Efficacy of Adjuvant Low Dose Rituximab and Plasma Exchange for Acquired TTP with Severe ADAMTS13 Deficiency — Results of the ART Study

Guidelines on the diagnosis and management of the thrombotic microangiopathic haemolytic anaemias.

Randomized clinical trials in thrombotic thrombocytopenic purpura: where do we go from here?

Is severe deficiency of ADAMTS-13 specific for thrombotic thrombocytopenic purpura? Yes

Recurrent Idiopathic Thrombotic Thrombocytopenic Purpura: A Role for Vaccination in Disease Relapse?

The Novel Use of Daratumumab for Pediatric TTP: A Case Series of Two Pediatric Patients with Refractory TTP

Caplacizumab as a single agent without plasma exchange in relapsed and refractory thrombotic thrombocytopenic purpura: A systematic review.

Thrombotic thrombocytopenic purpura and its diagnosis

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

Efficacy and Safety of Rituximab in Adult Patients with Idiopathic Relapsed or Refractory Thrombotic Thrombocytopenic Purpura (TTP). Results of a Spanish Multicenter Study.

To the editor: You know that wonderful feeling of clueless anticipation you get when you are on your way to a movie that you know nothing about but you know will be good? That is, what I was feeling last saturday on the bus ride to Dozza, a tiny hill town about an hour and a half east of Bologna. My original plan that day was to go to Florence, which I have heard is a decent place. My strictest policy during my time here is to say ''yes'' to every opportunity (within reason), and when my friend Jenny suggested we check out Dozza, I figured I might as well tag along.

Complement activation in thrombotic microangiopathies

Correction of ADAMTS13 Deficiency by In Utero Gene Transfer of Lentiviral Vector encoding ADAMTS13 Genes

Thrombotic thrombocytopenic purpura (TTP) is a rare disease which responds well to plasma exchange treatment in the majority of patients. We report on a patient with acute TTP caused by severe autoantibody-mediated ADAMTS-13 deficiency, in whom remission was not achieved by initial treatment consisting of plasma exchange (PE), plasma infusion and corticosteroids, followed by vincristine and splenectomy. In view of the ongoing activity of TTP, treatment was initiated with rituximab, a chimaeric monoclonal antibody directed against the CD 20 antigen present on B lymphocytes. The patient received 4 weekly infusions of 375 mg/m2, each administered after the daily PE session and withholding PE until 48 hours later. Three weeks after the last infusion of rituximab a complete clinical and laboratory remission of this first episode of acute refractory TTP was documented. A concise review of the literature on the role of rituximab in patients with a first episode of acute plasma-refractory TTP suggests that rituximab in that situation may produce clinical remission in a significant proportion of patients, result in a lowered plasma requirement and avoid the complications of salvage immunosuppressive therapy. The use of rituximab in acute refractory TTP appears to be safe, with no excess infectious complications. We conclude that rituximab should be considered in TTP patients with acquired ADAMTS-13 deficiency who fail to respond clinically after 7-14 days of standard treatment with daily PE and glucocorticoids.

Unraveling the immunologic response in thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is a rare but challenging disease for intensive care specialists. Patients with acute TTP frequently require admission to the intensive care unit because of organ dysfunctions due to the disease or because of the risk of sudden aggravation at the onset of the disease. This review aims at describing recent evolutions in the diagnosis and for the management of TTP for the use of intensive care specialists. The use of A Disintegrin and Metalloprotease with ThromboSpondin type 1 repeats (ADAMTS13) activity along with clinico-biological features to define TTP by most researchers' teams has led to easier interpretation of the literature. The main issues in TTP treatment in 2015 remain the indication and timing of introduction of anti-CD20 antibody rituximab for the treatment of inaugural TTP and the preemptive use of rituximab in asymptomatic patients with decreasing ADAMTS13 activity. The classification of thrombotic microangiopathies has evolved from a clinical to a pathophysiological definition. TTP is characterized by a severe ADAMTS13 deficiency that can be documented in vitro, along with anti-ADAMTS13 antibodies in most adult cases. Plasmapheresis and immunosuppressive therapy with steroids remain the standard of care for acute inaugural TTP. Anti-CD20 monoclonal antibody rituximab is safe and indicated in relapsing and/or refractory TTP. Its indication in inaugural TTP remains to be evaluated but is nevertheless recommended by experts. Novel therapies for TTP are still in preclinical phases.