Thrombotic Microangiopathy After Hematopoietic Stem Cell and Solid Organ Transplantation: A Review for Intensive Care Physicians.

Intensive care physicians may assume the primary care of patients with transplant-associated thrombotic microangiopathy (TA-TMA), an uncommon but potentially critical complication of hematopoietic stem cell transplants (HSCTs) and solid organ transplants. TA-TMA can have a dramatic presentation with multiple organ dysfunction syndrome (MODS) associated with high morbidity and mortality. The typical presenting clinical features are hemolytic anemia, thrombocytopenia, refractory hypertension, proteinuria and worsening renal failure. Intestinal involvement, with abdominal pain, nausea and vomiting, gastrointestinal bleeding, and ascites are also common. Cardiopulmonary involvement may develop from various causes including pulmonary arteriolar hypertension, pleural and pericardial effusions, and diffuse alveolar hemorrhage. Due to other often concurrent complications after HSCT, early diagnosis and effective management of TA-TMA may be challenging. Close collaboration between ICU and transplant physicians, along with other relevant specialists, is needed to best manage these patients. There are currently no approved therapies for the treatment of TA-TMA. Plasma exchange and rituximab are not recommended unless circulating factor H (CFH) antibodies or thrombotic thrombocytopenic purpura (TTP; ADAMTS activity < 10%) are diagnosed or highly suspected. The role of the complement pathway activation in the pathophysiology of TA-TMA has led to the successful use of targeted complement inhibitors, such as eculizumab. However, the relatively larger studies using eculizumab have been mostly conducted in the pediatric population with limited data on the adult population. This review is focused on the role of intensive care physicians to emphasize the clinical approach to patients with suspected TA-TMA and to discuss diagnosis and treatment strategies.

Clearance of VWF by hepatic macrophages is critical for the protective effect of ADAMTS13 in sickle cell anemia mice.

ABSTRACT: Although it is caused by a single-nucleotide mutation in the ß-globin gene, sickle cell anemia (SCA) is a systemic disease with complex, incompletely elucidated pathologies. The mononuclear phagocyte system plays critical roles in SCA pathophysiology. However, how heterogeneous populations of hepatic macrophages contribute to SCA remains unclear. Using a combination of single-cell RNA sequencing and spatial transcriptomics via multiplexed error-robust fluorescence in situ hybridization, we identified distinct macrophage populations with diversified origins and biological functions in SCA mouse liver. We previously found that administering the von Willebrand factor (VWF)-cleaving protease ADAMTS13 alleviated vaso-occlusive episode in mice with SCA. Here, we discovered that the ADAMTS13-cleaved VWF was cleared from the circulation by a Clec4f+Marcohigh macrophage subset in a desialylation-dependent manner in the liver. In addition, sickle erythrocytes were phagocytized predominantly by Clec4f+Marcohigh macrophages. Depletion of macrophages not only abolished the protective effect of ADAMTS13 but exacerbated vaso-occlusive episode in mice with SCA. Furthermore, promoting macrophage-mediated VWF clearance reduced vaso-occlusion in SCA mice. Our study demonstrates that hepatic macrophages are important in the pathogenesis of SCA, and efficient clearance of VWF by hepatic macrophages is critical for the protective effect of ADAMTS13 in SCA mice.

Occult recurrent breast cancer masquerading as thrombotic thrombocytopenic purpura.

GATA3 immunohistochemistry stain of the bone marrow biopsy required to diagnose recurrent metastatic breast cancer.

Endothelial VWF is critical for the pathogenesis of vaso-occlusive episode in a mouse model of sickle cell disease.

Vaso-occlusive episode (VOE) is a common and critical complication of sickle cell disease (SCD). Its pathogenesis is incompletely understood. von Willebrand factor (VWF), a multimeric plasma hemostatic protein synthesized and secreted by endothelial cells and platelets, is increased during a VOE. However, whether and how VWF contributes to the pathogenesis of VOE is not fully understood. In this study, we found increased VWF levels during tumor necrosis factor (TNF)-induced VOE in a humanized mouse model of SCD. Deletion of endothelial VWF decreased hemolysis, vascular occlusion, and organ damage caused by TNF-induced VOE in SCD mice. Moreover, administering ADAMTS13, the VWF-cleaving plasma protease, reduced plasma VWF levels, decreased inflammation and vaso-occlusion, and alleviated organ damage during VOE. These data suggest that promoting VWF cleavage via ADAMTS13 may be an effective treatment for reducing hemolysis, inflammation, and vaso-occlusion during VOE.

Recognizing and managing hereditary and acquired thrombotic thrombocytopenic purpura in infants and children.

We describe how infants and children with hereditary and acquired autoimmune thrombotic thrombocytopenic purpura (TTP) initially present and how they can be promptly diagnosed and effectively managed. These are uncommon disorders that are commonly misdiagnosed and can be rapidly fatal. TTP is caused by a severe deficiency of the plasma protease, A disintegrin and Metalloprotease with a ThromboSpondin type 1 motif, member 13 (ADAMTS13). Measurement of ADAMTS13 activity is becoming easily accessible. A common presentation of hereditary TTP is neonatal severe hemolysis and hyperbilirubinemia. However, the median age of diagnosis is not until 5.5 years. Plasma is effective treatment for exacerbations and for prophylaxis. Plasma may be replaced by recombinant ADAMTS13 when it becomes available. Acquired TTP is more frequent in older children, in whom it is more common in girls and is commonly associated with systemic lupus erythematosus. For acquired TTP, plasma exchange and immunosuppression are the current treatment for acute episodes; caplacizumab is now commonly used in adults and may replace plasma exchange.

Maintenance rituximab for relapsing thrombotic thrombocytopenic purpura: a case report.

BACKGROUND: Appropriate management to prevent relapses of acquired, autoimmune thrombotic thrombocytopenic purpura (TTP) is not clear. Rituximab (375 mg/m2 /week × 4) is effective treatment for acute episodes but it is not consistently effective for prevention of relapses. Maintenance rituximab, 375 mg/m2 /3 months for 2 years, is commonly used to prevent progression of follicular lymphoma, but the outcome of maintenance rituximab to prevent TTP relapses has been rarely reported. CASE REPORT: An 8-year-old girl was diagnosed with acquired TTP in 2008; her ADAMTS13 activity was less than 5%, with a functional inhibitor of greater than 8 Bethesda units/mL. She achieved remission with therapeutic plasma exchange, corticosteroids, and rituximab (375 mg/m2 /week × 4). During the following 6 years she had seven additional episodes. Each episode responded to therapeutic plasma exchange, sometimes requiring additional treatments (corticosteroids, rituximab, and cyclophosphamide). However, these treatments, as well as splenectomy and trials of cyclophosphamide and mycophenolate mofetil during clinical remissions, failed to prevent relapses. Her ADAMTS13 activity remained 8% or less throughout all of her remissions. Maintenance rituximab was begun in 2013: 500 mg (313 mg/m2 ) every 2-3 months × 5, then 600 mg (375 mg/m2 ) every 6 months × 2. After 1 year, her ADAMTS13 was 26%; after 2 years, 51%. During the past 3 years since stopping rituximab, she has remained well, with normal ADAMTS13 activity (70%-78%). CONCLUSION: Maintenance rituximab treatment may be effective for prevention of relapses in patients with acquired, autoimmune TTP, even when splenectomy and intensive immunosuppression, including multiple conventional courses of rituximab, fail to prevent subsequent relapses.

Management of antithrombotic therapy in adults with immune thrombocytopenia (ITP): a survey of ITP specialists and general hematologist-oncologists.

While patients with immune thrombocytopenia (ITP) and low platelet counts are at risk for bleeding, they are not protected against arterial and venous thrombotic events. Frequently, hematologists are asked to consult on a patient with ITP requiring an antiplatelet (AP) agent or anticoagulant (AC). No direct evidence exists to guide hematologists in weighing the risk of thrombosis against the risk of bleeding in patients with ITP. Therefore, we performed a survey to determine the preferred management of AP/AC therapy in ITP patients. The survey described hypothetical patient scenarios and asked respondents to recommend a minimum platelet count for initiation of AP/AC therapy. We surveyed both hematologists with an international reputation in treatment of ITP (n = 48) and also general hematologist-oncologists in Oklahoma (n = 97). Response rates were 38/48 (79%) for the ITP specialists and 46/97 (47%) for general hematologist-oncologists. Overall, recommended platelet thresholds for antithrombotic therapy were similar between ITP specialists and general hematologist-oncologists. Although both groups recommended a minimum platelet count of 50 × 109/L for AP and AC therapy in most scenarios, there was great variability in individual practice patterns among respondents. This study highlights the need for studies of patients with ITP who require AP/AC therapy to provide high-quality evidence for establishing optimal management strategies.

Microangiopathic Hemolytic Anemia and Thrombocytopenia in Patients With Cancer.

The unexpected occurrence of thrombotic microangiopathy (TMA), characterized by microangiopathic hemolytic anemia and thrombocytopenia, in a patient with cancer requires urgent diagnosis and appropriate management. TMA is a term used to describe multiple syndromes caused by microvascular thrombosis, including thrombotic thrombocytopenic purpura (TTP), Shiga toxin-mediated hemolytic uremic syndrome, and complement-mediated TMA. In patients with cancer, systemic microvascular metastases and bone marrow involvement can cause microangiopathic hemolytic anemia and thrombocytopenia. This occurs most often in patients with known metastatic cancer, but microangiopathic hemolytic anemia and thrombocytopenia may occur unexpectedly in patients without known metastatic disease or be the presenting features of undiagnosed cancer. TMA may also be caused by commonly used chemotherapy agents, either through dose-dependent toxicity or an acute immune-mediated reaction. These causes of TMA must be distinguished from TTP, which results from a severe deficiency of ADAMTS13 and is the most common cause of TMA among adults without cancer. The importance of this distinction is to avoid inappropriate use of plasma exchange, which is associated with major complications. Plasma exchange is the essential treatment for TTP, but it has no known benefit for patients with cancer-induced or drug-induced TMA. We will describe cancer-induced and drug-induced TMA using the experience of the Oklahoma TTP-Hemolytic Uremic Syndrome Registry and data from a systematic review of all published reports of drug-induced TMA. We will illustrate the principles of evaluation and management of these disorders with patients' stories.

The effect of an intense mentoring program on junior investigators' preparation for a patient-oriented clinical research career.

PROBLEM: There is a recognized need to translate scientific discoveries to patient-oriented clinical research (POCR). Several obstacles interfere with the successful recruitment and retention of physicians for POCR careers. APPROACH: The American Society of Hematology developed a yearlong educational and mentoring experience, the Clinical Research Training Institute (CRTI), for early-career physician-scientists from multiple institutions throughout the United States and Canada pursuing POCR careers. Several academic outcome measures of the 140 participants in the first seven years (2003-2010) of CRTI were evaluated by reviewing former trainee participants' curriculum vitae and survey responses. OUTCOMES: Ethnic, racial, and gender diversity of CRTI trainees was reflective of the proportions represented across U.S. hematology/oncology fellowship programs. Eighty-six percent (109/126) of trainees reported success establishing a POCR study; nearly half (62/126) had primarily research-focused jobs. Former CRTI trainees received at least 262 external grant awards and published 1,035 peer-reviewed manuscripts, 173 chapters, and 115 review articles. NEXT STEPS: Because mentorship is key to developing a successful career, the CRTI program is being modified to enhance longitudinal mentorship by CRTI faculty mentors and mentors at trainees' home institutions, as well as to encourage the establishment of collaborations and the potential for research project success. Efforts to make the CRTI experience available to more phy sicians, include more CRTI graduates as faculty, and increase participation by hematologists from backgrounds under represented in medicine are under way.

Autoimmune hemolytic anemia and thrombocytopenia attributed to an intrauterine contraceptive device.

BACKGROUND: Evans syndrome is a rare condition manifested by combined autoimmune hemolytic anemia (AIHA) and thrombocytopenia or neutropenia. It is often associated with other autoimmune disorders, immunodeficiencies, and non-Hodgkin's lymphoma. CASE REPORT: We describe a patient with Evans syndrome that may have been related to exposure to a polyethylene-based intrauterine contraceptive device (IUD). A 26-year-old white female presented with severe, symptomatic AIHA and subsequently developed severe thrombocytopenia. She had a refractory course resistant to multiple treatments including corticosteroids, intravenous immune globulin, rituximab, splenectomy, cyclophosphamide, cyclosporine, eculizumab, and plasma exchange. It was then noticed that her serum autoantibody agglutinated red blood cells (RBCs) in the presence of polyethylene glycol (PEG) but not in the absence of PEG nor when an alternative agglutination enhancing technique, low-ionic-strength solution, was used. Therefore, her polyethylene-containing IUD, which was a polyethylene frame with a levonorgestrel-releasing device, was removed. Norgestrel-dependent, platelet (PLT)-reactive antibodies were not identified by either flow cytometry or in vivo in a NOD/SCID mouse. Testing for PEG-dependent antibodies was not possible. Remission, with no requirement for RBC or PLT transfusions and return of her hemoglobin and PLT counts to normal, followed removal of the IUD. CONCLUSION: The patient's recovery after removal of the IUD and the PEG dependence of RBC agglutination suggested a possibility that the IUD may have been a contributing factor to the etiology of Evans syndrome in this patient.

Pregnancy outcomes following recovery from acquired thrombotic thrombocytopenic purpura.

UNLABELLED: Pregnancy may precipitate acute episodes of thrombotic thrombocytopenic purpura (TTP), but pregnancy outcomes in women who have recovered from acquired TTP are not well documented. We analyzed pregnancy outcomes following recovery from TTP associated with acquired, severe ADAMTS13 deficiency (ADAMTS13 activity <10%) in women enrolled in the Oklahoma TTP-HUS Registry from 1995 to 2012. We also systematically searched for published reports on outcomes of pregnancies following recovery from TTP associated with acquired, severe ADAMTS13 deficiency. Ten women in the Oklahoma Registry had 16 subsequent pregnancies from 1999 to 2013. Two women had recurrent TTP, which occurred 9 and 29 days postpartum. Five of 16 pregnancies (31%, 95% confidence interval, 11%-59%) in 3 women were complicated by preeclampsia, a frequency greater than US population estimates (2.1%-3.2%). Thirteen (81%) pregnancies resulted in normal children. The literature search identified 382 articles. Only 6 articles reported pregnancies in women who had recovered from TTP associated with acquired, severe ADAMTS13 deficiency, describing 10 pregnancies in 8 women. TTP recurred in 6 pregnancies. CONCLUSIONS: With prospective complete follow-up, recurrent TTP complicating subsequent pregnancies in Oklahoma patients is uncommon, but the occurrence of preeclampsia may be increased. Most pregnancies following recovery from TTP in Oklahoma patients result in normal children.

Management of primary immune thrombocytopenia, 2012: a survey of oklahoma hematologists-oncologists.

BACKGROUND: Management options for patients with primary immune thrombocytopenia (ITP) have increased, and treatment of patients with ITP has changed during the past 10 years. METHODS: To document current practice and to determine how current practice is related to recommendations of 2 recent practice guidelines for ITP, an International Consensus report and an American Society of Hematology (ASH) guideline, the authors surveyed practicing hematologists-oncologists in Oklahoma. Surveys were specific for children or adults. Each survey had 3 questions describing patients with a new diagnosis and patients who had not achieved remission with initial treatment. Questions were adapted from the clinical scenarios of the ASH guideline. RESULTS: Twelve (92%) Oklahoma pediatric hematologists-oncologists responded; 82 (81%) Oklahoma adult hematologists-oncologists responded. For a child with a new diagnosis of ITP, a platelet count of 8000/µL and minor bleeding, 5 (42%) hematologists-oncologists selected observation without drug treatment (recommended by both guidelines). For an adult with a platelet count of 9000/µL who had failed to respond to initial treatment with corticosteroids and IVIg, 32 (39%) selected splenectomy (recommended by the ASH guideline); 30 (37%) selected rituximab and 13 (16%) selected thrombopoietin-receptor agonists (both recommended by the International Consensus report). Hematologists-oncologists who had more years in practice were more likely to select splenectomy (P = 0.047). CONCLUSIONS: In a time of changing management for patients with ITP, these data document reported current management in Oklahoma and provide a basis for serial comparisons across time and for comparisons with other regions and comparison of management with patient outcomes.

Drug-induced thrombocytopenia in children.

BACKGROUND: Acute, immune-mediated thrombocytopenia may be caused by many different approved drugs as well as by other substances including vaccines, complementary and alternative medicines, herbal remedies, nutritional supplements, foods and beverages. All causes are described as drug-induced thrombocytopenia (DITP). Often the cause is not recognized, resulting in recurrent thrombocytopenia and inappropriate treatments. Systematic analysis of children (age less than 18 years) with suspected DITP has not been previously reported. PROCEDURES: (1) We searched 15 databases to identify articles describing children with thrombocytopenia as an adverse effect of drugs and other substances. Articles were reviewed to assign levels of evidence for an association of the suspected substance with thrombocytopenia. (2) Data from the BloodCenter of Wisconsin were reviewed to identify reports of drug-dependent, platelet-reactive antibodies in children with suspected DITP. RESULTS: Of 2,191 articles identified, 242 were selected for review. Seventy-two articles reporting 74 individual patients and nine groups of patients had evaluable data. Eleven individual patients and one group had definite evidence and 40 patients and three groups had probable evidence for an association of the suspected substance with thrombocytopenia. Thirty-two substances had a definite or probable association with thrombocytopenia. During 2008-2012, sera from 91 children with suspected DITP were tested and 21 had drug-dependent, platelet-reactive antibodies involving six substances. CONCLUSIONS: Drugs and other substances must be considered as potential causes of thrombocytopenia. Evidence from published reports and data for drug-dependent, platelet-reactive antibodies can help clinicians evaluate of children with unexpected thrombocytopenia.

Children and adults with thrombotic thrombocytopenic purpura associated with severe, acquired Adamts13 deficiency: comparison of incidence, demographic and clinical features.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) associated with severe, acquired ADAMTS13 deficiency is uncommonly reported in children. The incidence, demographic, and clinical features of these children, compared to adults, have not been described. PROCEDURES: This study focused on children (<18 years old) and adults with TTP associated with severe, acquired ADAMTS13 deficiency, defined as activity <10%. The incidence rates for TTP in children and adults were calculated from patients enrolled in the Oklahoma TTP-HUS (Hemolytic-Uremic syndrome) Registry, 1996-2012. To describe demographic and clinical features, children with TTP were also identified from a systematic review of published reports and from samples sent to a reference laboratory for analysis of ADAMTS13. RESULTS: The standardized annual incidence rate of TTP in children was 0.09 × 10(6) children per year, 3% of the incidence rate among adults (2.88 × 10(6) adults per year). Among the 79 children who were identified (one from the Oklahoma Registry, 55 from published reports, 23 from the reference laboratory), TTP appeared to be more common among females, similar to the relative increased frequency of women among adults with TTP, and more common in older children. Clinical data were available on 52 children; the frequency of severe renal failure, relapse, treatment with rituximab, and systemic lupus erythematosus in these children was similar to adults with TTP. CONCLUSIONS: TTP associated with severe, acquired ADAMTS13 deficiency is uncommon in children. The demographic and clinical features of these children are similar to the features of adults with TTP.

Evaluation of patients with microangiopathic hemolytic anemia and thrombocytopenia.

When a patient presents with unexpected microangiopathic hemolytic anemia and thrombocytopenia, the diagnosis of thrombotic thrombocytopenic purpura (TTP) is often considered. However, many different disorders, including many different systemic infections and malignancies, can cause thrombotic microangiopathy (TMA), with the clinical features of microangiopathic hemolytic anemia and thrombocytopenia. Other etiologies include severe hypertension, preeclampsia, systemic lupus erythematosus, adverse drug reactions, allogeneic hematopoietic stem cell transplantation, and abnormalities of complement regulation. This article focuses on distinguishing TTP from other etiologies of microangiopathic hemolytic anemia and thrombocytopenia, because consideration of the diagnosis of TTP requires an urgent decision for the initiation of plasma exchange treatment. Awareness of the many etiologies of TMA is essential for the appropriate evaluation of patients presenting with microangiopathic hemolytic anemia and thrombocytopenia and the appropriate diagnosis of TTP.