Transplant-associated thrombotic microangiopathy: theoretical considerations and a practical approach to an unrefined diagnosis.

Transplant-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of hematopoietic stem cell transplant (HSCT) with high morbidity and mortality. The triad of endothelial cell activation, complement dysregulation, and microvascular hemolytic anemia has the potential to cause end organ dysfunction, multiple organ dysfunction syndrome and death, but clinical features mimic other disorders following HSCT, delaying diagnosis. Recent advances have implicated complement as a major contributor and the therapeutic potential of complement inhibition has been explored. Eculizumab has emerged as an effective therapy and narsoplimab (OMS721) has been granted priority review by the FDA. Large studies performed mostly in pediatric patients suggest that earlier recognition and treatment may lead to improved outcomes. Here we present a clinically focused summary of recently published literature and propose a diagnostic and treatment algorithm.

Iron overload in the HCT patient: a review.

Iron overload (IO) is common in hematologic malignancies and hemoglobinopathies, largely due to red cell transfusion burden. End-organ damage from IO occurs via reactive oxygen species-mediated pathways. The impact of pretransplant IO on hematopoietic cell transplant (HCT) morbidity and mortality remains contentious; studies have shown mixed results, possibly due to variability in study population and design, as well as markers of IO. Ferritin has served as a traditional circulating marker of total body IO, but liver iron content by MRI appears to be a better marker of end-organ involvement. Novel surrogate markers including hepcidin, marrow Prussian blue staining, and labile plasma iron levels may prove to be more specific for HCT complications. Posttransplant phlebotomy, chelation, or both in combination remains the mainstays of treatment, though may ultimately be supplanted by pretransplant or peri-transplant use of bone marrow maturation agents or targeted chelation at time of highest IO risk. This review discusses the pathophysiology of IO in hematologic disease, the evidence supporting and refuting its negative impact on HCT outcomes, as well as current and future therapies.

Positive Value of a Women's Junior Faculty Mentoring Program: A Mentor-Mentee Analysis.

BACKGROUND: Recently appointed women faculty in academic medicine face many challenges during their careers and can become overwhelmed managing their multiple faculty roles as teacher, scholar, and clinician, in addition to their roles in personal life. Although a mentor can be invaluable in assisting a woman junior faculty member to adjust to faculty life and providing critical career guidance, not all medical institutions have faculty mentoring programs. We created a mentoring program specifically for our women junior faculty to address this issue at our own institution. MATERIALS AND METHODS: To assess the value of this program, we conducted a novel mentor-mentee paired-data analysis of annual surveys collected from 2010 to 2015. Of the 470 responses received, 83 were from unique mentees and 61 from unique mentors. RESULTS: Career development, research, and promotion were the top topics discussed among the mentoring pairs, followed by discussions of institutional resources and administration/service. There was high congruency among the mentoring pairs that they thought these discussions, as well as other conversations about mentee professional development and well-being, had been helpful. However in some instances, mentors felt they had not been helpful to their mentee, whereas their mentees felt otherwise; this finding speaks to the value and importance of mentees providing positive feedback to their mentors. Overall, both mentees and mentors thought that the mentees had significantly benefited from the mentorship. Unexpected outcomes of these relationships included promotion, grant applications/awards, articles, presentations, and professional memberships. The use of a Mentee Needs Assessment Form to individualize the mentoring relationship for each mentee may explain the high overall satisfaction and participant recommendations of the program. CONCLUSIONS: Our findings demonstrate the value in establishing mentoring programs specifically for women faculty, especially in environments in which other mentoring opportunities do not exist.

ST-elevation myocardial infarction and myelodysplastic syndrome with acute myeloid leukemia transformation.

Acute myocardial infarction and acute myeloid leukemia are rarely reported as concomitant conditions. The management of ST-elevation myocardial infarction (STEMI) in patients who have acute myeloid leukemia is challenging: the leukemia-related thrombocytopenia, platelet dysfunction, and systemic coagulopathy increase the risk of bleeding, and the administration of thrombolytic agents can be fatal. We report the case of a 76-year-old man who presented emergently with STEMI, myelodysplastic syndrome, and newly recognized acute myeloid leukemia transformation. Standard antiplatelet and anticoagulation therapy were contraindicated by the patient's thrombocytopenia and by his reported ecchymosis and gingival bleeding upon admission. He declined cardiac catheterization, was provided palliative care, and died 2 hours after hospital admission. We searched the English-language medical literature, found 8 relevant reports, and determined that the prognosis for patients with concomitant STEMI and acute myeloid leukemia is clearly worse than that for either individual condition. No guidelines exist to direct the management of STEMI and concomitant acute myeloid leukemia. In 2 reports, dual antiplatelet therapy, anticoagulation, and drug-eluting stent implantation were used without an increased risk of bleeding in the short term, even in the presence of thrombocytopenia. However, we think that a more conservative approach--balloon angioplasty with the provisional use of bare-metal stents--might be safer. Simultaneous chemotherapy for the acute myeloid leukemia is crucial. Older age seems to be a major risk factor: patients too frail for emergent treatment can die within hours or days.

Echocardiography-derived tricuspid regurgitant jet velocity is an important marker for the progression of sickle-cell disease.

BACKGROUND: Although echocardiography-derived tricuspid regurgitant jet velocity (TRV) is associated with increased mortality in sickle-cell disease (SCD), it is unclear whether increased TRV is a marker of multiorgan disease due to systemic vasculopathy or related to increased pulmonary artery systolic pressure with episodes of multiple acute chest syndrome (ACS). METHODS: Our study analyzed 148 consecutive patients with transthoracic echocardiography with TRV data, who came to our adult SCD Clinic at the Wake Forest Baptist Medical Center. For our analysis, we took TRV ≥ 2.5 m/s as elevated. Patients were followed on average for 9 years. RESULTS: TRV ≥ 3 m/s was significantly associated with increased mortality (p < 0.001), thromboembolism (p < 0.001), hospitalization for ACS (p < 0.001), supraventricular arrhythmia (p = 0.028), right ventricular (RV) dilation, decreased hemoglobin and increased creatinine. Patients with a progressive increase in TRV during follow-up had increased mortality (36.7 vs. 8.6%, p = 0.007) and increased ACS (45 vs. 5.7%, p < 0.001). Death was independently associated with TRV ≥ 3 m/s (p = 0.023), ACS (p = 0.001) and increased RV basal diameter (p = 0.003). CONCLUSIONS: TRV is an important global marker for the severity and progression of SCD, and carries a significant prognostic implication.

Successful treatment of intravenously abused oral Opana ER-induced thrombotic microangiopathy without plasma exchange.

In January 2013, the Centers for Disease Control and Prevention reported an illness associated with intravenous (IV) abuse of oral Opana ER (oxymorphone) in Tennessee. The clinical presentation of this syndrome was reported to resemble that of thrombotic thrombocytopenic purpura in the 15 patients reported; 12 were treated with plasma exchange. We report a similar case series of 15 patients with 18 episodes of thrombotic microangiopathy associated with recent IV abuse of oral Opana ER. In our series, we demonstrate that therapeutic plasma exchange is unnecessary; supportive care and treatment of underlying infections and renal dysfunction (without use of plasma exchange) resulted in clinical improvement in all patients. Thus, it appears that plasma exchange with associated costs and risks can be safely omitted in patients with thrombotic microangiopathy resulting from IV abuse of oral Opana ER.

Prolongation of QTc intervals and risk of death among patients with sickle cell disease.

BACKGROUND: Unexplained sudden death is common among patients with sickle cell diseases (SCD). QTc prolongation is a risk factor for fatal arrhythmias among adults. This study sought to identify the predictors for QTc prolongation and determine whether QTc prolongation is associated with increased mortality in patients with SCD. METHODS: We reviewed the electrocardiograms (EKG) and the transthoracic echocardiograms (TTE) of 140 consecutive adults (>18 years) with SCD from October 1996 to January of 2012. QTc prolongation was categorized into three gender-specific categories based on previous publications. Stepwise regression was performed to evaluate QTc interval and mortality as dependent variables. Hemolytic burden as reflected in laboratory evaluation, diastolic, and systolic TTE variables were included in this model. RESULTS: In a stepwise regression analysis, only increased tricuspid regurgitant jet velocity (TRV) (r = 0.483, P = 0.015) had a significant association with QTc interval. Among 49 (35%) patients, the QTc interval was persistently prolonged (PP) (>450 ms in men, >470 ms in women). Twenty-one patients (15%) died over 9 years of follow-up. PP QTc was associated with increased mortality (HR; 8.3 with 95% CI: 2.8-24.6, P < 0.001) compared with normal QTc. In stepwise regression analysis, along with increased TRV (P = 0.005) and acute chest syndrome (P < 0.001), prolonged QTc (P = 0.004) was independently associated with increased mortality. CONCLUSION: Prolonged QTc among the patients with SCD is an independent risk factor for increased mortality.

Mesenchymal stem cells contribute to endogenous FVIII:c production.

Besides the liver, it has been difficult to identify which organ(s) and/or cellular component(s) contribute significantly to the production of human FVIII:c (FVIII). Thus far, only endothelial cells have been shown to constitute a robust extrahepatic source of FVIII, possibly explaining both the diverse presence of FVIII mRNA in the body, and the observed increase in FVIII levels during liver failure. Here, we investigate whether human mesenchymal stem cells (MSC), ubiquitously present in different organs, could also contribute to FVIII production. MSC isolated from human lung, liver, brain, and bone marrow expressed FVIII message as determined by quantitative-RT-PCR. Using an antibody specific for FVIII, confocal microscopy, and umbilical cord-derived endothelial cells (HUVEC) as a negative control, we demonstrated that, in MSC, FVIII protein was not stored in granules; rather, it localized to the perinuclear region. Furthermore, functional FVIII was detected in MSC supernatants and cell lysates by aPTT and chromogenic assays. These results demonstrate that MSC can contribute at low levels to the functional FVIII pool, and advance the understanding of the physiology of FVIII production and secretion.

The therapeutic management of bleeding and thrombotic disorders complicating CNS malignancies.

OPINION STATEMENT: Patients with central nervous system (CNS) malignancies have a substantial risk for developing both thrombotic and bleeding disorders. The risk of venous thromboembolism (VTE) is substantially higher in these patients, both in the perioperative period and throughout their disease course. Patients with CNS malignancy harbor a latent hypercoagulability, which predisposes to VTE, as do postoperative immobility, hemiparesis, and other factors. The management of VTE in these patients is complex, given the significant morbidity and mortality associated with intratumoral hemorrhage. In the past, the perceived risk of intracranial hemorrhage limited the use of anticoagulation for the management of VTE with many favoring nonpharmacologic methods for prophylaxis and treatment. Inferior vena cava (IVC) filters have since lost favor at many centers given significant complications, which appear to be more frequent in patients with CNS malignancy. Recent studies have demonstrated safe and efficacious use of anticoagulation in these patients with a low incidence of intracranial hemorrhage. Treatment of established VTE is now recommended in this population with many centers favoring low-molecular-weight heparin (LMWH) versus oral warfarin for short- or long-term treatment. We advocate a multimodality approach utilizing compression stockings, intermittent compression devices, and heparin in the perioperative setting as the best proven method to reduce the risk of VTE. In the absence of a strict contraindication to systemic anticoagulation, such as previous intracranial hemorrhage or profound thrombocytopenia, we recommend LMWH in patients with newly diagnosed VTE and a CNS malignancy.

Long-term management of acquired thrombotic thrombocytopenic purpura using serial plasma ADAMTS13 measurements.

Although significant advances in the understanding of TTP pathophysiology have been made in the last 15 yr, none have yet impacted the empiric treatment paradigm for this disease for which plasmapheresis is the mainstay. Laboratory assays for ADAMTS13 activity and inhibitors can be used to confirm a clinical diagnosis, but the assays are not routinely used to guide treatment. The routine availability of ADAMTS13 testing has allowed our group to tailor plasmapheresis and immunosuppressive therapy in patients under active treatment for TTP. In addition, the concept of establishing immune tolerance, similar to the eradication of a factor VIII inhibitor in patients with congenital or acquired hemophilia, has emerged as an important strategy to prevent early relapse of TTP. With the expected incorporation of recombinant ADAMTS13 into the treatment algorithm over the next several years, we anticipate that readily available ADAMTS13 testing will play an important role in individualized therapy that incorporates enzyme replacement and establishment of immune tolerance.

Serum ferritin: Past, present and future.

BACKGROUND: Serum ferritin was discovered in the 1930s, and was developed as a clinical test in the 1970s. Many diseases are associated with iron overload or iron deficiency. Serum ferritin is widely used in diagnosing and monitoring these diseases. SCOPE OF REVIEW: In this chapter, we discuss the role of serum ferritin in physiological and pathological processes and its use as a clinical tool. MAJOR CONCLUSIONS: Although many aspects of the fundamental biology of serum ferritin remain surprisingly unclear, a growing number of roles have been attributed to extracellular ferritin, including newly described roles in iron delivery, angiogenesis, inflammation, immunity, signaling and cancer. GENERAL SIGNIFICANCE: Serum ferritin remains a clinically useful tool. Further studies on the biology of this protein may provide new biological insights.

Sickle cell trait and development of microvascular complications in diabetes mellitus.

BACKGROUND AND OBJECTIVES: Many African Americans (AA) have both sickle cell trait (SCT) and diabetes mellitus. The objective of this study was to determine whether individuals with diabetes mellitus and SCT have higher rates of microvascular complications relative to those without SCT. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a retrospective study comparing albuminuria, estimated GFR (eGFR), and microvascular complications in AA with diabetes on the basis of presence of SCT. The study included 821 outpatients who underwent hemoglobin A1c (HbA1c) testing, and presence of SCT was determined using the HbA1c assay. Medical record review and telephone interviews were performed for AA participants. RESULTS: Data were obtained on 376 AA patients (110 with SCT, 245 with neither SCT nor hemoglobin C trait, and 21 with hemoglobin C trait) and 445 European Americans. The mean eGFR and urinary protein excretion were similar between the three AA subgroups. Analysis revealed that 36.3% of AA nontrait and 22.7% of AA SCT participants had retinopathy, peripheral vascular disease, or end-stage kidney disease (P = 0.01). After adjustment for diabetes duration, age, insulin use, and gender, differences in the prevalence of microvascular complications were not observed. CONCLUSIONS: SCT does not increase the risk of microvascular complications in AA with diabetes mellitus.

Curcumin, a cancer chemopreventive and chemotherapeutic agent, is a biologically active iron chelator.

Curcumin is a natural product currently in human clinical trials for a variety of neoplastic, preneoplastic, and inflammatory conditions. We previously observed that, in cultured cells, curcumin exhibits properties of an iron chelator. To test whether the chelator activity of curcumin is sufficient to induce iron deficiency in vivo, mice were placed on diets containing graded concentrations of both iron and curcumin for 26 weeks. Mice receiving the lowest level of dietary iron exhibited borderline iron deficiency, with reductions in spleen and liver iron, but little effect on hemoglobin, hematocrit, transferrin saturation, or plasma iron. Against this backdrop of subclinical iron deficiency, curcumin exerted profound 2 effects on systemic iron, inducing a dose-dependent decline in hematocrit, hemoglobin, serum iron, and transferrin saturation, the appearance of microcytic anisocytotic red blood cells, and decreases in spleen and liver iron content. Curcumin repressed synthesis of hepcidin, a peptide that plays a central role in regulation of systemic iron balance. These results demonstrate that curcumin has the potential to affect systemic iron metabolism, particularly in a setting of subclinical iron deficiency. This may affect the use of curcumin in patients with marginal iron stores or those exhibiting the anemia of cancer and chronic disease.

Ferritin for the clinician.

Ferritin, a major iron storage protein, is essential to iron homeostasis and is involved in a wide range of physiologic and pathologic processes. In clinical medicine, ferritin is predominantly utilized as a serum marker of total body iron stores. In cases of iron deficiency and overload, serum ferritin serves a critical role in both diagnosis and management. Elevated serum and tissue ferritin are linked to coronary artery disease, malignancy, and poor outcomes following stem cell transplantation. Ferritin is directly implicated in less common but potentially devastating human diseases including sideroblastic anemias, neurodegenerative disorders, and hemophagocytic syndrome. Additionally, recent research describes novel functions of ferritin independent of iron storage.

The association between serum copper and anaemia in the adult Second National Health and Nutrition Examination Survey (NHANES II) population.

Though common in older adults, anaemia is unexplained in about one-third of cases. As a rare cause of anaemia and neutropenia, Cu deficiency could account for some cases of unexplained anaemia. We examined the relationship between serum Cu and unexplained anaemia among 11,240 participants in the Second National Health and Nutrition Examination Survey (NHANES II): 638 (5.7% of all adults) were anaemic; 421 (3.7%) were not explained by deficiencies of vitamin B12, folate or Fe, chronic illness or renal disease. Spline regression showed a U-shaped relationship between serum Cu levels and unexplained anaemia, indicating that both high and low serum Cu levels are associated with unexplained anaemia in adults. Chronic inflammation and mild Fe deficiency could account for the association between unexplained anaemia and elevated Cu levels. On the other hand, the finding of hypocupraemia in a subset of adults with unexplained anaemia suggests that Cu deficiency may be a common reversible cause of anaemia in adults.

Rapid quantitative assay of ADAMTS13 activity on an automated coagulation analyzer: clinical applications and comparison with immunoblot method.

Facile assays for ADAMTS13, the metalloprotease that is absent or impaired in thrombotic thrombocytopenic purpura, could allow for timely diagnosis and management of this potentially fatal hematologic disorder; unfortunately, available assays employ methodologies that restrict use to only a few reference laboratories, resulting in reporting delays. Measurement of ADAMTS13 on an automated analyzer could allow widespread accessibility by routine clinical laboratories. We adapted a previously published technique to demonstrate that ADAMTS13 activity could be measured on an Instrumentation Laboratory automated coagulation analyzer after plasma digestion of a commercial source of von Willebrand factor (VWF). Results were obtained using a commercially available immunoturbidimetric assay for residual VWF activity. Samples from 114 patients with suspected thrombotic microangiopathy were analyzed by both standard immunoblot and our new semiautomated method with excellent agreement, particularly at the clinically relevant low levels of ADAMTS13 activity. This new method is semiautomated and offers quantitative results within 2 hr; our modifications allow for widespread applicability on instrumentation already in use by routine clinical laboratories.