Use of recombinant, activated factor VII in the treatment of congenital factor VII deficiencies.

BACKGROUND AND OBJECTIVES: Factor VII (FVII) deficiency is a rare coagulation disorder, historically treated with prothrombin complex concentrates or plasma-derived FVII concentrates. We treated such patients (n = 17) with a recombinant, activated FVII preparation. MATERIALS AND METHODS: Twenty-seven spontaneous bleeding episodes were treated and 7 major and 13 minor surgical interventions were carried out. The dosages employed ranged from 8.08 to 70.5 Ig/kg body weight. RESULTS: A mean dose between 22 and 26 Ig/kg was sufficient to normalise the prothrombin time. Fifteen haemarthroses were treated with single doses and results were excellent in 13 cases. In 5/6 bleeding episodes of other types, the treatment gave either excellent or at least effective results. Haemostasis was secured in the 7 major and 13 minor surgical interventions. One patient developed antibodies 4-5 weeks after an extremely high dose. Otherwise, there were no side effects and no evidence of a thrombotic tendency. CONCLUSION: This recombinant concentrate is efficacious in FVII-deficient patients. It is safe since any risk of transmission of blood-borne viruses is eliminated.

Serum phospholipids are the main environmental determinants of activated factor VII in the most common FVII genotype. European Union Concerted Action "Clotart".

BACKGROUND AND OBJECTIVE: Numerous studies have emphasized the role of triglyceride-rich lipoproteins and of Factor VII (FVII) polymorphisms in determining levels of FVII activity. DESIGN AND METHODS: This study was undertaken to evaluate the role of other lipid fractions and the interaction between lipids and FVII in subjects with recognised genotypes. Volunteer subjects (n=459) from 5 European countries were studied. Blood samples were drawn irrespective of the time of day or fasting status. Levels of FVII activity (FVIIc), activated FVII (FVIIa) and FVII antigen (FVIIAg) were evaluated with reference to a number of lipid parameters (HDL-, LDL- and total cholesterol, triglycerides, phospholipids, lipoprotein(a), and apoliproptein A1). The two most common FVII polymorphisms were analyzed in combination (353R/Q and 5'F7; alleles M1/M2 and A1/A2, respectively). RESULTS: Homozygotes for the A1 and M1 alleles (M11/A11) had significantly higher FVII levels. At multiple regression analysis the strongest predictor of FVIIa and FVIIc was the concentration of phospholipids. This interaction was confined to the A11M11 genotype subjects. INTERPRETATION AND CONCLUSIONS: These data indicate that lipids contribute mainly to FVIIa levels through their phospholipid content, and that the degree of this contribution is strictly dependent on FVII genotypes.

Incidence of systemic thromboembolic lesions in acute myocardial infarction.

In a series of 1277 cases of acute myocardial infarction, 30 episodes of systemic, noncerebral, thromboembolic lesions in 22 patients have been detected. Locations most frequently involved were the extremities (60%), kidneys (16.6%), spleen (13.3%), and mesentery (10%). The incidence of thromboembolism has been higher in patients over the age of 60. In the great majority of cases, the myocardial infarction has been anterolateral, often with a superimposed pump failure. Mortality has been very high (54.5%), perhaps in relation to the advanced age of the patients and to the extension of the infarction. Embolism at the extremities has been well treated with Fogarty's catheter. Among patients whose postmortem examination has been performed a high incidence of ventricular aneurysm (3 of 7) and mural thrombosis (5 of 7) has resulted. In the cases of ventricular aneurysm, episodes of atrial fibrillation have always occurred.

Low plasma cell 3(H) thymidine incorporation in monoclonal gammopathy of undetermined significance (MGUS), smouldering myeloma and remission phase myeloma: a reliable indicator of patients not requiring therapy.

The kinetics of bone marrow plasma cells were evaluated by means of in vitro 3(H)thymidine incorporation in 143 patients with monoclonal gammopathies. Fifty-three patients had symptomatic multiple myeloma (MM) at diagnosis, nine were in stable remission, six in unstable remission, and 16 in the relapse phase. Thirty-seven patients were classified has having monoclonal gammopathy of undetermined significance (MGUS) and 22 as smouldering myeloma (SM). A thymidine labelling index (LI%) of greater than 3 at initial diagnosis predicted a very short survival. High LI% values (median 2.8 +/- 1.1) were also seen at relapse. However, the major new finding was that the LI% could be used to discriminate precisely between the SM-MGUS group and the MM patients including stage I disease (P less than 0.0001). Only one patient developed MM during follow up, that being 8 months after the initial diagnosis of SM. During the unmaintained stable remission (plateau) phase a low proliferative activity was also observed (LI% = 0.6 +/- 0.2). Thus the LI% was extremely useful in identification of both poor risk groups with a LI% greater than 3 and stable patients requiring no immediate therapy with a LI% less than 1. The ability to discriminate between MGUS and SM and stage I MM should prove particularly useful clinically.

Translocation and rearrangement of c-myc into immunoglobulin alpha heavy chain locus in primary cells from acute lymphocytic leukemia.

We report the molecular analysis of an 8;14 reciprocal chromosome translocation in a case of acute lymphocytic leukemia (L3 type). DNA from primary leukemic cells was analyzed on the basis of restriction endonuclease mapping by hybridization with various human c-myc and Ig heavy chain probes. The breakpoint of the translocation is within an approximately equal to 200-base-pair region in the first intron of the c-myc gene. The first, untranslated exon thereby remains on chromosome 8q-, whereas the whole protein-coding region is rearranged in the C alpha 1 locus on chromosome 14q+. RNA transfer blot analysis showed high levels of at least two different c-myc transcripts originated from the translocated gene. Both differ in size from the normal 2.2- and 2.4-kilobase transcripts. Both c-myc structure and expression were apparently normalized in remission phase. These studies demonstrate rearrangement and abnormal expression of c-myc in primary cells from an acute leukemia patient, thus adding to the concept of a key role for c-onc in human oncogenesis.

Cytokinetic studies in chronic lymphocytic leukemia. Relationship to other variables at diagnosis and survival.

In vitro 3H-thymidine labeling index (LI) of the marrow leukemic cells was determined at diagnosis in 70 patients with chronic lymphocytic leukemia (CLL). Very little labeling of leukemic lymphocytes was observed, median LI resulting as low as 0.05%. The initial LI was unrelated to age, sex, absolute number of circulating lymphocytes, degree of marrow lymphocytosis, clinical staging or survival. We conclude that the initial LI% of the marrow leukemic cells is neither a valid nor practical prognostic factor in patients with CLL.

Drug-induced kinetic perturbations of the marrow blasts in acute leukemia. Effects of the daunorubicin, cytosine arabinoside and 6-thioguanine combination.

Cell kinetic changes induced in the marrow blasts by treatment with a triple cytotoxic regimen including daunorubicin, cytosine arabinoside and 6-thioguanine (DAT) were investigated in 6 previously untreated acute nonlymphocytic leukemia patients. A decrease in the labeling and mitotic indices was consistently observed 24 h after administration of daunorubicin, suggesting a G2 block and a preferential lytic effect on the S-phase cells operated by the drug. Conversely, cytosine arabinoside and 6-thioguanine in combination induced a series of kinetic perturbations variable from case to case; however, three principal patterns of kinetic response were recogized and discussed in detail. Useful information for the planning of a more rational antileukemic therapy can be drawn from a systematic study of the kinetic effects induced by drug combinations.

Lack of prognostic significance of the pretreatment labeling and mitotic indices of marrow blasts in acute nonlymphocytic leukemia (ANLL).

The prognostic significance of the pretreatment growth characteristics of marrow blasts was examined in 37 patients with acute nonlymphocytic leukemia (ANLL) treated with a similar therapeutic regimen. Initial mitotic index (MI) and in vitro 3H-thymidine labeling index (LI) were broadly distributed showing no correlation to other initial variables, such as age or absolute blast count. No relationship whatsoever was observed between the pretreatment LI, MI and either the likelihood of achieving a complete remission or the remission and survival length. We conclude that the initial growth characteristics of marrow blasts do not play a significant role in predicting the therapeutic response in ANLL; age, modality of therapy and, possibly, the dynamic perturbations of the proliferative activity of the blast cells induced by treatment should be regarded as more reliable prognostic indicators in ANLL.