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Biomedical subjects

M A Laffan

Publications and source records attributed to M A Laffan.

12 recordsLinked to original sources
PubMed2005

Thrombin generation and phenotypic correlation in haemophilia A.

The clinical phenotype of patients with haemophilia A (HA) often differs between individuals with the same factor VIII (FVIII) gene defect (e.g. within the same family) or the same coagulant activity of FVIII (FVIII:C). We proposed that because the thrombin generation assay in platelet-poor plasma of HA patients provides more information [peak thrombin concentration, endogenous thrombin potential (ETP), rate of thrombin generation and lag-time] than a clot-based FVIII assay it might provide insight into these differences. We therefore investigated the relation between the results of the thrombin generation assay and the clinical severity in nine families with HA (23 patients with different phenotypes). We also examined the contribution of prothrombotic risk factors: (FV Leiden G1691A and prothrombin G20210A), the coagulant activity of FVIII and tissue factor (5'UTR) polymorphisms. Our data detect marked differences between individuals but these did not correlate with the reported clinical phenotype. These differences were also reflected in a marked difference in response to the therapeutic amounts of FVIII. This might account for differences in amounts of treatment consumption. Reduced peak and possibly rate of thrombin generation, rather than FVIII:C or ETP appear to represent the critical defects in FVIII-deficient plasma. We suggest that the analysis of parameters in thrombin generation is a useful tool to detect bleeding tendency in HA but not to predict the modulation of the haemorrhagic tendency in patients within families. However the presence of the other factors such as vessel wall components, protein C and platelets might need to be incorporated into this system.

Blood Coagulation↗
PubMed2001

Marked elevation of thrombin generation in patients with elevated FVIII:C and venous thromboembolism.

Elevated plasma factor VIII coagulant activity (FVIII:C, > 150 IU/dl) is a risk factor for venous thromboembolism (VTE). We hypothesized that increased FVIII:C may exert a prothrombotic effect by increasing basal thrombin generation. To test this hypothesis we have measured prothrombin fragment 1 + 2 (F1 + 2) and thrombin-antithrombin complex (TAT) in three groups: (i) patients with objectively confirmed VTE and elevated FVIII:C; (ii) patients with VTE and no detectable thrombophilia; and (iii) healthy age- and sex-matched control subjects. In the group of patients with elevated FVIII:C, TAT and F1 + 2 levels were increased in 85% and 78% of individuals respectively. This frequency of coagulation activation is dramatically higher than that reported for other recognized constitutional thrombophilias. In the group of patients with VTE but no proven thrombophilia, increased thrombin generation was present in 30% of individuals. Basal thrombin generation was significantly higher in patients with elevated FVIII:C compared with individuals with VTE but no documented thrombophilia (median TAT = 8.65 microg/l versus 2.95 microg/l, median F1 + 2 = 1.5 nmol/l versus 0.87 nmol/l; P < 0.0001, P < 0.001). Overall FVIII:C levels were strongly correlated with levels of thrombin generation (r= 0.5, P < 0001). The clinical significance of such markedly increased F1 + 2 and TAT levels in patients with high FVIII:C levels remains unclear.

Adult↗
PubMed2001

The relationship between ABO histo-blood group, factor VIII and von Willebrand factor.

ABO histo-blood group is a major determinant of plasma levels of factor VIII (FVIII) and von Willebrand factor (vWF). Blood group O individuals have significantly (approximately 25%) lower plasma levels of both glycoproteins. This association is of clinical significance. Low plasma levels of either FVIII or vWF have long been established as causes of excess bleeding. Conversely, there is accumulating evidence that elevated FVIII-vWF levels may represent an important risk factor for ischaemic heart disease and venous thromboembolic disease. In spite of the well-documented association between ABO blood group and FVIII-vWF levels, the underlying mechanism remains unknown. However, it has been established that the ABO effect is primarily mediated through a direct functional effect of the ABO locus on plasma vWF levels. Theoretically, ABO blood group may alter the rate of vWF synthesis or secretion within endothelial cells. Alternatively, ABO group may affect vWF plasma clearance rates. ABH antigenic determinants have been identified on the N-linked oligosaccharide chains of circulating vWF and FVIII, according to the blood group of the individual. It remains unclear whether these carbohydrate structures are responsible for mediating the effect of ABO blood group on plasma vWF levels.

ABO Blood-Group System↗
PubMed1996

The influence of factor VIII on measurement of activated protein C resistance.

Activated protein C resistance (APCR) has proved to be a frequent finding in association with thrombosis. The majority of patients with APCR have been found to be homozygous or heterozygous for the polymorphic variant factor V Q506 (factor V Leiden; FVQ506). However a small number of patients have APCR as assessed by functional tests but do not possess the FVQ506 polymorphism. Some of these cases are due to the presence of a lupus type anticoagulant but in this report we demonstrate that the remainder are almost entirely (nine out of ten) associated with an elevated level of FVIIIc. Spiking experiments in normal patient plasma and venous occlusion tests demonstrated that elevation of the FVIIIc results in a reduced APCR ratio and shortening of the APTT. Variation in FVIIIc, in conjunction with other factors, may therefore explain the variable phenotype associated with FVQ506 and the phenomenon of thrombosis associated APCR in the absence of FVQ506. We conclude that FVIIIc as well as FVQ506 should be taken into account when assessing thrombotic risk. APCR, elevated FVIIIc and shortened APTT have all been previously identified with an increased risk of thrombosis. It follows that resistance to APC may arise from a number of factors and is in itself a risk factor for thrombosis. The net effect of these factors is assessed in the functional test for APCR and it may be premature therefore to replace functional tests for APCR with DNA analysis alone.

Drug Resistance↗
PubMed1994

Aberrant rearrangements within the immunoglobulin heavy chain locus in hairy cell leukemia.

The cell surface expression of multiple immunoglobulin heavy chain (IGH) isotypes, preferentially observed in hairy cell leukemia (HCL), is incompatible with the deletion model of IGH class switching, and alternative models involving RNA-splicing have been proposed. To help discriminate between these possibilities we have examined the configuration of the IGH locus by DNA blot in 38 cases of HCL. Deletion of at least one allele of C mu/C delta was seen in 14 cases (37%). Of 12 cases in which IgG and/or IgA were expressed, three exhibited biallelic deletion of C mu/C delta compatible with deletional class-switching whereas the remaining 9 cases retained both alleles of C mu/C delta. These data indicate that both DNA deletion and RNA-splicing mechanisms of class-switching may operate in HCL. In a further 17 cases, other unexpected abnormalities of the IGH locus mapping to the JH-C mu intron in one of two patterns were observed. First, discordance between JH and C mu in BamHI DNA digests was found in 12 cases. Similar patterns were observed in only 4/91 cases of B-cell chronic lymphocytic leukemia and 0/15 of B-cell prolymphocytic leukemia. To preclude chromosomal translocations involving the JH-C mu intron, rearrangements of BCL1, BCL2, BCL3, and MYC were sought in 23 cases but none of the cases showed oncogene rearrangement to the intron. Second, abnormal-sized C mu fragments arising as a consequence of abnormalities of the JH-C mu intron were detected in HindIII, BgIII, and/or Xbal digests in 10/23 cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗
PubMed1988

Auto-anti-Jka in Evans' syndrome with negative direct antiglobulin test.

A patient presented with haemolytic anaemia and a negative direct antiglobulin test (DAT), and was found to have an IgG antibody with anti-Jka specificity in his serum. His red cells were typed as Jk(a-b+). Later he developed idiopathic thrombocytopenic purpura (ITP), and had a positive DAT due to anti-Jka bound to his red cells, which now typed as Jk(a+b+). Family studies suggested that the patient's true type was Jk(a+b+). Splenectomy and immunosuppression were required to treat the thrombocytopenia. The autoanti-Jka was no longer detectable following therapy.

Adult↗
PubMed1986

Hypercalcaemia in T cell acute lymphoblastic leukaemia: report of two cases.

Two young adults presenting with acute lymphoblastic leukaemia (ALL) associated with hypercalcaemia and osteolytic lesions were both found to have T cell ALL. Hypercalcaemia is a rare feature of ALL and has not previously been related to T cell disease. Both cases, in some respects, resembled (age between 10 and 20 years and low white cell count) the few other previously reported cases. In one of our cases increased concentrations of vitamin D3 seemed to have a role in the pathogenesis of the hypercalcaemia.

Adolescent↗