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D A Lane

Publications and source records attributed to D A Lane.

At least 55 records · Page 3Linked to original sources
PubMed1997

Epidemiology of coagulation factors, inhibitors and activation markers: The Third Glasgow MONICA Survey. II. Relationships to cardiovascular risk factors and prevalent cardiovascular disease.

Coagulation factor activity (fibrinogen, VII, VIII and IX), coagulation inhibitor activity (antithrombin, protein C, protein S), and coagulation activation markers (prothrombin fragment F1, 2; thrombin-antithrombin complexes) were measured in 746 men and 816 women aged 25-74 years, randomly sampled from the north Glasgow population in the Third MONICA Survey. After age-adjustment, significant associations with cardiovascular risk factors were observed. Serum cholesterol and triglyceride were associated with increases in factors VII and IX, as well as antithrombin, protein C and protein S; and with increased fibrinogen and factor VIII in women. Apart from factor VIII (related to blood pressure in men, but not in women), similar associations were observed for blood pressure and body mass index. Smoking status and/or smoking markers were related to fibrinogen, factor IX, antithrombin and protein S. Alcohol intake was related to protein S, and inversely to fibrinogen and antithrombin in men. Low social class was associated with fibrinogen, factor VIII, factor IX, and with antithrombin, protein S, and low protein C in men. Serum vitamin C was associated inversely with coagulation factors and coagulation inhibitors. The only associations of activation markers were with low serum vitamin C, and with alcohol consumption and low social class in men. Prevalent cardiovascular disease was associated only with fibrinogen. These associations of coagulation factors and inhibitors with cardiovascular risk factors are plausibly relevant to thrombotic risk in cardiovascular disease. In general, 'worse' values of risk factors are associated with increased plasma levels of both coagulation factors and inhibitors, without significant increase in coagulation activation markers. However, the association of lower serum vitamin C with increased coagulation activation markers is of potential therapeutic interest.

Adult↗
PubMed1997

Decrease in factor VII coagulant activity during percutaneous transluminal coronary angioplasty by heparin-mediated lipolytic action.

Levels of factor VII coagulant activity (FVII:C) and two-chain factor VIIa antigen (FVIIa:Ag) were measured in ten patients before and up to 6 h after receiving a bolus of heparin during percutaneous transluminal coronary angioplasty (PTCA). A significant and sustained post-heparin fall in the level of FVII:C was observed (approximately 30%) without any change in the level of FVIIa:Ag. The level of tissue factor antigen within the circulation remained unchanged. The observed decrease in FVII:C coincided with a significant decrease in triglyceride levels presumably due to lipoprotein and hepatic lipase released by the heparin. These findings appear to demonstrate a lipid (triglyceride) dependence of FVII:C. Thus, heparin may act indirectly as antithrombotic agent by limiting a lipid-dependent activation of the extrinsic pathway of coagulation.

Aged↗
PubMed1997

Hospital ship doctrine in the United States Navy: the Halsey effect on scoop- and-sail tactics.

Although hospital ships have a long history, naval strategists have paid little attention to their tactical employment in naval and amphibious warfare. Often employed as floating ambulances, operational doctrine for hospital ships did not permit their use as floating combat surgical hospitals until the final amphibious campaigns of World War II. Based on operational archives-ships' logs, war diaries, battle plans, and other official records-this essay traces the evolution of tactical doctrine on hospital ships from Guadalcanal to Inchon. Early in World War II, there were insufficient hospital ships to permit much flexibility in their employment. By the Philippine campaign in 1944, the increased availability of afloat medical assets prompted Third Fleet Commander Vice Admiral William F. Halsey to propose that the ships be used as acute surgical hospitals at the amphibious landing sites rather than as sea-going ambulances. Facing the prospect of a growing number of casualties for the major assaults being planned, Halsey needed to maximize medical and surgical efficacy and return-to-duty rates to conserve the fighting strength of his invasion forces. Admiral Chester A. Nimitz approved Halsey's proposal, and the battle plan at Iwo Jima combined the careful triage of casualties at the waterfront with early, forward employment of hospital ships. Despite more than 21,000 casualties at Iwo Jima, they were handled better than at any previous operation in the Pacific theater. The tactical doctrine for hospital ships suggested by Halsey has since been employed in every major amphibious operation, including Okinawa and Inchon, and has also been used in modern-era contingency and humanitarian missions.

Altruism↗
PubMed1997

Antithrombin: molecular basis of deficiency.

Antithrombin is a plasma protein regulator of coagulation proteinase activity, particularly that of thrombin. Its deficiency is a risk factor for venous thromboembolism. Considerable progress has been made in understanding the organisation and function of the antithrombin gene and protein, and the molecular basis of deficiency, all of which are reviewed, but briefly, here.

Antithrombin III↗
PubMed1997

Antithrombin and its inherited deficiency states.

Antithrombin is the primary inhibitor of thrombin that also inhibits many of the other activated serine proteinases involved in blood coagulation. A hypercoagulable state occurs when a deficiency of antithrombin exists in plasma; the deficiency may be either inherited or acquired. This failure to regulate adequately the activity of coagulation proteinases can, with additional provocation, result in clot formation and in the clinical presentation of thromboembolic disease. The structure and function of antithrombin, nature and heterogeneity of the molecular defects in the antithrombin gene associated with inherited antithrombin deficiency, prevalence and the natural history of inherited antithrombin deficiency are all reviewed here.

Antithrombin III↗
PubMed1997

Activation of coagulation and fibrinolysis in childhood diarrhoea-associated haemolytic uraemic syndrome.

Diarrhoea-associated haemolytic uraemic syndrome (D+ HUS) is usually caused by verotoxin producing Eschericia coli. We hypothesized that verotoxin binding to glomerular endothelial cells causes localised endothelial cell activation and thus activation of coagulation and reduction of fibrinolytic potential. We also proposed that treatment with fresh frozen plasma or dialysis would not affect these changes. Markers of activation of coagulation and fibrinolysis were measured in 30 children with acute D+ HUS serially, in healthy children and in children on dialysis. In acute D+ HUS, levels of thrombin-antithrombin III complex and prothrombin fragment 1+2 were significantly increased (p <0.001). The source of thrombin generation was unclear. Factor XIIa levels were increased in patients and controls with renal failure. Factor VIIa levels were not significantly raised in children with acute D+ HUS. D-dimers were increased, but fibrinolytic potential as measured by fibrin plate was reduced. Levels of plasminogen activator inhibitor antigen and activity and tissue plasminogen activator antigen were increased. Neither peritoneal dialysis nor administration of blood products, the most common treatments, altered parameters of coagulation or fibrinolysis.

Antithrombin III↗
PubMed1996

Identification of 19 protein S gene mutations in patients with phenotypic protein S deficiency and thrombosis. Protein S Study Group.

Protein S is a protein C-dependent and independent inhibitor of the coagulation cascade. Deficiency of protein S is an established risk factor for venous thromboembolism. We have used a strategy of specific amplification of the coding regions and intron/exon boundaries of the active protein S gene (PROS1) and direct single-strand solid phase sequencing, to seek mutations in 35 individuals with phenotypic protein S deficiency. Nineteen point mutations (16 novel) in 19 probands (or relatives of probands) with venous thromboembolism are reported here. Fifteen of the 19 mutations were expected to be causal and included 10 missense mutations (Lys9Glu, Glu26Ala, Gly54Glu, Cys145Tyr, Cys200Ser, Ser283Pro, Gly340Asp, Cys408Ser, Ser460Pro, and Cys625Arg). Three of the 15 mutations resulted in premature stop codons (delete T 635 producing a stop codon at position 126, Lys368stop and Tyr595stop) and two were at intron/exon boundaries (+1 G to A in intron d and +3 A to C in intron j). Of the remaining four mutations, three were within intronic sequence and one was a silent mutation within the coding region and did not alter amino acid composition. In two of the 10 missense mutations, reduced plasma protein S activity compared with antigen level suggested the presence of variant (type II) protein S.

Alleles↗
PubMed1996

Molecular genetics of antithrombin deficiency.

Antithrombin is the major proteinase inhibitor of thrombin and other blood coagulation proteinases. Antithrombin has two functional domains, a heparin binding site and a reactive centre (that complexes and inactivates the proteinase). Its deficiency results in an increased risk of venous thromboembolism. Appreciable progress has been made in recent years in understanding the structure and function of this protein, the genetic cause of inherited deficiency and its clinical consequence. The structure of antithrombin is now considered in terms of the models derived from X-ray crystallography, which have provided explanations for the function of its heparin interaction site and of its reactive loop. The structural organization of the antithrombin gene has been defined and numerous mutations have been identified that are responsible for antithrombin deficiency: these may reduce the level of the protein (Type I deficiency), alter the function of the protein (Type II deficiency, altering heparin binding or reactive sites), or even have multiple or 'pleiotropic effects' (Type II deficiency, altering both functional domains and the level of protein).

Antithrombin III↗
PubMed1996

Prenatal diagnosis in combined antithrombin and factor V gene mutation.

We report prenatal diagnosis in a family with combined antithrombin deficiency (type II heparin binding site) and factor V 506 Arg to Gln mutation. Both clinically unaffected parents are heterozygous for the antithrombin mutation, which results in a 99 Leu to Phe substitution, and the father is also heterozygous for the factor V gene defect. There is one daughter, homozygous for the antithrombin and heterozygous for the factor V mutations, who suffered a right-sided hemiparesis at the age of 4 months due to occlusion of the left middle cerebral artery and a large left sided infarct followed by further thromboembolic events. The family requested prenatal diagnosis and chorionic villi was sampled at 12 weeks gestation. The fetus was shown to be heterozygous for the antithrombin and factor V gene mutations, the same genotype as the unaffected father. No further intervention was considered necessary. To our knowledge this is the first report of prenatal diagnosis in antithrombin deficiency.

Antithrombins↗
PubMed1996

Oral contraceptives enhance the risk of clinical manifestation of venous thrombosis at a young age in females homozygous for factor V Leiden.

In 29 patients (17 females) homozygous Arg 506 Gln mutation (FV Leiden) was identified. 25 had been investigated because of venous thromboembolism (VTE); four asymptomatic patients were found during family studies. The first VTE had occurred significantly earlier in females (median age [m] 26 years, range 17-49) than in males (m=38 years, range 21-82) (P=0.01). 12 females (80%) had taken oral contraceptives (OC, estrogen content 0.02-0.1 mg) for 6-150 months prior to thrombosis. Further triggering conditions in females were hormone replacement (n=1) and pregnancy (n=2). In 8/10 males the first VTE had occurred spontaneously--in two after surgery. The sites of VTE were deep vein thrombosis, pulmonary embolism, caval vein thrombosis and superficial thrombophlebitis. From our data we conclude that OC medication is the most important precipitating factor for VTE in females with homozygous FV Leiden.

Adolescent↗
PubMed1996

Directed search for thrombomodulin gene mutations.

Thrombomodulin is a principle thrombin receptor located on the vascular endothelium. Thrombomodulin alters the specificity of thrombin, redirecting its procoagulant function to an anticoagulant function by making it a more efficient activator of protein C. While mutation of the genes of other components of this anticoagulant mechanism, protein C, protein S and factor V, is known to predispose towards venous thromboembolism, there are only a few reports of the investigation of thrombomodulin gene mutation. We present the design and evaluation of a strategy to investigate thrombomodulin gene mutation in arterial and venous thrombosis.

Cerebrovascular Disorders↗
PubMed1996

Factor V Leiden (FV R506Q) in families with inherited antithrombin deficiency.

We investigated the presence of the gene mutation of factor V, FV R506Q or factor V Leiden, responsible for activated protein C resistance, in DNA samples of 127 probands and 188 relatives from 128 families with antithrombin deficiency. The factor V mutation was identified in 18 families. Nine families were available to assess the mode of inheritance and the clinical relevance of combined defects. The factor V and antithrombin genes both map to chromosome 1. Segregation of the defects on opposite chromosomes was observed in three families. Co-segregation with both defects on the same chromosome was demonstrated in four families. In one family a de novo mutation of the antithrombin gene and in another a crossing-over event were the most likely explanations for the observed inheritance patterns. In six families with type I or II antithrombin deficiency (reactive site or pleiotropic effect), 11 of the 12 individuals with both antithrombin deficiency and the factor V mutation developed thrombosis. The median age of their first thrombotic episode was 16 years (range 0-19); this is low compared with a median age of onset of 26 years (range 20-49) in 15 of 30 carriers with only a defect in the antithrombin gene. One of five subjects with only factor V mutation experienced thrombosis at 40 years of age. In three families with type II heparin binding site deficiencies, two of six subjects with combined defects experienced thrombosis; one was homozygous for the heparin binding defect. Our results show that, when thrombosis occurs at a young age in antithrombin deficiency, the factor V mutation is a likely additional risk factor. Co-segregation of mutations in the antithrombin and factor V genes provides a molecular explanation for severe thrombosis in several generations. The findings support that combinations of genetic risk factors underly differences in thrombotic risk in families with thrombophilia.

Adolescent↗
PubMed1996

High purity factor IX and prothrombin complex concentrate (PCC): pharmacokinetics and evidence that factor IXa is the thrombogenic trigger in PCC.

Recent studies using assays for surrogate markers of thrombogenicity in man have demonstrated that activation of the coagulation system occurs following infusion of clinical doses of prothrombin complex concentrates (PCC) but not after the same doses of high-purity factor IX concentrates (HP-FIX) in patients with haemophilia B. Here we have investigated the mechanism of such thrombogenesis by applying assays that detect early-through to late-events in coagulation system activation in a pharmacokinetic cross-over study of 50 IU/kg PCC and a new HP-FIX product in haemophilia B patients. Satisfactory recoveries and half-lives were observed for both concentrates. HP-FIX caused no increases in thrombin-antithrombin III complex (TAT), prothrombin activation peptide fragment F1+2 (F1+2), factor X activation peptide (FXAP) or factor VIIa (FVIIa). In contrast the same dose of factor IX in the form of PCC was followed by significant increases over pre-infusion levels of TAT, F1+2 and FXAP, but not FVIIa. Elevations of FIXAP occurred after both HP-FIX and PCC but did not reach normal levels and were attributed to normalisation of the FIX concentration in those patients whose levels of FIXAP were initially low. We conclude that the thrombogenic trigger associated with PCC infusion occurs at the level of factor X activation. In the absence of any increase in FVIIa, we would attribute this to the likely presence of FIXa in the PCC.

Adult↗