Use of animal models of inherited and induced von Willebrand factor (VWF) deficiency continues to advance the knowledge of VWF-related diseases: von Willebrand disease (VWD), thrombotic thrombocytopenic purpura (TTP), and coronary artery thrombosis. First, in humans, pigs, and dogs, VWF is essential for normal hemostasis; without VWF bleeding events are severe and can be fatal. Second, the ADAMTS13 cleavage site is preserved in all three species suggesting all use this mechanism for normal VWF multimer processing and that all are susceptible to TTP when ADAMTS13 function is reduced. Third, while the role of VWF in atherogenesis is debated, arterial thrombosis complicating atherosclerosis appears to be VWF-dependent. The differences in the VWF gene and protein between humans, pigs, and dogs are relatively few but important to consider in the design of VWF-focused experiments. These homologies and differences are reviewed in detail and their implications for research projects are discussed. The current status of porcine and canine VWD are also reviewed as well as their potential role in future studies of VWF-related disorders of hemostasis and thrombosis.

Timothy C. Nichols

Dwight A. Bellinger

Elizabeth P. Merricks

Robin A. Raymer

Mark T. Kloos

Natalie DeFriess

Margaret V. Ragni

Thomas R. Griggs

Porcine and Canine von Willebrand Factor and von Willebrand Disease: Hemostasis, Thrombosis, and Atherosclerosis Studies

<i  >Introduction</i>.  Controversy remains over the optimal length of anticoagulation following idiopathic venous thromboembolism. We sought to determine if a longer, finite course of anticoagulation offered additional benefit over a short course in the initial treatment of the first episode of idiopathic venous thromboembolism. <i  >Data Extraction</i>.  Rates of deep venous thrombosis, pulmonary embolism, combined venous thromboembolism, major bleeding, and mortality were extracted from prospective trials enrolling patients with first time, idiopathic venous thromboembolism.  Data was pooled using random effects meta-regression. <i  >Results</i>. Ten trials, with a total of 3225 patients, met inclusion criteria. For each additional month of initial anticoagulation, once therapy was stopped, recurrent venous thromboembolism (0.03 (95&#x25; CI: &#x2212;0.28 to 0.35); <svg style="vertical-align:-0.12375pt" id="M1" height="9.75" version="1.1" viewBox="0 0 43.337502 9.75" width="43.337502"  xmlns="http://www.w3.org/2000/svg"    >
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</svg>), mortality (&#x2212;0.10 (95&#x25; CI: &#x2212;0.24 to 0.04); <svg style="vertical-align:-0.1575pt" id="M2" height="9.9624996" version="1.1" viewBox="0 0 43.337502 9.9624996" width="43.337502"  xmlns="http://www.w3.org/2000/svg"    >
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</svg>), and major bleeding (&#x2212;0.01 (95&#x25; CI: &#x2212;0.05 to 0.02); <svg style="vertical-align:-0.12375pt" id="M3" height="9.75" version="1.1" viewBox="0 0 43.337502 9.75" width="43.337502"  xmlns="http://www.w3.org/2000/svg"    >
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</svg>) rates measured in percent per patient years, did not significantly change. 
Conclusions: Patients with an initial idiopathic venous thromboembolism should be treated with 3 to 6 months of secondary prophylaxis with vitamin K antagonists.  At that time, a decision between continuing with indefinite therapy can be made, but there is no benefit to a longer (but finite) course of therapy.

Aaron B. Holley

Christopher S. King

Jeffrey L. Jackson

Lisa K. Moores

Different Finite Durations of Anticoagulation and Outcomes following Idiopathic Venous Thromboembolism: A Meta-Analysis

Although prothrombin is one of the most widely studied enzymes in biology, the role of the thrombin A-chain has been neglected in comparison to the other domains. This paper summarizes the current data on the prothrombin catalytic domain A-chain region and the subsequent thrombin A-chain. Attention is given to biochemical characterization of naturally occurring prothrombin A-chain mutations and alanine scanning mutants in this region. While originally considered to be simply an activation remnant with little physiologic function, the thrombin A-chain is now thought to play a role as an allosteric effector in enzymatic reactions and may also be a structural scaffold to stabilize the protease domain.

Isis S. R. Carter

Amanda L. Vanden Hoek

Edward L. G. Pryzdial

Ross T. A. MacGillivray

Thrombin A-Chain: Activation Remnant or Allosteric Effector?

Venous thromboembolism is a serious complication after total hip or knee surgery, and there is a well-established clinical need for thromboprophylaxis. However, in a large number of cases adequate administration of thromboprophylaxis does not seem to occur after total joint arthroplasty. A major challenge in the management of thromboprophylaxis is to balance the benefits of treatment with the risks, including bleeding complications. Another potential barrier to the optimal use of thromboprophylaxis could be the inconvenience of currently available agents. Many surgeons therefore adopt a conservative approach towards thromboprophylaxis. Simplifying therapy with more convenient, efficacious, and safe anticoagulants could change attitudes to anticoagulant use and improve adherence to thromboprophylactic guidelines.

Richard J. Friedman

Simplifying Thromboprophylaxis Could Improve Outcomes in Orthopaedic Surgery

Anticoagulant drugs reduce the risk of venous thromboembolic events after total hip and knee arthroplasty. However, the use of current drugs, such as low molecular weight heparins, is hampered by their subcutaneous route of administration. The use of vitamin K antagonists is hampered by the requirement for routine coagulation monitoring and dose titration to provide effective anticoagulation without an increased risk of bleeding and numerous food and drug interactions. Clearly, there is a need for new oral, fixed-dose anticoagulant drugs that do not require coagulation monitoring, while demonstrating similar or better efficacy and safety profiles when compared with current agents.

New Oral Anticoagulants for Thromboprophylaxis after Elective Total Hip and Knee Arthroplasty

Whilst poor response to clopidogrel is associated with adverse outcomes uncertainty exists as to how (a) response should be assessed and (b) poor responders managed.  We utilised VerifyNow P2Y12 and short Thrombelastography (TEG) to assess 900&#x2009;mg doses in (i) initial poor responders to 600&#x2009;mg and (ii) in a randomised comparison with 600&#x2009;mg.  
Blood was taken before and six hours post clopidogrel in (i) 30 volunteers receiving 600&#x2009;mg (poor responders received 900&#x2009;mg &#x3E; two weeks later) and (ii) 60 patients randomized 1 : 1 to 600&#x2009;mg or 900&#x2009;mg doses. Poor response was defined as TEG &#x25;Clotting Inhibition (&#x25;CIn) or VerifyNow Platelet Response Unit (PRU) reduction <svg style="vertical-align:-0.30096pt;width:10.825px;" id="M1" height="8.8500004" version="1.1" viewBox="0 0 10.825 8.8500004" width="10.825"  xmlns="http://www.w3.org/2000/svg">
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</svg>30&#x25;.  (i) Poor responders to 600&#x2009;mg had greater PRU reduction (45.0 versus 20.1&#x25;, <i>P</i> = 0.03) and greater &#x25;CIn (22.9 versus <svg style="vertical-align:-0.17555pt;width:38.174999px;" id="M2" height="11.1" version="1.1" viewBox="0 0 38.174999 11.1" width="38.174999"  xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,11.1)">
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</svg>&#x25;, <i  >P</i> = 0.01) after 900&#x2009;mg but (ii) there were no significant differences between the patient groups.  Near-patient assessment of response to clopidogrel is feasible and clinically useful. Whilst ineffective on a population basis 900&#x2009;mg doses increase the effect of clopidogrel in initial poor responders.

Alex R. Hobson

Zeshan Qureshi

Phil Banks

Nicholas Curzen

The Potential Value of Near Patient Platelet Function Testing in PCI: Randomised Comparison of 600&#x2009;mg versus 900&#x2009;mg Clopidogrel Loading Doses

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Thrombosis