Treatment Of Thrombotic Thrombocytopenic Purpura Research Articles

100 Years of Thrombotic Thrombocytopenic Purpura: A Story of Death and Life.

One hundred years ago, in 1924, the first description of a patient with a disease, now known as thrombotic thrombocytopenic purpura (TTP) was published by Dr. Eli Moschcowitz. In honor of this report, this article, written by distinguished specialists in TTP, reviews the increase in scientific knowledge on this disease during the last 100 years. It covers the scientific progress from plasma therapy, the first beneficial treatment for TTP, to the elucidation of the pathophysiology, the discovery of ADAMTS13, the development of assays and targeted therapies up to the modern treatment concepts, that improved the outcome of TTP from an incurable disease to a well understood and treatable disorder.

Phase II Study of Danazol with Plasma Exchange and Corticosteroids for the Treatment of Thrombotic Thrombocytopenic Purpura

Background: Ahn and colleagues reported a decrease in plasma exchange (PE)/plasma infusion requirement with danazol in seven cases of thrombotic thrombocytopenic purpura (TTP) (Ahn Blood 2006;108(11):1057a). We reported an increase in platelet count (PLT) within 24 hours with danazol in two of three cases of human immunodeficiency virus-associated TTP resistant to PE (Torri Transfusion 2010;50:86a). In 2009, we initiated a phase II study of danazol with PE and corticosteroids (CS) for the treatment of TTP. This trial was approved by the institutional review board and was registered at ClinicalTrials.gov (ID# NCT00953771). We report the final results. Aims: To determine if danazol reduces number of PE's, time to remission (TR), and length of stay (LOS) when administered with standard therapy for the initial treatment of TTP. Methods: Experimental Group (EG): Patients with TTP (PLT < 100,000/µL and microangiopathy) receive daily PE, prednisone 1 mg/kg, and danazol 600 mg. Following remission (PLT > 150,000/µL for three consecutive days), PE is tapered to every other day for one week then stopped. Then prednisone is tapered weekly over four weeks then stopped. After one week danazol is tapered by 200 mg weekly then stopped. Historical controls (HC): Patients treated for TTP at St. Luke's-Roosevelt Hospital Center with PE with or without CS from 2000 to 2007 (n=20). Relapse definition: PLT < 100,000/µL with microangiopathy > 30 days after remission. Total number of PE's, TR, LOS, and continuous response rates are compared between the 2 groups. Accrual target: 16 patients to detect a 40% decrease in the number of PE's with 80% power and a level of significance of 0.05.The study was terminated in 2018 due to low accrual. Results: Nine patients were enrolled. Mean number of PE's (days) was 14.8 (EG) and 16.1 (HC), mean TR (days) was 11.4 (EG) and 11 (HC), and mean LOS (days) was 27.3 (EG) and 24.9 (HC), p > 0.05. Four patients in HC had a total of 6 relapses at our institution at a median of 28.25 months, range 2.75 to 97 months after the initial event. One patient in EG relapsed 43 months after study enrollment. One patient in EG died from an unrelated cause. None of the additional seven patients in EG have relapsed during a median follow-up of 49 months, range 12 to 125 months. One episode of pulmonary edema and one episode of hypotension occurred in EG, for which treatment was not discontinued. Discussion: Our study shows that danazol does not reduce PE requirement, TR, or LOS during treatment of TTP, but may prevent relapse. This pattern of response is similar to that which has been observed with rituximab. In a phase 2 study of rituximab in conjunction with PE and CS for the treatment of TTP (Scully Blood 2011), in which results were compared with historical controls who did not receive rituximab, median number of PE's (days) and median LOS (days) were 16.5 and 16.5 in the rituximab group versus 18.0 and 20 in the historical control group, p=ns. Ten percent of patients relapsed at a median of 27 months in the rituximab group whereas 57% of patients relapsed at a median of 18 months in the historical control group. Of interest, the cost of rituximab 375 mg/m 2 weekly for 4 weeks as given would have been approximately $ 25,366.50. The cost of danazol in our protocol would have been approximately $ 2196.00. Caplacizumab is a humanized monoclonal antibody fragment that inhibits von Willebrand factor binding to platelet glycoprotein lb-IX-V. In a phase 3 study (Scully N Engl J Med 2019), caplacizumab in conjunction with PE and CS for the treatment of TTP led to reduced PE's, time to normalization of platelet counts, and LOS, but increased relapses in comparison with placebo. In 2020, the International Society on Thrombosis and Haemostasis strongly recommended adding CS to PE for the treatment of TTP and conditionally recommended adding rituximab and caplacizumab to PE and CS (Zheng J Thromb Haemost 2020). Conclusion: Danazol in conjunction with PE and CS may be a low-cost option to prevent relapses of TTP.

Proof-of-Concept in a Murine Model of Treatment of Thrombotic Thrombocytopenic Purpura Using Engineered Red Blood Cells Expressing Fragments of ADAMTS13 on Their Membrane

Thrombotic Thrombocytopenic Purpura (TTP) is due to congenital or acquired deficiency in A Disintegrin and Metalloproteinase with a Thrombospondin Type 1 Motif, Member 13 (ADAMTS13), a metalloproteinase responsible for the cleavage of the pro-coagulant glycoprotein von Willebrand Factor (vWF). Lack of ADAMTS13 activity causes induction of systemic platelet aggregation and microthrombi in small blood vessels by vWF multimers. Current treatment of TTP consists of daily plasma exchange and immune suppression but is costly and associated with high morbidity. A recombinant ADAMTS13 treatment for the congenital form is in advanced clinical trials but alternative treatment methodologies remain needed. We have developed methods to generate genetically engineered cultured red blood cells (cRBCs) from iPSCs which can be used as drug delivery vectors. We hypothesize that generating cRBCs with membrane-bound variants of ADAMTS13 could be a potential method of treatment for TTP. We have inserted at AAVS1, in human erythroid cells, constructs that contain globin-LCR driven MDTCS ADAMTS13 fusion transgenes with or without gain-of function mutations that confer resistance to ADAMTS13 auto-antibodies. We have shown using flow cytometry and a FRET assay that these erythroid cells express these fusion proteins at high levels and that membrane bound ADAMTS13 is enzymatically active. We have also shown that, as expected, the enzymatic activity of erythroid cells carrying the MDTCS fragment of ADAMTS13 with gain-of-function mutations is resistant to inhibition by plasma from TTP patients, while the wildtype version of the same fragment is not. To obtain an in vivo proof-of-concept that such erythroid cells can prevent TTP, we have generated rosa26 knock-ins and transgenic mice expressing the wildtype or gain-of-function variants of MDTCS ADAMTS13 and observed that RBCs from these animals have normal half-lives, and, as shown via FACS and FRET assays, express significant amounts of catalytically active ADAMTS13 on their RBC membranes. ADAMTS13 knock-out mice inoculated with large amounts of recombinant human vWF (rhvWF) have been shown to exhibit typical TTP symptoms including platelet drops, schistocytes formation and cardiac abnormalities providing a useful murine model for TTP. To determine if ADAMTS13 expressing RBCs could be used to prevent TTP symptoms, we transfused ADAMTS13 knock-out mice with either wild-type or ADAMTS13-RBCs up to 24 hours prior to inoculation with rhvWF. Mice transfused with ADAMTS13-RBCs displayed a significant reduction of ADAMTS13 symptoms including drastically reduced platelet drops, lack of schistocytes formation and absent cardiac abnormalities. We conclude that the membrane-bound MDTCS fragment of ADAMTS13 is capable of cleaving the full-length rhvWF in the presence of flow, in vivo. The above data provide a proof-of-concept that RBCs expressing membrane-bound ADAMTS13 fusion proteins can be used as a therapeutic for congenital and acquired TTP. Experiments are in progress to determine in vivo, the TTP antibody resistance of these cells in the presence of anti-ADAMTS13 auto-antibodies from TTP patients.

Immune thrombocytopenic purpura and thrombotic thrombocytopenic purpura — diagnostic difficulties and errors

   Introduction. When establishing a diagnosis of thrombotic thrombocytopenic purpura (TTP) for the first time, other diseases occurring with thrombocytopenia may be misdiagnosed.   Aim: to analyze diagnostic difficulties and errors of TTP.   Materials and methods. In total, 54 patients (44 women and 10 men) aged 18 to 83 years (median 33 years), who were diagnosed TTP from 2019 to 2023, were included in the study. Anamnesis, baseline hemoglobin, platelets, erythrocytes, lactate dehydrogenase and bilirubin serum concentrations, pre-established diagnoses, treatment, and outcomes were analyzed.   Results. Initially TTP was suspected only in 19 (35 %) patients. In 12 out of 54 patients immune thrombocytopenia (ITP) was initially misdiagnosed. Fisher-Evans syndrome was initially suspected in 3 patients. In sporadic cases, myelodysplastic syndrome, systemic lupus erythematosus / antiphospholipid syndrome, autoimmune hemolytic anemia were initially suspected. Among 15 women with associated with pregnancy TTP in 8 (53.3 %), HELLP syndrome was initially misdiagnosed. In total, 12 (22.2 %) of 54 TTP patients died. In 11/12 non-survival patients, TTP treatment was never started, because the doctors were waiting for the ADAMTS13 test results. A case report of Sequential Immune Thrombocytopenia (ITP) and TTP in the same Patient is described.   Conclusion. When thrombocytopenia is combined with hemolysis and in the absence of multiple organ pathology, it is difficult to differentiate ITP and TTP without examining the plasma activity of ADAMTS113. With a combination of ITP and TTP in the same patient, the study of ADAMTS13 plasma activity makes it possible to identify the leading mechanism of thrombocytopenia and choose treatment tactics.

OC 42.5 Hemorrhagic Risk of Caplacizumab in the Treatment of Thrombotic Thrombocytopenic Purpura a Pharmacovigilance Study from 2020–2022 FAERS Database

OC 42.5 Hemorrhagic Risk of Caplacizumab in the Treatment of Thrombotic Thrombocytopenic Purpura a Pharmacovigilance Study from 2020–2022 FAERS Database

Efficacy of Rituximab Combined with Plasma Exchange in the Treatment of Thrombotic Thrombocytopenic Purpura (TTP)

Objective: To analyze the curative effect of rituximab combined with plasma exchange in the treatment of thrombotic thrombocytopenic purpura. Methods: 70 patients with thrombotic thrombocytopenic purpura that were treated in our hospital from January 2022 to January 2023 were selected for this study. They were divided into two groups according the treatment method they were about to receive. The patients in the control group received plasma exchange. The observation group was given rituximab in addition to plasma exchange. Then, the therapeutic effects of the two groups were observed, and the incidence of adverse reactions was compared. Results: The rate of effectiveness of the treatment received in observation group and the control group was 97.14% and 82.86%, respectively. The treatment received in observation group had a better therapeutic effect (P < 0.05). The incidence of adverse reactions in the observation group (22.86%) was lower than that of the control group (5.71%) , with P < 0.05. Conclusion: Rituximab combined with plasma exchange is relatively more effective than plasma exchange alone, with less adverse reaction, making it a viable treatment option.

Retracted: The Efficacy and Safety of Plasma Exchange in the Treatment of Thrombotic Thrombocytopenic Purpura.

[This retracts the article DOI: 10.1155/2022/3519937.].

Solvent/detergent treated pooled human plasma can decrease the recurrence of allergic transfusion reactions in pediatric, adolescent, and young adult patients.

Octaplas is a solvent/detergent (S/D)-treated pooled human plasma indicated for the treatment of thrombotic thrombocytopenic purpura (TTP) as well as multiple coagulation factor deficiency in patients with liver disease or undergoing liver transplantation or cardiac surgery. We aimed at providing pediatric, adolescent, and young adult evidence for the decrease in allergic transfusion reactions (ATRs) with S/D-treated plasma. A single-center retrospective review of patient records was performed from January 2018 through July 2022 for patients who received S/D treated plasma (Octaplas™; Octapharma). A total of 1415 units of S/D-treated plasma were transfused to nine patients at our institution. Patient ages ranged from 13 months to 25 years old. The reason to initiate transfusion with S/D treated plasma in six patients was mild to severe ATR to plasma-containing products and the need for therapeutic plasma exchange (TPE) or plasma transfusions (PTs). TPE or PT was performed for various clinical indications. Average S/D treated plasma volume per TPE or PT ranged from 200 to 1800 mL per event. During the study period, since initiating transfusions with S/D treated plasma, there have been no allergic or other transfusion reactions reported among these patients. We have successfully utilized S/D treated plasma over the last 4.5 years for pediatric, adolescent, and young adult patients who otherwise would have suffered ATR due to necessary TPE or PT. S/D treated plasma is an additional tool that can be utilized by transfusion services, including pediatrics, to safely transfuse their patients.

A safe and effective use of caplacizumab in pregnancy-related acquired thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is not uncommonly seen in pregnancy, either with the first episode or with the exacerbation of known disease. The management of TTP in pregnancy can be challenging if there is refractoriness to the use of therapeutic plasma exchange (TPE) and high-dose corticosteroids. Caplacizumab, a vWF-directed humanized antibody fragment, is approved for the treatment of acquired TTP but there is sparse data on its use in pregnant patients. Antenatal and peripartum haemorrhage is a theoretical concern with the use of the medication in the obstetric population. However, as options for treatment of TTP in the patients who have refractory disease are significantly limited, off-label use of caplacizumab to achieve disease control and prevent maternofetal morbidity and mortality is a reasonable consideration. This article described the successful use of caplacizumab in a pregnant patient with acquired TTP and the associated favourable outcome. The patient suffered an exacerbation following initial TPE and became refractory to both plasma exchange and high-dose corticosteroids. Off-label use of caplacizumab resulted in hematologic recovery and successful delivery of a healthy neonate. This case represents a contribution to the sparse literature on the use of this effective medication in an often-challenging clinical situation.

Neurological complications as the hallmark symptoms of thrombotic thrombocytopenic purpura in sickle cell disease

Thrombotic thrombocytopenic purpura (TTP) is a type of microangiopathy, which is characterized by the formation of small blood clots in the vessels, leading to organ damage and low platelet count. In sickle cell disease (SCD), TTP can occur due to the activation of the coagulation system and damage to the endothelial cells lining the blood vessels. The importance of TTP in SCD lies in its potential to cause severe and life-threatening complications, including stroke, renal and heart failure. Early recognition and treatment of TTP in SCD are crucial to prevent these complications and improve outcomes. In this letter, we highlighted the significance of neurological complications in the diagnosis of TTP in SCD.

Therapeutic modalities in thrombotic thrombocytopenic purpura management among Jehovah’s Witness patients: A review of reported cases

IntroductionDevout members of the Jehovah’s Witness faith flatly refuse transfusions of white blood cells, red blood cells, platelets, and plasma. The latter agent is a mainstay in the treatment of thrombotic thrombocytopenic purpura (TTP). Alternative treatment options for Jehovah’s Witness patients are needed and reviewed herein. MethodsCases of TTP treatment among Jehovah’s Witnesses were obtained from the published literature. Key baseline and clinical data were extracted and summarized. ResultsA total of 13 reports spanning a 23-year period and 15 TTP episodes were identified. Median (IQR) age was 45.5 (29.0–57.5) and 12/13 (93%) patients were female. Neurologic symptoms were present in 7/15 (47%) episodes at presentation. Disease confirmation with ADAMTS13 testing was present in 11/15 (73%) of episodes. Corticosteroids and rituximab were employed in 13/15 (87%) and 12/15 (80%) of cases, respectively, with apheresis-based therapy employed in 9/15 (60%) episodes. For eligible cases, caplacizumab was used in 4/5 (80%) episodes; average time to platelet response was shortest in these cases. Sources of exogenous ADAMTS13 accepted by patients in this series included cryo-poor plasma, FVIII concentrate, and cryoprecipitate. Conclusions: Successful management of TTP within the boundaries of the Jehovah’s Witness faith is possible.

Systemic Lupus Erythematosus Presented by Thrombotic Thrombocytopenic Purpura: A Case Report

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening haematological condition which can be secondary to many disorders. Systemic lupus erythematosus (SLE) can present with thrombotic microangiopathy and the differentiation between them is quite difficult especially in people with no previous history of SLE. Thrombocytopenia and microangiopathic haemolytic anaemia (MAHA) characterized by schistocytes on the peripheral blood smear are the most consistent signs of TTP. Plasma exchange, the main treatment for TTP must be started urgently once the TTP diagnosis is established. We report a case of 20-year-old female with no previous medical problems, who was presented with severe illness and dizziness following tooth extraction and was found to have severe microangiopathic haemolytic anaemia, her platelet count was severely decreased and with subsequent diagnosis as TTP and plasma exchange and steroids were started and fulfilled the European League Against Rheumatism and the American College of Rheumatology 2019 (EULAR/ACR-2019) criteria for SLE. The patient showed satisfactory improvement. This study of case report was made for early diagnosis and immediate treatment of unusual presentation of SLE resulted in a good prognosis.�

Adolescent acquired thrombotic thrombocytopenic purpura: An analysis of the Pediatric Health Information System database

The outcomes and characteristics of acquired thrombotic thrombocytopenic purpura (TTP) in adolescents is poorly understood due to an absence of studies focused on this population. To better understand the life-threatening disorder in this age, we performed an analysis of adolescent patients (ages 10–21) with TTP in the Pediatric Health Information Systems database from 2009 to 2020. The primary outcomes evaluated were in-hospital mortality and rate of TTP relapse. Secondary outcomes included rates of hemorrhagic and thrombotic complications during hospitalizations for TTP. Patients were included if they had a thrombotic microangiopathy diagnostic code, ADAMTS13 lab obtained, and received therapeutic plasmapheresis. Patients that received treatment for other non-TTP microangiopathies were excluded. A total of 99 patients with 123 hospitalizations for TTP treatment were identified. In-patient mortality occurred in 6 % (n = 6) and TTP relapse in 20 % (n = 20) of the cohort. Median time from initial admission to relapse was 33 days (IQR 15, 92). A hemorrhagic complication was identified in 29 % (n = 36) and thrombotic complication in 15 % (n = 19) of the cohort. The presence of underlying comorbidities was not associated with TTP relapse and only a diagnosis of cancer was associated with increased mortality. The rate of mortality and relapse in adolescent TTP is lower than that seen in adult registries. Long term prospective studies are needed to understand the long-term consequences of adolescent onset acquired TTP.

Coagulation Factor VIII Enhances the Cleavage of Von Willebrand Factor By ADAMTS13 In Vivo

Introduction: Coagulation factor VIII (FVIII) and von Willebrand factor (VWF) circulate as a noncovalent complex. This interaction helps increase the half-life of circulating FVIII and modulates FVIII immunogenicity. Our previous studies demonstrate that FVIII accelerates VWF proteolysis by ADAMTS13 in vitro under fluidic shear or under certain pathophysiological conditions. However, the physiological relevance of the FVIII-enhanced VWF proteolysis remains questionable. Here, we sought to determine if addition of recombinant FVIII at various concentrations to mice with or without circulating ADAMTS13 or to patients with hereditary thrombotic thrombocytopenic purpura (TTP) affects plasma VWF multimer distribution and its antigen levels. Methods: Recombinant human B-domain deleted FVIII (rFVIII) was intravenously administered into wild-type (WT),Adamts13+/-(A13+/-) and Adamts13-/- (A13-/-) mice. Blood samples were collected prior to and 24 hours following rFVIII infusion. In addition, FVIII was stably expressed in fviii-/-mice via administration of AAV8-BDDFVIII. Moreover, plasma was collected from patients with hereditary TTP who were treated with plasma derived FVIII concentrates. Plasma VWF multimers and antigen levels were determined by SDS-agarose gel electrophoresis followed by Western blotting and enzyme-linked immunoassay (ELISA), respectively. Paired T and Mann Whitney tests were performed to determine the statistical significance of the difference between two groups. Results: Our results demonstrated that an infusion of rFVIII at a low dose (40 ug/kg) and a high dose (160 ug/kg) into WT mice resulted in a dramatic reduction in plasma VWF multimer sizes (Fig. 1) and VWF antigen levels (not shown). FVIII at high dose but not at low dose could also significantly reduce the sizes of VWF multimers in Adamts13+/- and Adamts13-/- mice (Fig. 1). The enhanced degradation of VWF multimers in Adamts13-/- mice suggests that other VWF-cleaving enzymes may participate in the degradation of VWF-FVIII complex. In either Adamts13+/- or Adamts13-/- mice, administration of rFVIII at both low and high doses didn't result in significant changes in VWF antigen levels (not shown). Furthermore, a simultaneous infusion of both rFVIII and recombinant murine ADAMTS13 (rADAMTS13) into Adamts13-/- mice resulted in similar changes in plasma VWF multimer distribution (Fig. 1) and antigen levels (not shown). Importantly, all mice tolerated well to the high dose of rFVIII infusion without major thrombotic events during weeks of follow-up. The restoration of plasma FVIII to 100-200% of normal levels in the fviii-/- mice with AAV8-mediated gene therapy also led to a profound degradation of plasma VWF multimers and significantly reduced plasma levels of VWF antigen (not shown). Finally, a similar pattern of dramatically reduced plasma VWF multimers was observed in 3 out of 4 patients with hereditary TTP following treatment with plasma-derived FVIII concentrates (not shown). Conclusions: Our results demonstrate that supplementation of FVIII at physiological or super-physiological concentrations dramatically accelerates the degradation of VWF multimers in mice and human. These findings further support our hypothesis that FVIII is a physiological cofactor of ADAMTS13 in regulating VWF homeostasis. Our findings may also offer a scientific explanation how FVIII concentrates or perhaps rFVIII might work for the treatment of hereditary TTP and other arterial thrombosis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The effects of shear stress on the interaction between ADAMTS13 and VWF

<p indent="0mm">Both ADAMTS13 (a disintegrin and metalloprotease with a thrombosspondin type-1 motif, member 13) and VWF (von Willebrand factor) are critical in the regulation of platelet adhesion in hemostasis and thrombosis. Dysregulation of their functions is associated with thrombotic thrombocytopenic purpura (TTP) and von Willebrand disease (VWD). VWF is a multimeric glycoprotein discovered by Erik A. von Willebrand in 1926. It can bind and stabilize coagulation factor VIII. In addition, it can mediate platelet adhesion by binding to the components of the blood vessel wall and the glycoprotein Ib (GPIb) on the platelet membrane. Under physiology, VWF is synthesized as a disulfide-linked dimer in the endoplasmic reticulum and transported into the Golgi apparatus for further processing. In the Golgi, the intra- and inter-VWF disulfide bonds are reorganized so that VWF can polymerize into macro-molecular helices and be packed into Weibel-Palade Bodies in a tubular form. Upon stimulation by blood vessel injury, packed VWF can be rapidly unwound and released into the blood vessels, forming millimeter-long protein fibers. Under the stretch of increased shear force at the injury site, the cryptic platelet binding site on the A1 domain of VWF will be exposed, enabling the recruitment and aggregation of platelets on VWF fibers for hemostasis. However, the accumulation of ultra-long VWF in the blood would lead to the formation of microthrombi, blocking blood vessels and capillaries and causing the failure of multiple organs. To prevent thrombosis, multimeric VWF is cleaved by ADAMTS13 into short fragments to reduce platelet binding and aggregation. As such, the length and distribution of VWF multimers, which ADAMTS13 regulates, are essential for the precise balance between hemostasis and thrombosis. Unlike other proteases, which are secreted in an inactive state and activated proteolytically, ADAMTS13 is secreted in an active form and circulates in the blood as an active enzyme. Its activity is regulated by VWF binding and shear stress. Under resting state, the head and the tail of ADAMTS13 interact with each other to mask the exosites of ADAMTS13 on its DTCS domains. VWF binding induces conformational changes of ADAMTS13 to expose its exosites. On the other hand, shear stress not only causes the conformational changes of VWF to expose its ADAMTS13 cleavage site on the VWF A2 domain, but also regulates the interactions between VWF and ADAMTS13. Studies have shown that, under shear stress, VWF and ADAMTS13 need to be properly aligned so that the VWF A2 domain can be positioned in the vicinity of the ADATS13 M domain for cleavage. In this article, we summarize recent progress in the structural and functional studies of VWF and ADAMTS13. Primarily, we focus on how the conformations and interactions between VWF and ADAMTS13 are regulated under static and shear force conditions. The collected information will be helpful for better understanding the regulation of ADAMTS13 and VWF activities under physiological and pathological conditions. Such understanding could facilitate the screening and development of novel therapeutics in the treatment of TTP and VWD.

The Efficacy and Safety of Plasma Exchange in the Treatment of Thrombotic Thrombocytopenic Purpura.

Background Thrombotic thrombocytopenic purpura (TTP) is a clinically rare thrombotic cardiovascular and microvascular disease. The purpose of this study was to observe the clinical efficacy and safety of plasma exchange in the treatment of TTP. Methods A total of 16 TTP patients who underwent plasma exchange from January 2015 to December 2020 were selected. The clinical data of all patients were collected for retrospective analysis. The effective rate of treatment, the changes of blood cell count before and after treatment, and adverse reactions during treatment were analyzed. Results A total of 50 plasma exchanges were performed in 16 TTP patients. After plasma exchange treatment, there were 4 invalid and 12 improved patients. The total effective rate of plasma exchange in patients with TTP was 75.0%. After treatment, platelet count (PLT) and hemoglobin (Hb) levels were significantly increased in TTP patients. Compared with before treatment, lactate dehydrogenase (LDH), indirect bilirubin (IBIL), total bilirubin (TBIL), and broken red blood cells were significantly reduced. In addition, 3 adverse reactions occurred in 50 plasmapheresis procedures, and the incidence of adverse reactions was 6.0%. Conclusion Plasma exchange therapy has a good therapeutic effect on TTP and can significantly improve abnormal blood cell count in patients with high safety.

Hemophagocytic lymphohistiocytosis: a rare disease unveiling the diagnosis of EBV-related large B cell lymphoma in a patient with HIV

BackgroundHemophagocytic lymphohistiocytosis (HLH) is a rare disease resulting from the overactivation of the immune system due to under regulation of cytotoxic lymphocytes, macrophages and natural killer (NK) cells. HLH is associated with malignancies, infections, autoimmune disorders and rarely AIDS and is rapidly fatal.Case presentationThis case report identified a 53 year old male with acquired immunodeficiency syndrome (AIDS) who presented with neutropenic fever of unknown origin. He had two previous hospitalizations prior to the hospitalization diagnosing HLH. The first led to a diagnosis of drug fevers in the setting of treatment for thrombotic thrombocytopenic purpura and subsequent hospitalization led to empiric treatment of hospital acquired pneumonia after workup for intermittent fevers was negative. He was discharged but readmitted 10 days after for recurrence of neutropenic fevers. During this final hospitalization, he was found to have elevated liver enzymes, ferritin, triglycerides and soluble IL-2 receptor with persistent fevers, new splenomegaly and bicytopenia meeting the 2004 HLH criteria. Bone marrow biopsy confirmed the diagnosis of HLH as well as EBV associated large B-cell lymphoma. The patient improved on treatment with steroids, rituximab, tocilizumab, and chemotherapy but ultimately passed away due to refractory septic shock from multi-drug resistant Klebsiella pneumoniae.ConclusionThis novel case highlights a patient diagnosed with HLH in the setting of several risk factors for the disease, including AIDS, B-cell lymphoma and EBV. Additionally, this case highlights the importance of early consideration of HLH in the setting of neutropenic fever without clear infectious etiology and search for malignancy associated reasons for HLH especially in immunocompromised patients.

Severe Thrombotic Thrombocytopenic Purpura (TTP) with Organ Failure in Critically Ill Patients.

Thrombotic thrombocytopenic purpura (TTP) is a multiorgan disorder. Organ dysfunction occurs as a consequence of widespread microvascular thrombosis, especially in the heart, brain and kidney, causing transient or partial occlusion of vessels, resulting in organ ischemia. Intensive care unit (ICU) admission varies between 40% and 100% of patients with TTP, either because of severe organ failure or in order to initiate emergency plasma exchange (PEx). Severe neurologic manifestations and cardiac involvement have been associated with higher mortality. Acute kidney injury, although usually less severe than that in hemolytic and uremic syndrome, is common during TTP. Initial management in the ICU should always be considered in TTP patients. The current treatment of TTP in the acute phase is based on urgent PEx, combined with corticosteroid therapy, B-cell-targeted immunotherapy, rituximab and inhibition of the interaction between ultra-large Von Willebrand factor multimers and platelets, using caplacizumab, a monoclonal antibody. ICU management permits close monitoring and the rapid introduction of life-sustaining therapies. This review details the epidemiology of TTP in the ICU, organ failures of critically ill patients with TTP, and the initial management of TTP patients in the ICU.

Rituximab related non-infectious lung injury complicating treatment of severe TTP in pregnancy – literature review and case-report

Background: Thrombotic thrombocytopenic purpura (TTP) in pregnancy is a rare but potentially life-threatening condition. Management of severe, refractory TTP during pregnancy is challenging and includes multidisciplinary approach. The prognosis of cases with a variety of hematological and autoimmune diseases, including TTP has changed profoundly after the rituximab therapy was introduced into clinical practice. However, adverse pregnancy outcomes associated with biological agents should be kept in mind and the decision to treat should be weighed by measurement of potential risks vs benefits. Case report: We reported the first documented case of noninfectious lung toxicity in pregnancy related to rituximab use for TTP treatment. 26 y/o patient at 23 weeks gestation initially presented to ED secondary to numbness, headache, and slurred speech with negative brain imaging. Her laboratory findings revealed severe deficiency of platelets, hemoglobin and ADAMT13 activity. She underwent multiple therapeutic interventions including plasmapheresis, intravenous immunoglobulins (IVIG), prednisone, and eventually required more often hospitalizations. Ultimately, the decision was made to proceed with rituximab therapy. After the third infusion of rituximab, she developed non-infectious lung injury without evidence of SARS-CoV-2 or other infections, pulmonary edema, or pulmonary embolism. The maternal condition worsened acutely resulting in significant desaturation that required intubation and eventual emergent premature delivery at 31-weeks’ gestation via C-section. Conclusion: Rituximab therapy for TTP management in pregnancy may be associated with significant adverse maternal-fetal outcomes. Risks and benefits of treatment should be discussed with each patient and during multidisciplinary communications. Physicians should maintain high index of suspicion for non-infectious lung injury associated with rituximab treatment in order to be able to diagnose this complication early and start treatment to avoid severe mortality and morbidity.

TTP: From empiricism for an enigmatic disease to targeted molecular therapies.

The 100th anniversary of the first description of Thrombotic Thrombocytopenic Purpura (TTP) as a disease by Dr. Eli Moschcowitz approaches. For many decades, TTP remained mostly a mysterious fatal condition, where diagnosis was often post‐mortem. Initially a pentad of symptoms was identified, a pattern that later revealed to be fallible. Sporadic observations led to empiric interventions that allowed for the first impactful breakthrough in TTP treatment, almost 70 years after its first description: the introduction of plasma exchange and infusions as treatments. The main body of knowledge within the field was gathered in the latest three decades: patient registries were set and proved crucial for advancements; the general mechanisms of disease have been described; the diagnosis was refined; new treatments and biomarkers with improvements on prognosis and management were introduced. Further changes and improvements are expected in the upcoming decades. In this review, we provide a brief historic overview of TTP, as an illustrative example of the success of translational medicine enabling to rapidly shift from a management largely based on empiricism to targeted therapies and personalized medicine, for the benefit of patients. Current management options and present and future perspectives in this still evolving field are summarized.