Cyclical Thrombocytopenia— a Rare but Fatal Imitator of Idiopathic Thrombocytopenia

Abstract

Learning Objective 1: Recognize the patterns needed for diagnosing cyclical thrombocytopenia

Learning Objective 2: Distinguish the potentially life threatening features of cyclical thrombocytopenia as compared to idiopathic thrombocytopenia

Case Report: A 42 year old female of Eastern European origin, with a past medical history of systemic lupus erythematosis (SLE), was referred to outpatient hematology for management of her presumed diagnosis of idiopathic thrombocytopenia (ITP). Previous treatments including Aspirin, Eltrombopag, Azathioprine, Prednisone, Rituximab, Intravenous Immunoglobulin (IVIG) and splenectomy had been unsuccessful in raising her platelet count. The patient experienced symptoms of thrombocytopenia which included diffuse petechiae, mucosal petechiae, self-limiting epistaxis and significant menorrhagia which required hysterectomy. Symptoms were intermittent and occurred approximately once a month.

Upon investigating the patient's previous lab work, a cyclic pattern of thrombocytopenia alternating with rebound thrombocytosis was revealed. A nadir of platelet count as low as 1000/mm3 with a peak count of as high as 2,000,000/mm3 was observed occurring approximately every 28 days. Interestingly, a similar pattern was noticed in the white blood cell levels. A correlation was also seen with her reproductive hormone levels, with luteinizing hormone running synchronously and estradiol cycling inversely to the platelet trends. This laboratory pattern, coupled with her lack of response to the aforementioned therapies, allowed us to make a diagnosis of cyclical thrombocytopenia (CT). Although the patient did not always experience symptoms during periods of rebound thrombocytosis, over the years, thrombotic events included lower extremity deep venous thrombosis and a myocardial infarction thought to be a result of peaked platelet levels.

Treatment since the diagnosis of CT was made included Eltrombopag, Romiplostim, and Prednisone with dose adjustment at two-week intervals depending on her most recent platelet levels. Hormone therapy was trialed using Premarin, a conjugated estrogen therapy. Concurrent management of SLE with Belimumab was also held for a period of time. A combination of these interventions decreased the life threatening peaks but failed to inhibit platelet nadirs.

Discussion: Cyclical thrombocytopenia is a rare but potentially life threatening condition. A recent literature review identified only 51 reported cases. Correlation with cyclical leukocytosis is found in a small subset of CT patients making it a more uncommon variant. Diagnosis is challenging and most patients are misdiagnosed with ITP. Differentiating CT from ITP is crucial to prevent life threatening thrombotic events. Differentiating factors include rebound cyclical thrombocytosis alternating with cyclical thrombocytopenia. These cycles typically occur every 28 days. CT patients may have a history of thrombotic events in addition to typical ITP symptoms and may fail to respond to conventional ITP therapies. CT predominantly affects pre-menopausal females, however, post-menopausal females and men may also be affected. The pathophysiology of CT is poorly understood. Multiple theories exist including intermittent autoimmune destruction of platelets, cyclical fluctuations of megakaryocytes, and abnormal biochemical signaling between cytokines and hematopoietic cells. An association with female reproductive hormones and a positive response to hormone therapy has also been documented in the literature. More research is needed to fully understand the pathogenesis of CT. Such an understanding may increase identification of the disease, provide better treatment modalities, and prevent poor outcomes in these patients.

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