Autoimmune Cytopenias

Presentation and Management

A 28-year-old female with a history of immune thrombocytopenia (ITP) was referred to the hematology department of a medical center after moving to the United States from Brazil in July 2018. She reported having been diagnosed with ITP at 11 years of age. Complications that she had experienced from ITP included petechiae, heavy and/or prolonged menses, gastrointestinal bleeding, and epistaxis. Since her diagnosis at age 11, she had been managed on varying doses of prednisone, ranging from 10 mg to 60 mg by mouth once daily, and her disease was relatively stable. While living in Brazil, she had also received 2 prior courses of rituximab and undergone a splenectomy, with no lasting effect. Her previous hematologist in Brazil had attempted to initiate treatment with eltrombopag; due to financial constraints, however, she could not obtain the medication and therefore moved the United States for further care.

Over the next 2 years (2018-2019), she was managed with varying doses of prednisone, eltrombopag, romiplostim, and fostamatinib. These medications had limited efficacy. In November 2019, treatment with avatrombopag was initiated, and the patient's platelet levels stabilized almost immediately. In May 2020, while on avatrombopag, she started to develop persisting headaches. She was seen by neurology specialists for evaluation and subsequently was admitted for a cerebral venous sinus thrombosis (CVST). This patient required a prolonged intubation and thrombectomy. Over the course of 3 weeks, her condition stabilized and she was discharged on therapeutic dose anticoagulation (apixaban at 10 mg by mouth twice daily for 7 days, then apixaban at 5 mg by mouth twice daily indefinitely).

While no definitive etiology was identified for her CVST, it is plausible that therapy with the thrombopoietin (TPO) receptor agonist avatrombopag, coupled with a hypercoagulable state caused by her ITP¹ and use of hormonal contraception, elevated her risk of this event. Notably, she had been using oral contraception for nearly 10 years, and she remained Covid negative throughout the period of her hospitalization. After the patient was discharged, her healthcare providers decided to taper her off avatrombopag and transition her back to alternative therapies for ITP.  

Discussion

The simplified overview of this case highlights a critically important scenario that clinicians may encounter when managing patients with ITP. Patients with chronic ITP are at an increased risk of venous thromboembolism (VTE), due to several factors. A prospective evaluation demonstrated that up to 10% of patients with chronic ITP — especially those with a history of splenectomy — will experience a thromboembolic event.^2-4 An additional risk factor is the use of a TPO receptor agonist (avatrombopag in this case). All of the agents in this drug class carry a warning for increased risk of VTE.⁵

While the etiology of the VTE event in this patient can be debated, patients with chronic ITP who have a thrombotic event will be subject to a short-term course of anticoagulation, and in many cases, long-term management. It is crucial to balance of risk of recurrent VTE with the risk of bleeding from thrombocytopenia (in the context of chronic ITP) for each patient. To date, there are no guidelines with strong recommendations for maintaining platelet levels above a certain value when the patient is receiving anticoagulation therapy.

In clinical practice, anticoagulation therapy is typically held when platelet levels decrease below 50,000/µL. In the setting of ITP, however, a patient’s platelet count may frequently fall below that threshold. Therefore, it is critical to determine, or estimate, the risk of bleeding in these patients. In patients with cancer, the risk of bleeding on anticoagulation is estimated at around 12%, and this risk may be even more elevated in patients with underlying thrombocytopenia.⁶ Selection of anticoagulation therapy requires careful consideration, and in some cases it might be reasonable to choose a drug for which a reversal agent is easily accessible, should a bleed occur (eg, idarucizumab for reversal of anticoagulant effects of dabigatran).

In summary, there is a paucity of data available to inform optimal management of anticoagulation in the setting of chronic ITP. This does present a clinical conundrum and underscores the need for close monitoring to balance the risk of recurrent VTE against bleeding risks in patients with ITP.

References

1. Balitsky AK, Kelton JG, Nazy I, et al. Use of anticoagulation in patients with immune thrombocytopenia. Blood. 2017;130(Suppl 1):2313.
2. Bennett I, Forssen U, Enger C, Nelson J. Risk of thromboembolic events among patients with chronic idiopathic thrombocytopenia purpura (ITP). Abstract 0307. In: Proceedings of the 13th Congress of the European Hematology Association; June 12-15, 2008; Copenhagan, Denmark. Haematologica. 2008;93(suppl 1):125.
3. McMillan R, Durette C. Long-term outcomes in adults with chronic ITP after splenectomy failure. Blood. 2004;104(4):956-960.
4. Vianelli N, Palandri F, Polverelli N, et al. Splenectomy as a curative treatment for immune thrombocytopenia: A retrospective analysis of 233 patients with a minimum follow up of 10 years. Haematologica. 2013;98(6):875-880.
5. Ghanima W, Cooper N, Rodeghiero F, et al. Thrombopoietin receptor agonists: Ten years later. Haematologica. 2019;104(6):1112-1123.
6. Prandoni P, Lensing AW, Piccioli A, et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood. 2002;100(10):3484-3488.