A bleeding disorder due to deficiency of alpha 2-antiplasmin.

The investigation of a 33 year old man with a lifelong bleeding tendency is described. Defective fibrinolysis was suspected in 1968, when clinical bleeding was corrected by administration of aminocaproic acid. The paper establishes the diagnosis as alpha 2-antiplasmin deficiency and describes its management with oral tranexamic acid.

Polycythaemia rubra vera transforming to acute lymphoblastic leukaemia with a common immunophenotype.

Lymphoblastic transformation of polycythaemia rubra vera is an extremely rare phenomenon. A case of a 76 year old man with polycythaemia rubra vera who developed acute lymphoblastic leukaemia (ALL) 16 years after his initial diagnosis is reported. Membrane markers showed a CD10 positive (common ALL) immunophenotype. To our knowledge this association has not been previously recorded. The rare occurrence of ALL in polycythaemia rubra vera may indicate that in a minority of patients clonal expansion of an abnormal pluripotent haemopoietic stem cell is responsible for the polycythaemia rubra vera disease phenotype.

Meningococcal septicaemia: treatment with protein C concentrate.

Meningococcal septicaemia is a devastating disease with the potential to develop severe vascular complications. The incidence in Northern Ireland has risen from 27 cases notified in 1992 to 56 notified in 1997. We describe the first use of protein C concentrate in addition to antithrombin III infusion in the management of a life-threatening case of meningococcal septicaemia in the Regional Intensive Care Unit, Royal Group of Hospitals, Belfast, UK. The rationale and the evidence to support the use of protein C concentrate are discussed. Despite the apparent efficacy and safety of this treatment, subsequent cases of meningococcal septicaemia have not received protein C concentrate due to a lack of availability.

Functional analysis of an unusual length polymorphism in the human antithrombin III (AT3) gene promoter.

The prevalence of the alternative alleles of an unusual length polymorphism in the promoter of the human antithrombin III (AT3) gene was determined in a sample of 155 unrelated individuals from the Northern Irish population. The 108bp L allele and the 32bp S allele occurred at frequencies of 0.21 and 0.79 respectively. Some homology was noted between the L-specific sequence and the region immediately downstream. Residual homology was also evident between the L and S sequences, suggesting that the S allele was derived from the L allele during evolution by partial deletion followed by sequence divergence. The functional significance of the polymorphism was investigated by transient transfection of AT3 promoter/luciferase reporter gene constructs into two human hepatoma cell lines in vitro. The promoter strength of the L allele was found to be 1.6-fold higher than the S allele in HepG2 cells whereas in Hep3B cells, the strength of the S allele was 1.7-fold higher than that of the L allele. In order to evaluate the phenotypic consequences of the AT3 promoter polymorphism in vivo, plasma samples from the 155 control individuals were assayed for antithrombin III (ATIII) activity. Mean activities of the different promoter polymorphism genotypes (SS, LL, SL) were not significantly different. These results suggest that the AT3 promoter polymorphism does not contribute to the variation in plasma ATIII activity that occurs in the general population.

Type I antithrombin deficiency: five novel mutations associated with thrombosis.

The genetic basis of Type I antithrombin deficiency has been investigated in six unrelated kindred with positive histories of thrombosis using a PCR amplification/direct sequencing approach. Four frameshift mutations, all introducing premature translation termination codons were identified. Thus, deletions, of a C at nucleotide position 2599 or 2600, a G at position 2601-2602 and a CT dinucleotide at position 7428-7429 were detected in three kindred and confirmed by restriction enzyme analysis. The identical insertion, of a T at nucleotide 2770, was observed in two apparently unrelated families. This finding may have been due to a founder effect since antithrombin gene polymorphism analysis showed all affected individuals to share a common haplotype. An in frame deletion of 6 bp at nucleotide position 2690-2696 causing the removal of codons 76 and 77 encoding Ile 76 and Phe 77 was also detected indicating that these amino acids are essential for stability of the mature antithrombin.

Mediastinal granulocytic sarcoma: a report of two cases.

We describe the cases of two patients who presented with granulocytic sarcoma with mediastinal involvement 15 and 21 months before development of acute myeloid leukemia. In both cases several bone marrow aspirates and trephine biopsy specimens, obtained at presentation and subsequently, revealed no evidence of leukemic infiltration. One case was originally misdiagnosed as large-cell non-Hodgkin's lymphoma, which resulted in inappropriate therapy. In both cases immunohistochemical staining revealed that tumor cells were positive for leucocyte common antigen but not for conventional B- or T-lymphoid-cell markers. Retrospective analysis revealed that tumor cells in both cases were positive for myeloid markers. Histopathologists should be aware that granulocytic sarcoma may occur in unusual extramedullary sites without evidence of bone marrow involvement. If inappropriate treatment is to be avoided, a diagnosis of granulocytic sarcoma should be considered when hemopoietic tumor cells do not stain with conventional antibodies against B- and T-lymphoid cells. Both histochemical and immunohistochemical staining should be performed in such cases to determine whether the cells are of myeloid lineage. A diagnosis of granulocytic sarcoma is not ruled out when bone marrow biopsy specimens show no evidence of leukemic infiltration.

The role of coagulation abnormalities in the development of Perthes' disease.

Recent reports have suggested an association between Perthes' disease and an underlying thrombophilic or hypofibrinolytic tendency. In Northern Ireland there is a high incidence of Perthes' disease (11.7 per 100,000 or 1 in 607 children) in a stable paediatric population. We reviewed 139 children with Perthes' disease and compared them with a control group of 220 aged- and gender-matched healthy primary schoolchildren with similar racial and ethnic backgrounds. There were no significant deficiencies of antithrombotic factors protein C, protein S, antithrombin III or resistance to activated protein C. A total of 53 (38.1%) of the children with Perthes' disease had a prolonged activated partial thromboplastin time (>38) compared with 13 (5.9%) of the control group (p < 0.001). Our findings have shown that using standard assays, thrombophilia secondary to antithrombotic factor deficiency or resistance to activated protein does not appear to be an aetiological factor for Perthes' disease. The cause of the prolonged activated partial thromboplastin time, usually associated with a clotting factor deficiency, is under further investigation.

Immune response to multiple skin test antigens in haemophiliacs.

Using seven skin test antigens the cell-mediated immune response was evaluated in 20 haemophiliacs, 10 human immunodeficiency virus (HIV) antibody-positive and 10 antibody-negative. Response rates were compared with 75 healthy males of similar age range. All haemophiliac patients displayed significant impairment of cell-mediated reactivity to the test antigens; however, there was no apparent correlation with HIV antibody status.

Human immunodeficiency virus infection in Northern Ireland 1980-1989.

To 31st December 1989, 71 persons are known to have attended medical practitioners in Northern Ireland with a diagnosis of Human Immunodeficiency Virus (HIV) infection. Twenty-one of these persons have had the diagnosis of Acquired Immune Deficiency Syndrome (AIDS) and 11 have died. The distribution of reports in the "at risk" categories of homosexual/bisexual males, injecting drug users, heterosexual males and females was significantly different (p less than 0.001) from those reported in the United Kingdom as a whole. Of tests for HIV infection carried out in patients attending the genitourinary medicine department of the Royal Victoria Hospital between 1987-1989, 0.16% have been positive. The prognostic value of the T4 lymphocyte count at presentation for the subsequent development of AIDS was significant (p = 0.0011). The commonest AIDS indicator disease diagnosed was Pneumocystis carinii pneumonia which was seen in seven of the 21 patients (33%).

An alternative strategy for identification of type IIA VWD mutations.

A 306 base pair segment of the von Willebrand's factor (VWF) gene between nucleotides 4627 and 4932 was amplified by PCR using DNA from a type IIA VWD patient. The amplified DNA was cloned in the plasmid pCRII. Clones of the VWF gene and pseudogene were distinguished by their KpnI restriction patterns. A series of six VWF gene clones was sequenced. A single C to T point mutation at nucleotide 4789 resulting in the substitution of arginine 834 by tryptophan was identified in four clones. This mutation, which destroys a BstEII restriction site, was also detected in amplified DNA of affected relatives of the patient. The method described avoids difficulties associated with strategies employed previously for identification of VWD mutations.

Menorrhagia in von Willebrand disease successfully treated with single daily dose tranexamic acid.

Four cases of menorrhagia in von Willebrand disease were successfully treated with tranexamic acid given in a single daily dose of 4 g for the first 3-5 days of the menstrual cycle. The pathophysiology and pharmacokinetics are discussed. The apparent improved efficacy and acceptability of this new dosing regime have been highlighted.

A pharmacokinetic study of an ion-exchange solvent-detergent-treated high-purity factor VIII concentrate. Haemophilia Directors for Scotland and Northern Ireland.

An ion-exchange chromatography purified factor VIII concentrate (Liberate) that had undergone a solvent-detergent viral inactivation treatment was compared with an intermediate-purity concentrate (Z8), which was terminally heated at 80 degrees C for 72 h, in 15 haemophilia A patients in a blinded crossover pharmacokinetic study. Both products achieved a peak level close to that predicted (100 IU/dl for Liberate and 103 IU/dl for Z8) and there were no significant differences in the recoveries achieved nor of any of the other pharmacokinetic parameters. We conclude that the pharmacokinetic properties of factor VIII:C, following solvent-detergent treatment and ion-exchange chromatography, are equivalent to those of the lower purity terminally heat-treated product (Z8), and it is therefore likely to be a clinically efficacious concentrate.