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Biomedical subjects

M Laffan

Publications and source records attributed to M Laffan.

At least 19 recordsLinked to original sources
PubMed2006

Use of recombinant activated factor VII in massive obstetric haemorrhage.

Massive obstetric haemorrhage is a life-threatening emergency that remains a major cause of maternal mortality. Conventional management is aimed at optimising uterine tone, replacing circulating volume and blood products, and surgery to achieve haemostasis. Recently there have been numerous reports of the (unlicensed) use of recombinant activated factor VII in the management of major obstetric haemorrhage. We report our experience of using it in the treatment of major post-partum haemorrhage in four previously healthy parturients. The published reports of recombinant activated factor VII use in post-partum haemorrhage (unrelated to pre-existing coagulopathies) are compared.

Adult↗
PubMed2004

Management of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors' Organization.

von Willebrand disease (VWD) is the commonest inherited bleeding disorder. The aim of therapy for VWD is to correct the two defects of haemostasis in this disorder, impaired primary haemostasis because of defective platelet adhesion and aggregation and impaired coagulation as a result of low levels of factor VIII. The objective of this guideline is to inform individuals making choices about the treatment and management of VWD including the use of therapeutic products. This is the second edition of this UK Haemophilia Centre Doctors' Organization (UKHCDO) guideline and supersedes the previous edition which was published in 1994.

Antifibrinolytic Agents↗
PubMed2004

The diagnosis of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors' Organization.

von Willebrand disease (VWD) is the commonest inherited bleeding disorder. However, despite an increasing understanding of the pathophysiology of VWD, the diagnosis of VWD is frequently difficult because of uncertainty regarding the relationship between laboratory assays and function in vivo. The objective of this guideline is to provide contemporary advice on a rational approach to the diagnosis of VWD. This is the second edition of this UK Haemophilia Centre Doctors' Organisation (UKHCDO) guideline and supersedes the previous edition which was published in 1997.

Hematologic Tests↗
PubMed2001

Prothrombotic disorders and abnormal neurodevelopmental outcome in infants with neonatal cerebral infarction.

BACKGROUND AND PURPOSE: The aim of this study was to evaluate the occurrence of prothrombotic disorders in a well-characterized cohort of infants with neonatal stroke and to document any association of prothrombotic disorders with the type of infarct seen on magnetic resonance imaging (MRI) and clinical outcome. METHODS: Twenty-four infants with perinatal cerebral infarction confirmed by neonatal MRI were enrolled in the study. All the infants and, when possible, both parents were tested to identify inherited and acquired prothrombotic disorders. RESULTS: None of the infants had a significant bleeding diathesis, but 10 (42%) had at least 1 prothrombotic risk factor. Five children showed heterozygosity for factor V Leiden, and 6 had high factor VIIIc concentrations. There was a striking association between the occurrence of these abnormalities and both the presence of cerebral hemorrhage on MRI and poor neurologic outcome. Eight of the 11 patients (73%) with hemiplegia or global developmental delay had factor V Leiden and/or raised factor VIIIc, whereas only 1 of the 13 patients (8%) with normal outcome had any prothrombotic risk factors. In particular, all 5 infants with factor V Leiden had hemiplegia, compared with only 4 of the 19 infants without factor V Leiden (21%). CONCLUSIONS: These data suggest that the presence of prothrombotic risk factors and, in particular, of the factor V Leiden mutation, is significantly associated with poor outcome after perinatal cerebral infarction.

Activated Protein C Resistance↗
PubMed2001

Elevated plasma factor VIII levels--a novel risk factor for venous thromboembolism.

An association between elevated plasma levels of FVIII:C and arterial thrombosis was first described 20 years ago. More recently a growing literature has centered on the potential role for elevated FVIII:C in venous thromboembolic disease. 25% of patients have plasma FVIII:C levels greater than 1500 IU/l six months following venous thrombosis. This increased FVIII:C appears unrelated to any ongoing acute phase reaction, and reflects a true increase in circulating FVIII protein. Furthermore the increase in FVIII:C is sustained in the vast majority of subjects for years following the thrombotic episode. Multivariate analysis of the Leiden thrombophilia study has demonstrated that increased FVIII is an independent risk factor for venous thromboembolism. Individuals with FVIII:C exceeding 1500 IU/l had a six-fold increased risk, compared to those with FVIII:C levels less than 1000 IU/l. Also, prospective follow-up has shown that patients with high FVIII:C levels are at increased risk for episodes of recurrent venous thrombosis. These findings support the theory that increased plasma levels of FVIII:C represent a constitutional prothrombotic tendency. However the mechanism underlying the elevation in FVIII remains unknown.

Factor VIII↗
PubMed2000

Bleeding symptoms and coagulation abnormalities in 337 patients with AL-amyloidosis.

Haemorrhage is a frequent manifestation of amyloidosis. We performed a retrospective clinical analysis of 337 patients with systemic immunoglobulin light-chain (AL)-amyloidosis, in whom whole-body serum amyloid P component (SAP) scintigraphy and a clotting screen had been performed. Abnormal bleeding was noted in 94 cases (28%), and the coagulation screen was abnormal in 172 cases (51%). The most common abnormalities were prolongation of the thrombin time (TT; 108 cases, 32%) and the prothrombin time (PT; 82 cases, 24%). In multivariate analysis, a prolonged PT was the only coagulation abnormality associated with abnormal bleeding (P = 0.0012), but this was independent of the whole-body amyloid load. Prolongation of the TT was associated with hepatic amyloid infiltration (P < 0.00001), with proteinuria (P < 0.001) and low serum albumin (P < 0.00001). In 154 patients who were studied further, subnormal factor X activity (FX:C) was found in 22 cases (14%). In cases with subnormal FX:C, the corresponding factor X antigen (FX:Ag) measurements were consistently higher (median FX:Ag/FX:C 2.5, range 0.81-9.25, n = 16) than cases with normal FX:C (median FX:Ag/FX:C 0.96, range 0.65-1.29, n = 28, P < 0.0001). No evidence was found of an FX inhibitor. Of the 48/154 (31%) cases with a prolonged TT, the reptilase time was also prolonged in 38/48 cases (79%). These data show that haemorrhage and abnormal coagulation are common in AL-amyloidosis and are multifactorial in origin. We provide evidence suggesting that hepatic amyloid infiltration and nephrotic syndrome are determinants of the TT. In most patients, prolongation of the PT was explained by reduction in FX:C, but this was not wholly explained by a reduction in FX:Ag.

Adult↗
PubMed2000

The antithrombotic effect of aprotinin: actions mediated via the proteaseactivated receptor 1.

BACKGROUND: Despite aprotinin being in widespread clinical use to prevent bleeding during cardiac surgery, there remains concern that such a powerful hemostatic agent may also be prothrombotic, particularly in relation to coronary vein graft occlusion. The major thrombin receptor on platelets, protease-activated receptor 1 (PAR1) requires proteolytic cleavage to transmit activating signals. Here we have investigated the effect of aprotinin on thrombin-induced PAR1 activation of platelets. METHODS AND RESULTS: Proteolysis-dependent and -independent responses of washed platelets were studied in vitro. Platelet aggregation induced by trypsin was dependent on PAR1 (inhibited by the PAR1-specific antagonist peptide, FLLRN) and was completely blocked by aprotinin at doses more than 100 KIU/mL. Aggregation in response to thrombin, 1 nmol/L, was predominantly mediated through PAR1 and was inhibited 42.6% to 86.6% (P <.05-.001) by pharmacologic doses of aprotinin (50-160 KIU/mL). Aprotinin did not inhibit the nonproteolytic agonists collagen, epinephrine, adenosine diphosphate, or phorbol 12-myristate 13-acetate. Furthermore, blockade of the thrombin response by aprotinin did not prevent subsequent platelet aggregation through collagen or epinephrine. Experiments with intraplatelet Ca(2+) fluxes, which provided an earlier measure of platelet activation, placed the effect of aprotinin proximal to the PAR1 activation event. Since aprotinin did not inhibit platelet responses to the nonproteolytic PAR1 agonist peptide, SFLLRN, this implied that aprotinin acted by preventing PAR1 receptor cleavage by thrombin. CONCLUSIONS: Aprotinin inhibits thrombin-induced platelet activation by preventing proteolysis of the PAR1 receptor. These findings argue against aprotinin being prothrombotic and suggest instead that aprotinin may have significant antithrombotic effects.

Analysis of Variance↗
PubMed2000

Elevation of FVIII: C in venous thromboembolism is persistent and independent of the acute phase response.

Recent literature has suggested a role for elevated FVIII:C in venous thromboembolic disease (VTED). However since FVIII:C is known to rise in response to an acute phase reaction, it is difficult to determine whether the increased FVIII:C precedes the thrombosis or represents a secondary reactive phenomenon. In an attempt to address this question, we followed 35 patients with confirmed VTED, raised FVIII:C level (>1.5 iu/ml) and no other thrombotic tendency. Serial measurements of FVIII:C, vWF:Ag, C-reactive protein and fibrinogen were performed. We hypothesized that a persistent increase in FVIII:C in the absence of any other measures of ongoing acute phase response, would support the idea that elevation of FVIII:C is a constitutional phenomenon. Of this initial group, 94% continued to have an elevated FVIII:C level throughout the period of follow up (median 8 months; range 3 to 39 months), with no significant difference between the FVIII:C levels determined at first estimation and those obtained during follow up (p = 0.58). Conversely, only 18% had evidence of an acute phase reaction when first assessed, and nonparametric ranking analysis demonstrated no correlation between FVIII:C and either C-reactive protein or fibrinogen (p = 0.315 and 0.425 respectively).We conclude that increased FVIII:C levels following VTED are persistent, independent of the acute phase reaction, and thus may represent a constitutional risk factor for VTED.

Acute-Phase Reaction↗
PubMed1999

Fibrinogen Bbeta14 Arg-->Cys: further evidence for a role in thrombosis.

A single base substitution (C-->T) in exon II of the Bbeta fibrinogen gene resulting in an Arg14-->Cys replacement was identified in a young woman with a history of recurrent thrombotic stroke. The patient's plasma showed prolongation of the thrombin and Reptilase times, and plasma fibrinogen, which was low when determined by chronometric assay (Clauss technique) was normal by clot weight. Dysfibrinogenaemia associated with the same mutation was identified in eight family members including two siblings with a history of venous and arterial thrombosis. Fibrin monomer polymerization with thrombin, Reptilase and Agkistrodon contortrix contortrix venom was defective. Polymerization studies revealed a reduced rate of polymerization compared with normal plasma, which improved on cooling from 37 degrees C to 20 degrees C. Plasma viscosity in the affected individuals was normal. Flow cytometric analysis of platelets from the proband and another affected member showed no increase in surface bound fibrinogen. Euglobulin clot lysis time was normal. The same point mutation has been described previously in individuals with thrombosis. This family adds further to the genotype-phenotype correlation of the dysfibrinogenaemias and provides strong evidence for a genuine association of fibrinogen BbetaArg14Cys with thrombosis. The mechanism underlying a causal relationship with the increased incidence of thrombosis remains obscure but a review of related dysfibrinogens suggests that the addition of a free thiol group rather than the loss of the thrombin cleavage site may be important.

Adult↗
PubMed1998

Raised factor VIII is associated with coronary thrombotic events.

Coagulation is triggered during the onset of myocardial infarction, resulting in vascular occlusion. However, a causal role for individual haemostatic factors in the development of thrombotic occlusion is not established. Three cases (all relatively young women) are reported of raised factor VIII associated with myocardial infarction. Two patients presented acutely with myocardial infarction at a relatively young age with no preceding history of angina. The other patient had had venous thrombosis when young and activated protein C resistance (APCR), without the presence of factor V Leiden. A functional relation exists between APCR and factor VIII; therefore, raised factor VIII may contribute to APCR and the increased thrombotic risk in patients without factor V Leiden. Factor VIII is an important risk factor for atherothrombotic events, including sudden death, in patients with vascular disease. These cases support the association of raised factor VIII with acute thrombotic events, even in patients without significant underlying atheromatous disease.

Activated Protein C Resistance↗
PubMed1998

Analysis of the F8 gene in individuals with high plasma factor VIII: C levels and associated venous thrombosis.

High FVIII:C levels have previously been shown to be an independent risk factor for thrombosis with 4.8 times higher potential risk of thrombosis in individuals with FVIII:C levels greater than 1.5 u/ml. Recently, we found that raised FVIII:C levels are largely attributable to elevated FVIII:Ag levels. The determinants of FVIII:Ag levels are unclear and might be partly genetic. The promoter of the F8 gene has recently been characterised we therefore investigated the promoter and the 3' terminus of the F8 gene for possible polymorphisms associated with raised FVIII:Ag levels in 62 selected individuals with a thrombotic tendency. We confirm previous reports that raised FVIII:C levels are largely attributable to an elevation in FVIII:Ag and this is also associated with elevation of vWF; non-O blood group: relatively short APTT and relatively low APC ratio. We screened 1140 bp of the proximal promoter including the protein binding sites identified by DNase I footprint analysis by SSCP, however no polymorphisms were identified. Direct DNA sequence analysis of the region -542 to +165 failed to identify any sequence polymorphisms. The recently described polymorphism in the polyadenylation cleavage site in the prothrombin gene associated with increased prothrombin activity prompted us to screen the region surrounding the 3' terminus of the F8 gene for polymorphisms but we found none.

Base Sequence↗
PubMed1997

Thrombophilia: an expanding group of genetic defects that predispose to thrombosis.

Thrombophilia is a term recently coined to describe the increased tendency of some patients to develop thrombosis. Although the term was originally used as a clinical description, the abnormalities of the coagulation system responsible can now be identified in approximately 50% of cases of thrombosis. Many of these disorders are hereditary and it is this group that are generally referred to as thrombophilia. Recent studies have begun to establish the mutations responsible for the hereditary thrombophilias and to assess their interactions with one another. However, it is also clear that many other factors remain undiscovered.

Blood Coagulation↗
PubMed1997

Late onset haemolysis and red cell autoimmunisation after allogeneic bone marrow transplant.

We reviewed the medical records of 293 patients who underwent allogeneic bone marrow transplants at the Hammersmith Hospital between 1989 and 1994. There was clinical evidence of an autoimmune reaction against red cells in nine patients. Seven of these patients had significant haemolysis; the other two had red cell autoagglutination. Haemolysis was resistant to treatment in three cases. Six of the nine patients had monoclonal Ig bands identified within 1 year of transplant. The autoimmune reaction could be classified broadly into two types: an early onset type (n = 4) beginning 2 to 8 months post-transplant associated with a cold antibody, and a late onset type (n = 5) beginning 6 to 18 months post-transplant associated with warm antibodies. The predominant antibody in the two categories described may reflect the kinetics of immune reconstitution post-transplant, since serum IgM levels typically return to normal 2 to 6 months post-transplant, while IgG levels may not reach normal levels until 12-18 months post-transplant. We speculate that unbalanced reconstitution of B and T cell lymphopoiesis post-transplant may favour emergence of oligoclonal proliferation and that some of the resulting antibodies may have activity against red cells.

ABO Blood-Group System↗
PubMed1997

A comparison between the platelet activating properties of different contrast media used in radiology and MRI.

Previous studies have demonstrated that some intravascular radiographic contrast media (CM) used in angiography, especially non-ionic monomers, may cause platelet activation. This study was designed to elucidate which properties of the CM were responsible for this activity. Platelet activation engendered by CM was studied using flow cytometry to detect platelet degranulation (as CD62 expression) and fibrinogen binding. In order to elucidate the relevant characteristics of the CM responsible, contrast agents of differing structures, properties, formulations and osmolalities were studied; ionic and non-ionic, monomeric and dimeric. Gadolinium chelate MR enhancing agents and saline solutions of differing osmolalities were also investigated. Ionic dimeric sodium meglumine ioxaglate, non-ionic dimeric iodixanol and non-ionic dimeric iotrolan did not produce increased degranulation compared with saline controls. However, all agents produced a mild increase in bound fibrinogen. Experiments using saline solutions demonstrated that these effects are not attributable to the high osmolality of some CM. The broad comparison facilitated by this study shows that previous generalizations regarding platelet activation by CM, based on an ionic-non-ionic division, are not valid. We presume that some chemical structural property of the compounds is responsible and it is of note that the chemically distinct gadolinium chelates, gadolinium DTPA and gadolinium DTPA-BMA, also caused platelet activation to a similar degree. CD62 expression correlated with fibrinogen binding suggesting that at least one common pathway of platelet activation is involved.

Angiography↗