Biomedical subjects

Jim Thom

Publications and source records attributed to Jim Thom.

8 recordsLinked to original sources

PubMed2006

The tissue factor pathway in ischemic stroke.

To explore the role of the the tissue factor (TF) pathway in ischemic stroke. We measured blood concentrations of markers of the TF pathway [TF antigen, free tissue factor pathway inhibitor antigen (TFPIf) and activity (TFPIac), and activated factor VII (FVIIa)] within 7 days (acute phase) and after 3-6 months (convalescence) in 150 patients with first-ever ischemic stroke and 150 community controls. During the acute phase, TF antigen and TFPIf were not significantly altered but TFPIac was increased (mean 1.27 versus 1.13 U/ml, P = 0.04) and FVIIa was decreased in cases compared with controls (mean 43.3 versus 57.9 mU/ml, P = 0.0004). After adjusting for baseline differences between cases and controls, increasing quartiles of TFPIf were independently associated with reduced odds of stroke, and reducing quartiles of FVIIa and increasing quartiles of TFPIac with increased odds of stroke. During the convalescent phase, FVIIa and TFPIac returned to normal but TF antigen and TFPIf were significantly decreased compared with controls [median TF antigen, 110 (follow-up) versus 155 pg/ml (controls), P = 0.0008; median TFPIf, 15.5 (follow-up) versus 23.3 ng/ml (controls), P = 0.002]. Alterations of blood concentrations of TF pathway markers are common in patients with acute ischemic stroke. The mechanisms are unclear but may relate to enhanced formation of TF-FVIIa complexes and upregulation and release of TFPI during the acute phase, and ongoing consumption of TF antigen and TFPIf during the chronic phase as the atherosclerotic plaque heals.

Aged↗

PubMed2006

The effects of tissue factor pathway inhibitor and anti-beta-2-glycoprotein-I IgG on thrombin generation.

BACKGROUND AND OBJECTIVES: Recent evidence suggests that autoantibodies to tissue factor pathway inhibitor (TFPI) and/or antiphospholipid antibodies (aPL) may contribute to upregulation of the tissue factor (TF) pathway of blood coagulation and the development of thrombotic complications in the antiphospholipid syndrome (aPS). The aim of this study was to determine the influence of aPL e.g. anti-beta-2-glycoprotein-I (anti-beta2GPI) and anti-prothrombin, on in vitro TF-induced thrombin generation in the presence and absence of TFPI. DESIGN AND METHODS: IgG fractions were collected from subjects with aPL (n=21) and normal controls (n=36). Anti-TFPI activity was determined after incubation of IgG isolated from control or subject plasma with pooled normal plasma using an amidolytic assay for TFPI. The influence of IgG fractions and purified aPL (anti-beta2GPI and anti-prothrombin) on TF-induced in vitro thrombin generation was determined using a chromogenic assay of thrombin activity. RESULTS: Patients with aPL had significantly elevated thrombin generation (median [interquartile range]) compared to normal controls (112.0 [104.0-124.0]% vs 89.9 [85.7-100.9]%, respectively; p<0.001). Thrombin generation was significantly correlated with anti-TFPI activity in patients with aPL (r(s)=0.452; p=0.039). It was also demonstrated that anti-beta2GPI, but not anti-prothrombin IgG antibodies, significantly enhanced TF-induced thrombin generation in the presence of TFPI, using both purified and patients' samples. INTERPRETATION AND CONCLUSIONS: Our findings support the hypothesis that anti-beta2GPI IgG antibodies accelerate thrombin generation in the presence of TFPI and may contribute to hypercoagulability in patients with aPS.

Adult↗

PubMed2005

Laboratory diagnosis of von Willebrand disorder: use of multiple functional assays reduces diagnostic error rates.

Regular multilaboratory surveys of laboratories primarily in Australia, New Zealand, and Southeast Asia have been conducted over the past 8 years to evaluate testing proficiency in the diagnosis of von Willebrand disorder (VWD). We have reassessed the findings of these surveys with a particular emphasis on the diagnostic errors and error rates associated with particular tests or test panel limitations. The 37 plasma samples dispatched to survey participants include 9 normal samples, 4 type 1 VWD samples, 8 type 2 VWD samples (2A x 3, 2B x 3, 2M x 1, and 2N x 1), and 4 type 3 VWD samples. In addition to providing numerical test results, participant laboratories (average, n = 35) were asked to provide diagnostic interpretations of their test results regarding whether VWD was evident and, if so, the probable subtype. Although laboratories usually provided correct interpretative responses, diagnostic errors occurred in a substantial number of cases. On average, type 1 VWD plasma was misidentified as type 2 VWD plasma in 11% of cases, and laboratories that performed the ristocetin cofactor assay for von Willebrand factor (VWF:RCo) without performing the collagen-binding activity assay for VWF (VWF:CB) were 6 times more likely to make such an error than those that did perform the VWF:CB. Similarly, type 2 VWD plasma samples were misidentified as type 1 or type 3 VWD in an average of 20% of cases, and laboratories that performed the VWF:RCo without the VWF:CB were 3 times more likely to make such an error than those that performed the VWF:CB. Finally, normal plasma was misidentified as VWD plasma in an average of 5% of cases, and laboratories that performed the VWF:RCo without the VWF:CB were 10 times more likely to make such an error than those that performed the VWF:CB. We conclude that laboratories are generally proficient in their testing for VWD and that diagnostic error rates are substantially reduced when test panels are more comprehensive and include the VWF:CB.

Asia, Southeastern↗

PubMed2004

Evaluation of the phospholipid-rich dilute Russell's viper venom assay to monitor oral anticoagulation in patients with lupus anticoagulant.

The International Normalized Ratio (INR) is generally recommended to monitor anticoagulant therapy in patients treated with warfarin. However, there has been concern about the validity of the INR to monitor warfarin therapy in patients with lupus anticoagulant, particularly when there is prolongation of the baseline INR. An alternative approach is to use a chromogenic factor X assay that is not sensitive to lupus anticoagulant. However, this assay is expensive, not widely available, and does not have an established therapeutic range. We hypothesized that the phospholipid-rich dilute Russell viper venom time (prdRVVT), a simple, rapid and inexpensive assay, might be suitable to monitor warfarin therapy in this situation since Russell's viper venom directly activates coagulation factor X while the phospholipid in the reagent reduces or negates any effect of lupus anticoagulant on the assay. We measured the INR, chromogenic factor X, and prdRVVT in 50 patients stabilized on warfarin for at least 6 weeks, 12 of whom had lupus anticoagulant, and 37 patients not taking warfarin, 17 of whom had lupus anticoagulant. Factor X was negatively correlated with INR in anticoagulated patients both in the absence (r = -0.45, P = 0.01) and presence (r = -0.43, P = 0.17) of lupus anticoagulant. The prdRVVT was also strongly correlated with INR in anticoagulated patients without lupus anticoagulant (r = 0.60, P < 0.0001) but there was no correlation in the presence of lupus anticoagulant (r = -0.13, P = 0.68). Our results suggest that the prdRVVT is not suitable for monitoring warfarin therapy in patients with lupus anticoagulant.

Anticoagulants↗

PubMed2004

Anti-tissue factor pathway inhibitor activity in subjects with antiphospholipid syndrome is associated with increased thrombin generation.

BACKGROUND AND OBJECTIVES: Immunoglobulin G (IgG) fractions from subjects with antiphospholipid syndrome (aPS) have previously been demonstrated to have inhibitory activity against tissue factor pathway inhibitor (TFPI). This may contribute to the development of a prothrombotic state by impaired regulation of the tissue factor (TF) pathway. This study investigated the effect that IgG fractions from aPS subjects containing anti-TFPI activity have on in vitro TF-induced thrombin generation. DESIGN AND METHODS: TFPI and anti-TFPI activities were determined in normal controls (n=29) and aPS subjects (n=57). TFPI activity was determined using an amidolytic assay based on the generation of factor Xa. Anti-TFPI activity was determined after incubating IgG isolated from a control or subject plasma with pooled normal plasma, using the TFPI activity assay. The influence of IgG fractions from controls (n=10) and subjects (n=23) on TF-induced in vitro thrombin generation was determined using a chromogenic assay of thrombin activity. RESULTS: TFPI activity in controls (1.13+/-0.25 U/mL) was significantly lower than in subjects (1.30+/-0.42 U/mL) (p < 0.05). Anti-TFPI activity was significantly higher in subjects than controls (p = 0.0001). TF-induced thrombin generation was positively associated with anti-TFPI activity (r = 0.356; p > 0.05), with increased levels of each demonstrated in 5 subjects. INTERPRETATION AND CONCLUSIONS: Anti-TFPI activity was confirmed in 65% of aPS subjects. IgG fractions demonstrated a variable ability to interfere with TFPI function and TF-induced thrombin generation. Cross-reacting antiphospholipid antibodies and/or other entities may interfere with TFPI function, resulting in a net increase in thrombin generation and an increased thrombotic risk.

Adult↗

PubMed2003

Protein Z in ischemic stroke and its etiologic subtypes.

BACKGROUND AND PURPOSE: Protein Z is a vitamin K-dependent plasma protein whose significance in arterial thrombosis remains uncertain. The objectives of this study were to determine the association between protein Z, ischemic stroke, and etiologic subtypes of ischemic stroke. METHODS: We conducted a case-control study of 173 hospital cases of first-ever ischemic stroke and 186 randomly selected community controls. Using established criteria, we classified cases of stroke by etiologic subtype. Protein Z concentrations were measured during the first 7 days and at 3 to 6 months after the acute stroke event. RESULTS: Blood levels of protein Z measured within 7 days of acute stroke were significantly higher in cases than in controls (geometric mean, 1.46 versus 1.16 microg/mL; P<0.0001). Compared with the lowest tertile, the upper 2 tertiles of protein Z were associated with an adjusted odds ratio (OR) of ischemic stroke of 1.75 (95% CI, 1.00 to 3.07) for the second tertile and 3.07 (95% CI, 1.73 to 5.45) for the upper tertile. The adjusted odds of ischemic stroke caused by large-artery atherothrombosis was nearly 8-fold greater for those with protein Z concentrations in the upper tertile compared with the lower tertile (OR, 7.91; 95% CI, 3.11 to 20.14). The adjusted odds of ischemic stroke due to small-artery disease (OR, 1.79; 95% CI, 0.83 to 3.87) and cardioembolism (OR, 1.80; 95% CI, 0.58 to 5.64) was also increased among individuals with protein Z concentrations in the upper tertile compared with the lower tertile, but not significantly so. There was no significant difference between mean protein Z concentrations among cases in the convalescent phase (3 months) after stroke and age- and sex-matched controls. CONCLUSIONS: There is a strong, independent relationship between elevated blood levels of protein Z and ischemic stroke during the acute phase, particularly ischemic stroke due to large-artery atherothromboembolism, which is no longer evident during the convalescent phase. These results are consistent with the notion that protein Z is either an important factor in the pathogenesis of ischemic stroke due to large-artery atherothromboembolism or an acute phase reactant. Further studies are required to elucidate whether protein Z has a causative or prognostic role in acute arterial thrombosis.

Age Distribution↗

PubMed2003

Endothelial and platelet activation in acute ischemic stroke and its etiological subtypes.

BACKGROUND AND PURPOSE: Activation of endothelial cells and platelets is an important mediator of atherothrombosis. Markers of endothelial cell and platelet activation such as soluble adhesion molecules can be measured in plasma. We hypothesized that patients with acute ischemic stroke would have increased blood concentrations of soluble E-selectin and von Willebrand factor (vWF), primarily reflecting activation of endothelial cells, and increased concentrations of soluble P-selectin and platelet-derived microvesicles (PDM), primarily reflecting activation of platelets, compared with healthy controls. We also hypothesized that these markers would be differentially elevated in ischemic stroke caused by large- and small-artery atherothrombosis compared with cardiogenic embolism. METHODS: We conducted a case-control study of 200 hospital-referred cases of first-ever ischemic stroke and 205 randomly selected community controls stratified by age, sex, and postal code. Using established criteria, we classified cases of stroke by etiological subtype in a blinded fashion. The prevalence of vascular risk factors and blood concentrations of E-selectin, P-selectin, vWF antigen, and PDM were determined in stroke cases within 7 days and at 3 to 6 months after stroke and in controls. RESULTS: Mean blood concentrations of soluble E-selectin, P-selectin, and PDM within 7 days of stroke onset were all significantly higher in cases compared with controls. At 3 to 6 months after stroke, the mean blood concentrations of E-selectin and P-selectin fell significantly below that of controls, and PDM concentrations remained elevated. There was a strong, graded, and independent (of age, sex, and vascular risk factors) association between increasing blood concentrations of E-selectin during the acute phase and all etiological subtypes of ischemic stroke, particularly ischemic stroke caused by large-artery atherothrombosis. There was also a significant, graded, and independent association between increasing blood concentrations of vWF during the acute phase and ischemic stroke caused by large-artery atherothrombosis. CONCLUSIONS: We have demonstrated significant associations between acute elevation of blood markers of endothelial cell and platelet activation and ischemic stroke and between acute elevation of blood markers of endothelial cell activation and ischemic stroke caused by large-artery atherothrombosis. Persistent elevated blood concentrations of PDM may be a marker of increased risk of ischemic stroke.

Acute Disease↗

PubMed2002

A comparative multi-laboratory assessment of three factor VIII/von Willebrand factor concentrates.

Five expert laboratories have participated in a cross-laboratory study to co-evaluate and compare three commercial Factor VIII/von Willebrand factor (VWF) concentrates. A total of nine factor concentrate lots were evaluated, comprising AHF (High Purity) (AHF HP; x3), Biostate (x3) and Humate/Haemate (x3). All laboratories blind tested for FVIII: C, VWF: Ag and VWF: CB, four tested for VWF: RCo, and one performed VWF: Multimers. The study yielded inter-laboratory CVs for VWF: Ag and FVIII:C around 10-15%, and for VWF:CB and VWF:RCo around 20%, significantly lower than those of previous multi-laboratory surveys. All three lots of AHF HP contained in the vicinity of 25 U/ml FVIII:C, around 60-75 U/ml of VWF:Ag, but only 30-45 U/ml of VWF:CB and 40-50 U/ml of VWF:RCo (thus, CB/Ag ratio around 0.5-0.6 and RCo/Ag ratio around 0.6-0.7). Study determined that FVIII: C and VWF: RCo levels were similar to manufacturer assigned levels. Some loss of the high molecular weight (HMW) multimers was observed, together with an intense low molecular weight (LMW) VWF band consistent with some reduction or proteolysis of HMW VWF. All three lots of Humate/Haemate contained in the vicinity of 23-32 U/ml of FVIII:C, 70-105 U/ml of VWF: Ag, 50-90 U/ml of VWF: CB and VWF: RCo (i.e. CB/Ag ratio around 0.6-0.9 and RCo/Ag ratio around 0.6-1.1). Study-determined FVIII: C and VWF: RCo levels were similar to manufacturer-assigned levels. The LMW multimer band seen with AHF HP was also observed with Humate/Haemate. All three lots of Biostate contained in the vicinity of 40-55 U/ml of FVIII:C, 105-170 U/ml of VWF:Ag, 90-150 U/ml of VWF:CB, and 90-135 U/ml of VWF:RCo (i.e. CB/Ag and RCo/Ag ratios around 0.7-1.0). Study-determined FVIII:C levels were similar to manufacturer-assigned levels. The LMW multimer band seen with AHF HP was not observed with Biostate. The defined pattern of increasing CB/ Ag from AHF HP to Humate/Haemate and Biostate was consistently observed in study data from each of the five laboratories. In conclusion, study findings indicate some differences in the retention of functional/ HMW VWF between factor concentrates, and this is expected to have significant implications in terms of clinical efficacy for therapy in VWD.

Dimerization↗