About

Rodney M. Camire, Ph.D., is a Professor of Pediatrics (Hematology) at the Perelman School of Medicine at the University of Pennsylvania. He is a member of The Children's Hospital of Philadelphia Research Institute, the UPENN Cardiovascular Institute, the CHOP Raymond G. Perelman Center for Cellular and Molecular Therapeutics, and the UPENN-CHOP Blood Center for Patient Care and Discovery. Dr. Camire serves as Associate Chief Scientific Strategy Officer at The Children's Hospital of Philadelphia Research Institute. His research focuses on understanding the molecular basis of blood coagulation to better comprehend disorders of hemostasis and develop new therapeutic approaches. His laboratory investigates the components of the blood coagulation system, their interaction with activated cells, and how disturbances in their function lead to bleeding and thrombosis. His work includes enzymology, biochemistry, and molecular genetics of enzyme complexes involved in blood coagulation, employing kinetic, biophysical, structural approaches, and in vivo models. Key areas of investigation include the molecular mechanisms of procofactor activation, structural correlates of protease function, imaging coagulation reactions in vivo, and gene therapy strategies for hemophilia A and B through protein modifications. Dr. Camire's contributions aim to translate biochemical insights into therapeutic innovations for bleeding and clotting disorders.

Research topics

• Chemistry
• Medicine
• Biochemistry
• Biology
• Molecular biology

Selected publications

• Rational design of a novel engineered factor X with chimeric activation peptide as bypassing agent for haemophilia

  Journal of Thrombosis and Haemostasis · 2026-05-01

  articleOpen access

  BACKGROUND: While replacement therapy in Haemophilia A (HA) and B (HB) has provided remarkable improvements, the development of neutralizing antibodies remains a significant complication, with rational engineering of bypassing molecules being a relevant issue. OBJECTIVES: To develop a human factor X (FX) variant containing a FIX-derived chimeric activation peptide (AP) driving FVIII or FIX deficiency bypass. METHODS: Engineered variants were expressed and purified, and activation/activity properties were evaluated through functional assays, also in plasma with inhibitors from HA and HB patients. RESULTS: significantly shortened the clotting time in plasma from patients with high-titer anti-FVIII or anti-FIX inhibitory antibodies, with efficacy levels comparable with those of well-established bypassing agents. CONCLUSIONS: as a promising and versatile bypassing agent able to sustain coagulation across multiple haemophilic contexts including inhibitors presence, while maintaining favourable activation profiles.

  PublisherDOI

• Identification of Regulatory Loci for Megakaryocyte and Hepatocyte Coagulation Factor V Expression in Mice

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-19 · 1 citations

  preprintOpen access

  Abstract Background Factor V (FV) plays a central role in the coagulation cascade, acting in both a procoagulant and anticoagulant manner. The majority of FV is produced by the liver hepatocytes. In humans, FV is endocytosed by megakaryocytes, whereas in mice, FV is synthesized by megakaryocytes. Little is known about the genomic factors regulating FV transcription in humans and mice. Objective To investigate genomic regulatory mechanisms for coagulation FV levels in the hepatocytes and megakaryocytes of inbred mice. Methods Plasma and platelet FV levels were measured via ELISA in 5 mouse strains. A cross between the CAST/EiJ and DBA/2J strains was performed to generate 146 genetically informative F2 mice for analysis of circulating and platelet FV. Plasma and platelet FV levels were measured by ELISA for the F2 mice and whole genome genotyping for each F2 was performed using the TransnetYX MiniMUGA genotyping array. The genotyping and phenotyping data collected from these mice were then analyzed using quantitative trait loci (QTL) analysis. Results and Conclusions We identified one significant locus controlling plasma FV levels on Chromosome 1, ∼57.7 million base pairs upstream of the FV structural gene. We also identified a significant QTL for platelets on Chromosome 14 when sex was included as an interactive covariate, with additional suggestive loci present on Chromosomes 15 and 2. Our findings provide foundational information regarding the cell-type and sex-specific control of FV expression, establishing the basis for further investigations aimed at fine-mapping these loci and understanding how FV expression is regulated. Essentials Coagulation Factor V (FV, gene name F5 ) is primarily expressed in hepatocytes in humans but in hepatocytes and megakaryocyte/platelets in mice. Plasma and megakaryocyte/platelet F5 expression varies significantly between inbred mouse strains. We identified significant loci controlling plasma and platelet F5 expression in mice. Platelet F5 expression is influenced by biological sex.

  PublisherOA PDFDOI

• Blood Coagulation Factor <scp>IX</scp>: Structure, Function, and Regulation

  IUBMB Life · 2025-05-01 · 4 citations

  reviewOpen accessSenior author

  Blood coagulation factor IX plays a crucial role in the intrinsic pathway of coagulation by generating factor Xa, ultimately leading to thrombin formation. Over the past 50 years, extensive research has deepened our understanding of the biology, physiology, pathology, biochemistry, and molecular genetics of factor IX. This wealth of knowledge has revealed how the factor IX gene and protein evolved, how factor IX is regulated, how it functions within the coagulation cascade, and how structural changes affect its function. In this review, we will summarize current knowledge on the biology of factor IX, with a focus on its structure-function relationships, gene structure, and regulation.

  PublisherOA PDFDOI

• 4 Engineered FVIII variants without clotting activity accelerate proteolytic cleavage of VWF by ADAMTS13 under shear: Implication for a potential novel therapy of TTP

  American Journal of Clinical Pathology · 2025-11-01

  articleOpen access

  Abstract Background Previous studies have demonstrated that factor VIII (FVIII) can bind von Willebrand factor (VWF) and accelerate its proteolytic cleavage by ADAMTS13 under mechanical shear. Plasma derived FVIII and recombinant FVIII concentrates are shown to reducing circulating ultra large VWF multimers in wild-type mice and in patients with hereditary thrombotic thrombocytopenic purpura (TTP). These results suggest that FVIII may be useful for treatment of TTP. However, an increased plasma level of FVIII may be a risk factor for venous thrombosis that limits its therapeutic use. We aim to reengineer FVIII to create FVIII variant that exhibits no clotting activity but may retain its binding to VWF that enhances ADAMTS13-dependent proteolysis of VWF proteolysis by ADAMTS13 under shear. Methods We used site-directed mutagenesis, recombinant protein expression and purification, shear-dependent cleavage assay and one stage clotting assay to fully characterize two FVIII variants (R372Q and R1689C). Results Purified recombinant FVIII-SQ and its variant exhibited molecular sizes of 165 kDa (single chain), 93 kDa (heavy chain), and 80 kDa (light chain) on a denatured and reduced gel in the absence of thrombin activation. Thrombin cleaved both heavy and light chains at R372, R740, and R1689 to generate 3 small fragments in FVIII-SQ. However, thrombin did not cleave at R372 or R1689 in the R372Q or R1689C variant as expected. Furthermore, no specific clotting activity was detected in R372Q and R1689C variants by one-stage clotting assay. Most importantly, recombinant R372Q and R1689C variants were able to accelerate the proteolytic cleavage of recombinant multimeric VWF by ADAMTS13 under shear in a concentration-dependent manner with the maximal increase of 3 to 6 folds. Conclusions Reengineered FVIII variants without clotting activity may be further explored for therapy of TTP and perhaps other arterial thrombosis through binding VWF and accelerating its proteolysis by ADAMTS13 under shear. The therapeutic efficacy may be accomplished without the increased risk of potential venous thrombosis.

  PublisherOA PDFDOI

• Identification of genetic loci regulating plasma and platelet factor v expression in mice

  Blood · 2025-11-03

  articleOpen access

  Abstract Background:Factor V (FV) is a protein in the coagulation cascade found in two circulating compartments: 80% in plasma and 20% in platelet alpha-granules. Human FV is made by liver hepatocytes, contributing to the FV in the plasma, and plasma FV is endocytosed by megakaryocytes and stored in platelet alpha granules. In mice, hepatocytes produce plasma FV, and megakaryocytes directly produce platelet FV. FV deficiency causes bleeding of the mucosal lining as well as post-trauma. Complete absence of FV in humans results in increased bleeding. In mice, FV deficiency is incompatible with life. Currently, little is known about the genetic regulation of this important protein at the center of coagulation. Hypothesis:Inbred mouse strains have significant differences in their FV antigen levels in the platelets and the plasma. We can leverage these differences to identify genetic loci responsible for regulating FV in inbred mice. Methods:We isolated platelets and plasma from inbred mouse strains: C57BL/6J (B6), DBA/2J (DBA), A/J, CAST/EiJ (CAST), and 129S1/SvImJ (129S1). FV levels were measured in these strains via a mouse specific FV ELISA. To generate genetically informative mice for further analysis, we crossed the CAST and DBA strains to make the CASTD2F1 (F1) generation. We crossed the F1 mice to produce 146 CASTD2F2 (F2) mice, which were genetically informative due to meiotic recombination. We isolated platelets (n=85) and plasma (n=61) from F2 mice to measure the FV antigen levels. Tail biopsies were taken from 146 F2 mice, two DBA females, and two CAST males and sent for whole genome genotyping using TransnetYX MiniMUGA. The genotyping and phenotyping data were used to run two independent quantitative trait loci (QTL) analyses, for plasma and platelet FV expression levels, to investigate potential genomic loci controlling FV expression. Results:In platelets, significant FV expression differences were observed between DBA and CAST (p=0.0033), with no sex differences within the strains. There was a significant difference between male CAST and male DBA mice (p=0.0336). In plasma, CAST and DBA mice had no significant differences in their antigen levels when sexes were grouped. We found a significant difference between female CAST and female DBA mice (p=0.0044) and sex differences within the two strains (CAST p=0.0236, DBA p=0.0011). Based on these findings, we performed a DBA x CAST intercross to produce F2 offspring. We analyzed 85 F2 mice for platelet FV levels via QTL to identify genetic loci controlling platelet FV, with no significant or suggestive peaks in our initial run. Adding sex as an interactive covariate led us to identify one significant peak on Chromosome (Chr) 14 (LOD 3.45, significance threshold 2.32, p=0.00641) and one suggestive peak on Chr15 (LOD 1.64, suggestive 20% threshold 1.58, p=0.17844). With sex as an additive covariate, we found a suggestive peak on Chr 2 (LOD 3.66, suggestive threshold 2.78, p=0.113). Tissue Factor Pathway Inhibitor (TFPI) and a modifier of FV PLXDC2 are located on Chr 2, a significant distance from our mapped region, suggesting that potential effects of these loci are due to higher order interactions. Analysis of 61 F2 mice for plasma FV levels via QTL analysis identified a significant peak on Chr 1 (LOD 5.24, significance threshold 4.21, p=0.00641). Accounting for sex as both an interactive and additive covariate showed an increased LOD score at Chr 1 (LOD 6.79, significance threshold 6.34, p=0.0246). The mouse FV gene is located on Chr 1 within our minimally significant recombinant interval, but it is a substantial distance from the main significance peak. Within our peak region, we identified a serpin cluster that includes Serpinb2 (PAI-2), a known member of the coagulation cascade. Presently, there are no known links between serpins and FV levels, but it is possible that alterations in PAI-2 or other serpins could affect FV expression. Conclusions:Our findings support our hypothesis that strain-dependent differences in FV platelet and plasma levels exist in inbred mouse strains. We identified loci responsible for regulating FV levels in the CAST and DBA mice. Future work of identifying the specific regulatory elements controlling platelet and plasma FV expression will increase our understanding of cell-type specific gene regulation. This may reveal novel targets or strategies for modulating FV in humans, which could be used to treat hemostatic disease.

  PublisherOA PDFDOI

• Response to TFPI-inhibition in severe factor v deficiency with a novel compound heterozygous mutation

  Blood · 2025-11-03

  articleOpen access

  Abstract Introduction Coagulation factor V (FV) plays a central role in blood clot formation. FV has both procoagulant and anticoagulant properties making it a key regulator of thrombin generation. Congenital deficiency of FV is rare (1 in 1 million births) and presents with mild to severe bleeding complications in the affected individuals. Low to undetectable antigen levels and low functional activity is a hallmark of homozygous or compound heterozygous mutations in the F5 gene. Heterozygous individuals have about 50% normal FV antigen expression and are asymptomatic. Prior studies have shown that plasma tissue factor pathway inhibitor-alpha (TFPIα) levels correlate with plasma FV. It is thought in FV deficiency reduced levels of TFPIα may blunt the bleeding phenotype making it an important and unique modifier of FV deficiency. Patient history Here, we describe a case of a 14 year old male with severe FV deficiency (&amp;lt;1% FV activity). He had intracranial hemorrhage during infancy and has been admitted multiple (8) times for bleeding episodes and treated with plasma transfusions. Bleeds were either from sports participation or spontaneous joint and muscle bleeds. His mother is clinically asymptomatic with no bleeds despite past caesarean births and has FV level of ~50%. Methods Genomic DNA from the consented patient was isolated from peripheral blood and then outsourced to PreventionGenetics (USA) for a F5 gene testing and analyses using Next-Gen sequencing. FV activity was determined with standard one-stage clotting assay. Plasma and platelet FV antigens were measured and visualized by immunoassays and western blotting analyses using FV-specific polyclonal and monoclonal (mAb) antibodies, respectively. Free plasma protein S was measured with a commercial ELISA kit (Asserachrom®, Stago). Thrombin generation assays (TGA) were triggered with low tissue-factor concentration and thrombin generation assessed with anti-TFPIα mAbs and in mixing studies with pooled normal plasma. Results Genetic analyses revealed compound heterozygous mutations in the F5 gene: one in exon 3 (c254T&amp;gt;G) resulting in Leu-57 to Arg (Leu57Arg; legacy numbering) change and a second in exon 13 (A&amp;gt;C/T) leading to a nonsense mutation (Leu906*; legacy numbering). Plasma prothrombin time was 46.6 (reference range: 11.1-13.5 sec) and activated partial thromboplastin time was 156.2 (reference range: 25.0-37.0 sec). Plasma FV antigen was 3.3% of normal measured by ELISA and undetectable via western blotting analyses. Since TFPI is a known modifier of FV, we observed that total plasma, and platelet TFPIα levels were 62%, and 46%, of normal, respectively, and free protein S was normal (130.3 ± 0.3 nM). It is established that inhibiting TFPI's major function enhances thrombin generation in the context of bleeding. To assess this, we first blocked TFPI function using an anti-K2 mAb in a TGA. We found that the effect on peak thrombin was undetectable and similar to the unmodified patient plasma. However, adding a cocktail of anti-TFPI mAbs targeting each of its domains (K1, K2, K3 and C-term domains) to the patient's plasma shortened the lag time and enhanced peak thrombin by ~30% of normal suggesting blocking all molecular interactions of TFPI in the context of reduced FV antigen has a detectable procoagulant effect. Furthermore, in mixing studies assessed by TGA, 10% pooled normal plasma was enough to restore both peak thrombin and lag time in the patient's plasma to levels seen in normal healthy control plasma. Conclusions We identified a compound heterozygous mutation in a severe FV deficiency patient including a previously reported Leu57Arg variant and a novel Leu906* nonsense variant that is not reported in the clinical F5 gene database. In silco analyses suggest that a hydrophobic to basic amino acid substitution at position 57 may alter protein folding and function. A termination at Leu906* leads to nonsense mediated decay of mRNA and no translation consistent with reduced FV antigen in the patient. Further, we demonstrated in this study that complete inhibition of TFPI function, an important modifier of FV, promotes thrombin generation at low plasma FV levels in severe FV deficiency.

  PublisherOA PDFDOI

• Basic regions of factor V and tissue factor pathway inhibitor mediate heavy chain and acidic region interactions on factor V revealed by tethered chemical cleavage

  Journal of Thrombosis and Haemostasis · 2025-05-12

  articleOpen accessSenior author
  PublisherOA PDFDOI

• HTRS2025.P1.47 Procoagulant Enhancement of Inherited Factor X Deficiency with Emicizumab

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

  articleOpen access

  Non-adherence to DOACs was defined as PDC < 0.80.Recurrent thrombosis, stroke, major bleeding and clinically relevant non-major bleeding (CRNMB) events were collected.Results: 57 patients were started on DOACs: 53 (93%) were treated with rivaroxaban and 4 (7%) with apixaban.46 (81%) were for the indication of venous thromboembolism, 5 (9%) were for stroke, 4 (7%) were for venous malformation, and 2 (3%) were for atrial fibrillation.The median age was 14 years (range: 0.6-17), and the mean duration of treatment exposure was 6.7 months ( 4.5).The mean PDC was 0.87 (0.17); 26.3% were non-adherent patients (PDC < 0.80).Eight (14%) patients prematurely self-discontinued DOACs during their treatment period.Two of these patients experienced recurrent thrombotic events (one had recurrent stroke, the other had recurrent venous thromboembolism) and resumed their DOAC during the hospital admission.There were no major bleeding events; eight (14%) experienced CRNMB.Seven (37%) of 19 post-menarchal patients experienced heavy menstrual bleeding which accounted for 89% of the CRNMB events.Conclusions: Our ongoing real-world study suggests more than one quarter of patients had poor DOAC adherence.Premature self-discontinuation of DOAC may lead to recurrent thrombotic events.Targeted interventions to enhance DOAC adherence in children are urgently needed.Other: 1.

  PublisherOA PDFDOI

• HTRS2025.P1.48 Human Lymphatic Fluid Supports Coagulation Driven Primarily by the Extrinsic Pathway

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

  articleOpen accessSenior author
  PublisherDOI

• Plasma growth factors maintain constitutive translation in platelets to regulate reactivity and thrombotic potential

  Blood Advances · 2024-01-01 · 18 citations

  articleOpen access

  ABSTRACT: Mechanisms of proteostasis in anucleate circulating platelets are unknown and may regulate platelet function. We investigated the hypothesis that plasma-borne growth factors/hormones (GFHs) maintain constitutive translation in circulating platelets to facilitate reactivity. Bio-orthogonal noncanonical amino acid tagging (BONCAT) coupled with liquid chromatography-tandem mass spectrometry analysis revealed constitutive translation of a broad-spectrum translatome in human platelets dependent upon plasma or GFH exposure, and in murine circulation. Freshly isolated platelets from plasma showed homeostatic activation of translation-initiation signaling pathways: phosphorylation of p38/ERK upstream kinases, essential intermediate MNK1/2, and effectors eIF4E/4E-BP1. Plasma starvation led to loss of pathway phosphorylation, but it was fully restored with 5-minute stimulation by plasma or GFHs. Cycloheximide or puromycin infusion suppressed ex vivo platelet GpIIb/IIIa activation and P-selectin exposure with low thrombin concentrations and low-to-saturating concentrations of adenosine 5'-diphosphate (ADP) or thromboxane analog but not convulxin. ADP-induced thromboxane generation was blunted by translation inhibition, and secondary-wave aggregation was inhibited in a thromboxane-dependent manner. Intravenously administered puromycin reduced injury-induced clot size in cremaster muscle arterioles, and delayed primary hemostasis after tail tip amputation but did not delay neither final hemostasis after subsequent rebleeds, nor final hemostasis after jugular vein puncture. In contrast, these mice were protected from injury-induced arterial thrombosis and thrombin-induced pulmonary thromboembolism (PE), and adoptive transfer of translation-inhibited platelets into untreated mice inhibited arterial thrombosis and PE. Thus, constitutive plasma GFH-driven translation regulates platelet G protein-coupled receptor reactivity to balance hemostasis and thrombotic potential.

  PublisherOA PDFDOI

Recent grants

• Hemostasis and Thrombosis: Chemistry, Biology and Physiology

  NIH · $33.0M · 2018–2029

• NIH Grant P01HL074124

  NIH · $16.1M · 2015

• NIH Grant R01HL088010

  NIH · $1.6M · 2013

• Mechanisms Regulating Factor V Activation and Function

  NIH · $946k · 2016–2020

• NIH Grant F32HL010343

  NIH · $38k

Frequent coauthors

• Valder R. Arruda

  92 shared

• Matthew W. Bunce

  Children's Hospital of Philadelphia

  65 shared

• Mortimer Poncz

  Children's Hospital of Philadelphia

  61 shared

• Katherine A. High

  Rockefeller University

  61 shared

• Lacramioara Ivanciu

  Children's Hospital of Philadelphia

  44 shared

• Peter J. Larson

  Jackson Laboratory

  43 shared

• Cornelis van ‘t Veer

  Amsterdam University Medical Centers

  42 shared

• Joost C.M. Meijers

  Amsterdam University Medical Centers

  42 shared

Labs

• Rodney M. Camire LaboratoryPI