David Lillicrap

Queen's University, Kingston, Ontario, Canada

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Publications (267)1396.14 Total impact

  • 11/2015; 2:15033. DOI:10.1038/mtm.2015.33
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    ABSTRACT: The enigma that is factor VIII immunogenicity remains ever pertinent in the treatment of hemophilia A. Development of neutralizing antibodies against the therapeutic protein in 25-30% of patients likely depends on the appropriate activation of the innate immune response shortly following antigen encounter. Our understanding of this important immunological synapse remains ill-defined. In this review, we examine the three distinct factors contributing to the fate of factor VIII almost immediately after infusion: the characteristics of the protein, the cell, and the microenvironment. We propose a continuum between clearance and antigen presentation that facilitates removal of FVIII from circulation leading to either tolerance or immunity.
    Cellular Immunology 11/2015; DOI:10.1016/j.cellimm.2015.10.011 · 1.92 Impact Factor
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    David Lillicrap ·

    Blood 02/2015; 125(13). DOI:10.1182/blood-2015-01-613588 · 10.45 Impact Factor
  • Rydz N · Grabell J · Lillicrap D · James PD ·
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    ABSTRACT: In a normal population, VWF plasma levels (VWF:Ag) and VWF activity (VWF:RCo) increase by approximately 0.17 and 0.15 IU mL(-1) per decade, but the influence of age is unknown in patients with type 1 von Willebrand disease (VWD). In a retrospective cohort study, the medical records of 31 type 1 VWD patients over the age of 30, who had been followed for ≥5 years, were reviewed for baseline clinical data and previously performed VWF:Ag, VWF:RCo and factor VIII levels (FVIII:C). VWF multimer analysis was normal in 28/31 cases performed. Mean age at diagnosis was 33 (range 16-60 years), and duration of follow-up ranged from 5 to 26 years (mean 11 years). Patients had 2-10 time points of VWD testing (mean of 5.2). The mean VWF:Ag, VWF:RCo and FVIII:C at time of diagnosis were 0.44 IU mL(-1) 0.34 IU mL(-1) and 0.75 IU mL(-1) . At last follow-up, the mean VWF:Ag, VWF:RCo and FVIII:C were significantly increased to 0.71 IU L(-1) , 0.56 IU mL(-1) and 0.90 IU mL(-1) (P ≤ 0.001, <0.001, and 0.0081 respectively). Here 18/31 patients had VWF:Ag, VWF:RCo and FVIII: C levels that increased into the normal range. The rate of change in VWF:Ag, VWF:RCo and FVIII was 0.30 IU mL(-1) (0.21-0.39, CI 95%, P < 0.0001), 0.20 IU mL(-1) per decade (0.13-0.27, CI 95%, P = 0.0001) and 0.20 IU mL(-1) (0.11-0.29, CI 95%, P = 0.0011). Patients with type 1 VWD experience age-related increases to VWF:Ag and VWF:RCo which can result in normalization of VWF levels. Further studies are required to determine if the bleeding phenotype resolves with the increases in VWF:Ag and VWF:RCo levels. © 2015 John Wiley & Sons Ltd.
    Haemophilia 02/2015; 18(5). DOI:10.1111/hae.12664 · 2.60 Impact Factor
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    ABSTRACT: The rising incidence of neutralizing antibodies (inhibitors) against therapeutic factor VIII prompted the conduct of studies to answer the question as to whether this rise is related to the introduction of recombinant factor VIII products. The present article summarizes current opinions and results of non-clinical and clinical studies on the immunogenic potential of recombinant compared to plasma-derived factor VIII concentrates. Numerous studies provided circumstantial evidence that von Willebrand factor, the natural chaperone protein present in plasma-derived factor VIII products, plays an important role in protecting exogenous factor VIII from uptake by antigen presenting cells and from recognition by immune effectors. However, the definite contribution of von Willebrand factor in reducing the inhibitor risk and in the achievement of immune tolerance is still under debate. Copyright© Ferrata Storti Foundation.
    Haematologica 02/2015; 100(2):149-156. DOI:10.3324/haematol.2014.112821 · 5.81 Impact Factor
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    ABSTRACT: We report an 11-month-old boy with severe hemophilia A who had regular exposure to factor VIII (FVIII) intended to reduce the risk of developing an inhibitor. He developed a high-titer inhibitor (peak titer 19 BU) that disappeared within 6 weeks of starting immune tolerance induction (ITI). Anti-FVIII IgG4 peaked briefly compared with anti-FVIII IgG1 and the Bethesda titer. Neither rapid resolution of an inhibitor after prophylaxis nor this behavior of anti-FVIII IgG4 has been previously reported. Transient anti-FVIII IgG4 may be a marker of an attenuated anti-FVIII response induced by prophylactic FVIII therapy.
    Journal of Pediatric Hematology/Oncology 11/2014; 37(4). DOI:10.1097/MPH.0000000000000287 · 0.90 Impact Factor
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    David Lillicrap ·
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    ABSTRACT: Details of the pathophysiologic mechanisms that underlie complex disorders, such as the thrombo-occlusive events associated with myocardial infarction, stroke, and venous thromboembolism, are challenging to address. Recent advances have been made through the application of genome-wide association studies (GWAS) to identify genetic loci associated with plasma levels of procoagulant proteins and risk of thrombotic disease. GWAS have consistently identified the gene encoding syntaxin-binding protein 5 (STXBP5) in this context. STXBP5 is expressed in both endothelium and platelets, and SNPs within the STXBP5 locus have been associated with plasma levels of vWF and increased venous thrombosis risk. In this issue of the JCI, two complementary reports from the laboratories of Charles Lowenstein and Sidney Whiteheart describe studies that highlight the complexity of the function of STXBP5 in control of storage granule development and exocytosis in platelets and endothelium. Together, these studies demonstrate that STXBP5 differentially regulates exocytosis in these two cell types. While STXBP5 facilitates granule release from platelets, it inhibits secretion from the Weibel-Palade bodies (WPBs) of endothelial cells.
    Journal of Clinical Investigation 09/2014; 124(10):1-3. DOI:10.1172/JCI77511 · 13.22 Impact Factor
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    ABSTRACT: Background Routine prophylaxis with replacement factor VIII (FVIII)—the standard of care for severe hemophilia A—often requires frequent intravenous infusions (3–4 times per week). A FVIII molecule with an extended half-life could reduce infusion frequency. The A-LONG study established the safety, efficacy and prolonged pharmacokinetics of recombinant FVIII Fc fusion protein (rFVIIIFc) in previously treated adolescents and adults with severe hemophilia A.Objective In this post-hoc analysis, we investigated the relationship between subjects’ prestudy (FVIII) and on-study (rFVIIIFc) regimens.Methods We analyzed two subgroups of subjects: prior prophylaxis and on-study individualized prophylaxis (n=80), and prior episodic treatment and on-study weekly prophylaxis (n=16). Subjects’ prestudy dosing regimens and bleeding rates were compared with their final rFVIIIFc regimen and annualized bleeding rate (ABR) in the last 3 months on study. Dosing regimen simulations based on population pharmacokinetics models for rFVIII and rFVIIIFc were performed.ResultsCompared with their prestudy regimen, 79/80 (98.8%) subjects on individualized rFVIIIFc prophylaxis decreased their infusion frequency. Overall ABRs were low, with comparable factor consumption. Longer dosing intervals, including 5-day dosing, were associated with higher baseline von Willebrand factor antigen levels. Simulated dosing regimens predicted a greater proportion of subjects with steady-state FVIII activity trough levels ≥1 IU/dL (1%) with rFVIIIFc versus equivalent rFVIII regimens.Conclusion These results suggest that patients on rFVIIIFc prophylaxis can reduce their infusion frequency compared with their prior FVIII regimen while maintaining low bleeding rates, affording more patients trough levels ≥1 IU/dL compared with rFVIII products utilizing more frequent dosing regimens.This article is protected by copyright. All rights reserved.
    Journal of Thrombosis and Haemostasis 09/2014; 12(11). DOI:10.1111/jth.12723 · 5.72 Impact Factor
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    ABSTRACT: Rare missense mutations in the von Willebrand factor (VWF) A3 domain that disrupt collagen binding, have been found in patients with a mild bleeding phenotype. However, the analysis of these aberrant VWF-collagen interactions has been limited. Here, we have developed mouse models of collagen binding mutants and analyzed the function of the A3 domain using comprehensive in vitro and in vivo approaches. 5 loss-of-function (p.S1731T, p.W1745C, p.S1783A, p.H1786D, A3 deletion) and 1 gain-of-function (p.L1757A) variant were generated in the mouse VWF cDNA. The results of these various assays were consistent, although the magnitude of the effects were different: the gain-of-function (p.L1757A) variant showed consistent enhanced collagen binding while the loss-of-function mutants showed variable degrees of functional deficit. We further analyzed the impact of direct platelet-collagen binding by blocking glycoprotein VI (GPVI) and integrin α2β1 in our ferric chloride murine thrombosis model. The inhibition of GPVI demonstrated a comparable functional defect in thrombosis formation to the VWF(-/-) mice whereas α2β1 inhibition demonstrated a milder bleeding phenotype. Furthermore, a delayed and markedly reduced thrombogenic response was still evident in VWF(-/-), GPVI and α2β1 blocked animals, suggesting that alternative primary hemostatic mechanisms can partially rescue the bleeding phenotype associated with these defects.
    Blood 07/2014; 124(11). DOI:10.1182/blood-2013-09-521484 · 10.45 Impact Factor
  • Laura L Swystun · David Lillicrap ·
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    ABSTRACT: In this issue of Blood, Yee et al1 have demonstrated that expression or infusion of a truncated von Willebrand factor (VWF) fragment containing the factor VIII (FVIII)-binding D′D3 region of VWF is sufficient to stabilize endogenous FVIII levels in VWF-deficient mice. In the absence of the carrier function of VWF, FVIII is susceptible to rapid proteolysis and clearance resulting in markedly reduced plasma levels of FVIII that contribute to a bleeding diathesis.
    Blood 07/2014; 124(3):313-5. DOI:10.1182/blood-2014-06-578955 · 10.45 Impact Factor
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    ABSTRACT: The Canadian Hemophilia Assessment and Resource Management System (CHARMS) tracks factor concentrates (FC) from the sole suppliers, Canadian Blood Services (CBS) and Hema-Quebec (HQ), to hospitals and to patients' homes. Patients FC infusion data are entered into CHARMS at Canadian Hemophilia Treatment Centres (HTCs) then exported to the national database (CentrePoint). From 2000 to 2009, 2260 registered haemophilia A or B patients received FVIII (1 009 097 765 IU) and FIX (272 406 859 IU). Over 91% of FVIII and over 84% of FIX was infused at home. Utilization of FVIII progressively increased; this was accounted for by an increase in the number of patients treated (r = 0.97; P < 0.001), there being a linear relationship between the increase in utilization and the increase in number of patients treated (P < 0.001). There was also a correlation with the annual amount used per patient (r = 0.95; P < 0.001). Utilization of FIX did not increase over time. The highest proportional utilization of both FVIII and FIX was for prophylaxis, and this proportion progressively increased being, in year 10 (2009), 77% and 66% for FVIII and FIX respectively. The proportion used for bleeding remained steady; in year 10 that proportion was 14% for FVIII and 26% for FIX, the use per patient for bleeding decreasing. The HTC-based CHARMS tracking system is essential, in Canada, for analysing indications for infusion, for predicting utilization and planning for future needs.
    Haemophilia 07/2014; 20(4):e251-9. DOI:10.1111/hae.12477 · 2.60 Impact Factor
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    ABSTRACT: The objective of this study was to evaluate the inhibitor development (ID) in previously untreated patients (PUPs) with severe haemophilia A (FVIII ≤ 0.01 IU mL−1). All Canadian Haemophilia Treatment Centres completed a questionnaire on patients born between September 2005 and August 2010 and followed for up to 7 years. Eligible patients had at least 20 exposure days (ED) or had developed an inhibitor. The odds ratio (OR) and 95% confidence intervals (95% CI) for risk factors to develop an inhibitor were estimated using unconditional logistic regression. A total of 99 haemophilia A PUPs were studied. Thirty-four (34%) developed an inhibitor (24/34 of high titre). Inhibitors developed in 25/63 (40%) patients with a high-risk mutation. ID was most frequent in Aboriginals (86%). Dose intensity (IU kg−1 day−1 X number of ED) at first exposure to factor VIII (FVIII) was associated with a crude OR increase of 1.10 (95% CI: 0.99–1.23) with each increase of 100 dose-intensity units. Haemarthrosis and intracranial bleeding as the indication for first exposure to FVIII concentrate were associated with a crude OR for ID of 7.63 (95% CI: 2.14–27.17) and 5.08 (95% CI: 1.11–23.31) respectively. ID according to FVIII concentrate used was: Advate ® 18/50 (36%), Kogenate FS® or Helixate FS® 15/36 (42%), Wilate® 0/11 and Xyntha® 1/2. In multivariate analysis, Aboriginal ethnicity (OR = 11.69; 95% CI: 1.11–122.86) and haemarthrosis (OR = 4.49; 95% CI: 1.08–18.61) were statistically significant. The cumulative incidence of ID in severe haemophilia A PUPs was 34% and varied according to ethnicity, type of bleeding at first ED, type of FVIII product and dose intensity at first exposure.
    Haemophilia 06/2014; 20(6). DOI:10.1111/hae.12479 · 2.60 Impact Factor
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    ABSTRACT: Ex vivo gene therapy strategies avoid systemic delivery of viruses thereby mitigating the risk of vector associated immunogenicity. Previously, we delivered autologous FVIII-expressing blood outgrowth endothelial cells (BOECs) to hemophilia A mice and showed that these cells remain sequestered within the implanted matrix and provide therapeutic levels of FVIII. Prior to translating this strategy into the canine model of hemophilia A, we increased cFVIII transgene expression by at least 100-fold with the use of the EF1α promoter and a strong endothelial enhancer element. BOECs isolated from hemophilia A dogs transduced with this lentiviral vector express levels of cFVIII ranging between 1.0 to 1.5 U/mL/10(6) cells/24 hours. Autologous BOECs have been implanted into the omentum of 2 normal and 3 hemophilia A dogs. These implanted cells formed new vessels in the omentum. All three hemophilia A dogs treated with FVIII-expressing autologous BOECs developed anti-FVIII IgG2 antibodies, but in only two of the dogs were these antibodies inhibitory (≤5 BU). Factor VIII antigen levels >40%, in the absence of FVIII coagulant function, were detected in the circulation for up to a year after a single gene therapy treatment, indicating prolonged cellular viability and synthesis of FVIII.
    Blood 05/2014; 123(26). DOI:10.1182/blood-2013-12-545780 · 10.45 Impact Factor
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    K. H. High · A. Nathwani · T. Spencer · D. Lillicrap ·
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    ABSTRACT: After many reports of successful gene therapy studies in small and large animal models of haemophilia, we have, at last, seen the first signs of success in human patients. These very encouraging results have been achieved with the use of adeno-associated viral (AAV) vectors in patients with severe haemophilia B. Following on from these initial promising studies, there are now three ongoing trials of AAV-mediated gene transfer in haemophilia B all aiming to express the factor IX gene from the liver. Nevertheless, as discussed in the first section of this article, there are still a number of significant hurdles to overcome if haemophilia B gene therapy is to become more widely available. The second section of this article deals with the challenges relating to factor VIII gene transfer. While the recent results in haemophilia B are extremely encouraging, there is, as yet, no similar data for factor VIII gene therapy. It is widely accepted that this therapeutic target will be significantly more problematic for a variety of reasons including accommodating the larger factor VIII cDNA, achieving adequate levels of transgene expression and preventing the far more frequent complication of antifactor VIII immunity. In the final section of the article, the alternative approach of lentiviral vector-mediated gene transfer is discussed. While AAV-mediated approaches to transgene delivery have led the way in clinical haemophilia gene therapy, there are still a number of potential advantages of using an alternative delivery vehicle including the fact that ex vivo host cell transduction will avoid the likelihood of immune responses to the vector. Overall, these are exciting times for haemophilia gene therapy with the likelihood of further clinical successes in the near future.
    Haemophilia 05/2014; 20(s4). DOI:10.1111/hae.12411 · 2.60 Impact Factor
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    D. Lillicrap · K. Fijnvandraat · E. Santagostino ·
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    ABSTRACT: It is known that a large number of both genetic and environmental factors contribute to the risk of inhibitor development, but underlying pathogenetic mechanisms are still under investigation. The clinical research on inhibitors towards factor VIII (FVIII) is challenged by the fact that this is an infrequent event occurring in a rare disease. Therefore, it is widely accepted that complementary studies involving animal models can provide important insights into the pathogenesis and treatment of this complication. In this respect, mouse models have been studied for clues to FVIII immunogenicity, natural history of immunity and for different approaches to primary and secondary tolerance induction. In the clinical setting, the type of FVIII product used and the occurrence of product switching are considered important factors which may have an influence on inhibitor development. The evaluation of data currently available in the literature does not prove unequivocally that a difference in the immunogenicity exists between particular FVIII products (e.g. recombinant vs. plasma-derived, full length vs. B-domainless). In addition, national products switches have occurred and, in this context, switching was not associated with an enhanced inhibitor risk. In contrast with severe haemophilia A, patients with moderate and mild haemophilia A receive FVIII treatment infrequently for bleeds or surgery. In this condition the inhibitor risk is low but remains present lifelong, requiring continuous vigilance, particularly after intensive FVIII exposure.
    Haemophilia 05/2014; 20(s4). DOI:10.1111/hae.12412 · 2.60 Impact Factor
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    ABSTRACT: The development of neutralizing antibodies to factor VIII (FVIII) is the most serious complication of therapy for haemophilia A. There is now excellent documentation that a large number of both genetic and environmental factors contribute to the risk of FVIII inhibitor incidence. One of the environmental factors that has been proposed as an influence on this complication is the occurrence of FVIII product switching. There are only a small number of clinical studies that have addressed this question, and thus, the amount of objective information available to assess this association is limited. In this review, in addition to summarizing past evidence pertinent to this subject, we present the results of a complementary strategy, a Delphi analysis, to add to the considerations of product switching and FVIII immunogenicity. With the imminent arrival in the clinic of several new FVIII products, the haemophilia community must be prepared to collect prospectively controlled data to better address this important management issue.
    Haemophilia 03/2014; 20(2):200-6. DOI:10.1111/hae.12283 · 2.60 Impact Factor
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    ABSTRACT: Gene- or cell-based therapies aimed at creating delivery systems for coagulation factor VIII (FVIII) protein have emerged as promising options for hemophilia A treatment. However, several issues remain to be addressed regarding the efficacies and adverse events of these new classes of therapies. To improve an existing cell-based therapy involving the subcutaneous transplantation of FVIII-transduced blood outgrowth endothelial cells (BOECs), we employed a novel cell-sheet technology that allows individual dispersed cells to form a thin and contiguous monolayer without traditional bioabsorbable scaffold matrices. Compared to the traditional methodology, our cell-sheet approach resulted in longer-term and 3-5-fold higher expression of FVIII (up to 11% of normal) in recipient hemophilia A mice that lacked a FVIII humoral immune response due to transient immunosuppression with cyclophosphamide. Histological studies revealed that the transplanted BOEC sheets were structured as flat clusters, supporting the long-term expression of therapeutic FVIII in plasma from an ectopic subcutaneous space. Our novel tissue-engineering approach using genetically modified BOEC sheets could aid in development of cell-based therapy that will allow safe and effective in vivo delivery of functional FVIII protein in patients with hemophilia A.
    PLoS ONE 12/2013; 8(12):e83280. DOI:10.1371/journal.pone.0083280 · 3.23 Impact Factor
  • Natalia Rydz · Jayne Leggo · Shawn Tinlin · Paula James · David Lillicrap ·
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    ABSTRACT: A reference genotyping laboratory was established in 2000 at Queen's University, Kingston, to provide genetic testing for Hemophilia A (HA) and B (HB) and create a Canadian mutation database. Canadian hemophilia treatment centers and genetics clinics provided DNA and clinical information from November 2000 to March 2011. The factor VIII (F8) gene was analyzed in 1177 patients (47% of HA population) and 787 female family members and the factor IX (F9) gene in 267 patients (47% of HB population) and 123 female family members, using Southern Blot, PCR, conformation sensitive gel electrophoresis, and/or direct sequencing. The mutation detection rates for HA and HB were 91% and 94%, respectively. 380 different F8 mutations were identified: inversions of intron 22 and intron 1, 229 missense, 45 nonsense, 8 deletions, 70 frameshifts, 25 splice site and one compound mutation with a splice site and intron 1 inversion. Of these mutations, 228 were novel to the Hemophilia A Database (HADB, http://hadb.org.uk/). A total 125 different F9 mutations were identified: 80 missense, 12 frameshift, 12 splice site, 9 nonsense and 7 promoter mutations, 3 large deletions, and 2 compound mutations with both missense and nonsense changes. Of these mutations, 36 were novel to the International Haemophilia B Mutation database (http://www.kcl.ac.uk/ip/petergreen/haemBdatabase.html). The Canadian F8 and F9 mutation database reflects the allelic heterogeneity of HA and HB, and is similar to previously described populations. This report represents the largest and longest duration experience of a national hemophilia genotyping program documented, to date.
    American Journal of Hematology 12/2013; 88(12). DOI:10.1002/ajh.23557 · 3.80 Impact Factor
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    David Lillicrap ·
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    ABSTRACT: von Willebrand disease (VWD) is the most common autosomally inherited bleeding disorder. The disease represents a range of quantitative and qualitative pathologies of the adhesive glycoprotein von Willebrand factor (VWF). The pathogenic mechanisms responsible for the type 2 qualitative variants of VWF are now well characterized, with most mutations representing missense substitutions influencing VWF multimer structure and interactions with platelet GPIbα and collagen and with factor VIII. The molecular pathology of type 3 VWD has been similarly well characterized, with an array of different mutation types producing either a null phenotype or the production of VWF that is not secreted. In contrast, the pathogenetic mechanisms responsible for type 1 VWD remain only partially resolved. In the hemostasis laboratory, the measurement of VWF:Ag and VWF:RCo are key components in the diagnostic algorithm for VWD, although the introduction of direct GPIbα-binding assays may become the functional assay of choice. Molecular genetic testing can provide additional benefit, but its utility is currently limited to type 2 and 3 VWD. The treatment of bleeding in VWD involves the use of desmopressin and plasma-derived VWF concentrates and a variety of adjunctive agents. Finally, a new recombinant VWF concentrate has just completed clinical trial evaluation and has demonstrated excellent hemostatic efficacy and safety.
    Hematology 11/2013; 2013(1):254-60. DOI:10.1182/asheducation-2013.1.254 · 0.81 Impact Factor
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    Meera Chitlur · Georges E Rivard · David Lillicrap · Ken Mann · Midori Shima · Guy Young ·
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    ABSTRACT: Hemostasis involves complex interactions between procoagulant proteins, their natural inhibitors, blood cells, and endothelium. Assessment of hemostasis involves plasma-based assays which screen and measure levels of factors and measurement of platelet number and function. Recently, there has been a growing interest in the use of global hemostasis assays like thrombelastography which measures the viscoelastic changes occurring during clot formation in the study of hemophilia[1]. This manuscript describes the recommended methodology for the use of thrombelastography in patients with hemophilia developed by the ISTH-SSC WP on standardization of thromboelastography.
    Journal of Thrombosis and Haemostasis 11/2013; 12(1). DOI:10.1111/jth.12458 · 5.72 Impact Factor

Publication Stats

6k Citations
1,396.14 Total Impact Points


  • 1987-2015
    • Queen's University
      • • Department of Pathology and Molecular Medicine
      • • Department of Medicine
      Kingston, Ontario, Canada
  • 2006-2014
    • Queen's University Belfast
      Béal Feirste, N Ireland, United Kingdom
  • 1989-2014
    • Queens University of Charlotte
      New York, United States
    • University of Ottawa
      • Department of Medicine
      Ottawa, Ontario, Canada
  • 2013
    • Kingston University
      England, United Kingdom
  • 2010
    • The Children's Hospital of Philadelphia
      • Department of Pediatrics
      Philadelphia, Pennsylvania, United States
  • 2005
    • Dalhousie University
      • Department of Chemistry
      Halifax, Nova Scotia, Canada
  • 2002
    • Radboud University Medical Centre (Radboudumc)
      • Department of Human Genetics
      Nymegen, Gelderland, Netherlands
  • 1993
    • Howard Hughes Medical Institute
      Ашбърн, Virginia, United States
  • 1986
    • Kingston General Hospital
      Kingston, Ontario, Canada