Jorge Di Paola, MD
Research Profile

Von Willebrand disease (VWD) is the most common inherited bleeding disorder in humans. It is caused by abnormalities in the von Willebrand factor (VWF), and it is characterized by incomplete penetrance and variable expressivity. VWF levels exhibit a high degree of variability in the population. High factor VIII levels, which are in part controlled by the level of VWF in plasma, have been associated with increased thrombosis.

The aim of our research is to identify genetic loci that are modifiers of VWF levels, and disease susceptibility in humans. Through linkage mapping, using large pedigrees we aim to discover genes that exert a modifier effect. Eventually, these newly discovered gene variants would constitute modifiers for other clinical conditions involving bleeding and thrombosis such as cardiovascular disease, hemophilia, menorrhagia, and excessive post surgical and post partum bleeding.

In close collaboration with Steven Lentz from the Department of Internal Medicine we are also interested in pathways involved in platelet activation. Shawn Jobe, recipient of a National Hemophilia Foundation training fellowship and a member of our laboratory, is currently working on the "coated" platelet phenomenon described originally by George Dale at the University of Oklahoma.

Coated platelets are represented by a subpopulation of platelets that upon stimulation with dual agonists (particularly collagen plus thrombin) retain alpha granule proteins on their surface. Dr. Jobe is characterizing these platelets in a murine model. Keala Clark, a third year fellow in the Pediatric Critical Care Program is investigating the role of chloride in platelet activation. His model involves the use of platelets from the CLC3 null mouse developed by Fred Lamb at the Division of Pediatric Critical Care. CLC3 is a protein originally cloned by the Lamb's laboratory and is thought to be involved in chloride transport through cell membranes.

Lab Members:

• Alejandro Raimondi, MD
• Shawn Jobe, MD, PhD
• Keala Clark, MD
• Jesse Hinckley MSTP
• Keith Crouch
• Kaye Wagner, MD
• Mary Rickard
• Brie Nixon

Affiliations:

• Department of Pediatrics
• Division of Hematology/Oncology
• Hemophilia Treatment Center

Model System:

• Genetic studies of VWD and rare platelet disorders: We perform association and linkage studies. We recruit unrelated individuals with VWD and family members. For linkage analysis we recruit large pedigrees. In collaboration with Amy Shapiro at the Indiana Hemophilia and Thrombophilia Center we have identified characterized and collected blood samples from a single Amish pedigree from northern Indiana diagnosed with VWD. This pedigree, the largest ever described for this disease, is composed of 758 individuals and represents a unique source in the search of modifiers for VWF levels and bleeding.
• Platelet studies: murine (i.e. factor XIII and CLC3 null mice) and human.

Clinical Trials:

• Hemophilia Related Clinical Trials

Recent Publications:

Publications

1. Jorge Di Paola, Qining Qian, Todd Goldman, Margaret I. Malik, Shivanand R. Patil, Brian C. Schutte. "Breakpoint of a balanced translocation (X: 14) (q 27.1; q32.33) in a girl with severe hemophilia B maps proximal to the factor IX gene" Journal of Thrombosis and Hemostasis 2004 Mar; 2(3):437-40.
2. Shawn Jobe, Patricia Donohue, Jorge Di Paola "Deep venous thrombosis and Turner Syndrome" Journal of Pediatric Hematology Oncology. 2004 Apr; 26(4): 272.
3. Jorge Di Paola "Product selection issues in the management of hemophilia B". Blood Coagulation and Fibrinolysis. 2004 Jun; 15 Suppl 1:S17-8.
4. Amy D. Shapiro, Jorge Di Paola, Alice Cohen, John Pasi, Margaret A. Heisel, Victor S. Blanchette, W. Keith Hoots, Jeanne D. Lusher, Claude Negrier, Chantal Rothschild, and David A. Roth, for the Recombinant Factor IX Study Group "The safety and efficacy of recombinant human blood coagulation factor IX in previously untreated patients with severe and moderately severe hemophilia B" Blood, 2005 Vol 105, N 2: 518-525
5. Jorge Di Paola, Astanand Juggesur, Todd Goldman, Jaime Reiland, Dan Tallman, Cecilia Sayago, Jeff Murray "Platelet Membrane Glycoprotein Ibα and Integrin α2β1 Polymorphisms: Gene Frequencies, Linkage Disequilibrium in a Population Diversity Panel" Journal of Thrombosis and Haemostasis. 2005; 3: 1511-21.
6. Determinants of bleeding severity in Von Willebrand disease, Jorge Di Paola, Current Hematology Reports 2005 Sep; 4(5): 345-9.
7. Shawn Jobe, Lorie Leo, Joshua Eastvold, Timothy Ratliff and Steven Lentz, and Jorge Di Paola # "Role of FcRγ and FXIII in coated platelet formation" Blood 2005 Aug 16; [Epub ahead of print] (# Corresponding author).
8. Miltiadis Douvoyiannis, John Widness, Jorge Di Paola "Renal vein thrombosis" Pediatr Rev. 2005 Dec; 26(12): 461-6.
9. Pharmacokinetics and Dose Linearity of von Willebrand Factor / Factor VIII Concentrate (Humate-P®) in Elective Surgery in von Willebrand Disease Patients.Jorge Di Paola, J. Gill, J. Bernstein, C. Leissinger, L. Valentino, C. Friedman, S. Knaub. (Submitted)
10. A missense mutation in exon 28 (C4120T) of the Von Willebrand Factor gene is the cause of VWD in a large Amish pedigree. Jorge Di Paola, Jeffrey Murray, Steven Lentz, Robert Montgomery, Cecilia Sayago, Kai Wang, Tracy Burns and Amy Shapiro. (In preparation)
11. Heritability of blood counts in a large Amish pedigree. Jorge Di Paola, Amy Shapiro, Kai Wang and Trudy Burns (in preparation)

Book Chapters

1. Thomas J. Raife and Jorge Di Paola "Transfusion of the Pediatric Surgery, Trauma, and Intensive Care Unit Patient" in Handbook of Pediatric Tranfusion. Hylliard, Strauss, Luban. Elsevier. 2004.
2. Shawn Jobe and Jorge Di Paola "Congenital and acquired disorders of platelet function" in Consultative Hemostasis and Thrombosis. Kitchens, Alving, Kessler. Elsevier (in preparation)