Douglas B Cines

University of Pennsylvania, Filadelfia, Pennsylvania, United States

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Publications (278)2294.6 Total impact

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    ABSTRACT: Approximately one-half of patients who develop clinical atherosclerosis have normal or only modest elevations in plasma lipids, indicating additional mechanisms contribute to pathogenesis. In view of increasing evidence that inflammation contributes to atherogenesis, we studied the effect of human neutrophil α-defensins (α-defs) on low density lipoprotein (LDL) trafficking, metabolism, vascular deposition and atherogenesis using transgenic mice expressing human α-defs in their polymorphonuclear leukocytes (Def+/+). Def+/+ mice develop α-def/LDL complexes that accelerate the clearance of LDL from the circulation accompanied by enhanced vascular deposition and retention of LDL, induction of endothelial cathepsins, increased endothelial permeability to LDL and the development of lipid streaks in the aortic roots when fed a regular diet and at normal plasma levels of LDL. Transplantation of bone marrow from Def+/+ to WT mice increased LDL clearance, increased vascular permeability and increased vascular deposition of LDL, while transplantation of WT bone marrow to Def+/+ mice prevented these outcomes. The same outcome was obtained by treating Def+/+ mice with colchicine to inhibit release of α-defs. These studies identify a potential new link between inflammation and the development of atherosclerosis.
    Journal of Biological Chemistry 10/2015; DOI:10.1074/jbc.M115.669812 · 4.57 Impact Factor
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    ABSTRACT: Heparin-induced thrombocytopenia (HIT) is characterized by a high incidence of thrombosis, unlike other antibody-mediated causes of thrombocytopenia. We have shown that monocytes complexed with surface-bound platelet factor 4 (PF4) activated by HIT antibodies contribute to the prothrombotic state in vivo, but the mechanism by which this occurs and the relationship to the requirement for platelet activation via FcγRIIA is uncertain. Using a microfluidic model and human or murine blood, we confirmed that activation of monocytes contributes to the prothrombotic state in HIT and showed that HIT antibodies bind to monocyte FcγRIIA, which activates spleen tyrosine kinase (Syk) and leads to the generation of tissue factor and thrombin. The combination of direct platelet activation by HIT immune complexes through FcγRIIA and transactivation by monocyte-derived thrombin markedly increases annexin and factor Xa binding to platelets, consistent with the formation of procoagulant coated platelets. These data provide a model of HIT wherein a combination of direct FcγRIIA-mediated platelet activation and monocyte-derived thrombin contributes to thrombosis in HIT and identifies potential new targets for lessening this risk.
    Blood 10/2015; DOI:10.1182/blood-2013-11-539262 · 10.45 Impact Factor
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    ABSTRACT: Heparin-induced thrombocytopenia (HIT) is an autoimmune thrombotic disorder caused by immune complexes containing platelet factor 4 (PF4), antibodies to PF4 and heparin or cellular glycosaminoglycans (GAGs). Here we solve the crystal structures of the: (1) PF4 tetramer/fondaparinux complex, (2) PF4 tetramer/KKO-Fab complex (a murine monoclonal HIT-like antibody) and (3) PF4 monomer/RTO-Fab complex (a non-HIT anti-PF4 monoclonal antibody). Fondaparinux binds to the 'closed' end of the PF4 tetramer and stabilizes its conformation. This interaction in turn stabilizes the epitope for KKO on the 'open' end of the tetramer. Fondaparinux and KKO thereby collaborate to 'stabilize' the ternary pathogenic immune complex. Binding of RTO to PF4 monomers prevents PF4 tetramerization and inhibits KKO and human HIT IgG-induced platelet activation and platelet aggregation in vitro, and thrombus progression in vivo. The atomic structures provide a basis to develop new diagnostics and non-anticoagulant therapeutics for HIT.
    Nature Communications 09/2015; 6:8277. DOI:10.1038/ncomms9277 · 11.47 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):4164-4164. DOI:10.1158/1538-7445.AM2015-4164 · 9.33 Impact Factor
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    ABSTRACT: A safety analysis of pooled data from clinical studies of romiplostim, a thrombopoietin (TPO) receptor agonist, in which patients with immune thrombocytopaenia (ITP) received romiplostim, placebo, or medical standard of care (SOC) Rodeghiero et al. (Eur J Haematol 91:423-436, 2013), has been updated. Included are data from 14 trials spanning 2002-2011; placebo- and SOC-arm data are pooled. Most patients (n = 1059) were female (61 %) and Caucasian (85 %); 38 % had undergone splenectomy; 23 were children. Mean (SD) baseline platelet count was 20.6 (16.5) × 10(9)/L. Mean (SD) weekly dose of romiplostim was 4.2 (2.8) µg/kg; total exposure was 1520 patient-years. Overall, 921 patients received romiplostim only, 65 received placebo/SOC only, and 73 received placebo/SOC followed by romiplostim. Rates of haemorrhage (romiplostim, 205/100 patient-years; placebo/SOC, 263/100), thrombosis (both, 5.5/100 patient-years), haematological malignancy/myelodysplastic syndrome (romiplostim, 0.5/100 patient-years; placebo/SOC, 2.7/100), and non-haematological tumours (romiplostim, 2.2/100 patient-years; placebo/SOC, 3.6/100) were comparable among groups. Bone marrow reticulin was reported in 17 patients and collagen in one patient receiving romiplostim; one patient receiving placebo/SOC had reticulin reported. Three patients developed neutralizing antibodies to romiplostim, but not to endogenous TPO. This integrated analysis of the safety profile of romiplostim in patients with ITP is consistent with previously reported studies; no new safety concerns emerged.
    International journal of hematology 07/2015; 102(3). DOI:10.1007/s12185-015-1837-6 · 1.92 Impact Factor
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    ABSTRACT: For several decades, researchers have used erythrocytes for drug delivery of a wide variety of therapeutics in order to improve their pharmacokinetics, biodistribution, controlled release and pharmacodynamics. Approaches include encapsulation of drugs within erythrocytes, as well as coupling of drugs onto the red cell surface. This review focuses on the latter approach, and examines the delivery of red blood cell (RBC)-surface-bound anti-inflammatory, anti-thrombotic and anti-microbial agents, as well as RBC carriage of nanoparticles. Herein, we discuss the progress that has been made in surface loading approaches, and address in depth the issues relevant to surface loading of RBC, including intrinsic features of erythrocyte membranes, immune considerations, potential surface targets and techniques for the production of affinity ligands.
    Therapeutic delivery 07/2015; 6(7):795-826. DOI:10.4155/tde.15.34
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    ABSTRACT: Heparin-induced thrombocytopenia (HIT) is an iatrogenic complication of heparin therapy caused by antibodies to a self-antigen, platelet factor (4) and heparin. The reasons why antibodies form to PF4/heparin, but not to PF4 bound to other cellular glycosaminoglycans are poorly understood. To investigate differences in cellular responses to cell-bound PF4 and PF4/heparin complexes, we studied the internalization of each by peripheral blood-derived monocytes, dendritic cells and neutrophils. Using unlabeled, fluorescently-labeled antigen and/or labeled monoclonal antibody to PF4/heparin complexes (KKO), we show that PF4/heparin complexes are taken up by monocytes in a heparin-dependent manner and are internalized by human monocytes and dendritic cells, but not by neutrophils. Complexes of PF4/low-molecular weight heparin and complexes composed of heparin and murine PF4, protamine, or lysozyme are internalized similarly, suggesting a common endocytic pathway. Uptake of complexes is mediated by macropinocytosis, as shown by inhibition using cytochalasin D and amiloride. Internalized complexes are transported intact to late endosomes, as indicated by co-staining of vesicles with KKO and lysosomal associated membrane protein-2 (LAMP-2). Lastly, we show cellular uptake is accompanied by expression of MHCII and CD83 co-stimulatory molecules. Taken together, these studies establish a distinct role for heparin in enhancing antigen uptake and activation of the initial steps in the cellular immune response to PF4-containing complexes. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Thrombosis and Haemostasis 05/2015; 13(8). DOI:10.1111/jth.13003 · 5.72 Impact Factor
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    ABSTRACT: ADAMTS13 metalloprotease cleaves von Willebrand factor (VWF), thereby inhibiting platelet aggregation and arterial thrombosis. An inability to cleave ultra large VWF resulting from hereditary or acquired deficiency of plasma ADAMTS13 activity leads to a potentially fatal syndrome, thrombotic thrombocytopenic purpura (TTP). Plasma exchange is the most effective initial therapy for TTP to date. Here, we report characterization of transgenic mice expressing recombinant human ADAMTS13 (rADAMTS13) in platelets and its efficacy in inhibiting arterial thrombosis and preventing hereditary and acquired antibody-mediated TTP in murine models. Western blotting and fluorescent resonance energy transfer (FRETS) assay detect full-length rADAMTS13 protein and its proteolytic activity, respectively, in transgenic (Adamts13(-/-)Plt(A13)), but not in wild type (WT) and Adamts13(-/-) (KO) platelets. The expressed rADAMTS13 is released upon stimulation with thrombin and collagen, but less with 2MesADP. Platelet-delivered rADAMTS13 is able to inhibit arterial thrombosis after vascular injury and prevent the onset and progression of Shigatoxin-2 or recombinant murine VWF (rmVWF)-induced TTP syndrome in mice despite lack of plasma ADAMTS13 activity resulting from the ADAMTS13 gene deletion or the antibody-mediated inhibition of plasma ADAMTS13 activity. These findings provide a proof-of-concept that platelet-delivered ADAMTS13 may be explored as a novel treatment for arterial thrombotic disorders including hereditary and acquired TTP in the presence of anti-ADAMTS13 autoantibodies. Copyright © 2015 American Society of Hematology.
    Blood 03/2015; 125(21). DOI:10.1182/blood-2014-07-587139 · 10.45 Impact Factor
  • Adam Cuker · Eline T Luning Prak · Douglas B Cines ·
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    ABSTRACT: Primary immune thrombocytopenia (ITP) in adults often assumes a chronic course that requires persistent monitoring and treatment. Medical therapy has traditionally been viewed as a means of temporarily raising the platelet count with little or no potential to induce long-term platelet responses off treatment. However, several recent studies have tested the hypothesis that intensive medical therapy administered early in the disease course may ameliorate or even cure ITP. In this review, we propose a biological rationale for medical intervention that simultaneously targets the innate and adaptive immune responses administered early in the course of disease. We also critically examine data on long-term outcomes after single-agent and multi-agent medical therapy. Intensive regimens that target inflammation and adaptive immunity (e.g., combination high-dose dexamethasone and rituximab) appear to improve response rates at 6 to 12 months compared with standard first-line therapy (e.g., prednisone, high-dose dexamethasone alone) in newly diagnosed patients. Controlled trials with extended follow-up are needed to determine whether these intensive regimens induce more cures compared with standard treatment or merely delay relapse at the expense of potentially greater toxicity. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.
    Seminars in Thrombosis and Hemostasis 03/2015; 41(04). DOI:10.1055/s-0034-1544001 · 3.88 Impact Factor
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    ABSTRACT: Persistent intracranial hemorrhage (ICH) is a major cause of death and disability after traumatic brain injury (TBI) for which no medical treatment is available. Delayed bleeding is often ascribed to consumptive coagulopathy initiated by exposed brain tissue factor. We examined an alternative hypothesis, namely that marked release of tissue type plasminogen activator (tPA) followed by delayed synthesis and release of urokinase plasminogen activator (uPA) from injured brain leads to post-traumatic bleeding by causing premature clot lysis. Using a murine model of severe TBI, we found ICH is reduced in tPA(-/-) and uPA(-/-) mice but increased in PAI(-/-) mice compared to wild-type (WT) mice. tPA(-/-), but not uPA(-/-), mice developed a systemic coagulopathy post-TBI. Tranexamic acid inhibited ICH expansion in uPA(-/-), but not in tPA(-/-) mice. Catalytically inactive tPA-S(481)A inhibited plasminogen activation by tPA and uPA, attenuated ICH, lowered plasma D-dimers, lessened thrombocytopenia and improved neurological outcome in WT, tPA(-/-) and uPA(-/-) mice. ICH expansion was also inhibited by tPA-S(481)A in WT mice anticoagulated with warfarin. These data demonstrate that protracted endogenous fibrinolysis induced by TBI is primarily responsible for persistent ICH and post-TBI coagulopathy in this model and offer a novel approach to interrupt bleeding. Copyright © 2015 American Society of Hematology.
    Blood 02/2015; 125(16). DOI:10.1182/blood-2014-08-588442 · 10.45 Impact Factor
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    ABSTRACT: Background: Existing approaches for measuring hemostasis parameters require multiple platforms, can take hours to provide results, and generally require 1-25 mL of sample. We developed a diagnostic platform that allows comprehensive assessment of hemostatic parameters on a single instrument and provides results within 15 min using 0.04 mL of blood with minimal sample handling. Methods: T2 magnetic resonance (T2MR) was used to directly measure integrated reactions in whole blood samples by resolving multiple water relaxation times from distinct sample microenvironments. Clotting, clot contraction, and fibrinolysis stimulated by thrombin or tissue plasminogen activator, respectively, were measured. T2MR signals of clotting samples were compared with images produced by scanning electron microscopy and with standard reference methods for the following parameters: hematocrit, prothrombin time, clot strength, and platelet activity. Results: Application of T2MR methodology revealed conditions under which a unique T2MR signature appeared that corresponded with the formation of polyhedral erythrocytes, the dynamics and morphology of which are dependent on thrombin, fibrinogen, hematocrit, and platelet levels. We also showed that the T2MR platform can be used for precise and accurate measurements of hematocrit (%CV, 4.8%, R(2) = 0.95), clotting time (%CV, 3.5%, R(2) = 0.94), clot strength (R(2) = 0.95), and platelet function (93% agreement with light transmission aggregometry). Conclusions: This proof-of-concept study demonstrates that T2MR has the potential to provide rapid and sensitive identification of patients at risk for thrombosis or bleeding and to identify new biomarkers and therapeutic targets with a single, simple-to-employ analytic approach that may be suitable for routine use in both research and diverse clinical settings.
    Clinical Chemistry 06/2014; 60(9). DOI:10.1373/clinchem.2014.223735 · 7.91 Impact Factor
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    American Journal of Hematology 06/2014; 89(6):E11-E11. · 3.80 Impact Factor
  • Douglas B Cines · Adam Cuker · John W Semple ·
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    ABSTRACT: Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by antibody-mediated platelet destruction. The platelet, as an accessible target, has made ITP an attractive disorder in the study of autoimmunity. However, the pathogenesis of ITP has proven complex with diverse pre-existing challenges to the immune system in the form of infection, genetic predisposition, underlying autoimmune repertoire, inhibition of platelet production, perturbations of cell mediated affector and effector pathways, sequestered harbors within lymphoid organs, and responsiveness to intervention. This chapter surveys key new insights into the pathogenesis of ITP and attempts to integrate them into a model that may serve as a template for future investigation.
    La Presse Médicale 03/2014; 43(4). DOI:10.1016/j.lpm.2014.01.010 · 1.08 Impact Factor
  • F. Mahdi · A. Kuo · Z. Shariat???madar · D. B. Cines · A. H. Schmaier ·

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    ABSTRACT: Contraction of blood clots is necessary for hemostasis, wound healing and to restore flow past obstructive thrombi, but little has been known about the structure of contracted clots or the role of erythrocytes in contraction. We found that contracted blood clots develop a remarkable structure, with a meshwork of fibrin and platelet aggregates on the exterior of the clot and a close-packed, tessellated array of compressed polyhedral erythrocytes within. The same results were obtained after initiation of clotting with various activators and also with clots from reconstituted human blood and mouse blood. Such close-packed arrays of polyhedral erythrocytes, or polyhedrocytes, were also observed in human arterial thrombi taken from patients. The mechanical nature of this shape change was confirmed by polyhedrocyte formation from the forces of centrifugation of blood without clotting. Platelets (with their cytoskeletal motility proteins) and fibrin(ogen) (as the substrate bridging platelets for contraction) are required to generate the forces necessary to segregate platelets/fibrin from erythrocytes and to compress erythrocytes into a tightly packed array. These results demonstrate how contracted clots form an impermeable barrier important for hemostasis and wound healing and help explain how fibrinolysis is greatly retarded as clots contract.
    Blood 12/2013; 123(10). DOI:10.1182/blood-2013-08-523860 · 10.45 Impact Factor
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    Lubica Rauova · Douglas B Cines ·
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    ABSTRACT: In this issue of Blood, Betapudi and colleagues report that anti-β2-glycoprotein I (β2GPI) antibodies stimulate the release of endothelial cell microparticles (EMPs) via a nonmuscle myosin II motor protein-dependent pathway that involves phosphorylation of its regulatory light chains. The results of this study suggest that inhibiting nonmuscle myosin II phosphorylation in endothelial cells (ECs) may block potentially deleterious microparticles from being released into the circulation.
    Blood 11/2013; 122(23):3707-8. DOI:10.1182/blood-2013-09-522482 · 10.45 Impact Factor
  • William M Armstead · John Riley · Douglas B Cines · Abd Al-Roof Higazi ·
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    ABSTRACT: Babies are frequently exposed to cerebral hypoxia and ischemia (H/I) during the perinatal period as a result of stroke, problems with delivery or post delivery respiratory management. The sole FDA approved treatment for acute stroke is tissue-type plasminogen activator (tPA). Endogenous tPA is upregulated and potentiates impairment of pial artery dilation in response to hypotension after H/I in pigs. Mitogen-activated protein kinase (MAPK), a family of at least 3 kinases, ERK, p38 and JNK, is also upregulated after H/I, with ERK contributing to impaired vasodilation. This study examined the hypothesis that H/I aggravates the vascular response to two important procontractile mediators released during CNS ischemia, endothelin-1 (ET-1) and thromboxane, which is further enhanced by tPA and ERK MAPK. Cerebral hypoxia (pO2 35 mmHg for 10 min via inhalation of N2) followed immediately by ischemia (global intracranial pressure elevation for 20 min) was produced in chloralose anesthetized piglets equipped with a closed cranial window. H/I aggravated pial artery vasconstriction induced by ET-1 and the thromboxane mimetic U 46619. Potentiated vasoconstrictor responses were blocked by EEIIMD, an inhibitor of tPA's signaling and vascular activities, but unchanged by its inactive analogue EEIIMR. The cerebrospinal fluid concentration of ERK MAPK determined by ELISA was increased by H/I, potentiated by tPA, but blocked by EEIIMD. The ERK MAPK antagonist U 0126 blocked H/I augmented enhancement of ET-1 and U 46619 vasoconstriction. These data indicate that H/I aggravates ET-1 and thromboxane mediated cerebral vasoconstriction by upregulating endogenous tPA and ERK MAPK.
    Neurocritical Care 11/2013; 20(1). DOI:10.1007/s12028-013-9906-2 · 2.44 Impact Factor
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    ABSTRACT: Heparin-induced thrombocytopenia (HIT) is a thrombotic complication of heparin therapy mediated by antibodies to complexes between platelet factor 4 (PF4) and heparin or cellular glycosaminoglycans. However, only a fraction of patients with anti-PF4/heparin antibodies develop HIT, implying that only a subset of these antibodies is pathogenic. The basis for the pathogenic potential of anti-PF4/heparin antibodies remains unclear. To elucidate the intrinsic PF4-binding properties of HIT-like monoclonal antibody (KKO) vs. non-pathogenic antibody (RTO) at the single-molecule level, we utilized optical trap-based force spectroscopy to measure the strength and probability of binding of surface-attached antibodies with oligomeric PF4 to simulate interactions on cells. To mimic the effect of heparin in bringing PF4 complexes into proximity, we chemically cross-linked PF4 tetramers using glutaraldehyde. Analysis of the force histograms revealed that KKO-PF4 interactions had approximately 10-fold faster on-rates than RTO-PF4 and apparent equilibrium dissociation constants differed ≈10-fold with similar force-free off-rates (koff=0.0031 and koff=0.0029 s(-1)). Qualitatively similar results were obtained for KKO and RTO interacting with PF4/heparin complexes. In contrast to WT PF4, KKO and RTO showed lower and similar binding probabilities to cross-linked PF4K50E, which forms few if any oligomers. Thus, formation of stable PF4 polymers results in much stronger interactions with the pathogenic Ab without a significant effect on the binding of the non-pathogenic Ab. These results suggest a fundamental difference in the antigen-binding mechanisms between model pathogenic and non-pathogenic anti-PF4 antibodies that might underlie their distinct pathophysiological behaviors.
    Journal of Biological Chemistry 10/2013; 288(46). DOI:10.1074/jbc.M113.481598 · 4.57 Impact Factor
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    ABSTRACT: Thrombopoietin-receptor agonists (TPOra) are the only treatments for immune thrombocytopenia (ITP) for which evidence of efficacy and safety from randomized, placebo-controlled trials is available. We sought to determine the long-term tolerability of the TPOra romiplostim, with a particular focus on thrombosis, bleeding, bone marrow reticulin, neoplasms/haematological malignancies and fatal events. Data from 13 romiplostim clinical trials in which 653 ITP patients received romiplostim for up to 5 years (921.5 patient-years) were pooled; subject incidence rates and exposure adjusted event rates (per 100 patient-years) were calculated. The rate of thrombotic events (6% of patients; 7.5 events/100 patient-years) did not appear to increase over time; 7 events were associated with platelet counts >400 x 10(9) /L and 10 with romiplostim doses exceeding current recommendations. Serious and grade ≥3 bleeding each occurred in approximately 8% of patients (~11 events/100 patient-years). Adverse events of bone marrow reticulin were recorded for 12 patients (1.8%; 1.3 events/100 patient-years; confirmed by bone biopsy in 10 patients), and bone marrow collagen for 1 patient (0.2%; 0.1 events/100 patient-years; confirmed by trichrome staining). Neoplasms and haematological malignancies occurred in 2.1% and 0.8% of patients, respectively (2.2 and 0.7 events/100 patient-years). Fatal events occurred in 3.7% of patients (2.6 events/100 patient-years; 4 events treatment-related). Romiplostim is the TPOra for which the longest duration of safety data is available. Our data demonstrate that long-term romiplostim treatment is well tolerated, with no new safety signals, even in patients treated for up to 5 years. This article is protected by copyright. All rights reserved.
    European Journal Of Haematology 08/2013; 91(5). DOI:10.1111/ejh.12181 · 2.07 Impact Factor

Publication Stats

13k Citations
2,294.60 Total Impact Points


  • 1984-2015
    • University of Pennsylvania
      • • Department of Medicine
      • • Department of Pathology and Laboratory Medicine
      • • Department of Pathology
      • • Division of Hematology/Oncology
      Filadelfia, Pennsylvania, United States
  • 2007-2013
    • William Penn University
      Filadelfia, Pennsylvania, United States
    • University of California, Santa Barbara
      • Department of Chemical Engineering
      Santa Barbara, California, United States
    • University of Illinois at Chicago
      Chicago, Illinois, United States
  • 2002-2013
    • University of Toronto
      • • Department of Laboratory Medicine and Pathobiology
      • • Department of Paediatrics
      Toronto, Ontario, Canada
    • University of New Mexico
      Albuquerque, New Mexico, United States
  • 2012
    • Weill Cornell Medical College
      New York, New York, United States
  • 1983-2008
    • Hospital of the University of Pennsylvania
      • • Department of Pathology and Laboratory Medicine
      • • Department of Obstetrics and Gynecology
      • • Division of Hematology/Oncology
      Philadelphia, PA, United States
  • 2006
    • Harvard University
      Cambridge, Massachusetts, United States
    • University of Texas Health Science Center at Tyler
      Tyler, Texas, United States
  • 1998-2006
    • The Children's Hospital of Philadelphia
      • Division of Hematology
      Philadelphia, Pennsylvania, United States
  • 2004
    • University of Pittsburgh
      Pittsburgh, Pennsylvania, United States
    • Justus-Liebig-Universität Gießen
      • Department of Internal Medicine
      Gieben, Hesse, Germany
  • 2003
    • The Scripps Research Institute
      • Department of Cell and Molecular Biology
      La Jolla, CA, United States
  • 2002-2003
    • Louisiana State University in Shreveport
      Shreveport, Louisiana, United States
  • 2001
    • Case Western Reserve University
      • Division of Hematology and Oncology
      Cleveland, OH, United States
  • 2000
    • McGill University
      Montréal, Quebec, Canada
  • 1999
    • Tel Aviv Sourasky Medical Center
      • Hematology
      Tell Afif, Tel Aviv, Israel
  • 1995-1998
    • University of Michigan
      • Division of Hematology and Oncology
      Ann Arbor, Michigan, United States
  • 1997
    • University of California, Los Angeles
      Los Angeles, California, United States
    • Tel Aviv University
      • Sackler Faculty of Medicine
      Tell Afif, Tel Aviv, Israel
  • 1988-1994
    • Temple University
      • Department of Medicine
      Filadelfia, Pennsylvania, United States
  • 1991
    • Cornell University
      • Department of Obstetrics and Gynecology
      Итак, New York, United States