Refractory Thrombocytopenic Purpura Research Articles

The Use of Caplacizumab in COVID-19-Related TTP

Introduction Thrombotic Thrombocytopenic Purpura (TTP) is a rare but feared hematological disorder encountered in the inpatient setting. COVID-19-associated TTP is a lesser understood phenomenon, with slightly different symptomology and clinical course. Prompt identification is essential since TTP is a medical emergency which carries a 90% risk of mortality if untreated. Several aspects of treatment, including the use of agents like caplacizumab as monotherapy and therapy duration, are poorly defined in the literature. In this case report, we discuss one such case of post-COVID TTP and explore the therapeutic challenges that clinicians should be aware of when using caplacizumab. Case A 49-year-old female presented with brief changes in mentation and confusion, as well as an associated headache, sore throat, myalgias, and fever for 10 days. The patient tested positive for the COVID-19 antigen 3 days prior to presentation. The patient was hemodynamically stable on arrival, although tachycardic to 94 beats per minute. Initial labs revealed acute normocytic anemia (Hb 7.4 g/dl from a baseline of 12.1 g/dl) and acute, severe thrombocytopenia (9 K/ul from a baseline of 217 K/ul) with schistocytes present on peripheral blood smear. Elevated lactate dehydrogenase (LDH) and low haptoglobin suggested hemolysis. PT, INR, PTT, d-dimer, fibrinogen, and fibrin degradation product (FDP) did not suggest disseminated intravascular coagulation (DIC). TTP was highly suspected with a PLASMIC score of 7. Therapeutic plasma exchange (TPE) was started emergently on day of admission. Additional treatments that were administered include methylprednisolone (1g daily for 3 days), rituximab (375mg/m2), and caplacizumab (11mg before and after TPE on Day 1, then 11 mg daily thereafter). Caplacizumab was administered daily through Day 4, then stopped because our hospital pharmacy could not procure the drug. Nevertheless, by day 4, platelets had improved to >150 K/ul and LDH to <200 IU/l for 2 consecutive days. From Day 4 to Day 10, TPE was given every other day. However, on day 10 the platelets decreased to 11 K/ul. Both daily TPE and caplacizumab was re-initiated. ADAMTS 13 level was <2% at admission and Day 9, later increased to 54.1% on Day 15. ADAMTS 13 antibody levels were >164 U/ml on the day of admission, 67 U/ml on Day 9, and undetectable on Day 15. The patient was discharged on Day 22 and completed a 30-day course of caplacizumab. Follow-up showed sustained remission at 2.5 months with ADAMSTS13 level of 90.8%, platelet count 130 K/ul and the LDH level of 136 U/l. Discussion Caplacizumab is a bivalent anti-VWF immunoglobulin approved in 2019 for treating acquired TTP in conjunction with TPE and other immunosuppressive therapies. The TITAN trial showed significantly lower 30-day exacerbations in the caplacizumab group compared to the placebo group, but a higher rate of relapse in the caplacizumab group in the following month. Patients in the caplacizumab group received fewer TPE sessions overall. Paradoxically HERCULES trial showed 67% lower recurrence in the caplacizumab group. These results in the HERCULES trial were attributed to caplacizumab treatment lengths that could be expanded based on ADAMTS13 activity <10%. In our case, given the high bleeding risk and lack of cost-effectiveness while inpatient, caplacizumab was discontinued and TPE decreased to alternate day dosing following adequate clinical response. It is difficult to predict whether premature discontinuation of caplacizumab or early weaning of TPE triggered recurrence, since both therapies were discontinued on Day 5. This case demonstrates a clinical conundrum of whether caplacizumab can lead to early discontinuation of TPE with inadequate clearance of ADAMTS13 antibody, leading to early relapses. A review of current literature and our experience suggest that Caplacizumab may be very effective in improving platelet count and reducing relapse rates, especially when decisions to discontinue the drug are based on ADAMTS-13 levels. However, lack of cost-effectiveness is a limiting factor, and high bleeding risks must be considered before deciding to start caplacizumab in patients with refractory or severe TTP.

Successful Treatment with Bortezomib for Refractory Thrombotic Thrombocytopenic Purpura Associated with Systemic Lupus Erythematosus.

Thrombotic thrombocytopenic purpura (TTP) is a life- threatening disease that can be secondary to systemic lupus erythematosus (SLE). The fist- line treatments of TTP are steroid, immunosuppressor and plasm exchange (PE). However, some patients may have a poor response to these treatments. Bortezomib is a selective proteasome inhibitor and widely used to treat patients with multiple myeloma (MM). In recent years, bortezomib has been used to treat patients with refractory TTP. Here we report a patient with refractory TTP associated with SLE and had a successful treatment with bortezomib.

Prognostic value of dynamic cardiac biomarkers in patients with acquired refractory thrombocytopenic purpura: A retrospective study in Chinese population.

IntroductionThrombotic thrombocytopenic purpura (TTP) is becoming a curable disease with the introduction of therapeutic plasma exchange (TPE). However, cardiovascular complications remain essential causes of mortality in patients with refractory TTP, while the association of cardiac biomarkers with the prognosis of TTP warrants further investigation.MethodsPatients admitted to the First Affiliated Hospital of Soochow University for refractory TTP from 2013 through 2020 were included in this retrospective study. Clinical characteristics were collected from electronic health records. Biomarker levels on admission and post TPE were recorded. Logistic regression was adopted to identify risk factors for mortality.ResultsA total of 78 patients with refractory TTP were included in this study. Twenty‐one patients died during hospitalization, with a mortality rate of 26.9%. High‐sensitivity cardiac troponin T (hs‐cTnT), N‐terminal probrain natriuretic peptide (NT‐proBNP), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ratios (AAR) were increased in deceased patients compared with the survival group. Multivariate analysis showed that AAR after TPE was associated with overall mortality (OR: 4.45, 95% CI 1.09–18.19). The areas under the receiver operator characteristic curve (AUC) of AAR, hs‐cTnT, and NT‐proBNP for the association with mortality were 0.814, 0.840, and 0.829, respectively.ConclusionHigher post‐TPE cardiac biomarker levels are associated with increased in‐hospital mortality in patients with refractory TTP.

Cytomegalovirus induced refractory TTP in an immunocompetent individual: a case report

BackgroundThrombotic thrombocytopenic purpura (TTP) is a rare, potentially fatal disease with multisystem involvement. Cytomegalovirus (CMV) infection as a cause of refractory TTP, has been reported only in immunocompromised individuals. We report a case of CMV-induced refractory TTP in an immunocompetent individual.Case presentationA 35-year-old, previously healthy Sri Lankan man, presented with fever for 3 days with gum bleeding and progressive drowsiness. His Glasgow coma scale score was 10/15. He did not have papilloedema or neck stiffness. Laboratory evaluation showed a severe thrombocytopenia with microangiopathic haemolytic anaemia. There was marginal renal impairment and normal coagulation profile. Non-contrast CT scan of brain was normal. A diagnosis of thrombotic thrombocytopenic purpura was made. Despite daily plasma exchanges and high-dose steroids, he failed to achieve the expected therapeutic response, thus demonstrating refractory TTP. On exploring for possible causes of refractoriness to treatment, a clinically significant PCR titre of CMV was detected. Treatment of CMV infection lead to complete recovery of TTP. His disease course was further complicated with spontaneous spinal haemorrhage leading to neurological sequelae.Discussion and conclusionsThis is the first report of CMV induced refractory TTP in an immunocompetent adult. It is also the first report of clinically significant spontaneous spinal haematoma in TTP. These two rare occurrences should be considered when patients with refractory TTP do not improve as expected.

Long term follow up of congenital thrombotic thrombocytopenic purpura (Upshaw-Schulman syndrome) on hemodialysis for 19 years: a case report

BackgroundThrombotic thrombocytopenic purpura (TTP) is frequently associated with renal abnormalities, but there have been few reports about renal abnormalities in patients with hereditary TTP. In particular, little is known about the long-term prognosis of patients with childhood-onset congenital TTP.Case presentationWe report a Japanese patient with congenital TTP (Upshaw–Schulman syndrome) who was followed for 19 years after initiation of hemodialysis when he was 22 years old. At the age of 6 years, the first episode of purpura, thrombocytopenia, and proteinuria occurred without any precipitating cause. He underwent living-related donor kidney transplantation from his mother, but the graft failed after 5 months due to recurrence of TTP. Even after resection of the transplanted kidney and resumption of regular hemodialysis, TTP became refractory to infusion of fresh frozen plasma (FFP). Therefore, splenectomy was performed and his disease remained in remission for 10 years. However, TTP recurred at the age of 39 years. Plasma activity of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type I domain 13) was less than 3%, while ADAMTS13 inhibitor was not detected (< 0.5 Bethesda units/mL). The patient died suddenly after hemodialysis at the age of 41 years. Subsequent genetic analysis of this patient and his parents revealed two different heterozygous mutations of ADAMTS13, including a missense mutation in exon 26 (c.T3650C causing p.I1217T) inherited from his father and a missense mutation in exon 21 (c.G2723A causing p.C908Y) inherited from his mother. The former mutation has not been detected before in Japan, while the latter mutation is common in Japan. A retrospective review showed that serum C3 levels were consistently low while C4 levels were normal during follow-up, and C3 decreased much further during each episode of TTP.ConclusionCongenital TTP was diagnosed from the clinical, biochemical, and genetic findings. Infusion of FFP controlled each thrombotic episode, but the effect was limited and of short duration. Review of the complement profile in this patient suggested that a persistently low serum C3 level might be associated with refractory TTP and a worse renal prognosis.

Dose Adjustment and Use of Alternative Eltrombopag Dosing Regimens for the Treatment of Patients with Chronic Immune (Idiopathic) Thrombocytopenic Purpura (ITP)

Abstract 4657 Introduction:Recently, the therapeutic approach of patients with chronic refractory thrombocytopenic purpura has dramatically improved since the adoption, as second-line treatment, of two new thrombopoietin receptor agonists, Eltrombopag and Romiplostim.Purpose: Reporting the experience of our Center on the efficacy, dosing regimens and safety of the administration of Eltrombopag in refractory ITP patients.Material and Methods: We studied retrospectively 300 patients in our Center with a diagnosis of ITP. One hundred eighty five patients were classified as refractory ITP after multiple cycles of treatment. Fourteen patients with refractory ITP were treated with Eltrombopag during the last two years. We studied dose adjustment, the time to response and duration of response as well adverse events. A partial response (PR) was defined as achieving a platelet count of ≥ 50×103/ml, while a complete response (CR) as achieving a platelet count of ≥ 150 × 103/mL.Results: The patients were six men and eight women with a median age of 68.5 years (39.0 to 84.0 years). These patients had tried and failed numerous previous treatment regimens (2 to 8), including 6 patients who had received the thrombopoietin receptor agonist Romiplostim, 2 patients with splenectomy, as well as 2 patients in PR, who needed a higher platelet count due to concomitant disease. The median time from ITP diagnosis to Eltrombopag administration was 20.5 months (0.3 to 235.9 months) and the initial median platelet count was 34×103/mL. Twelve out of 14 patients (12/14 ) responded (85.71%), 10 CR (71.42%) and 2 PR (14.29%) with a mean platelet count of 294 × 103/mL (an increase of 260.5 x103/mL). The median time to response was 17 days (5–64 days) and the response was durable in 9/ 10 patients (90%). Forty per cent of patients required a dose increase at the Day 22 visit. The starting dose was 25mg once daily of Eltrombopag and administered over 6 cycles. If the patientxs platelet number was >200 x103/mL the treatment was interrupted. The next cycle started when the patient’s platelet count was <20 x103/mL. The dose of Eltrombopag was increased to 75mg daily when a patient’s platelet count remained < 50 x103/mL. The number of patients who had Eltrombopag dose increases to 75mg were 3 (21%), 2(14%) and 2 (14%) in cycles 1, 2 and 3, respectively. One patient (7%) experienced a serious side effect such as thromboembolic disease (right leg deep venous thrombosis and pulmonary embolism).Conclusions: Despite the small number of patients in this study, our results agree with those of similar large studies from other Centers. Since Eltrombopag is an oral therapy and does not require hospitalization, is an easy, effective, alternative therapy, which improves the quality of life of patients with refractory ITP. In most cases dose adjustment and use of alternative Eltrombopag dosing regimens is needed. Disclosures:No relevant conflicts of interest to declare.

Efficiency of curative and prophylactic treatment with rituximab in ADAMTS13-deficient thrombotic thrombocytopenic purpura: a study of 11 cases

AbstractThrombotic thrombocytopenic purpura (TTP) is a life-threatening disease that occurs mainly in young adults. Acquired cases are usually a result of antibodies directed against ADAMTS13 (a disintegrin-like and metalloprotease [reprolysin type] with thrombospondin type 1 motif 13), a protease that cleaves the von Willebrand factor multimers. Prognosis has been improved by plasma therapy, but some acute severe forms are refractory to this treatment and achieving a sustained remission is still a challenge in chronic relapsing forms. We therefore conducted a multicentric open-label prospective trial to test the efficacy of rituximab, an anti–B-cell monoclonal antibody, as a curative and prophylactic treatment in patients with TTP as a result of anti-ADAMTS13 antibodies. Six patients were included during an acute refractory TTP episode. Five patients with severe relapsing TTP and persistent anti-ADAMTS13 antibodies were prophylactically treated during remission. All patients received 4 weekly infusions of rituximab. The target of treatment was to restore a significant ADAMTS13 plasma activity (> 10%). Treatment with rituximab led to clinical remission in all cases of acute refractory TTP. In all patients, anti-ADAMTS13 antibodies disappeared, and a significant (18%-75%) plasma ADAMTS13 activity was detected following treatment. Tolerance of rituximab was good. Rituximab is a promising first-line immunosuppressive treatment in patients with acute refractory and severe relapsing TTP related to anti-ADAMTS13 antibodies.

Immune ablation and stem cell transplantation for severe Evans syndrome and refractory thrombocytopenic purpura.

Immune ablation and stem cell transplantation for severe Evans syndrome and refractory thrombocytopenic purpura

Therapieergebnisse der chronischen Autoimmunthrombozytopenie des Erwachsenen

118 patients suffering from thrombocytopenic purpura (87 women and 31 men, mean age 29 and 32 years, respectively) were retrospectively investigated with respect to therapeutic response (TR), remission rate (RR), and the long-term success rate (LR) of different treatment modalities. Splenectomy gave the most favourable outcome: TR in 92% of the patients and LR in 73%. Using treatment with prednisolo-neTR was achieved in 69% and LR in 16%. Azathioprine led to TR in 52% and LR in 27% of the patients. 104 patients (86%) achieved remission after therapy consisting of steroids, splenectomy, and immunosuppression. However, 17patients (14%) did not respond to these therapeutic modalities. The therapy of these patients with refractory thrombocytopenic purpura is still an unresolved problem.

Slow Infusion of Vincristine in the Treatment of Refractory Thrombocytopenic Purpura

Eight patients with idiopathic thrombocytopenic purpura (ITP), who were refractory to glucocorticoid therapy, were given slow infusions of vincristine (VCR) over a 4- to 6-hour period at weekly intervals for 4 weeks. Three patients showed a return to normal platelet counts maintained for 3 months or longer. A transient recovery was observed in 1 patient and a partial response was observed in 3 patients. All patients tolerated therapy well, without side effects. In conclusion, therapy with slow infusion of VCR can be effective in refractory ITP.

Ectopic pancreatic tissue in the gastric antrum

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Treatment of refractory thrombocytopenic purpura with cyclophosphamine.

Cyclophosphamide, an immunosuppressive agent, was administered as an additional mode of therapy to 30 patients with idiopathic thrombocytopenic purpura (ITP) refractory to conventional management. Of 22 previously tested by splenectomy an excellent response was achieved in 12, who remained in complete hematologic remission for 14-96 months after therapy was discontinued; a fair response in 3, with definite increase in platelets, but not to normal levels; and a poor response in 7 who failed to improve. Of 8 nonsplenectomized patients who failed to respond to steroids or maintain a response after steroids were discontinued, 4 were considered excellent, 1 required continued therapy to remain in remission (good response), 2 were fair, and 1 was poor. Remission was observed in 2-10 weeks in both groups and appeared to be related to duration of disease; presence of disease for less than 1 year was associated with a much better response to treatment (11 of 15) when compared with disorders lasting over 2 years (6 of 15). Cyclophosphamide therapy offers additional means of treating patients with ITP who fail to respond to conventional therapy and may serve as an alternative to splenectomy when surgery is contraindicated.