Case Studies in PNH

Diagnostic Challenges: Interactive Case Studies

These cases display the variable presentations of PNH and provide healthcare professionals with insight into diagnosing the disease.

47-year-old female with cytopenia and DVT

PNH Diagnostic Timeline

June 2005	Ob/gyn performed exploratory laparotomy due to endometriosis Patient prescribed danazol postsurgery
July 2005	Patient developed mild cytopenia and hematuria postsurgery Test results: Platelet count: 98,000 μL Hemoglobin: 9 g/dL Ob/gyn referred patient to hem/onc Bone marrow biopsy results normal
August 2005	Hem/onc initiated erythropoietin Hemoglobin normalized Test results: LDH: 272 IU/L (ULN=200) Platelet count: 109,000 μL
October 2005	Persistent fatigue and thrombocytopenia prompted hem/onc to test for PNH via flow cytometry; only received qualitative results	Diagnosis: PNH
February 2006	Patient developed DVT Patient completed standard 6-month anticoagulation course
January 2007	Hem/onc ordered flow cytometry for continued patient monitoring Test results: Granulocyte clone: 64% RBC type II clone: 36% RBC type III clone: 3% LDH: 296 IU/L (ULN=200)

Key Takeaways

• Unexplained cytopenia is a trigger for PNH testing
• LDH alone does not indicate PNH
• Clear reporting of both qualitative and quantitative results is critical for assessing
  next steps
• Severity, frequency, and location of thrombotic events in PNH are unpredictable

Please note that personally identifying characteristics of the patients, physicians, and geographic locations have been removed or changed where possible to maintain patient confidentiality. Every effort has been made, however, to preserve the integrity of the learning objectives of these cases.

1. Borowitz MJ, Craig FE, DiGiuseppe JA, et al; for Clinical Cytometry Society. Cytometry Part B Clin Cytometry. doi:10.1002/cyto.b.20525.

28-year-old female with AA and pancytopenia

PNH Diagnostic Timeline

June 2007	Patient complained of excessive uterine bleeding Internal Medicine diagnosed patient with pancytopenia during routine CBC Bone marrow evaluation consistent with AA Patient asymptomatic except for complaints of mild fatigue Hem/onc consulted First evaluation using flow cytometry did not reveal the presence of a PNH clone Test results: LDH: 185 IU/L (ULN=200) Hematocrit: 20% WBC: 2700 μL Platelet count: 57,000 μL Haptoglobin: 88 mg/dL
December 2007	Patient retested via flow cytometry due to persistent AA/pancytopenia Test results: Granulocyte clone: 6.7% RBC type II clone: 0.2% RBC type III clone: 4.3%	Diagnosis: PNH
December 2008	Test results: Granulocyte clone: 8.7% RBC type II clone: 3.0% RBC type III clone: 4.9%
December 2009	Test results: LDH: 401 IU/L (ULN=200) Granulocyte clone: 12.3% RBC type II clone: 3.8% RBC type III clone: 6.7%

Key Takeaways

• AA is a trigger for early PNH testing
• Continued PNH monitoring may identify clonal expansion

Please note that personally identifying characteristics of the patients, physicians, and geographic locations have been removed or changed where possible to maintain patient confidentiality. Every effort has been made, however, to preserve the integrity of the learning objectives of these cases.

1. Borowitz MJ, Craig FE, DiGiuseppe JA, et al; for Clinical Cytometry Society. Cytometry Part B Clin Cytometry. doi:10.1002/cyto.b.20525.

57-year-old female with AA, hepatic vein thrombosis, and low levels of hemolysis

PNH Diagnostic Timeline

1997	AA treated and resolved
1998	Presented with thrombocytopenia after hepatitis vaccine
1999	Referred to hem/onc for continued thrombocytopenia Patient presented with mild impairment of daily activities, moderate exercise intolerance, and insomnia
2000	Treated with iron replacement therapy due to excessive uterine bleeding
2003	LDH test results within normal limits: 134 IU/L (ULN=200) Platelet count: 60,000 μL
2006	Patient presented with abdominal pain and partial hepatic vein thrombosis Warfarin treatment administered for 6 months Thrombocytopenia persisted
2007	Test results: LDH: 430 IU/L (ULN=200) Hemoglobin: 10.8 g/dL Granulocyte clone: 92.44% RBC type II clone: 0.05% RBC type III clone: 52%	Diagnosis: PNH

Key Takeaways

• AA and continued thrombocytopenia are triggers for PNH testing
• LDH alone does not indicate PNH
• Severity, frequency, and location of thrombotic events in PNH are unpredictable

Please note that personally identifying characteristics of the patients, physicians, and geographic locations have been removed or changed where possible to maintain patient confidentiality. Every effort has been made, however, to preserve the integrity of the learning objectives of these cases.

1. Borowitz MJ, Craig FE, DiGiuseppe JA, et al; for Clinical Cytometry Society. Cytometry Part B Clin Cytometry. doi:10.1002/cyto.b.20525.

72-year-old male with refractory anemia-myelodysplastic syndrome (RA-MDS)

PNH Diagnostic Timeline

May 2006	Patient diagnosed with RA-MDS Patient initiated on erythropoietin
January 2008	Patient presented with severe fatigue, impaired QoL, mild dyspnea, and dizziness
May 2009	Patient unresponsive to supportive care treatment, including RBC transfusions Hematologist tested for PNH via flow cytometry Bone marrow biopsy revealed normal cytogenetics Test results: Granulocyte clone: 9% RBC clone: 4.7% LDH: 380 IU/L (ULN=200) Hemoglobin: 8.5 g/dL Platelet count: 145,000 μL	Diagnosis: PNH
March 2010	Transfusion requirements increased PRBCs weekly Severe fatigue, exercise intolerance, and impaired QoL continued
April 2010	Hematologist orders flow cytometry to monitor PNH due to continuing and worsening symptoms, and found that the PNH clone had expanded Granulocyte clone: 30% RBC clone: 17% LDH: 570 IU/L (ULN=200) Platelet count: 77,000 μL

Key Takeaways

• RA-MDS is a trigger for PNH testing
• Continued PNH monitoring may identify clonal expansion

Please note that personally identifying characteristics of the patients, physicians, and geographic locations have been removed or changed where possible to maintain patient confidentiality. Every effort has been made, however, to preserve the integrity of the learning objectives of these cases.

1. Borowitz MJ, Craig FE, DiGiuseppe JA, et al; for Clinical Cytometry Society. Cytometry Part B Clin Cytometry. doi:10.1002/cyto.b.20525.

37-year-old female with Coombs-negative hemolytic anemia, pulmonary embolism, and Budd-Chiari syndrome

PNH Diagnostic Timeline

1999	Patient presented to internal medicine with severe anemia and hemoglobinuria Diagnosed with Coombs-negative hemolytic anemia Symptoms managed with folic acid, oral iron, and steroids
2001	Patient presented with severe fatigue, impaired quality of life, and mild jaundice Hematologist ordered flow cytometry Test results: Granulocyte clone: 96% RBC type II clone: 60% RBC type III clone: 0.04% Hemoglobin: 5.8 g/dL Reticulocyte count: 10%	Diagnosis: PNH
2007	Test results: LDH: 7959 IU/L (ULN=200)
2009	Patient hospitalized due to simultaneous pulmonary embolism and Budd-Chiari syndrome Placed on heparin and warfarin Test results: LDH: 1244 IU/L (ULN=200)

Key Takeaways

• Coombs-negative hemolytic anemia and hemoglobinuria are triggers for PNH testing
• Severity, frequency, and location of thrombotic events in PNH are unpredictable

Please note that personally identifying characteristics of the patients, physicians, and geographic locations have been removed or changed where possible to maintain patient confidentiality. Every effort has been made, however, to preserve the integrity of the learning objectives of these cases.

1. Borowitz MJ, Craig FE, DiGiuseppe JA, et al; for Clinical Cytometry Society. Cytometry Part B Clin Cytometry. doi:10.1002/cyto.b.20525.

33-year-old female with portal vein thrombosis, liver failure and transplant, and cerebral vascular accident

PNH Diagnostic Timeline

March 2009	Patient presented to ER with abdominal pain, fatigue, and mildly impaired QoL Diagnosed with extensive portal vein thrombosis via ultrasound and MR venogram Evaluated for liver transplant due to liver failure Flow cytometry negative for PNH; however, hospital lab evaluated RBCs alone — WBCs not evaluated
April 2009	Patient received liver transplant Posttransplant, patient had multiple thromboses, even on adequate anticoagulation Thromboses treated with thrombolytics and embolectomy Subsequent to these interventions, patient experienced additional thrombotic events (portal vein thromboses; CVA)
October 2005	MD retested for PNH cells using commercial lab due to: Continued poor outcomes Low haptoglobin New information regarding testing WBCs in addition to RBCs with appropriate sensitivity Patient died due to additional CVA before receiving test results Test results: Granulocyte clone: 86% RBC type II clone: 5% RBC type III clone: 4% LDH: 339 IU/L (ULN=200) Hemoglobin: 9.4 g/dL Haptoglobin: <5 mg/dL	Diagnosis: PNH

Key Takeaways

• Unexplained thrombosis is a trigger for early PNH testing
• Perform flow cytometry on granulocytes and at least 1 additional cell line
• Severity, frequency, and location of thrombotic events in PNH are unpredictable

Please note that personally identifying characteristics of the patients, physicians, and geographic locations have been removed or changed where possible to maintain patient confidentiality. Every effort has been made, however, to preserve the integrity of the learning objectives of these cases.

1. Borowitz MJ, Craig FE, DiGiuseppe JA, et al; for Clinical Cytometry Society. Cytometry Part B Clin Cytometry. doi:10.1002/cyto.b.20525.

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