What is the cause of cyclical thrombocytopenia (thrombocyte deficiency) mutation?

From the Guidelines

Cyclical thrombocytopenia, particularly when associated with small platelet size, should prompt consideration of Wiskott-Aldrich Syndrome (WAS) or X-linked thrombocytopenia (XLT), with diagnosis and management guided by identification of a WAS mutation and assessment of clinical severity. The condition is characterized by periodic fluctuations in platelet counts, often with an underlying genetic mutation affecting platelet production. Key features that distinguish WAS from other forms of thrombocytopenia include the presence of small platelets, eczema, recurrent infections, and autoimmune phenomena 1.

Diagnosis and Management Considerations

• Diagnosis: Should involve a definitive molecular diagnosis by finding a known deleterious WAS mutation and/or abnormal WAS protein expression, which might be helpful for prognosis 1.
• Clinical Features: Include thrombocytopenia with small platelets, eczema, recurrent infections, and autoimmune phenomena. The presence of these features, along with the identification of a WAS mutation, guides the diagnosis and management of the condition.
• Treatment Approaches: May involve thrombopoietin receptor agonists, immunosuppressive therapy, and management of infections and autoimmune complications. The choice of treatment depends on the severity of the clinical manifestations and the presence of specific complications.

Specific Treatment Options

• Thrombopoietin Receptor Agonists: Such as eltrombopag or romiplostim, may be used to manage thrombocytopenia.
• Immunosuppressive Therapy: With corticosteroids or other agents, may be beneficial in managing autoimmune components.
• Infection Management: Prophylaxis against opportunistic infections, such as PCP, is crucial in patients with significant immunodeficiency.

Monitoring and Adjustment

Regular monitoring of platelet counts and clinical status is essential to adjust treatment accordingly and manage potential complications effectively. The condition's cyclic nature and potential for severe infections and autoimmune phenomena necessitate a proactive and adaptive management approach.

From the Research

Cyclical Thrombocytopenia Mutation

• Cyclical thrombocytopenia (CTP) is a rare disease characterized by periodic fluctuation of the platelet count, with an unknown and likely heterogeneous pathogenesis 2.
• The disease is often misdiagnosed as primary immune thrombocytopenia (ITP), with patients receiving ITP-specific therapies that may not be effective in the long term 2.
• CTP can be diagnosed by frequent platelet count monitoring, which reveals a typical pattern of periodic platelet cycling, and an early diagnosis can prevent exposure to potentially harmful therapies 2.
• The bleeding phenotype in CTP is usually mild, consisting of mucocutaneous bleeding at the time of nadir platelet count, although severe bleeding can occur but is rare 2.
• Some patients with CTP may respond to treatments such as cyclosporine A or danazol, but most do not respond to any therapy, and spontaneous remissions can occur even after many years 2.

Pathogenesis and Genetic Factors

• The aetiology of CTP remains uncertain, but it is thought to involve intrinsic oscillatory factors defined by the homeostatic regulation of platelet count, presenting as reciprocal platelet/thrombopoietin oscillations and stable oscillation periodicity 3.
• CTP patients may possess pathogenic factors destabilizing the platelet homeostatic system, creating opportunities for external perturbations to initiate and sustain exaggerated platelet oscillations 3.
• Germline and somatic genetic variants, such as those of MPL, STAT3, or DNMT3A, may play a pathogenic role in thrombocytopenia-related CTP, and the JAK2 V617F or BCR::ABL1 translocation may drive underlying myeloproliferative diseases and contribute to hydroxyurea-induced CTP 3.

Treatment Options

• Romiplostim and eltrombopag are thrombopoietin receptor agonists that have been shown to be effective in treating immune thrombocytopenia (ITP) as a second-line treatment, with romiplostim appearing to have slightly fewer adverse effects and higher costs 4.
• A systematic review and network meta-analysis found that romiplostim and eltrombopag were the best options for platelet response outcome in adult persistent ITP patients, with romiplostim ranking highest for platelet count and having a good balance between short-term efficacy and serious adverse events 5.
• Romiplostim has also been used to treat thrombocytopenia following allogeneic stem cell transplantation, with promising results in a case series, although randomized clinical trials are needed to fully understand its role in this setting 6.