Biomedical subjects

A K C Chan

Publications and source records attributed to A K C Chan.

6 recordsLinked to original sources

PubMed2006

Covalent antithrombin-heparin complexes.

Unfractionated heparin (UFH) and low molecular weight heparin (LMWH) have been utilized as primary anticoagulants for thrombosis prophylaxis and treatment. However, a number of biophysical and safety limitations have led to development of new anticoagulants. Covalent antithrombin-heparin (ATH) complexes may address many of these issues. Early ATH products were prepared that had increased intravenous half-lives relative to UFH but lacked any improvement in anti-factor Xa activity or had no catalytic activity or reactivity against thrombin. However, a recent conjugate developed by Chan et al. has displayed a number of superior properties. Chan et al. ATH has an increased direct thrombin inhibition rate and can catalyze coagulant enzyme inhibition by exogenous antithrombin with very high specific activity. Unlike UFH, clot-bound thrombin is readily inhibited by ATH and, at similar antithrombotic efficacy, the ATH has improved bleeding profiles compared to heparins. Given the preclinical findings, Chan et al. ATH may warrant clinical trial testing for control of clot propagation.

Animals↗

PubMed2006

Effect of substrate and fibrin polymerization inhibitor on determination of plasma thrombin generation in vitro.

BACKGROUND: Thrombin generation potential, a critical haemostatic measure, can be determined by continuous detection of total thrombin or direct subsampling. However, differences between methods exist in area under the curve or peak thrombin calculated. Also, impact of anticoagulants on thrombin generation may vary depending on mode of analysis. OBJECTIVE: We studied the effect of components on thrombin generation in the presence or absence of anticoagulants. METHODS: The continuous method was conducted with plasma +/- fibrin(ogen) +/- fibrin polymerization inhibitor. Plasma contained slow-reacting TG5134 substrate at 37 degrees C and reaction was started with dilute thromboplastin in CaCl(2)/Tris buffer. Absorbance (405 nm) was recorded over time and free thrombin calculated from total thrombin activity. For the subsampling method, similar plasma mixtures +/- TG5134 were reacted and free thrombin measured directly as the difference in activity against S2238 substrate of timed subsamples taken into EDTA or EDTA + antithrombin + heparin. RESULTS: Slow-reacting substrate in the continuous method acted as a competitor for thrombin, giving delayed but greater free thrombin than direct subsampling. These differences persisted to varying extents with all anticoagulants tested. In either method, presence of polymerization inhibitor increased the amount of free thrombin. Continuous method detection of alpha(2)macroglobulin complexes was hampered by sensitivity limits leading to inordinate free thrombin calculations. Especially with hirudin, although free thrombin remained at the end of the subsampling method, continuous method calculations assumed no residual free thrombin. CONCLUSION: In vitro plasma thrombin generation is delayed and increased by slow-acting substrate and fibrin polymerization inhibitor.

Adult↗

PubMed2004

Increased anticardiolipin antibody IgG titers do not predict recurrent stroke or TIA in children.

BACKGROUND: Increased anticardiolipin antibody (ACLA) immunoglobulin (Ig) G titers are commonly found in children with arterial ischemic stroke (AIS) or TIA (AIS/TIA). The associated risk of recurrent thromboembolism is unknown. OBJECTIVE: To determine the risk of recurrent thromboembolism associated with persistently increased ACLA titers of the IgG isotype in children with AIS/TIA. METHODS: The authors studied a cohort of children surviving first AIS/TIA tested by standardized ELISA for beta2-glycoprotein I-dependent ACLA of the IgG isotype. Children with ACLA titers >15 IgG phospholipid (GPL) units (per manufacturer's cutoff point) on more than two occasions > or =6 weeks apart were classified as ACLA-positive (ACLA+) and compared with ACLA-negative (ACLA-) children with respect to recurrent thromboembolic events (AIS/TIA, sinovenous thrombosis, and extracerebral thromboembolism). RESULTS: The authors recruited 34 ACLA+ children and 151 ACLA- children. Most ACLA+ children (30/34; 88%) had ACLA titers < or =40 GPL units. During the follow-up period (median duration, 2.8 years for ACLA+ children and 3.0 years for ACLA- children), AIS/TIA recurred in 26% of ACLA+ children and in 38% of ACLA- children; none developed sinovenous thrombosis or extracerebral thromboembolism. Based on survival analysis, this difference was nonsignificant (p = 0.54). Using binary partition evaluation, no titer criteria for ACLA positivity (range, 0 to 60 GPL units) predicted recurrent AIS/TIA. CONCLUSION: In children surviving arterial ischemic stroke/TIA, increased anticardiolipin antibody immunoglobulin G titers do not predict recurrent thromboembolism.

Antibodies, Anticardiolipin↗

PubMed2003

Use of low molecular mass heparin (enoxaparin) in newborn infants: a prospective cohort study of 62 patients.

OBJECTIVE: To detail low molecular mass heparin (enoxaparin) use in the first few months of life. DESIGN: Prospective, consecutive cohort of unselected newborn infants. METHODS: Newborn infants were divided into groups by gestational age, underlying condition, hepatic and renal function, thrombocytopenia, and prothrombin time (PT/INR). Groups were analysed with respect to many aspects of enoxaparin treatment using multivariate methods. RESULTS: Sixty two newborn infants received enoxaparin representing 5.39 treatment years. Thromboembolic events (TEs) occurred predominantly in the lower and upper venous system in the presence of indwelling catheters (69%). Preterm infants required longer than full term infants to achieve an anti-(factor Xa) level in the target range (six versus two days). Preterm infants required higher doses of enoxaparin than full term infants to maintain anti-(factor Xa) levels in the target range (2.1 v 1.7 mg/kg/12 h). Infants with congenital heart disease (CHD) required less enoxaparin than those without CHD to maintain an anti-(factor Xa) level in the target range (1.7 v 2.1 mg/kg/12 h). Impaired renal and liver function influenced the number of dose changes needed (three versus one a month). Complete or partial resolution of TE was accomplished in 59% of newborn infants. Four infants developed major bleeds (1.2% per patient year). Recurrent TE and clot extension occurred in three infants (0.9% per patient year). CONCLUSIONS: Preterm infants are more difficult to treat with enoxaparin than full term infants. Enoxaparin appears to be an alternative to treatment with standard heparin or no treatment.

Anticoagulants↗

PubMed2003

Nuclear beta catenin as a potential prognostic and diagnostic marker in patients with colorectal cancer from Hong Kong.

AIMS: To study the expression of nuclear beta catenin in patients with colorectal cancer, colorectal adenoma, and colorectal polyps to elucidate its role in carcinogenesis, and its potential for prognosis and diagnosis. METHODS: The expression of nuclear beta catenin was studied by immunohistochemistry using paraffin wax embedded specimens. Sixty specimens each of colorectal carcinoma, colorectal adenoma, colorectal polyp, and normal colorectal specimens were analysed. The potential for prognosis was assessed by correlating nuclear beta catenin expression in 60 and 75 patients with colorectal cancer with lymph node metastasis and survival, respectively. The diagnostic capacity was explored by comparing nuclear beta catenin expression in 60 patients with colorectal cancer with other cytokeratin 20 (CK20) positive adenocarcinomas, namely: 30 colonic mucinous adenocarcinomas, 30 gastric adenocarcinomas, 27 pancreatic adenocarcinomas, and 12 ovarian mucinous adenocarcinomas. RESULTS: Nuclear beta catenin expression was highly associated with progression of colorectal tissue from normal epithelial tissue, polyps, adenomas, to carcinomas (r = 0.875; p < 0.0001). Nineteen patients with colorectal adenoma who subsequently developed colorectal carcinoma had higher nuclear beta catenin expression than those with colorectal adenomas alone (p < 0.0001). Moreover, those patients with colorectal cancer and high nuclear beta catenin expression had a higher incidence of lymph node metastasis (chi(2) = 16.99; p < 0.005) and shorter overall survival (p < 0.0001). Finally, nuclear beta catenin expression in colorectal adenocarcinomas was significantly higher than in other CK20 positive adenocarcinomas. CONCLUSIONS: Nuclear beta catenin expression is a potential prognostic factor in patients with colorectal cancer, and together with CK20, it could be used to identify colorectal carcinoma in the Hong Kong population.

Adenoma↗

PubMed2002

Blood-compatible biomaterials by surface coating with a novel antithrombin-heparin covalent complex.

Covalent antithrombin-heparin complex (ATH) was covalently grafted to a polycarbonate urethane (Corethane) endoluminal graft (a kind gift of Corvita Corporation) after being activated using 0.3% m/m NaOCl in 0.15 M phosphate pH 6.0. ATH graft density (1.98 x 10(-7) mol/m2) was 6 times the maximum amount of unfractionated heparin (UFH) that could be bound to polycarbonate urethane surfaces. Surface-bound ATH could be stored in sterile 0.15 M NaCl at 4 degrees C for at least 2 months with good antithrombotic activity before being implanted into rabbits. Analysis of ATH-coated tubing showed that it contained significant direct thrombin inhibitory activity. In vivo testing in a rabbit model was compared to non-activated non-coated surfaces, activated-non-coated surfaces, hirudin-coated surfaces and antithrombin (AT)-coated surfaces. The weight of the clot generated in the ATH-coated graft tubing was significantly less than the weight of the clot generated within the hirudin-coated graft (p = 0.03 with a 1-tailed Student's t test). The anticoagulant nature of ATH grafts in vivo was shown to be due to bound ATH because boththe AT-coated surfaces and non-coated but activated surfaces showed similar thromboresistant efficacy to that of untreated material (ANOVA; p < 0.05). Apart from the direct antithrombin activity that contributed to much of the prolonged patency in vivo, surface-bound ATH likely catalyzed AT inhibition of thrombin, as evidenced by a significant number of 125I-AT binding sites (> or = 1.5 x 10(-8) mol/m2). Thus, ATH appears to be a good candidate for coating cardiovascular devices, such as endoluminal grafts, with high levels of substitution and significant long-term blood-compatibility.

Animals↗