About

Mortimer Poncz, MD, is a Professor of Pediatrics (Hematology) at the Perelman School of Medicine at the University of Pennsylvania. His research focuses on the megakaryocyte-platelet-thrombus axis, specifically on how hematopoietic stem cells differentiate into megakaryocytes and how these cells release platelets. His laboratory investigates the biology and pathobiology of platelet-specific proteins, chemokines such as Platelet Factor 4 (PF4)/Platelet Basic Protein (PBP), and the integrin alphaIIb/beta3 receptor, with a particular emphasis on their roles in thrombosis and inflammation. Dr. Poncz's work includes studying the regulation of gene expression in megakaryocytes, the function of platelets in thrombus development, and the molecular mechanisms underlying hematopoiesis and thrombosis. He has contributed to understanding the role of platelet proteins in disease processes and has been involved in various projects utilizing murine models of thrombosis, gene therapy for bleeding disorders, and the regulation of platelet activity in health and disease.

Research topics

• Medicine
• Internal medicine
• Immunology

Selected publications

• Treatment of Canine Hemophilia A via Intraosseous Delivery of a Platelet-Specific Factor VIII-Lentiviral Vector

  UNC Libraries · 2026-02-06

  articleOpen access1st authorCorresponding
  PublisherDOI

• Graft-derived VWF drives platelet activation and thrombocytopenia during porcine liver xenotransplantation to brain-dead human recipients

  Journal of Clinical Investigation · 2026-03-10 · 1 citations

  articleOpen access

  BACKGROUNDGenetically engineered porcine livers are being developed as a bridge therapy for acute liver failure, providing detoxification and restoration of hepatic protein synthesis. Severe xenograft-associated thrombocytopenia remains a major limitation, and human mechanistic data are scarce.METHODSPlatelet kinetics were characterized in 3 human decedents undergoing extracorporeal cross-circulation with transgenic porcine livers. Platelet counts, transfusion requirements, and clearance patterns were assessed to distinguish consumption from marrow suppression or hypersplenism. Antibody- and complement-directed inhibitors were administered to test immune-mediated mechanisms. Mechanistic studies focused on porcine von Willebrand factor-dependent (pVWF-dependent) platelet activation, including ex vivo blockade with the anti-VWF nanobody caplacizumab, a VWF-directed antibody fragment that prevents VWF-platelet binding. A fourth decedent received caplacizumab during porcine liver perfusion.RESULTSIn all 3 initial cases, 80%-90% of circulating and transfused platelets were rapidly cleared, a pattern inconsistent with marrow suppression or hypersplenism. Antibody and complement inhibition failed to ameliorate thrombocytopenia. Recipient plasma induced robust pVWF-mediated platelet activation analogous to human type IIb von Willebrand disease, which was completely abrogated ex vivo by caplacizumab. In a fourth decedent treated with caplacizumab, aberrant platelet activation was prevented, although full hematologic recovery was limited by preexisting disseminated intravascular coagulation.CONCLUSIONSEarly thrombocytopenia during porcine liver xenotransplantation appears to be primarily driven by pVWF-mediated platelet activation rather than by classical immune or splenic mechanisms. Targeted VWF blockade with agents such as caplacizumab may mitigate platelet loss and improve the safety profile of extracorporeal porcine liver support in acute liver failure.

  PublisherDOI

• Treatment of Canine Hemophilia A via Intraosseous Delivery of a Platelet-Specific Factor VIII-Lentiviral Vector

  Open MIND · 2026-01-01

  article1st authorCorresponding

• Murine hematopoietic progenitor cell lines with erythroid and megakaryocyte potential

  Nature Communications · 2025-08-07 · 1 citations

  articleOpen access

  Red blood cells and platelets derive from bi-potential bone marrow megakaryocyte-erythroid progenitors, but their study is constrained by cell scarcity and limited experimental systems. Here we show that conditional expression of a virally transduced, regulated form of Hoxa7 enables expansion of murine cells resembling megakaryocyte-erythroid progenitors (Hoxa7-TPO), which undergo erythro-megakaryocytic differentiation upon Hoxa7 inactivation. The close relationship of Hoxa7-TPO cells to megakaryocyte-erythroid progenitors is supported by genetic and phenotypic analyses, and mature Hoxa7-TPO-derived red blood cells and platelets are largely indistinguishable from their primary counterparts. Genetic knock-out studies in Hoxa7-TPO cells recapitulate the key function of Klf1 and Nfe2 in red blood cell and platelet development, respectively, while disruption of the von Willebrand receptor gene Gp1ba recapitulates features of human Bernard-Soulier syndrome. Hence, we developed a versatile experimental system for expansion and differentiation of megakaryocyte-erythroid progenitors to study red blood cell and platelet development and model human diseases.

  PublisherOA PDFDOI

• Treatment of canine hemophilia A via intraosseous delivery of a platelet-specific factor VIII–lentiviral vector

  Blood Vessels Thrombosis & Hemostasis · 2025-10-25

  articleOpen access

  1. Hemophilia A dogs treated with intraosseous infusions of platelet-specific FVIII-LVs achieved partial phenotypic correction. 2. Canine FVIII could be detected in platelets over 2 years and bleeding events were significantly reduced in treated hemophilia A dogs. Hemophilia A (HemA) is a genetic disease resulting from a factor VIII (FVIII) deficiency. Traditional protein infusions to treat HemA are costly, inconvenient, and requires repeated dosing. We demonstrated previously that intraosseous (IO) gene therapy via delivery of lentiviral vectors (LVs) into bone marrow targeting FVIII expression in platelets successfully treated HemA mice. To facilitate the translation of this novel strategy to clinical application, we investigated the treatment of HemA dogs using IO gene therapy. The VSVG-pseudotyped G-cF8-LV incorporating a platelet-specific promoter Gp1bα and canine F8 gene was injected into the tibia or iliac bones of 4 HemA dogs. All dogs recovered well from the procedure and had blood chemistry values within normal ranges. Canine FVIII can be detected in platelets with the highest expression around 40-50 days post-procedure and the expression persisted for the experimental duration in all treated dogs. Copy numbers of the transgene were persistently detected from the genomic DNA isolated from peripheral mononuclear blood cells. The shortened whole blood clotting time and improved parameters evaluated by thromboelastography testing in multiple time points indicated improved hemostasis after gene therapy. Furthermore, the IO gene therapy was well tolerated and did not produce any toxicity in treated dogs. Most significantly, the treated dogs experienced fewer bleeding events per year after gene therapy than prior. Our study demonstrated a potentially safe and effective in vivo gene therapy strategy for treating people with HemA.

  PublisherDOI

• Platelet-activating antibodies to the chemokine, platelet factor 4, in cerebral malaria differ from those in heparin-induced thrombocytopenia and vaccine-induced thrombotic thrombocytopenia.

  Blood · 2025-11-03

  articleOpen accessSenior author

  Abstract Background: Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection, primarily affecting children, with a mortality rate near 20% and no targeted treatment. Recent studies have identified platelet-activating autoantibodies in patients with CM, detected using commercial heparin-induced thrombocytopenia (HIT) assay (Immunocor), suggesting a potential autoimmune component in CM-associated thromboinflammation (PMID:38652559). We hypothesized, that in CM, platelet factor 4 (PF4) released from activated platelets serves as an immunogenic antigen that triggers the production of anti-PF4 antibodies contributing to thromboinflammation and disease severity. Aim: To characterize the epitope specificity of anti-PF4 antibodies in CM, and determine whether their properties mirror those associated with HIT or vaccine-induced immune thrombotic thrombocytopenia (VITT). Methods & Results: We studied 66 plasma samples from Malawi that were previously used in our study (IV, KS & KK; along with five CM samples and five control samples from asymptomatic community children in Uganda. The Malawi samples included 22 CM with positive (OD>0.4) and 22 CM samples negative (OD≤0.4) antibodies to human (h) PF4/polyanion complexes (hPF4/P) and 22 uncomplicated malaria (UM) samples also negative for hPF4/P antibodies, as determined using the Immucor PF4 ELISA. All five Uganda CM samples—and none of the control samples—tested positive for hPF4 antibodies. We found that anti-PF4 antibodies in CM patients react with PF4 alone independent of heparin. To assess the pathogenic potential, we tested whether CM plasma positive for hPF4 antibodies could activate murine platelets derived from PF4-deficient mice, with or without expression of human FcγRIIA. Platelet activation was dependent on the presence of both FcγRIIA and exogeneous hPF4 (p < 0.0001). To determine whether anti-hPF4 antibodies in CM patient samples recognize the previously defined HIT or VITT PF4 epitope, we performed competitive binding assays using increasing amounts of a HIT-like monoclonal antibody KKO (0-5 µg/ml), and a VITT-like monoclonal antibody 1E12 (0-5 µg/ml), respectively. Neither KKO nor 1E12 inhibited the binding of CM-derived anti-hPF4 antibodies. Increasing concentrations of 1E12 actually enhanced CM anti-PF4 IgG binding to hPF4 up to a threefold increase observed at ≥1 µg/ml of 1E12 compared to binding in the absence of 1E12 (p<0.01). Finally, we assessed cross-reactivity to related chemokines stored in platelet α-granules—namely mouse PF4 (mPF4) and both human and mouse neutrophil-activating peptide 2 (NAP2/CXCL7). Using ELISA, we found that CM samples positive for hPF4 antibodies exhibited significantly higher binding to mPF4 (p < 0.05), hNAP2 (p < 0.001), and mNAP2 (p < 0.05), compared to healthy controls. Conclusions: These findings identify a subset of patients with CM that had high-titer, FcγRIIA-dependent, platelet-activating anti-PF4 antibodies that do not map to the canonical HIT or VITT epitopes. Their cross-reactivity with conserved regions of related chemokines supports the hypothesis that the shared antigenic target lies within the conserved C-terminal heparin-binding domain of these chemokines.and suggests a distinct autoimmune response potentially driven by malaria-induced platelet activation. This highlights a novel mechanism of thromboinflammation in CM and points to PF4-targeted autoimmunity as a contributor to disease severity. Future studies will aim to map this antigenic site and evaluate the thrombogenic potential of CM antibodies in vivo as well as the ability of anti-PF4 blocking antibodies to ameliorate the severity of the CM.

  PublisherOA PDFDOI

• Antiphospholipid syndrome (APS) is the newest member of the PF4 immunothrombotic family: Mechanistic and therapeutic insights

  Blood · 2025-11-03

  articleOpen accessSenior author

  Abstract Background: APS is an autoimmune thromboinflammatory disorder characterized by venous, arterial, and microvascular thrombosis, adverse pregnancy outcomes and thrombocytopenia. A major antigenic target is b2-glycoprotein I (b2GPI). Prior observations showed: i. b2GPI can bind the platelet chemokine, platelet factor 4 (PF4), which enhances binding of APS antibodies (Abs), ii. b2GPI binds extruded chromatin from neutrophils (neutrophil extracellular traps or NETs), which also enhances APS Ab binding, and iii. PF4 binds avidly to NETs. In other immunothrombotic disorders, such as heparin-induced thrombocytopenia (HIT), PF4:NET complexes contribute to thrombosis. Aim: We proposed that PF4 released from platelets binds to NETs, enhancing the binding of b2GPI to the NETs and that PF4:b2GPI:NET complexes are important in the pathobiology of thrombosis in APS. Methods & Results: Dynamic light scattering (DLS) studies showed PF4 and b2GPI form antigenic complexes with DNA that bind isolated APS IgG. These findings were confirmed in a NET-lined microfluidic system, where the NETs bound 5-10 times more b2GPI in the presence of PF4 (25 µg/ml) than in its absence (p<0.0001) and subsequently enhanced APS IgG binding four-fold (p<0.005). IgG from 16 randomly selected individuals who met clinical criteria for APS and had “triple-positive” serology required the addition of β2GPI and PF4 to initiate platelet, fibrin, C1q, and C5b-9 deposition on injured human umbilical vein endothelial cell (HUVEC)-lined microfluidic channels. This effect was not seen with IgG from healthy controls. In vivo studies in mice that express PF4: wildtype (WT) mice, mice expressing only human PF4 (hPF4+) or hPF4 plus FcgRIIA (hPF4+/FcgRIIA+) were compared to mice lacking murine PF4 (mPF4-/-). We found that passive inoculation with APS IgG slowed neutrophil rolling on the uninjured venous endothelium and enhanced neutrophil adhesion and enhanced platelet- and neutrophil-rich thrombosis in laser-injured cremaster venules and arterioles in all mice EXCEPT mPF4-/- mice, which were comparable to mice infused with healthy-donor control IgGs. hPF4+/FcgRIIA+ mice had more neutrophils and neutrophil-derived extracellular vesicles incorporated within venule and arteriole thrombi as compared to mPF4-/- mice. As an independent approach, we tested three anti-PF4 monoclonal (mo) Abs, each having different specificities and effects on PF4: RTO, which disaggregates PF4 tetramers; deglycosylated (DG) 1E12, which blocks PF4 binding to NETs; and an IgG4 version of KKO (G4KKO), which crosslinks PF4:NETs. DLS studies showed that RTO and 1E12 disaggregated PF4:b2GPI:DNA immune complexes, whereas G4KKO formed larger complexes that sterically blocked binding of APS IgG. All 3 Abs inhibited thrombosis in the injured HUVEC system. In mice, G4KKO prevented enhanced neutrophil-venous endothelial interaction when infused prophylactically. G4KKO blocked thrombosis in both venule and arteriole models, when given prophylactically or therapeutically post-APS IgG exposure. Conclusions: PF4:β2GPI:NETs complexes are recognized by triple-positive APS IgG, as demonstrated by all 16 APS IgG samples tested to date. This finding reveals a previously unrecognized similarity between APS and other PF4-mediated immunothrombotic disorders, such as HIT and vaccine-induced immune thrombotic thrombocytopenia (VITT). Notably, each of the three anti-PF4 monoclonal antibodies — each disrupting PF4:β2GPI:NET immune complexes — significantly reduced thrombosis, particularly when administered prophylactically. As these moAbs do not alter hemostasis, they are a potential complementary therapy to standard anticoagulants. Future studies will address the importance of PF4 in other forms of APS that do not involve high-titer anti-β2GPI antibodies.

  PublisherOA PDFDOI

• Platelet factor 4 regulates hematopoietic stem cell aging

  Blood · 2025-09-08 · 6 citations

  article

  ABSTRACT: Hematopoietic stem cells (HSCs) responsible for blood cell production and their bone marrow regulatory niches undergo age-related changes, affecting immune responses and predisposing individuals to hematologic malignancies. Here, we show that the age-related alterations of the megakaryocytic niche and associated downregulation of platelet factor 4 (PF4) are pivotal mechanisms driving HSC aging. PF4-deficient mice display several phenotypes reminiscent of accelerated HSC aging, including lymphopenia, increased myeloid output, and DNA damage, mimicking physiologically aged HSCs. Remarkably, recombinant PF4 administration restored old HSCs to youthful functional phenotypes characterized by improved cell polarity, reduced DNA damage, enhanced in vivo reconstitution capacity, and balanced lineage output. Mechanistically, we identified low-density lipoprotein receptor and C-X-C motif chemokine receptor 3 as HSC receptors transmitting the PF4 signal, with double knockout mice exhibiting exacerbated HSC aging phenotypes similar to PF4-deficient mice. Furthermore, human HSCs across various age groups also respond to the youthful PF4 signaling, highlighting its potential for rejuvenating aged hematopoietic systems. These findings pave the way for targeted therapies aimed at reversing age-related HSC decline, with potential implications in the prevention or improvement of the course of age-related hematopoietic diseases.

  PublisherDOI

• Transcription factor RUNX1 regulates coagulation factor XIII-A (F13A1): decreased platelet-megakaryocyte F13A1 expression and clot contraction in RUNX1 haplodeficiency

  Research and Practice in Thrombosis and Haemostasis · 2025-01-01

  articleOpen access

  Background: a transglutaminase that cross-links fibrin and induces clot stabilization. FXIII-A is synthesized by hematopoietic cells, megakaryocytes, and monocytes. Objectives: in RHD. Methods: We performed studies in platelets, human erythroleukemia (HEL) cells, and human CD34+ cell-derived megakaryocytes including on clot contraction in cells following small inhibitor RNA knockdown (KD) of RUNX1 or F13A1. Results: downregulation in human megakaryocytes. Conclusion: activation.

  PublisherDOI

• HTRS2025.O6B.1 Abstract Travel Award Antiphospholipid syndrome (APS) is another platelet factor 4 (PF4) :neutrophil extracellular trap (NET)-dependent immunothrombotic disorder

  Research and Practice in Thrombosis and Haemostasis · 2025-11-01

  articleOpen accessSenior author

  thrombin-mediated platelet activation similarly resulted in decreased intraluminal platelet accumulation during the post-hemostatic period (p=0.0009,WT vs Par4-/-) that was associated with hemostatic plug failure and rebleeding episodes.Finally, we found that increasing platelet sensitivity to thrombin via deletion of the PAR regulator GRK6 ameliorated excess bleeding in the context of FVIII-deficiency (p=0.0256,WT vs PF4Cre;Grk6fl/fl, both treated with FVIII inhibitor).Conclusions: Taken together, these results indicate that thrombin generated downstream of the intrinsic tenase is essential for sustained platelet responses over time after the initial cessation of bleeding.A critical role for the intrinsic tenase is to localize thrombin generation within the intraluminal component of hemostatic plugs to facilitate PARmediated platelet activation that is required to maintain hemostasis.These findings provide new insights into distinct roles of the extrinsic and intrinsic tenases in regulating the spatiotemporal distribution of thrombin generation during hemostasis.They further show that enhancing platelet sensitivity to thrombin may be a novel rebalancing approach to ameliorate bleeding in coagulation disorders.

  PublisherOA PDFDOI

Recent grants

• NIH Grant U01HL099656

  NIH · $8.6M · 2017

• NIH Grant R01HL037419

  NIH · $1.8M · 1997

• Biology and Application of Platelet-Delivered Factor VIII

  NIH · $2.3M · 2016–2020

• NIH Grant R01HL084006

  NIH · $2.3M · 2012

• NIH Grant P01HL064190

  NIH · $25.4M · 2017

Frequent coauthors

• Douglas B. Cines

  University of Pennsylvania

  342 shared

• M. Anna Kowalska

  Polish Academy of Sciences

  295 shared

• Lubica Rauova

  Children's Hospital of Philadelphia

  286 shared

• Gowthami M. Arepally

  Duke Medical Center

  189 shared

• Khalil Bdeir

  University of Pennsylvania

  96 shared

• Michele P. Lambert

  Children's Hospital of Philadelphia

  91 shared

• Bruce S. Sachais

  79 shared

• Deborah L. French

  79 shared