF molecule that is processed to a lesser extent than normal vWF.

Alleles↗
PubMed1993

Desmopressin-induced thrombocytopenia in type I platelet discordant von Willebrand disease.

Thrombocytopenia after desmopressin (DDAVP) infusion is usually observed in patients with type IIB von Willebrand disease (vWD). No other subtypes of vWD with thrombocytopenia after DDAVP have been reported so far. We describe here the occurrence of thrombocytopenia after DDAVP in a 39 year old male and his son with phenotypic characteristics of type I vWD, "platelet discordant subtype." After DDAVP, the abnormal ristocetin cofactor/von Willebrand factor antigen ratio in plasma was not corrected and the bleeding time remained markedly prolonged. Platelet count dropped 30 min after DDAVP (from 279 to 96 x 10(3)/microL in the propositus and from 298 to 116 x 10(3)/microL in his affected son) and returned to normal at 60 min. Platelet clumping was evident on peripheral blood smears obtained after infusion. These cases indicate that after DDAVP thrombocytopenia can occur in vWD other than type IIB.

Adult↗
PubMed1993

Multimeric pattern of plasma and platelet von Willebrand factor is normal in uremic patients.

Several studies have reported increased von Willebrand factor (vWF) levels in plasma of uremic patients, with a normal multimeric pattern. Two recent studies, however, have shown a reduction of the larger multimers of plasma vWF and one has also found low levels of platelet vWF in uremic patients with prolonged bleeding time (BT). We have measured plasma and platelet vWF and analyzed its multimeric pattern in 20 uremic patients, 11 with a prolonged BT and 9 with a normal BT. For Plasma vWF, no difference for vWF:Ag, RiCof, and ristocetin-induced platelet agglutination was found between the two groups with normal and prolonged BT. The multimeric pattern of plasma vWF, as evaluated by densitometric scanning of the electrophoretic gels, was normal in both groups. For platelet vWF, vWF:Ag and RiCof content was similar in the two groups. The multimeric pattern was indistinguishable from that of normal platelets. In conclusion, our study does not confirm the presence of a structural defect of plasma vWF and the reduction of platelet vWF content in uremia.

Adult↗
PubMed1993

Symptomatic type II protein C deficiency caused by a missense mutation (Gly 381-->Ser) in the substrate-binding pocket.

A patient with recurrent deep vein thrombosis and heterozygous type II deficiency, characterized by reduced protein C activity in both amidolytic and clotting functional assays, was investigated by direct sequencing of PCR fragments derived from the coding portion of the protein C gene. AG (8856) to A transition was noted in the patient which was not present in healthy controls. This mutation is predicted to cause the substitution of Ser for Gly 381, an evolutionari'y conserved residue in the substrate binding pocket of serine-proteases (Gly 216, chymotrypsin numbering). A computer model of the structure of the serine-protease domain indicates that the properties of the altered protein C molecule can be explained on the basis of steric hindrance between the substituted serine and the substrate arginine side chains.

Adult↗
PubMed1993

Preliminary study to identify cancer patients at high risk of venous thrombosis following major surgery.

This study investigated whether the pre-surgical plasma levels of TAT and F1 + 2 of patients undergoing major surgery for localized tumours could identify patients at higher risk of thrombosis, and how heparin prophylaxis affected in vivo coagulation after cancer surgery. We measured the pre- and post-operative levels of TAT, F1 + 2, total factor VII (FVIIt) and zymogen FVII (FVIIz) in 117 cancer patients, with and without heparin prophylaxis. The end points of this study were DVT, initially detected by 125I-fibrinogen uptake test and confirmed by ascending venography. Pre-operative [TAT] and [F1 + 2] of the cancer patients were significantly higher than those of age-matched control subjects (n = 50) (P < 0.005 and P < 0.05, respectively); pre-operative [FVII] was not significantly different. One of the 83 patients receiving prophylaxis, and 8/34 not receiving prophylaxis developed post-operative DVT. Of the parameters evaluated, only the pre-operative [TAT] > 3.5 ng/ml identified patients at higher risk for post-operative DVT. Heparin reduced plasma TAT levels and FVII consumption following surgery, suggesting that heparin modulates coagulation associated with cancer surgery. The results of this study also suggest that the pre-operative [TAT] may identify patients with higher risk for post-operative DVT.

Adult↗
PubMed1992

Comparison of four virus-inactivated plasma concentrates for treatment of severe von Willebrand disease: a cross-over randomized trial.

Until recently, cryoprecipitate has been the treatment of choice in patients with severe von Willebrand disease (vWD) because it can transiently correct low plasma levels of factor VIII coagulant activity (FVIII:C) and shorten or normalize the prolonged bleeding time (BT), the two laboratory hallmarks of the disease. However, cryoprecipitate may still transmit blood-borne viruses, whereas the development of virucidal methods have rendered plasma concentrates containing FVIII:C and von Willebrand factor (vWF) safer. To establish their potential usefulness in the treatment of vWD, we compared the effect of four virus-inactivated concentrates on FVII:C and vWF plasma levels and the BT (template method) in 10 patients with severe vWD using a crossover randomized design. The concentrates were an intermediate-purity, pasteurized FVIII-vWF concentrate; an intermediate-purity, dry-heated FVIII-vWF concentrate; a solvent/detergent-treated vWF concentrate, containing little FVIII; and a high-purity solvent/detergent-treated FVIII-vWF concentrate. All concentrates were equally effective in attaining normal and sustained levels of FVIII:C postinfusion, although peak levels were more delayed after the vWF concentrate. The effect of concentrates on the BT, however, was less uniform and satisfactory. The pasteurized FVIII-vWF concentrate transiently corrected, completely or partially, the BT in 8 of 10 patients, the dry-heated and solvent/detergent FVIII/vWF concentrates in five, whereas in no patient did the vWF concentrate correct the BT according to the criteria used in this study. These effects on the BT were not related to the plasma levels of ristocetin cofactor activity-attained postinfusion (100 U/dL or more in the majority of patients) or to the multimeric structure of vWF in concentrates (defective in larger multimers in all cases). In conclusion, even though virus-inactivated concentrates can be used to increase FVIII:C levels in patients with severe vWD, none of the concentrates studied by us consistently normalizes the BT in a sustained fashion.

Bleeding Time↗