REFRACTORY ITP SURVEY:
  1. Case Vignettes:
  2. A 3 year-old previously healthy F presents with diffuse bruising, petechiae, and a few wet purpura over the oral mucosa. She is found to have isolated thrombocytopenia (4k), with platelet size variance on smear review (including large and giant platelets), and some reactive-appearing lymphocytes, but no blasts or other morphological abnormalities consistent with a diagnosis of Acute ITP. Parents are extremely anxious about ongoing injuries for this active toddler, and also live ~3 hours from the nearest major medical center. Therefore, the decision is made to proceed with frontline platelet-directed therapy. She receives IVIG 1 g/kg, and although cutaneous symptoms are slightly improved ~5 days later, platelet count remains <10k. She is started on oral prednisone 4 mg/kg/day divided BID at this point; and CBC one week later reveals platelet count remaining fairly unchanged, at 12k. She has had no major bleeding events, but continues to have some mild intermittent wet purpura, and diffuse cutaneous symptoms; with significant anxiety from parents. Blood type is A-; so the decision is made to proceed with a second dose of IVIG 1 g/kg following which, symptoms briefly improve, but return to baseline within 1 week, at the time CBC reveals platelet count remaining at 10k.
  3. Would you consider this refractory ITP? Yes/No
  4. Would you work this patient up for alternate etiologies of thrombocytopenia at this time (vs. continued observation, or second-line management)? Yes/No
  5. If so, what additional work-up would you obtain? (check all that apply)
  6. HIV
  7. Hepatitis
  8. H. Pylori
  9. CMV and/or EBV
  10. ANA Profile
  11. Immunoglobulins
  12. Lymphocyte subsets
  13. Complement levels
  14. ALPS work-up
This patient continues to have cutaneous symptoms and platelet count fluctuating between 10k and 30k over the next several months, but no major bleeding events. After ~1 year, parents feel that patient’s quality of life is suffering significantly (due to activity and environment restrictions), and they would like to be able to send her to pre-K safely, without major restrictions. Therefore, the decision is made to initiate second-line therapy, and parents choose TPO-RA therapy. After several weeks of therapy, patient shows minimal platelet response with romiplostim; and is transitioned to eltrombopag therapy. Again, cutaneous symptoms are improved, but platelet count remains fairly unchanged (<50k).
Would you consider this refractory ITP? Yes/No
Would you work this patient up for alternate etiologies of thrombocytopenia at this time (vs. continued observation, or second-line management)? Yes/No
If so, what additional work-up would you obtain? (check all that apply)
  1. HIV
  2. Hepatitis
  3. H. Pylori
  4. CMV and/or EBV
  5. ANA Profile
  6. Immunoglobulins
  7. Lymphocyte subsets
  8. Complement levels
  9. ALPS work-up
Given continued concern from parents, lifestyle restrictions, and intermittent minor bleeding events, the decision is made to continue pursuing other potential second-line therapies. She is treated with rituximab (375 mg/m2/week x4), and shows an excellent clinical and platelet response (100k – 200k range).
Would you consider this refractory ITP? Yes/No
Would you work this patient up for alternate etiologies of thrombocytopenia at this time (vs. continued observation, or second-line management)? Yes/No
If so, what additional work-up would you obtain? (check all that apply)
  1. HIV
  2. Hepatitis
  3. H. Pylori
  4. CMV and/or EBV
  5. ANA Profile
  6. Immunoglobulins
  7. Lymphocyte subsets
  8. Complement levels
  9. ALPS work-up
After ~9 months, patient’s platelet counts again begin trending downward, eventually to her former baseline ~10k – 30k; and similar clinical symptoms return. The decision is made to proceed with splenectomy at this point, and patient responds very well with post-surgical platelet count to a peak of ~500k.
Would you consider this refractory ITP? Yes/No
Would you work this patient up for alternate etiologies of thrombocytopenia at this time (vs. continued observation, or second-line management)? Yes/No
If so, what additional work-up would you obtain? (check all that apply)
  1. HIV
  2. Hepatitis
  3. H. Pylori
  4. CMV and/or EBV
  5. ANA Profile
  6. Immunoglobulins
  7. Lymphocyte subsets
  8. Complement levels
  9. ALPS work-up
  10. A 4 year-old previously healthy M presents with diffuse bruising and petechiae, along with recent epistaxis episodes, all resolving in <5 minutes. He is found to have isolated thrombocytopenia (6k), with platelet size variance on smear review (including large and giant platelets), and some reactive-appearing lymphocytes, but no blasts or other morphological abnormalities consistent with a diagnosis of Acute ITP. Given his lack of significant bleeding symptomatology, and parental comfort level, the decision is made to proceed with thorough education, return precautions, and observational management. Patient returns in ~2-3 weeks, with no major bleeding events or concerns, and platelet count remaining <10k. Observation is continued. However, ~2 weeks later, patient presents with hematuria, and is admitted for platelet-directed therapy. IVIG 1 g/kg is administered, but platelet count remains ~unchanged over the subsequent 48 hours, and patient’s hematuria persists, with Hgb dropping from 11.8 to 9 g/dL. IV methylprednisolone is initiated, at 30 mg/kg (max 1 g) IV daily doses; but the following day, patient’s hematuria has not improved, and Hgb is now 8 g/dL. Patient is DAT negative, blood type O+, and has no evidence of renal dysfunction. Therefore, anti-D immune globulin 75 mcg/kg is administered; but again, patient’s platelet count remains <10k over the next ~36 hours (on continued methylprednisolone as well), with Hgb trending down to ~7 g/dL. Romiplostim 10 mcg/kg is administered x1, and patient is planned for slow platelet drip/transfusion.
  11. Would you consider this refractory ITP? Yes/No
  12. Would you work this patient up for alternate etiologies of thrombocytopenia at this time (+/- continued emergent/second-line ITP management)? Yes/No
If so, what additional work-up would you obtain? (check all that apply)
  1. HIV
  2. Hepatitis
  3. H. Pylori
  4. CMV and/or EBV
  5. ANA Profile
  6. Immunoglobulins
  7. Lymphocyte subsets
  8. Complement levels
  9. ALPS work-up
  10. An 8 year-old M presents with increased bruising and episodes of epistaxis over the past ~month, and is found to have isolated thrombocytopenia (to 18k), with elevated immature platelet fraction (13%), and smear review showing platelet size variance (including large and giant platelets), and no other morphological abnormalities (including of RBC’s or WBC’s). Thyroid function, renal function, liver function, and nutritional evaluation is all within normal limits; and he is diagnosed with Acute ITP. Given lack of significant bleeding symptomatology or risk, observational management is recommended. Throughout ~3-4 months of follow-up, symptoms are unchanged, and platelet count remains between 10k - 20k. However, he subsequently presents with worsening epistaxis, now lasting up to 15-20 minutes before resolving, occurring more frequently, and resulting in a mild anemia (Hgb ~10 g/dL). The decision is made to proceed with platelet-directed therapy, and he is given IVIG 1 g/kg, with excellent clinical response. Additionally, platelet count 3 days later has increased to 170k; and remains >100k for ~4 weeks. About 2 months after IVIG therapy, however, patient again develops worsening epistaxis/bleeding, and is found to have platelet count 15k. He is ~6 months from initial diagnosis, with persistent ITP; and declines any “long-term” treatment options. However, as symptoms persist/worsen, he requests to proceed with another dose of IVIG. He is given another 1 g/kg; but this time with peak platelet count to 80k, and returning to baseline (between 10k-20k) within ~2 weeks. Subsequently, he wishes to proceed with a trial of short-term prednisone, and receives 2 mg/kg/day divided BID for 2 weeks with excellent response (platelet count to 120k near the end of 2 weeks’ prednisone therapy). However, platelet count returns to baseline within ~2 weeks. He continues observation for another ~month; but again requests short-term prednisone therapy when epistaxis worsens. Peak platelet count is ~70k, and returns to baseline within ~1 week of therapy. Discussions are re-initiated regarding second-line treatment options, given patient’s lack of sustained response to front-line/rescue treatment options, and the persistent need for ITP therapy, in light of his persistent bleeding symptoms.
  11. Would you consider this refractory ITP? Yes/No
  12. Would you work this patient up for alternate etiologies of thrombocytopenia (vs. proceeding with second-line ITP management)? Yes/No
If so, what additional work-up would you obtain? (check all that apply)
  1. HIV
  2. Hepatitis
  3. H. Pylori
  4. CMV and/or EBV
  5. ANA Profile
  6. Immunoglobulins
  7. Lymphocyte subsets
  8. Complement levels
  9. ALPS work-up
  10. A 13 year-old F presents with increased bruising and mild menorrhagia over the past 1-2 months, and is found to have isolated thrombocytopenia (to 13k), with elevated immature platelet fraction (12%), and smear review showing platelet size variance (including large and giant platelets), and no other morphological abnormalities (including of RBC’s or WBC’s). Thyroid function, renal function, liver function, and nutritional evaluation is all within normal limits; and she is diagnosed with Acute ITP. Given lack of significant bleeding symptomatology or risk, observational management is recommended. Throughout ~3-4 months of follow-up, however, she reports extreme fatigue, preventing her from participating in prior extracurricular activities or completing school work as before. She is treated for iron deficiency (with improvement in iron stores); and initiated on hormonal control for menorrhagia (with regulation of cycles and flow per report); although remaining non-anemic throughout this period of follow-up. No platelet-directed therapy is initiated throughout these first 3-4 months, and platelet count remains unchanged, between 10k - 20k. She begins to report falling grades in school; and parents are very concerned with her level of fatigue, and inability to participate in routine activities. Therefore, patient is treated with a one-time course of prednisone (2 mg/kg/day), with excellent platelet response, to a peak of 160k, and some improvement in fatiguethroughout this course of short-term prednisone therapy. At ~6 months from time of diagnosis, discussion regarding potential second-line therapies are initiated, and she chooses a trial of eltrombopag therapy. Again, platelet response is achieved (to ~100k, stably); with no notable side effects; but she reports only slight improvement in fatigue after ~2-3 months of TPO-RA therapy.
  11. Would you consider this refractory ITP? Yes/No
  12. Would you work this patient up for alternate etiologies of thrombocytopenia (vs. continuing with second-line ITP-directed management and/or evaluating for secondary ITP)? Yes/No
If so, what additional work-up would you obtain? (check all that apply)
  1. HIV
  2. Hepatitis
  3. H. Pylori
  4. CMV and/or EBV
  5. ANA Profile
  6. Immunoglobulins
  7. Lymphocyte subsets
  8. Complement levels
  9. ALPS work-up
Categorical Questions:
  1. Is a patient who does not respond at all to first line therapies refractory? Y/N
  2. Is a patient who has a transient response to first line treatments but quickly loses that response refractory? Y/N
  3. Is a patient who requires ongoing treatment to maintain a response refractory? Y/N
  4. Is a patient who fails to respond to one or more second line treatments (regardless of first line therapy responses) refractory?
  5. Is a patient with ongoing symptoms (fatigue) regardless of platelet count responses refractory? Y/N