Caplacizumab treatment for acquired refractory thrombotic thrombocytopenic purpura.

Abstract

Thrombotic Thrombocytopenic Purpura (TTP) is caused by reduced activity of von Willebrand factor (VWF) cleaving protease ADAMTS13 which causes the formation of blood clots in small blood vessels throughout the body.1 TTP presents as a microangiopathic haemolytic anaemia and thrombocytopenia. TTP can also present with renal insufficiency, neurologic symptoms, gastrointestinal symptoms and cardiac symptoms such as chest pain and heart failure. Acquired TTP is a rare condition reported in approximately three cases per one million adults per year.2 Diagnosis of TTP is based on reduced (<10) levels of ADAMTS13 activity taken together with the clinical context. Diagnosis of TTP can be made by clinical judgement as well as PLASMIC score, which is based on seven components, to determine risk of TTP and a score of 6–7 is highly predictive of ADAMTS13 activity of ≤10%, with a sensitivity of approximately 91%.3 Identifying and initiating treatment early is critical as TTP is associated with a 90% mortality rate in 10 days if left untreated.4 Standard of care treatment for TTP consists of rituximab, plasma exchange and steroids. Refractory TTP is described as platelet counts not doubling in four to seven days after initiation of treatment. Caplacizumab, an anti-VWF bivalent variable-domain-only immunoglobulin fragment that inhibits interaction between VWF multimers and platelets, was approved for treatment of refractory TTP recently, in February 2019.5 Caplacizumab is the first targeted therapy that blocks the formation of blood clots,6 and this therapy has been demonstrated to reduce time to resolution of thrombocytopenia in refractory TTP cases. Here we describe the case of a 39-year-old female with a medical history of asthma, depression, hyperlipidemia and discoid lupus who presented with the complaint of one week of weakness and headache. She was found to be severely thrombocytopenic with a platelet count of up to 3 × 109/l, anaemic with a haemoglobin level of 70 g/l and hyperbilirubinaemia; manual review of the peripheral smear showed 2+ schistocytes. Microangiopathic haemolytic anaemia was confirmed by elevated lactate dehydrogenase (LDH), undetectable haptoglobin and a negative direct antiglobulin test. Laboratory results were also notable for acute kidney injury with creatinine 1·2 mg/dl (baseline creatinine 0·8 mg/dl) (Fig 1). There was a high suspicion for TTP given the laboratory findings of thrombotic microangiopathy with significant non-immune haemolytic anaemia. This patient had a PLASMIC score of 6. She was immediately started on urgent plasma exchange. After one week of daily plasma exchange at one plasma volume and prednisone 1 mg/kg, the patient's platelet count did not improve (remained at 3 × 109/l). The patient was then started on four doses of weekly rituximab (375 mg/m2). After the first dose of rituximab, her platelet count did not respond appropriately (platelets 5 × 109/l). The diagnosis of TTP was confirmed eight days later when pretreatment ADAMTS13 activity level showed severe deficiency at <5% and a detectable ADAMTS13 inhibitor was present at 1·4 Bethesda units (normal <0·4) in serum. Her clinical course was complicated by worsening renal function (creatinine increased to 1·47 mg/dl), headaches and neurologic symptoms. She developed worsening headache with weakness in the left arm, and became increasingly encephalopathic and menorrhagic. Because her clinical status worsened and the hrombocytopenia was refractory despite treatment with standard therapies for TTP, treatment with daily caplacizumab was initiated. The first dose of 11 mg intravenous (IV) caplacizumab was administered prior to plasma exchange and then another dose of caplacizumab, 11 mg subcutaneous, was administered post plasma exchange. On subsequent days, she was continued on 11 mg subcutaneous daily caplacizumab. After three days of treatment with caplacizumab, the patient had an appropriate response with an increase in platelets to 38 × 109/l. After a total of five days on caplacizumab, she had a substantial increase in platelets to 115 × 109/l. Creatinine also improved to 1·17 mg/dl and LDH improved to 827 U/l. The patient was ultimately treated with plasma exchange (1·5 × plasma volume) daily for one month and then every third day for two weeks. Daily caplacizumab was continued until 30 days after the last plasma exchange session. She also received four doses of weekly rituximab (375 mg/m2 weekly) and a prolonged steroid taper for 13 weeks. Repeat ADAMST13 inhibitor level was obtained after one week of treatment with caplacizumab, ADAMTS13 inhibitor level was <0·4 and ADAMTS13 activity level was 76% indicating that her TTP had resolved. Caplacizumab interferes with VWF and platelet interactions, thereby preventing the consumption of platelets into microthrombosis and consequently preventing progression of tissue ischaemia.7 The mortality associated with TTP is highest in the acute phase due to microthrombotic complications. Thus, initiating timely and effective therapies is imperative. Plasmapheresis is standard of care treatment and should be initiated immediately once there is concern for TTP. Despite great improvement in outcomes with the use of plasma exchange, the mortality among patients with acquired TTP remains 10–20%.8 In this patient there was an insufficient platelet response as well as new neurologic symptoms consistent with refractory TTP. In refractory TTP patients are at highest risk for end organ complications and escalating effective therapies as rapidly as possible is critical given the increased risk of morbidity and mortality. In the HERCULES phase 3 trial, treatment with caplacizumab in patients with TTP has been shown to normalize platelets with a median time of 2·69 days [95% confidence interval (CI), 1·89–2·83] vs. placebo 2·88 days (95% CI, 2·68–3·56; P = 0·01) and patients who received caplacizumab were 1·55 times as likely to have a normalization of the platelet count as those who received placebo. In addition, treatment with caplacizumab prevented the development of refractory TTP.7 Thus, caplacizumab results in a more rapid resolution of TTP episodes, rapidly improves thrombocytopenia, and prevents increased morbidity and mortality by decreasing the formation of microthrombosis. Possible side effects of caplacizumab including haemorrhage, epistaxis, headaches and cost of the medication may be a possible barrier to hospitals carrying this therapy in their pharmacy. Our case exemplifies the benefit of caplacizumab in refractory TTP when standard therapies did not help. Thus, when refractory TTP is recognized caplacizumab should be initiated to prevent increased risk of mortality. *Primary Author