Research

Our lab focuses on the genetics and genomics of hemostasis and thrombosis and the mechanisms of platelet activation. We are currently engaged in research on von Willebrand disease, platelet disorders, and basic hemostasis.

We have 20 years of experience with molecular genetics, genomics and transcriptomics and we have an established track record of gene discovery and genetic studies in hematology, hemostasis and thrombosis.1-8 Using NGS, our team led to the discoveries of genetic causes of congenital thrombocytopenia and tackled the complexity of the genetics of VWD and low VWF. 6, 7, 9-15 Our expertise in NGS in Hemostasis and Thrombosis has been recently recognized by the American Society of Hematology and the NHLBI as Dr. Di Paola has been designated the Chair of the Working Group in Platelet Genomics for the Clinical Genome Resource (ClinGen) which is in charge of curating all gene variants worldwide that have been associated with congenital thrombocytopenias.16

More recently our research focused on thrombo-inflammation and in megakaryopoiesis and its role on bone marrow homeostasis during inflammation, ageing, and myeoloproliferative neoplasms.

State of the Art Equipment & Techniques

Our lab utilizes confocal and intravital imaging techniques to study hemostasis and thrombosis in vitro and in vivo. Assays routinely used in the lab to identify biomarkers of blood related disorders and to test novel therapeutics include:

  • Microfluidics
  • Folts modified model of arterial thrombosis
  • Models of thrombo-inflammation
  • Mechanical injury models
  • Atherosclerosis plaque models
Citations
  1. Di Paola J, Jugessur A, Goldman T, Reiland J, Tallman D, Sayago C, Murray JC. Platelet glycoprotein I(b)alpha and integrin alpha2 beta1 polymorphisms: gene frequencies and linkage disequilibrium in a population diversity panel. Journal of thrombosis and haemostasis : JTH. 2005;3(7):1511-21. Epub 2005/06/28. doi: 10.1111/j.1538-7836.2005.01273.x. PubMed PMID: 15978109.
  2. Di Paola J, Goldman T, Qian Q, Patil SR, Schutte BC. Breakpoint of a balanced translocation (X:14) (q27.1;q32.3) in a girl with severe hemophilia B maps proximal to the factor IX gene. Journal of thrombosis and haemostasis : JTH. 2004;2(3):437-40. Epub 2004/03/11. PubMed PMID: 15009460.
  3. Di Paola J, Federici AB, Mannucci PM, Canciani MT, Kritzik M, Kunicki TJ, Nugent D. Low platelet alpha2beta1 levels in type I von Willebrand disease correlate with impaired platelet function in a high shear stress system. Blood. 1999;93(11):3578-82. PubMed PMID: 10339461.
  4. Hinckley JD, Abbott D, Burns TL, Heiman M, Shapiro AD, Wang K, Di Paola J. Quantitative trait locus linkage analysis in a large Amish pedigree identifies novel candidate loci for erythrocyte traits. Mol Genet Genomic Med. 2013;1(3):131-41. doi: 10.1002/mgg3.16. PubMed PMID: 24058921; PMCID: PMC3775389.
  5. Hinckley J, Di Paola J. Genetic basis of congenital platelet disorders. Hematology Am Soc Hematol Educ Program. 2014;2014(1):337-42. doi: 10.1182/asheducation-2014.1.337. PubMed PMID: 25696876.
  6. Kahr WH, Hinckley J, Li L, Schwertz H, Christensen H, Rowley JW, Pluthero FG, Urban D, Fabbro S, Nixon B, Gadzinski R, Storck M, Wang K, Ryu GY, Jobe SM, Schutte BC, Moseley J, Loughran NB, Parkinson J, Weyrich AS, Di Paola J. Mutations in NBEAL2, encoding a BEACH protein, cause gray platelet syndrome. Nature genetics. 2011;43(8):738-40. doi: 10.1038/ng.884. PubMed PMID: 21765413.
  7. Noetzli L, Lo RW, Lee-Sherick AB, Callaghan M, Noris P, Savoia A, Rajpurkar M, Jones K, Gowan K, Balduini CL, Pecci A, Gnan C, De Rocco D, Doubek M, Li L, Lu L, Leung R, Landolt-Marticorena C, Hunger S, Heller P, Gutierrez-Hartmann A, Xiayuan L, Pluthero FG, Rowley JW, Weyrich AS, Kahr WH, Porter CC, Di Paola J. Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia. Nature genetics. 2015;47(5):535-8. doi: 10.1038/ng.3253. PubMed PMID: 25807284; PMCID: PMC4631613.
  8. Fabbro S, Kahr WH, Hinckley J, Wang K, Moseley J, Ryu GY, Nixon B, White JG, Bair T, Schutte B, Di Paola J. Homozygosity mapping with SNP arrays confirms 3p21 as a recessive locus for gray platelet syndrome and narrows the interval significantly. Blood. 2011;117(12):3430-4. doi: 10.1182/blood-2010- 12-322990. PubMed PMID: 21263149; PMCID: PMC3069679.
  9. Kahr WH, Lo RW, Li L, Pluthero FG, Christensen H, Ni R, Vaezzadeh N, Hawkins CE, Weyrich AS, Di Paola J, Landolt-Marticorena C, Gross PL. Abnormal megakaryocyte development and platelet function in Nbeal2(-/-) mice. Blood. 2013;122(19):3349-58. doi: 10.1182/blood-2013-04-499491. PubMed PMID: 23861251; PMCID: PMC3953091.
  10. Tomberg K, Khoriaty R, Westrick RJ, Fairfield HE, Reinholdt LG, Brodsky GL, Davizon-Castillo P, Ginsburg D, Di Paola J. Spontaneous 8bp Deletion in Nbeal2 Recapitulates the Gray Platelet Syndrome in Mice. PLoS One. 2016;11(3):e0150852. doi: 10.1371/journal.pone.0150852. PubMed PMID: 26950939; PMCID: PMC4780761.
  11. Chen J, Hinckley JD, Haberichter S, Jacobi P, Montgomery R, Flood VH, Wong R, Interlandi G, Chung DW, Lopez JA, Di Paola J. Variable content of von Willebrand factor mutant monomer drives the phenotypic variability in a family with von Willebrand disease. Blood. 2015;126(2):262-9. doi: 10.1182/blood-2014-11-613935. PubMed PMID: 26019279; PMCID: PMC4497966.
  12. Lavin M, Aguila S, Schneppenheim S, Dalton N, Jones KL, O’Sullivan JM, O’Connell NM, Ryan K, White B, Byrne M, Rafferty M, Doyle MM, Nolan M, Preston RJS, Budde U, James P, Di Paola J, O’Donnell JS. Novel insights into the clinical phenotype and pathophysiology underlying low VWF levels. Blood. 2017;130(21):2344-53. doi: 10.1182/blood-2017-05-786699. PubMed PMID: 28916584.
  13. Di Paola J. Determinants of bleeding severity in von Willebrand disease. Curr Hematol Rep. 2005;4(5):345-9. Epub 2005/09/01. PubMed PMID: 16131434.
  14. Branchford BR, Di Paola J. Making a diagnosis of VWD. Hematology Am Soc Hematol Educ Program. 2012:161-7. doi: 10.1182/asheducation-2012.1.161. PubMed PMID: 23233576.
  15. Gupta S, Heiman M, Duncan N, Hinckley J, Di Paola J, Shapiro AD. Variable bleeding phenotype in an Amish pedigree with von Willebrand disease. Am J Hematol. 2016. doi: 10.1002/ajh.24474. PubMed PMID: 27414491. PMCID: PMC5031525.
  16. Rehm HL, Berg JS, Brooks LD, Bustamante CD, Evans JP, Landrum MJ, Ledbetter DH, Maglott DR, Martin CL, Nussbaum RL, Plon SE, Ramos EM, Sherry ST, Watson MS, ClinGen. ClinGen–the Clinical Genome Resource. The New England journal of medicine. 2015;372(23):2235-42. doi: 10.1056/NEJMsr1406261. PubMed PMID: 26014595; PMCID: PMC4474187.

Current Projects

von Willebrand Factor & von Willebrand disease

Effects of pathological flow on VWF Genomics | The Bioinformatics Core of the Zimmerman Program

Platelet Research & Disorders

Thrombo-Inflammation in Mice Deficient for Platelet α-granules ETV6 related thrombocytopenia Role of platelet hyperreactivity and mitochondrial dysfunction in aging and Myeloproliferative Neoplasms (MPN)

Basic Hemostasis

Tissue Factor Pathway Inhibitor (TFPI) Studying coagulation under flow