The Molecular Biology of Paroxysmal Nocturnal Hemoglobinuria (PNH)

This study is designed to better understand the molecular biology of paroxysmal nocturnal hemoglobinuria (PNH) and to determine if prion protein (PrP) functions in long term hematopoietic stem cell renewal.

Study Overview

• Status: Completed
• Conditions: Hemoglobinuria, Paroxysmal

Detailed Description

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by hemolytic anemia, thrombosis, and variable cytopenia. It can be associated with significant morbidity including acute kidney failure, cerebral infarction, mesenteric infarction, Budd-Chiari syndrome, aplastic anemia, and leukemic transformation. The average survival time from diagnosis is 15 years.

PNH is an acquired clonal disorder of the hematopoietic stem cell. Two distinct populations of hematopoietic cells exist in each PNH patient: one non-clonal population of normal cells, and one clonal population of PNH cells. The clonal population of PNH cells is identified by a mutation in the PIG-A gene that results in absence of the glycophosphatidylinositol (GPI) anchor of several surface proteins. Consequently, these surface proteins are unable to perform their functions on the cell surface. Deficiency of two of these surface proteins, CD55 (decay accelerating factor) and CD59 (membrane inhibitor of reactive lysis) that prevent complement mediated destruction, have been shown to underlie the clinical presentation of PNH. Identifying the mutation causing the predominant clones may help us better understand the molecular biology of PNH. When this is accomplished, new therapies to control and eventually cure the disease can be designed.

In addition, we propose to determine the function of PrP in human hematopoietic stem cells. PrP is a glycoprotein attached to the cell membrane by a glycosylphosphatidylinositol (GPI) anchor. In PNH, a disorder whose pathogenesis lies in the absence of GPI anchors, PrP expression is reduced in monocytes and granulocytes from the PNH clone.

• Study Type: Observational
• Enrollment (Actual): 10

Contacts and Locations

Study Locations

• United States
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients with paroxysmal nocturnal hemoglobinuria (PNH)

Description

Inclusion Criteria:

1. Subjects suspected of or diagnosed with Paroxysmal Nocturnal Hemoglobinuria (PNH)
2. Age > 7

Exclusion Criteria:

1. Those not meeting the inclusion criteria

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Affected Population; Subjects suspected of having Paroxysmal Nocturnal Hemoglobinuria (PNH)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Identify the mutation causing the predominant clones through analysis of extracted DNA/RNA from erythroid colonies	After sample is obtained

Secondary Outcome Measures

Outcome Measure	Time Frame
Reconfirmation of PrP expression in human granulocytes, hematopoietic progenitors and stem cells	After sample is obtained
Analysis of PrP function in human long term hematopoietic stem cells	After sample is obtained

Collaborators and Investigators

• Sponsor: University of Utah
• Collaborators: National Institutes of Health (NIH)

Publications and helpful links

General Publications

• Durig J, Giese A, Schmucker U, Kretzschmar HA, Duhrsen U. Decreased prion protein expression in human peripheral blood leucocytes from patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol. 2001 Mar;112(3):658-62. doi: 10.1046/j.1365-2141.2001.02602.x.
• Risitano AM, Holada K, Chen G, Simak J, Vostal JG, Young NS, Maciejewski JP. CD34+ cells from paroxysmal nocturnal hemoglobinuria (PNH) patients are deficient in surface expression of cellular prion protein (PrPc). Exp Hematol. 2003 Jan;31(1):65-72. doi: 10.1016/s0301-472x(02)01011-1.
• Zhang CC, Steele AD, Lindquist S, Lodish HF. Prion protein is expressed on long-term repopulating hematopoietic stem cells and is important for their self-renewal. Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2184-9. doi: 10.1073/pnas.0510577103. Epub 2006 Feb 7.

Study record dates

Study Major Dates

• Study Start: May 1, 2006
• Primary Completion (ACTUAL): December 1, 2010
• Study Completion (ACTUAL): December 1, 2010

Study Registration Dates

• First Submitted: July 23, 2008
• First Submitted That Met QC Criteria: July 23, 2008
• First Posted (ESTIMATE): July 25, 2008

Study Record Updates

• Last Update Posted (ESTIMATE): August 9, 2011
• Last Update Submitted That Met QC Criteria: August 5, 2011
• Last Verified: August 1, 2011

More Information

Terms related to this study

• Keywords: Paroxysmal Nocturnal Hemoglobinuria; Hematopoietic stem cells; PIG-A Mutation; Prion Protein; Clonal disorder
• Additional Relevant MeSH Terms: Urologic Diseases; Urological Manifestations; Bone Marrow Diseases; Hematologic Diseases; Urination Disorders; Anemia; Proteinuria; Anemia, Hemolytic; Myelodysplastic Syndromes; Hemoglobinuria; Hemoglobinuria, Paroxysmal
• Other Study ID Numbers: 17790; R01HL5077-12