Bone Marrow Failure Disorders

Presentation and History

The patient is a 64-year-old male with a past medical history significant for hyperlipidemia; bipolar disorder, for which he has received lithium treatment for the past 5 years; and aplastic anemia successfully treated 5 months ago with antithymocyte globulin (ATG), cyclosporine (CSA), and eltrombopag.

At a 5-month routine follow-up for his aplastic anemia, he reported right lower extremity swelling and tenderness along his calf on dorsiflexion of his ankle. He reported that prior to ATG/CSA treatment, he had dark urine every morning as well as significant muscle and joint pain affecting his ability to walk.

Doppler ultrasound of his right lower extremity was positive for nonocclusive deep vein thrombosis (DVT) of the anterior tibial vein. The diagnostic workup also included CBC with differential, which showed a WBC of 4.8 K/µL, Hgb of 9.6 g/dL, and platelet count of 61,000/µL. Hemolysis studies showed an elevated reticulocyte count, elevated LDH, low haptoglobin levels, normal bilirubin levels, and direct antiglobulin test (DAT; also known as the Coombs test) negative results. Flow cytometry was positive for paroxysmal nocturnal hemoglobinuria (PNH).

Differential Diagnosis

The differential diagnoses in this case include nonautoimmune hemolytic anemias such as hereditary red blood cell membrane or enzymatic defects; drug-induced hemolysis; paroxysmal cold hemoglobinuria; and bone marrow disorders including aplastic anemia, myelodysplastic syndrome, and primary myelofibrosis.

Diagnosis and Recommendations for Treatment

As mentioned, Doppler ultrasound of the patient’s right lower extremity was positive for nonocclusive DVT of the anterior tibial vein. Given his history of aplastic anemia, which can co-occur with PNH, hemolysis studies were performed and were positive for DAT or Coombs-negative hemolysis. While flow cytometry for PNH was near normal when performed during a previous aplastic anemia workup, repeated testing showed an increased PNH clone number, confirming the diagnosis of PNH.

With confirmation of PNH and symptomatic, nonprovoked DVT, the patient was started on anticoagulation therapy. PNH treatment was also initiated with ravulizumab-cwvz, a long-acting C5 complement inhibitor.

It is important to be aware that PNH can co-occur with other bone marrow disorders. With aplastic anemia, the PNH clone may be small or near normal when first tested, due to the marrow being aplastic. After successful treatment for aplastic anemia and restoration of normal hematopoiesis, the PNH clone can expand to cause complications including DAT or Coombs-negative hemolysis, dark urine, anemia, or unprovoked thrombosis.

After patients are treated for aplastic anemia or other bone marrow disorders, the PNH clone should always be rechecked using flow cytometry if hemolysis is suspected or an unprovoked thrombosis occurs. Additionally, all patients should receive the meningococcal vaccine prior to starting any complement inhibitor therapy. If treatment is urgent and cannot be delayed, recommendations are for the patient to receive prophylactic antibiotics until there is an opportunity to receive this vaccine.

The advanced practice provider should educate the patient about signs and symptoms of PNH, thrombosis, and meningitis. It may also be helpful to collaborate with an anticoagulation specialist to determine if long-term treatment is necessary and to seek advice regarding management and follow-up.