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Ho P.,Northern Health | Ho P.,Florey Institute of Neurosciences and Mental Health | Ho P.,University of Melbourne | Lim H.Y.,Northern Health | And 7 more authors.
Thrombosis Research | Year: 2016

Introduction Isolated distal deep venous thrombosis (IDDVT) is traditionally associated with less severe clinical sequelae, with ongoing debate on multiple aspects of its management. Despite numerous studies evaluating its acute management, there remains a paucity of data evaluating long-term complications such as recurrence and subsequent malignancy. We aim to evaluate the characteristics of IDDVT in institutions that routinely perform whole leg ultrasonography, and the risks of recurrence and complications in comparison to major venous thromboembolism (major VTE; defined as above-knee or proximal DVT and pulmonary embolism (PE)). Methods Retrospective evaluation of consecutive IDDVT and major VTE from July 2011 to December 2012 in a hospital network in Melbourne, Australia. Patients were followed up for a minimum of 24 months. Patients with active malignancy were excluded. Results Of 1024 VTE cases, there were 164 non-cancer patients (92 males, 72 females, median age of 61 years) with IDDVT. Compared to major VTE, IDDVT was more likely to be provoked (73% vs 59%, p < 0.01), has shorter duration of anticoagulation (median 3.5 months vs 6.0 months, p < 0.01) and less clinically significant bleeding (2.4% vs 6.7%, p = 0.05), independent of duration of therapy. Recurrence was non-inferior compared to major VTE (10% vs 7%, p = 0.36) and 60% recurred with major VTE. Three (1.8%) were subsequently diagnosed with cancer (vs 1.9% in major VTE, p = 0.97). Conclusions IDDVT has non-inferior rates of recurrence and subsequent cancer detection compared to major VTE and hence, its clinical significance should not differ from major VTE. Further studies are required to determine the adequate length of anticoagulation. © 2016 Elsevier Ltd. All rights reserved.

Tsun Wong A.K.,Australian Center for Blood Diseases
Expert Review of Hematology | Year: 2013

Platelets are anucleated fragments produced by megakaryocytes that circulate in the blood. Platelets are involved in the initial cellular response to damaged endothelium and migrate to this area to prevent excessive bleeding. What is becoming more acknowledged over the last few decades is that blood flow (hemodynamics) plays a critical role in platelet function. The purpose of this review is to summarize the current understanding of platelet biology with particular focus on the role of hemodynamics. The emerging concept of shear microgradients, which are challenging the traditional model of platelet function, will also be introduced in the review. © 2013 Expert Reviews Ltd.

Wang X.,Baker IDI Heart and Diabetes Institute | Palasubramaniam J.,Baker IDI Heart and Diabetes Institute | Gkanatsas Y.,Baker IDI Heart and Diabetes Institute | Hohmann J.D.,Baker IDI Heart and Diabetes Institute | And 13 more authors.
Circulation Research | Year: 2014

RATIONALE:: Fibrinolysis is a valuable alternative for the treatment of myocardial infarction when percutaneous coronary intervention is not available in a timely fashion. For acute ischemic stroke, fibrinolysis is the only treatment option with a very narrow therapeutic window. Clinically approved thrombolytics have significant drawbacks, including bleeding complications. Thus their use is highly restricted, leaving many patients untreated. OBJECTIVE:: We developed a novel targeted fibrinolytic drug that is directed against activated platelets. METHODS AND RESULTS:: We fused single-chain urokinase plasminogen activator (scuPA) to a small recombinant antibody (scFvSCE5), which targets the activated form of the platelet-integrin glycoprotein IIb/IIIa. Antibody binding and scuPA activity of this recombinant fusion protein were on par with the parent molecules. Prophylactic in vivo administration of scFvSCE5-scuPA (75 U/g body weight) prevented carotid artery occlusion after ferric chloride injury in a plasminogen-dependent process compared with saline (P<0.001), and blood flow recovery was similar to high-dose nontargeted urokinase (500 U/g body weight). Tail bleeding time was significantly prolonged with this high dose of nontargeted urokinase, but not with equally effective targeted scFvSCE5-scuPA at 75 U/g body weight. Real-time in vivo molecular ultrasound imaging demonstrates significant therapeutic reduction of thrombus size after administration of 75 U/g body weight scFvSCE5-scuPA as compared with the same dose of a mutated, nontargeting scFv-scuPA or vehicle. The ability of scFvSCE5-scuPA to lyse thrombi was lost in plasminogen-deficient mice, but could be restored by intravenous injection of plasminogen. CONCLUSIONS:: Targeting of scuPA to activated glycoprotein IIb/IIIa allows effective thrombolysis and the potential novel use as a fibrinolytic agent for thromboprophylaxis without bleeding complications. © 2014 American Heart Association, Inc.

Niederleithner H.,Medical University of Vienna | Heinz M.,Medical University of Vienna | Tauber S.,Medical University of Vienna | Tauber S.,University of Vienna | And 8 more authors.
Journal of Investigative Dermatology | Year: 2012

Wnt signals contribute to melanoma progression by boosting their proliferation and survival. Initially, we expected that activated Wnt signaling also improves their proficiency to recruit blood and lymph vessels. To assess this, we added cell culture supernatants (SNs) of Wnt1 and Wnt1 melanoma to endothelial spheroids. Whereas SNs of Wnt1 - melanoma cells induced lymphatic sprouts, those of Wnt1 + cells were unable to do so and this was restored by vascular endothelial growth factor C (VEGF-C). Subsequent testing of several human melanoma lines revealed that Wnt1 suppressed their VEGF-C expression. This Wnt1 effect did not depend on glycogen synthase kinase-3Β (GSK3Β), Β-catenin, or activator protein-1, but was blocked by cyclosporine A (CsA). To analyze Wnt1 effects in melanoma in vivo, we selected Wnt1 melanoma cell lines, overexpressed Wnt1, and injected them subepidermally into severe combined immunodeficient (SCID) mice. We found reduced VEGF-C expression, reduced lymphangiogenesis, and delayed metastasis to sentinel nodes in Wnt1 as compared with Wnt1 - melanoma (P<0.05). Concomitant overexpression of VEGF-C or feeding of animals with CsA restored lymphangiogenesis and metastasis in Wnt1 + melanoma. In conclusion, Wnt1 is anti-lymphangiogenic by suppressing melanoma-derived VEGF-C expression. © 2012 The Society for Investigative Dermatology.

Lim H.Y.,Northern Health | Ng C.,Austin Health | Donnan G.,Florey Institute of Neurosciences and Mental Health | Nandurkar H.,Australian Center for Blood Diseases | And 4 more authors.
Journal of Thrombosis and Thrombolysis | Year: 2016

Cerebral venous thrombosis (CVT) is a rare venous thrombotic event. We review our local experience in the management of CVT in comparison to other venous thromboembolism (VTE) with specific focus on risk factors for thrombotic recurrence. Retrospective evaluation of consecutive CVT presentations from January 2005 to June 2015, at two major tertiary hospitals in Northeast Melbourne, Australia. This population was compared to a separate audit of 1003 consecutive patients with DVT and PE. Fifty-two patients (30 female, 22 male) with a median age of 40 (18–83) years, presented with 53 episodes of CVT. Twenty-nine episodes (55 %) were associated with an underlying risk factor, with hormonal risk factors in females being most common. The median duration of anticoagulation was 6 months with 11 receiving life-long anticoagulation. Eighty-one percent had residual thrombosis on repeat imaging, which was not associated with recurrence at the same or distant site. Nine (17 %) had CVT-related haemorrhagic transformation with two resultant CVT-related deaths (RR 22.5; p = 0.04). All three VTE recurrences occured in males with unprovoked events (RR 18.2; p = 0.05) who were subsequently diagnosed with myeloproliferative neoplasm (MPN). Compared to the non-cancer VTE population, non-cancer CVT patients were younger, had similar rate of provoked events and VTE recurrence, although with significantly higher rate of MPN diagnosis (RR 9.30 (2.29–37.76); p = 0.002) CVT is a rare thrombotic disorder. All recurrences in this audit occurred in male patients with unprovoked events and subsequent diagnosis of MPN, suggesting further evaluation for MPN may be warranted in patients with unprovoked CVT. © 2016 Springer Science+Business Media New York

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