Refractory severe idiopathic thrombocytopenia and treatment challenges

Introduction:

Refractory idiopathic thrombocytopenia (ITP) is a disease that does not respond to or relapses after splenectomy, requires treatment to reduce the risk of clinically significant bleeding, and is a challenging case to treat.

Presentation of the Case:

A 39-year-old male with a history of chronic ITP presented with a platelet count of 1000/µl and prostatitis. He was started on Ciprofloxacin and started intravenous immunoglobulin along with intravenous methylprednisolone. Then Rituximab was started on day fourth. Since his platelet remained 0/µl, Mycophenolate mofetil (Cellcept) was started on day 14th. Next, a dose of Romiplostim on day 19th was given. Eltrombopag (Promacta) and Tavlesse were started on day 23th and platelets rose to 96×10³/µl on day 26th and then 418×10³/µl.

Discussion:

Normally, refractory ITP patients who do not respond to first-line treatments require a combination therapy of one to two medicines of the second line, like thrombopoietin receptor agonists. However, this patient’s thrombocytopenia neither responded to first-line treatment nor second-line treatment with Promacta/Romiplostin plus immunosuppressives or Tavlesse.

Conclusion:

Refractory ITP, who has not responded to first-line and second-line treatments, requires treatment with a combination of all first-line and second-line treatments. Furthermore, Promacta, Tavlesse, and Romiplostim have a big role to play in helping the patient.

Introduction

Highlights

• Life-threatening severe thrombocytopenia and management.

• Patients with chronic refractory idiopathic thrombocytopenia (ITP) cannot maintain a platelet count above 20 000/mm³ for an appreciable time.

• Role of combination of all first-line and second-line treatments for ITP treatment

• Promacta, Tavlesse, and Romiplostim have a big role in helping patients with chronic refractory ITP.

Chronic refractory idiopathic thrombocytopenia (ITP) may be defined as the failure of any modality to maintain the platelet count above 20 000/mm³ for an appreciable time without unacceptable toxicity1. An International Working Group defined refractory ITP as a disease that does not respond to or relapse after splenectomy and requires treatment to reduce the risk of clinically significant bleeding2. Refractory ITP is a challenging case to treat and may be associated with poor outcomes3,4. After ruling out every single possible secondary cause of thrombocytopenia, such as infection, and drugs, a patient can diagnosed with ITP. A complete blood count and blood smear can be invaluable diagnostic information to differentiate between other pathologies, but sometimes patients must endure a painful bone marrow biopsy.

Case Report

A 39-year-old Caucasian male with a history of chronic ITP since the age of 8 presented to our hospital as a direct admission from his oncologist for a platelet count of 1000/µl. He had a history of splenectomy at age 8 and reported having 12 episodes of acute flares of ITP. His family history was unremarkable. He did not take any medicine on a daily base. He denied any psychiatric history.

Before seeking treatment for this flare-up, he noticed petechia on both legs up to the knees over several days, bruising with just touching his skin, and most recently, some oral ulcers that started bleeding constantly. Also, he reports chronic fatigue over several years that has worsened in the past months. He admits to never taking medications between flare-ups and having no family history of ITP or autoimmune disorders. Unfortunately, he was not able to brush his teeth without significant bleeding and pain. As a child, he was not able to play any contact sports and was immunocompromised after a splenectomy at such a young age. Vital signs were stable. The patient was pale and had bruising diffusely over the lower extremities.

All routine laboratory tests, including a complete metabolic panel, were normal except for platelets down to 1000/µl then 0, and leukocytes reaching just over 28 000/µl (Table 1). He was complaining of lower abdominal pain and urinary symptoms.

Table 1.

Patients’s complete blood cell (CBC) results during admission

	Day 1	Day 2	Day 3	Day 4–18	Day 19	Day 20–24	Day 25	Day 26	Day 27
WBC 103/µl	28.1	24.3	16.1	8.1–12.5	8.3	7.4–12.3	5.5	5.5	17.2
HGB (g/dl)	10.9	9.9	10.1	9.9–11.5	6.1	7.5–8.1	7.1	8.3	8.4
HCT (%)	31.6	29.5	29.6	29.5–33.1	18.4	22.9–24.7	22.1	25.0	25.6
PLT 103/µl	1	1	0	0–1	0	0–1	1	96	418

HCT indicates hematocrit; PLT, platelet; WBC, white blood cells.

The patient was admitted to the hospital for treatment of sepsis secondary to acute prostatitis and severe thrombocytopenia. The work has been reported in line with the SCARE 2020 criteria5. Ciprofloxacin was started on admission for antibiotic treatment of acute prostatitis. Intravenous (i.v.) immunoglobulin for the first 5 days along with an i.v. methylprednisolone high dose of 1 g/day for 2 days was given for the critically low platelet count that dropped to 0/µl and the patient was on oral dexamethasone during his admission. The patient did not respond to first-line treatment of ITP, and his platelets remained 0/µl so Rituximab was started on day fourth and the patient received weekly treatment during his hospitalization.

Throughout this time, the patient’s complaints were deep abdominal pain, easy bruising, and oral mucosal bleeding, but the computed tomography (CT) scan of the abdomen demonstrated prostatitis and did not show any active bleeding. His platelet remained 0/µl so 1 unit of platelets was given on day 12th without any response. Mycophenolate mofetil (Cellcept) was started on day 14th and continued for 1 week. Two units of blood were transfused for acute anemia with hemoglobin 6.1 g/dl on day 19th that was subsequently stabilized. An anemia panel, blood culture, and peripheral blood smear did not show any other hematologic disorders except ITP. The patient’s bone marrow biopsy on the previous admission several years ago confirmed ITP. Next, a dose of Romiplostim on day 19th was given along with Aminocaproic acid (Amicar) for his oral mucosal bleeding and hematuria. Due to a shortage of Amicar, after initial administration, this was switched to Tranexamic acid, and the patient-reported mucosal bleeding, and his abdominal pain and hematuria improved.

CellCept and Tranexamic acid were both stopped on the day 22th. Eltrombopag (Promacta) and Tavlesse were started on the day 23th due to the patient stating he had a positive response to these drugs in the past. Platelets rose to 96×10³/µl on day 26th and then 418×10³/µl (Table 1). Finally, after almost 1-month of hospitalization and several treatments, his platelets were stable enough to be discharged.

Discussion

This patient had severe, refractory chronic ITP that did not respond to first-line treatment, remained at 0–1/µl, and required several immunosuppressive and platelet booster medicines during his admission. Most feared symptoms like headache, vision change, focal weakness, or Altered Mental Status needs stat workup with a CT scan of the brain. This patient did not have these symptoms, just he was complaining of abdominal pain, and with a CT scan of the abdomen, we ruled out acute bleeding.

During the entire hospitalization, the patient was on either i.v. or per Oral steroids. He was started first with high-dose methylprednisolone 1 g/daily for 2 days then switched to dexamethasone 40 mg per Oral/daily. Eltrombopag (Promacta) was given for the first 3 days and then resumed during the last couple of hospitalization. Promacta consists of an active substance called eltrombopag, an oral thrombopoietin receptor agonist that stimulates megakaryocytopoiesis6. Mycophenolate mofetil (CellCept) was added during the treatment process, and it inhibits lymphocyte T cell & B cell proliferation, thereby suppressing cell-mediated immune responses and antibody formation7.

Fostamatinib (Tavlesse) was only given for the first 2 days and then resumed again 3 days before the final platelet response, the original dose was increased towards the end of the hospital course. Tavlesse can take up to 8 weeks to show its full effects8.

Rituximab (Rituxan) – an anti-CD20 monoclonal antibody, also takes time to have effects. Romiplostim (Nplate) – a biologic response modifier that helps with platelet production in the treatment of severe ITP, was originally given before admission and again on day 19th along with Aminocaproic acid. This was a challenging, refractory ITP case that required several immunosuppressive and platelet booster medicines.

At first, he did not respond to first-line treatment and required a combination of first-line and second-line treatment. Furthermore, Promacta, Tavlesse, and Romiplostim have a big role to play in helping the patient (Table 2).

Table 2.

Platelet responses to different treatments

Treatment	Platelet response (increased PLT)
Steroid	No response
Intravenous immunoglobulin	No response
Rituximab	No response
CellCept	No response
Romiplostim	Delayed response
Promacta	Responded and platelet count increased
Tavlesse	Responded and platelet count increased
Combination of first-line and second-line treatment	Responded and platelet count increased

PLT indicates platelet.

Conclusion

It is difficult to prove this patient responded to which medicines specifically. Possibly, after suppressing immunity and controlling the inflammation phase with several immunosuppressive medicines, Promacta, Tavlesse, and Romiplostim boosted his platelets. Normally, refractory ITP patients who do not respond to first-line treatments require a combination therapy of 1–2 medicines like thrombopoietin receptor agonists; Promacta/Romiplostin plus immunosuppressive or Tavlesse. Refractory ITP, who has not responded to first-line and second-line treatment, requires treatment with a combination of all first-line and second-line treatments. Furthermore, Promacta, Tavlesse, and Romiplostim have a big role to play in helping the patient.

Ethical approval

This case report has been approved by IRB.

Consent

Informed consent was obtained from the patient for the publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal upon request. This patient signed informed consent for this presentation.

Sources of funding

This study is not supported by any sponsors, and there is no available funding for this study to declare.

Author contributions

A.S.: study design, data analysis, and writing. B.J. and M.H.: data collection and writing. H.P.: study design and data analysis.

Conflicts of interest disclosure

The authors have no competing interests to declare.

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Guarantor

Anahita Shahnazi.

Peer review

This is a noncommissioned paper that has undergone external peer review according to journal policy.

Patient perspective

Finally my patients responded: I’m delighted with my platelet and treatment.