Acquired thrombotic thrombocytopenic purpura and atypical hemolytic uremic syndrome successfully treated with eculizumab

Abstract

Acquired idiopathic thrombotic thrombocytopenic purpura is a life-threatening disease with a mortality of up to 90%, if not promptly recognized and treated. We report a 64-year-old woman with this condition who presented with left-sided weakness and seizure-like activity preceded by headache and easy bruising. She did not achieve optimal response to plasma exchange, corticosteroids, rituximab, and vincristine. We initiated treatment with eculizumab, following which she had durable remission that continued for 30 months after discontinuation of the drug. We later found that our patient has homozygous deletion in two closely related genes, complement factor H–related 1 and complement factor H–related 3.

We report an unusual case of thrombotic microangiopathy with ADAMTS13 <5% and an inhibitor that did not respond to conventional treatment for thrombotic thrombocytopenic purpura (TTP), but was treated successfully with eculizumab. The patient later tested positive for a classic mutation in the alternate complement pathway consistent with concurrent atypical hemolytic uremic syndrome.

CASE PRESENTATION

A 64-year-old black woman with diabetes mellitus and hypertension presented with left-sided weakness and seizure-like activity preceded by 2 days of headaches and 2 weeks of easy bruising. On admission, her vital signs and physical exam were unremarkable. Her basic metabolic profile, antinuclear antibody panel, and testing for hepatitis, HIV, and anti-phospholipid antibody were negative. Her hemoglobin was 9.0 g/dL, platelets were 13 K/μL, lactate dehydrogenase was 954 IU/L, haptoglobin was <30 mg/dL, and blood smear showed 4 to 5 schistocytes/high power field. ADAMTS13 activity was <5%, and there was an inhibitor level of 1.1 Bethesda units. Her complement 3 level was 75.3 (normal 90–180 mg/dL), and complement 4 was <10 mg/dL (normal 15–45 mg/dL).

On hospital day 1, she was started on oral prednisone and daily therapeutic plasma exchange. After 6 days of plasma exchange without signs of improvement, the first dose of rituximab 375 mg/m² was given on hospital day 7. During the second week of hospitalization, the patient developed delirium and altered mental status. Magnetic resonance imaging of the brain showed small left frontal and right occipital lobe infarcts. On hospital day 13, vincristine 2 mg intravenous was given, and on hospital day 14 she received a second dose of rituximab. Her renal function was still normal. Due to declining mental status, severe thrombocytopenia, and continued hemolysis, a decision was made on hospital day 17 to stop plasma exchange and administer eculizumab 900 mg. After the second dose of eculizumab on hospital day 24, her platelets improved to 117 K/μL and continued to rise (Figure). Eculizumab 900 mg was given weekly for 4 weeks for a total of 4 doses, after which ADAMTS13 activity was 75% and the inhibitor was undetectable. Eculizumab 1200 mg was then given every 2 weeks, for a total of 4 doses. The last dose of eculizumab was on day 90, at which time her blood work was normal, with ADAMTS13 activity of 73% and a negative inhibitor screen. Eculizumab was stopped after 8 doses at the patient's request, and after approximately 3 years of close follow-up her labs remained normal.

Figure.

Response to eculizumab in a patient with severe acquired idiopathic thrombotic thrombocytopenic purpura refractory to standard treatment. Daily plasma exchange (TPE) and steroids were begun on admission, and vincristine and weekly rituximab infusions were initiated as shown. Lactate dehydrogenase (LDH) was 729 U/L on admission, increasing to 1620 on day 14. Plasma exchange was discontinued, and eculizumab, 900 mg intravenously, was added on day 17. Rapid improvement in mental status and laboratory abnormalities occurred following administration of eculizumab. Her platelet count normalized within 15 days, and her ADAMTS13 activity normalized by day 30.

We sent blood for atypical hemolytic uremic syndrome 12-gene panel testing to Machaon Diagnostics Laboratory 2.5 years after the diagnosis. The testing revealed a large homozygous deletion in complement factor H–related 1 and complement factor H–related 3 genes. Also, the patient had a heterozygous missense variant (c.3019 G>T; V1007L) in exon 19 of complement factor H. She had heterozygous polymorphism (IVS9-78G>A) within an intron in MCP/CD46. Complement factor H autoantibody was not detected.

DISCUSSION

Thrombotic thrombocytopenic purpura is characterized by a congenital or acquired deficiency of the von Willebrand factor cleaving protein ADAMTS13. Anti-ADAMTS13 autoantibodies contribute to the pathogenesis of acquired TTP (1, 2). Idiopathic TTP caused by ADAMTS13 deficiency tends to relapse (3), although rituximab has been reported to decrease the risk of relapse (4). Atypical hemolytic uremic syndrome is caused by alternate complement pathway dysregulation due to mutations in complement factor H, factor I, factor B, or membrane cofactor protein (3). There are reports of patients with atypical hemolytic uremic syndrome having reduced levels of ADAMTS13; however, these patients did not have an ADAMTS13 inhibitor, as was seen in our patient (5). There is a case of congenital ADAMTS13-deficient TTP that was also found to have a heterozygous mutation in the complement factor H gene (6).

Recent studies have described the importance of the complement system in all forms of thrombotic microangiopathies. Excessive alternate complement pathway activity has been reported to occur in a significant number of TTP patients, indicating the presence of concurrent defects in ADAMTS13 and complement regulation (7). Evidence that complement activation might play a role in pathogenesis of TTP suggests a role for complement-inhibiting drugs in this disease. There is one reported case of congenital TTP that was successfully treated with eculizumab in spite of negative atypical hemolytic uremic syndrome genetic testing (8). There is one other case in the literature where a refractory acquired TTP was treated successfully with eculizumab. This patient was also found to have complement factor H gene polymorphism, which could explain the response to the eculizumab (9).

Theorizing that our patient either had concurrent atypical hemolytic uremic syndrome or had TTP with a dysregulated alternate complement pathway, we initiated treatment with the anti–complement 5 monoclonal antibody eculizumab, following which the patient had durable remission that continued for 30 months after discontinuation of the drug. We later found out that our patient had a large homozygous deletion in complement factor H–related 1 and complement factor H–related 3 genes in the alternate complement pathway. This could explain the durable remission that she achieved with eculizumab.

This case, along with the other two reported cases with simultaneous occurrence of severe idiopathic TTP and the presence of alternate complement pathway mutations, argues for a common shared pathogenesis in TTP and atypical hemolytic uremic syndrome disease processes. Identifying the underlying complement genetic defects in severe ADAMTS13-deficient patients may help us to predict the poor response of this subset of TTP patients to plasma exchange and to explore different treatment options.