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Golledge J.,James Cook University | Clancy P.,James Cook University | Maguire J.,University of Newcastle | Lincz L.,Hunter Haematology Research Group | Koblar S.,University of Adelaide
Cardiovascular Research | Year: 2011

The extracellular matrix protein tenascin C (TnC) is expressed in a variety of embryonic tissues, but its expression in adult arteries is co-incident with sites of vascular disease. TnC expression has been linked to the development and complications of intimal hyperplasia, pulmonary artery hypertension, atherosclerosis, myocardial infarction, and heart failure. This review identifies the growing collection of evidence linking TnC with cardiovascular disease development. The transient upregulation of this extracellular matrix protein at sites of vascular disease could provide a means to target TnC in the development of diagnostics and new therapies. Studies in TnC-deficient mice have implicated this protein in the development of intimal hyperplasia. Further animal and human studies are required to thoroughly assess the role of TnC in some of the other pathologies it has been linked with, such as atherosclerosis and pulmonary hypertension. Large population studies are also warranted to clarify the diagnostic value of this extracellular matrix protein in cardiovascular disease, for example by targeting its expression using radiolabelled antibodies or measuring circulating concentrations of TnC. © 2011 The Author.


Maduwage K.,University of Newcastle | Maduwage K.,University of Peradeniya | O'Leary M.A.,Calvary Materials Newcastle | Scorgie F.E.,Hunter Haematology Research Group | And 9 more authors.
PLoS Neglected Tropical Diseases | Year: 2014

Venom recurrence or persistence in the circulation after antivenom treatment has been documented many times in viper envenoming. However, it has not been associated with clinical recurrence for many snakes, including Russell’s viper (Daboia spp.). We compare the recovery of coagulopathy to the recurrence or persistence of venom in patients with Russell’s viper envenoming. The study included patients with Russell’s viper (D. russelii) envenoming presenting over a 30 month period who had Russell’s viper venom detected by enzyme immunoassay. Demographics, information on the snake bite, and clinical effects were collected for all patients. All patients had serum collected for venom specific enzyme immunoassay and citrate plasma to measure fibrinogen levels and prothrombin time (international normalised ratio; INR). Patients with venom recurrence/persistence were compared to those with no detectable recurrence of venom. There were 55 patients with confirmed Russell’s viper envenoming and coagulopathy with low fibrinogen concentrations: 31 with venom recurrence/persistence, and 24 with no venom detected post-antivenom. Fibrinogen concentrations increased and INR decreased after antivenom in both the recurrence and non-recurrence patients. Clinical features, laboratory parameters, antivenom dose and length of hospital were similar for both groups. Pre-antivenom venom concentrations were higher in patients with venom recurrence/persistence with a median venom concentration of 385 ng/mL (16–1521 ng/mL) compared to 128 ng/mL (14–1492 ng/mL; p = 0.008). Recurrence of Russell’s viper venom was not associated with a recurrence of coagulopathy and length of hospital stay. Further work is required to determine if the detection of venom recurrence is due to the venom specific enzyme immunoassay detecting both venom-antivenom complexes as well as free venom. © 2014 Maduwage et al.


Maduwage K.P.,University of Newcastle | Maduwage K.P.,University of Peradeniya | Scorgie F.E.,Hunter Haematology Research Group | Lincz L.F.,Hunter Haematology Research Group | And 3 more authors.
Thrombosis Research | Year: 2016

Background Animal models are used to test toxic effects of snake venoms/toxins and the antivenom required to neutralise them. However, venoms that cause clinically relevant coagulopathy in humans may have differential effects in animals. We aimed to investigate the effect of different procoagulant snake venoms on various animal plasmas. Methods Prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen and D-dimer levels were measured in seven animal plasmas (human, rabbit, cat, Guinea pig, pig, cow and rat). In vitro clotting times were then used to calculate the effective concentration (EC50) in each plasma for four snake venoms with different procoagulant toxins: Pseudonaja textilis, Daboia russelli, Echis carinatus and Calloselasma rhodostoma. Results Compared to human, PT and aPTT were similar for rat, rabbit and pig, but double for cat and cow, while Guinea pig had similar aPTT but double PT. Fibrinogen and D-dimer levels were similar for all species. Human and rabbit plasmas had the lowest EC50 for P. textilis (0.1 and 0.4 μg/ml), D. russelli (0.4 and 0.1 μg/ml), E. carinatus (0.6 and 0.1 μg/ml) venoms respectively, while cat plasma had the lowest EC50 for C. rhodostoma (11 μg/ml) venom. Cow, rat, pig and Guinea pig plasmas were highly resistant to all four venoms with EC50 10-fold that of human. Conclusions Different animal plasmas have varying susceptibility to procoagulant venoms, and excepting rabbits, animal models are not appropriate to test procoagulant activity. In vitro assays on human plasma should instead be adopted for this purpose. © 2015 Elsevier Ltd. All rights reserved.


PubMed | University of New South Wales, University of Colombo, District Hospital Hingurakgoda, University of Peradeniya and 2 more.
Type: Journal Article | Journal: PLoS neglected tropical diseases | Year: 2015

Russells viper envenoming is a major problem in South Asia and causes venom induced consumption coagulopathy. This study aimed to investigate the kinetics and dynamics of venom and clotting function in Russells viper envenoming.In a prospective cohort of 146 patients with Russells viper envenoming, we measured venom concentrations, international normalised ratio [INR], prothrombin time (PT), activated partial thromboplastin time (aPTT), coagulation factors I, II, V, VII, VIII, IX and X, and von Willebrand factor antigen. The median age was 39 y (16-82 y) and 111 were male. The median peak INR was 6.8 (interquartile range [IQR]: 3.7 to >13), associated with low fibrinogen [median,<0.01 g/L; IQR: <0.01-0.9 g/L), low factor V levels [median,<5%; IQR: <5-4%], low factor VIII levels [median,40%; IQR: 12-79%] and low factor X levels [median, 48%; IQR: 29-67%]. There were smaller reductions in factors II, IX and VII over time. All factors recovered over 48 h post-antivenom. The median INR remained >3 at 6 h post-antivenom but had reduced to <2, by 24 h. The aPTT had also returned to close to normal (<50 sec) at 24 h. Factor VII, VIII and IX levels were unusually high pre-antivenom, median peak concentrations of 393%, 307% and 468% respectively. Pre-antivenom venom concentrations and the INR (r = 0.20, p = 0.02) and aPTT (r = 0.19, p = 0.03) were correlated (non-parametric Spearman analysis).Russells viper coagulopathy results in prolonged aPTT, INR, low fibrinogen, factors V, VIII and X which recover over 48 h. Severity of clotting abnormalities was associated with venom concentrations.


Enjeti A.K.,Hunter Haematology Research Group | Enjeti A.K.,Hunter New England Health | Enjeti A.K.,Hunter Medical Research Institute | Lincz L.F.,Hunter Haematology Research Group | And 7 more authors.
Thrombosis Research | Year: 2010

Introduction: Microparticles (MP) are small membrane bound cellular particles that play an important role in thrombosis. This study was carried out to evaluate if increased numbers or procoagulant potential of circulating MP contribute to the heterogeneity in occurrence of thrombosis in heterozygotes carrying Factor V Leiden (FVL) mutation. Methods: Levels of circulating platelet (CD41a), endothelial (CD62e) as well as leukocyte (CD45) derived MP from 45 FVL heterozygous individuals were enumerated by flow cytometry and compared with normal controls. Functional studies included enzyme linked immunoassay based prothrombinase activity (ELISA) and modified dilute Russell Viper venom test (DRVVT). Results: Circulating MP were significantly higher in the FVL cohort compared to the controls (median = 2100 vs. 1508 MP/μl, respectively p = 0.0021).All subsets of MP (platelet, endothelial and leukocyte) were significantly elevated in the FVL group, the most striking disparity seen in the number of CD45 positive leukocyte MP. Despite the differences in the number of MP between the controls and FVL cohorts, there was no significant difference in the prothrombinase activity recorded by the ELISA (2.0 vs 2.4 PS equivalents; p = 0.7374) or clotting time assessed by the DRVVT (47 vs 46 sec, p = 0.8118). When the FVL cohort was considered alone there was no significant difference in MP parameters between FVL subjects with or without a history of thrombosis. Conclusions: This is the first study on circulating MP levels in subjects who are heterozygote for factor V Leiden. We report that circulating platelet and leukocyte MP are elevated in carriers of this mutation and may be important contributors to risk of thrombosis. © 2009 Elsevier Ltd All rights reserved.


Phang M.,Hunter Medical Research Institute | Lincz L.,Hunter Haematology Research Group | Seldon M.,Hunter Haematology Research Group | Garg M.L.,Hunter Medical Research Institute
Journal of Nutritional Biochemistry | Year: 2012

Background: Dietary supplementation with omega-3 fatty acids has been associated with reduced incidence in thrombotic events. In addition, administration of n-3 polyunsaturated fatty acids (PUFAs) has been shown to rectify elevated platelet microparticle (MP) number and procoagulant activity in post myocardial infarction patients. However, it is unknown whether supplementation can alter these parameters in healthy individuals and if such effects are immediate or require long-term supplementation. We have previously demonstrated a gender-specific effect of LCn-3PUFA supplementation on platelet aggregation in healthy human subjects. Here we extend these findings to include the acute effects of supplementation with EPA- or DHA-rich oils on circulating MP levels and activity in healthy subjects. Design: A placebo-controlled trial was conducted in healthy males and females (n=30). MP activity, MP levels and platelet aggregation were measured at 0 and 24 h postsupplementation with either a placebo or EPA- or DHA-rich oil. Results: Both EPA and DHA effectively reduced platelet aggregation at 24 h postsupplementation relative to placebo (-13.3%, P=006 and -11.9%, P=016, respectively), but only EPA reduced MP activity (-19.4%, P=003). When grouped by gender, males showed a similar reduction in both platelet aggregation and MP activity (-20.5%, P=008; -22%, P=008) following EPA, while females showed significantly reduced platelet aggregation (-13.7%, P=04) but not MP activity after DHA only. Conclusion: EPA and DHA exert gender-dependent effects on platelet aggregation and platelet MP activity, but not on MP levels. With respect to thrombotic disease risk, males may benefit more from EPA supplementation. © 2012 Elsevier Inc.


Lincz L.F.,Hunter Haematology Research Group | Lincz L.F.,University of Newcastle | Lincz L.F.,Hunter Medical Research Institute | Scorgie F.E.,Hunter Haematology Research Group | And 6 more authors.
Thrombosis Research | Year: 2012

Introduction: Inheritance of Factor V Leiden (FVL) is associated with an increased but variable level of risk for thrombosis. We have previously shown that FVL heterozygotes have elevated levels of circulating pro-coagulant microparticles (MP). Here we sought to determine if these subjects differed in their plasma levels of FVL and if this was related to MP concentrations and/or history of thrombosis. Materials and Methods: The Hemoclot Quanti. V-L clotting assay was used to specifically measure FVL in plasma samples from 44 known carriers (12 M, 32 F; aged 46 ± 13 years). Circulating MP were quantified by flow cytometry using fluorochrome conjugated antibodies to platelet (CD41a), leukocyte (CD45), and endothelial (CD62e) surface markers, and MP prothrombinase activity was determined by ELISA. Results: The cohort was found to have a mean FVL of 49.5 ± 5.6% and this was positively correlated to the total number of circulating CD41a + MP (R = 0.31, p = 0.03) but not to other MP subsets or to MP prothrombinase activity. The amount of FVL relative to normal factor V (FVL/FV clotting ratio) was calculated and found to be highly variable, ranging from 0.37 to 0.69, and significantly correlated with a history of thrombosis (n = 14; p = 0.04). Conclusions: This is the first study to investigate the relationship between varying levels of FVL and plasma derived MP. These results are consistent with our previous findings of an increase in MP levels in carriers of FVL as compared to controls, and suggest a role for FVL/FV ratio in predicting risk of thrombosis in carriers of FVL. © 2011 Elsevier Ltd. All rights reserved.


Phang M.,Hunter Medical Research Institute | Scorgie F.E.,Hunter Haematology Research Group | Seldon M.,Hunter Haematology Research Group | Garg M.L.,Hunter Medical Research Institute | Lincz L.F.,Hunter Haematology Research Group
Journal of Nutritional Biochemistry | Year: 2014

Background: LCn-3PUFA comprised of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) offer cardioprotection involving a decrease in coagulant activity; however, the evidence is equivocal. We have previously demonstrated that the acute (24. h) effects and chronic (4. weeks) effects of LCn-3PUFA supplementation on platelet aggregation in human subjects are sex specific. This study investigated the mechanisms of the sex-dependent effects of LCn-3PUFA with 4. weeks supplementation of EPA-rich vs. DHA-rich oils on procoagulant and platelet activity in healthy subjects. Design: A double-blinded, placebo-controlled randomised trial was conducted in 94 healthy adults: male (. n=41) and female (. n=53). Platelet coagulation parameters including factors I, II, V, VII, VIII, IX, X, vWF:Ag and endogenous thrombin potential were measured at baseline and 4. weeks postsupplementation with EPA-rich or DHA-rich oil capsules. Results: We have previously reported that platelet aggregation is specifically reduced by supplementation with EPA in males and DHA in females. This sex-specific effect was also observed for decreases in plasma levels of Factor II (-7.9±3.8%, P=.026), Factor V (-6.5±4.5%, P=.022) and vWF:Ag (-7.3±2.1%, P=.034) and was most pronounced in males supplemented with EPA. In contrast, DHA-mediated reduction in platelet aggregation in females was not accompanied by any significant changes in the coagulation parameters tested. Conclusion: Significant interactions between sex and specific LCn-3PUFA exist to reduce procoagulant activity differentially in males vs. females and could have profound effects on managing risk of thrombotic disease. © 2014 Elsevier Inc.


PubMed | Hunter Haematology Research Group and Hunter Medical Research Institute
Type: Journal Article | Journal: The Journal of nutritional biochemistry | Year: 2014

LCn-3PUFA comprised of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) offer cardioprotection involving a decrease in coagulant activity; however, the evidence is equivocal. We have previously demonstrated that the acute (24 h) effects and chronic (4 weeks) effects of LCn-3PUFA supplementation on platelet aggregation in human subjects are sex specific. This study investigated the mechanisms of the sex-dependent effects of LCn-3PUFA with 4 weeks supplementation of EPA-rich vs. DHA-rich oils on procoagulant and platelet activity in healthy subjects.A double-blinded, placebo-controlled randomised trial was conducted in 94 healthy adults: male (n=41) and female (n=53). Platelet coagulation parameters including factors I, II, V, VII, VIII, IX, X, vWF:Ag and endogenous thrombin potential were measured at baseline and 4 weeks postsupplementation with EPA-rich or DHA-rich oil capsules.We have previously reported that platelet aggregation is specifically reduced by supplementation with EPA in males and DHA in females. This sex-specific effect was also observed for decreases in plasma levels of Factor II (-7.9 3.8%, P=.026), Factor V (-6.5 4.5%, P=.022) and vWF:Ag (-7.3 2.1%, P=.034) and was most pronounced in males supplemented with EPA. In contrast, DHA-mediated reduction in platelet aggregation in females was not accompanied by any significant changes in the coagulation parameters tested.Significant interactions between sex and specific LCn-3PUFA exist to reduce procoagulant activity differentially in males vs. females and could have profound effects on managing risk of thrombotic disease.


Isbister G.K.,University of Newcastle | Buckley N.A.,University of New South Wales | Page C.B.,University of Newcastle | Page C.B.,Princess Alexandra Hospital | And 4 more authors.
Journal of Thrombosis and Haemostasis | Year: 2013

Background: Venom-induced consumption coagulopathy (VICC) is a major effect of snake envenoming. Objectives: To investigate whether fresh frozen plasma (FFP) given after antivenom resulted in more rapid correction of coagulation. Patients/Methods: This was a multicenter open-label randomized controlled trial in patients with VICC of FFP vs. no FFP within 4 h of antivenom administration. Patients (> 2 years) recruited to the Australian snakebite project with VICC (International Normalized Ratio [INR] > 3) were eligible. Patients were randomized 2 : 1 to receive FFP or no FFP. The primary outcome was the proportion with an INR of < 2 at 6 h after antivenom administration. Secondary outcomes included time from antivenom administration to discharge, adverse effects, major hemorrhage, and death. Results: Of 70 eligible patients, 65 consented to be randomized: 41 to FFP, and 24 to no FFP. Six hours after antivenom administration, more patients randomized to FFP had an INR of < 2 (30/41 [73%] vs. 6/24 [25%]; absolute difference, 48%; 95% confidence interval 23-73%; P = 0.0002). The median time from antivenom administration to discharge was similar (34 h, range 14-230 h vs. 39 h, range 14-321 h; P = 0.44). Seven patients developed systemic hypersensitivity reactions after antivenom administration - two mild and one severe (FFP arm), and three mild and one severe (no FFP). One serious adverse event (intracranial hemorrhage and death) occurred in an FFP patient with pre-existing hypertension, who was hypertensive on admission, and developed a headache 6 h after FFP administration. Post hoc analysis showed that the median time from bite to FFP administration was significantly shorter for non-responders to FFP than for responders (4.7 h, interquartile range [IQR] 4.2-6.7 h vs. 7.3 h, IQR 6.1-8 h; P = 0.002). Conclusions: FFP administration after antivenom administration results in more rapid restoration of clotting function in most patients, but no decrease in discharge time. Early FFP administration (< 6-8 h) post-bite is less likely to be effective. © 2013 International Society on Thrombosis and Haemostasis.

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