Background
Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease caused by germline predisposition or acquired autoantibodies. It is characterized by thrombotic microangiopathy (TMA), thrombocytopenia, neurologic symptoms, renal dysfunction, and fever.1 Only a minority of patients present with all of these symptoms, which overlap with other clinical conditions, posing a diagnostic challenge.2 Acquired TTP occurs due to development of inhibitory antibodies against von Willebrand factor (VWF)–cleaving protease ADAMTS13 (a disintegrin and metalloprotease with thrombospondin motif-13), which specifically cleaves multimeric VWF at the Tyr1605-Met1606 peptide bond of the A2 domain.3 Various clinical conditions, such as pregnancy, infections, malignancies, autoimmunity, stem cell transplantation, and certain drugs, can cause TMA.4,5 Drug-induced TMA can be classified into either immune-mediated or non–immune-mediated cytotoxicity, and is commonly seen with the use of antibiotics, chemotherapy, immunosuppressants, narcotics, and cardiac medications.6,7
We report a case of TTP due to the development of antibodies to ADAMTS13 in association with pegylated interferon alfa-2a (pegIFNa) use in a patient with polycythemia vera (PV) that resolved after discontinuation of pegIFNa, and treatment with therapeutic plasma exchange (TPE), corticosteroids, rituximab, and splenectomy.
Case Report
A 47-year-old Ashkenazi Jewish woman was diagnosed with PV 5 years prior to presentation. She had a stroke at age 39 years when her WBC count was 13 x 109/L, hematocrit was 42%, and platelet count was 678 x 109/L. Her protein C, protein S, antithrombin III, factor V Leiden, and antinuclear antibody levels and erythrocyte sedimentation rate were normal at that time. She was on oral contraceptives, which were thought to have contributed to the stroke, and her high blood counts were considered to be reactive. She developed significant fatigue and depression after the stroke, limiting her ability to work. She was referred to our department 3 years after the stroke for a persistently elevated CBC count. Her WBC count was 13.02 x 109/L, RBC count was 5.30 M/mcL, hemoglobin level was 16.7 g/dL, hematocrit was 49%, mean corpuscular volume was 92.4 fL, and platelet count was 866 x 109/L. Her erythropoietin level was 4 mU/mL. She had a positive JAK2V617F mutation, erythropoietin-independent erythroid colonies, and a marrow morphology consistent with PV.8,9
She was treated with hydroxyurea at 1 g/d for a brief period and then started on pegIFNa as part of a randomized clinical trial. She experienced a hematologic remission within a few months of treatment, and her JAK2V617F allelic burden in clonal granulocytes markedly improved from 21% and remained detectable at <1% for a long time. Her hematopoiesis converted from clonality to polyclonality, determined by X chromosome transcriptional quantitative analysis.10 After 48 months of therapy with pegIFNa, she presented to the emergency department with an intense headache and generalized weakness. A head CT did not show any acute intracranial process. Her WBC count was 6.8 x 109/L, hemoglobin level was 5.7 g/dL, and platelet count was 18 x 109/L (previously normal at a clinic visit 6 weeks earlier). Her lactate dehydrogenase (LDH) level was 1,002 U/L (normal, 100–253 U/L), she had elevated reticulocytes at 11.3%, an indirect bilirubin level of 2.1 mg/dL, a creatinine level of 0.9 mg/dL, negative direct antiglobulin test results, a haptoglobin level <10 mg/dL, a D-dimer value of 2.1 mcg/mL, a fibrinogen level of 399 mg/dL, a prothrombin time of 13.1 seconds, a partial thromboplastin time of 34 seconds, and her urine had 2 RBCs per high power field with an increased urobilinogen level of 4 mg/dL. Numerous schistocytes were present on peripheral smear, raising concern for TMA. Her pegIFNa was discontinued and prednisone at 1 mg/kg was started. TPE was initiated with 1 volume of exchange, using fresh frozen plasma as replacement fluid. Her ADAMTS13 activity was <5% with an inhibitor level of 1.5 inhibitor units, confirming the diagnosis of TTP.
She responded well to TPE initially, with her platelet count increasing to 100 x 109/L by the seventh day of hospitalization, then gradually declining with a simultaneous increase of LDH. She was started on rituximab at 375 mg/m2 on day 9 of hospitalization and underwent laparoscopic splenectomy on day 11, after which her platelet count normalized in 4 days (Figure 1). Repeat ADAMTS13 activity level was 6% and her inhibitor level was 0.5 inhibitor units on day 14. She completed 4 doses of weekly rituximab and received a steroid taper for 1 month. Her VWF multimer analysis showed ultralarge multimers in all samples during the acute TTP episode and interestingly preceded her TTP clinical presentation (Figure 2). They subsequently normalized on repeat testing 4 months later.
In a follow-up visit 2 months after onset of TTP, her WBC count and hemoglobin level were normal, but her platelet count was 852 x 109/L and remained elevated on subsequent testing. Repeat JAK2V617F allelic burden on real-time PCR was 0.7%, indicating that the increased platelet count was likely secondary to splenectomy, and we elected to monitor her JAK2V617F allelic burden along with her CBC count to further guide management. Her repeat ADAMTS13 level was >100% and her inhibitor level was undetectable at <0.4 inhibitor units. Similar to previous reports,11 she may have prolonged clinical remission from the pegIFNa she received, and may not need therapy for PV. Her WBC count and hemoglobin level have remained normal, and her platelet count has been mostly around 500 x 109/L on follow-up visits. If her JAK2V617F allelic burden or blood counts increase in the future, we plan to treat her with hydroxyurea or ruxolitinib.
Discussion
PegIFNa is an antiviral agent that also has antitumoral activity and is better tolerated than the conventional interferon (IFNa). It is commonly used in the treatment of viral hepatitis and several malignancies, including myeloproliferative disorders,
Clinical course of patient who developed thrombotic thrombocytic purpura in association with pegylated interferon alfa-2a use. Changes in (A) platelet count and (B) lactate dehydrogenase (LDH) levels are depicted, showing transient response to corticosteroids and therapeutic plasma exchange (TPE) with subsequent refractory disease.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 6; 10.6004/jnccn.2017.0108
Clinical course of patient who developed thrombotic thrombocytic purpura in association with pegylated interferon alfa-2a use. Changes in (A) platelet count and (B) lactate dehydrogenase (LDH) levels are depicted, showing transient response to corticosteroids and therapeutic plasma exchange (TPE) with subsequent refractory disease.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 6; 10.6004/jnccn.2017.0108
Clinical course of patient who developed thrombotic thrombocytic purpura in association with pegylated interferon alfa-2a use. Changes in (A) platelet count and (B) lactate dehydrogenase (LDH) levels are depicted, showing transient response to corticosteroids and therapeutic plasma exchange (TPE) with subsequent refractory disease.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 6; 10.6004/jnccn.2017.0108
The exact mechanism for IFNa-associated TTP is unknown, as autoantibodies were found in some, but not all, reported cases with low ADAMTS13.13,19 IFNa is known to exert complex immunomodulatory effects on endothelial cells, alter the expression of cell surface markers, and increase leukocyte adherence to the vascular endothelium. They may also initiate the development of autoantibodies against ADAMTS13 or endothelial cells, causing endothelial cell damage to release ultralarge VWF multimers that are highly
Multimeric analysis of von Willebrand factor. Note ultra-large multimers throughout the patient's hospitalization. (A) Normal control pooled plasma. (B) At clinic visit 6 weeks before development of thrombotic thrombocytopenic purpura (TTP). (C) At admission with TTP. (D, E) After 5 days of plasma exchange. (F, G) At refractory disease with decreased platelet counts.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 6; 10.6004/jnccn.2017.0108
Multimeric analysis of von Willebrand factor. Note ultra-large multimers throughout the patient's hospitalization. (A) Normal control pooled plasma. (B) At clinic visit 6 weeks before development of thrombotic thrombocytopenic purpura (TTP). (C) At admission with TTP. (D, E) After 5 days of plasma exchange. (F, G) At refractory disease with decreased platelet counts.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 6; 10.6004/jnccn.2017.0108
Multimeric analysis of von Willebrand factor. Note ultra-large multimers throughout the patient's hospitalization. (A) Normal control pooled plasma. (B) At clinic visit 6 weeks before development of thrombotic thrombocytopenic purpura (TTP). (C) At admission with TTP. (D, E) After 5 days of plasma exchange. (F, G) At refractory disease with decreased platelet counts.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 6; 10.6004/jnccn.2017.0108
All of the treatment options and risks and benefits were considered in our patient, and, due to rapidly declining platelet count, splenectomy was performed in addition to rituximab, because it was shown in previous reports to induce rapid response and lower relapse rates.22,24
Conclusions
We suggest considering TTP in the differential diagnosis when there is a precipitous decrease of platelets or evidence of TMA in patients with PV being treated with IFNa. Clinicians should be watchful of this complication and immediately discontinue IFNa in these cases, and promptly initiate necessary treatment to prevent fatal complications. Our patient had elevated blood counts after splenectomy, and her low JAK2V617F allelic burden helped to differentiate postsplenectomy elevation in counts from PV. We are periodically monitoring her JAK2V617F allelic burden along with CBC to help guide management.
References
- 1.↑
Amorosi EL, Ultmann JE. Thrombotic thrombocytopenic purpura: report of 16 cases and review of the literature. Medicine (Baltimore) 1966;45:139–160.
- 2.↑
George JN. How I treat patients with thrombotic thrombocytopenic purpura: 2010. Blood 2010;116:4060–4069.
- 3.↑
Tsai HM, Lian EC. Antibodies to von Willebrand factor–cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med 1998;339:1585–1594.
- 5.↑
Kwaan HC, Gordon LI. Thrombotic microangiopathy in the cancer patient. Acta Haematol 2001;106:52–56.
- 6.↑
Sarode R, Bandarenko N, Brecher ME et al.. Thrombotic thrombocytopenic purpura: 2012 American Society for Apheresis (ASFA) consensus conference on classification, diagnosis, management, and future research. J Clin Apher 2014;29:148–167.
- 7.↑
Reese JA, Bougie DW, Curtis BR et al.. Drug-induced thrombotic microangiopathy: experience of the Oklahoma Registry and the Blood Center of Wisconsin. Am J Hematol 2015;90:406–410.
- 8.↑
Prchal JF, Axelrad AA. Letter: bone-marrow responses in polycythemia vera. N Engl J Med 1974;290:1382.
- 9.↑
Tefferi A, Thiele J, Orazi A et al.. Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel. Blood 2007;110:1092–1097.
- 10.↑
Swierczek SI, Piterkova L, Jelinek J et al.. Methylation of AR locus does not always reflect X chromosome inactivation state. Blood 2012;119:e100–109.
- 11.↑
Kiladjian JJ, Cassinat B, Chevret S et al.. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood 2008;112:3065–3072.
- 12.↑
Zuber J, Martinez F, Droz D et al.. Alpha-interferon-associated thrombotic microangiopathy: a clinicopathologic study of 8 patients and review of the literature. Medicine (Baltimore) 2002;81:321–331.
- 13.↑
Deutsch M, Manesis EK, Hadziyannis E et al.. Thrombotic thrombocytopenic purpura with fatal outcome in a patient with chronic hepatitis C treated with pegylated interferon-a/2b. Scand J Gastroenterol 2007;42:408–409.
- 14.↑
Yagita M, Uemura M, Nakamura T et al.. Development of ADAMTS13 inhibitor in a patient with hepatitis C virus-related liver cirrhosis causes thrombotic thrombocytopenic purpura. J Hepatol 2005;42:420–421.
- 15.↑
Vial T, Descotes J. Immune-mediated side-effects of cytokines in humans. Toxicology 1995;105:31–57.
- 16.↑
Sacchi S, Kantarjian H, O'Brien S et al.. Immune-mediated and unusual complications during interferon alfa therapy in chronic myelogenous leukemia. J Clin Oncol 1995;13:2401–2407.
- 17.↑
Ramos-Casals M, Garcia-Carrasco M, Lopez-Medrano F et al.. Severe autoimmune cytopenias in treatment-naive hepatitis C virus infection: clinical description of 35 cases. Medicine (Baltimore) 2003;82:87–96.
- 18.↑
Shammas F, Meyer P, Heikkila R et al.. Thrombotic microangiopathy in a patient with chronic myelogenous leukemia on hydroxyurea. Acta Haematol 1997;97:184–186.
- 19.↑
Kitano K, Gibo Y, Kamijo A et al.. Thrombotic thrombocytopenic purpura associated with pegylated-interferon alpha-2a by an ADAMTS13 inhibitor in a patient with chronic hepatitis C. Haematologica 2006;91(8 Suppl):ECR34.
- 20.↑
Ravandi-Kashani F, Cortes J, Talpaz M et al.. Thrombotic microangiopathy associated with interferon therapy for patients with chronic myelogenous leukemia: coincidence or true side effect? Cancer 1999;85:2583–2588.
- 21.↑
Moake JL, McPherson PD. Abnormalities of von Willebrand factor multimers in thrombotic thrombocytopenic purpura and the hemolyticuremic syndrome. Am J Med 1989;87:9N–15N.
- 22.↑
Sayani FA, Abrams CS. How I treat refractory thrombotic thrombocytopenic purpura. Blood 2015;125:3860–3867.
- 23.↑
Rialon KL, Speicher PJ, Ceppa EP et al.. Outcomes following splenectomy in patients with myeloid neoplasms. J Surg Oncol 2015;111:389–395.
- 24.↑
Dubois L, Gray DK. Case series: splenectomy: does it still play a role in the management of thrombotic thrombocytopenic purpura? Can J Surg 2010;53:349–355.
