Hemoglobin Alpha Chain Variant Zara Associated With Familial Asymptomatic Hypoxemia.

Numerous hemoglobin (Hb) gene mutations have been identified, leading to a spectrum of phenotypes ranging from asymptomatic carrier states to complicated hemolytic anemias. We report a rare case of asymptomatic hypoxemia in a father and his teenage daughter both of whom were found to be carriers of Hb gene variant Zara. Workup for alternative cardiovascular causes of hypoxemia was unremarkable. Further sequencing of the alpha globin locus showed both individuals to be heterozygous for the Hb Zara c.274C>A (p.Leu92Ile) variant of unknown significance in the alpha2-globin gene. This is the first documented association of this Hb variant with familial asymptomatic hypoxemia, highlighting the importance of evaluating for hemoglobinopathies in patients with reduced oxygen saturation.

Current State of Pediatric Reference Intervals and the Importance of Correctly Describing the Biochemistry of Child Development: A Review.

Importance: Appropriately established pediatric reference intervals are critical to the clinical decision-making process and should reflect the physiologic changes that occur during healthy child development. Reference intervals used in pediatric care today remain highly inconsistent across a broad range of common clinical biomarkers. Observations: This narrative review assesses biomarker-specific pediatric reference intervals and their clinical utility with respect to the underlying biological changes occurring during development. Pediatric reference intervals from PubMed-indexed articles published from January 2015 to April 2021, commercial laboratory websites, study cohorts, and pediatric reference interval books were all examined. Although large numbers of pediatric reference intervals are published for some biomarkers, very few are used by clinical and commercial laboratories. The patterns, extent, and timing of biomarker changes are highly variable, particularly during developmental stages with rapid physiologic changes. However, many pediatric reference intervals do not capture these changes and thus do not accurately reflect the underlying biochemistry of development, resulting in significant inconsistencies between reference intervals. Conclusions and Relevance: There is a need to correctly describe the biochemistry of child development as well as to identify strategies to develop accurate and consistent pediatric reference intervals for improved pediatric care.

Use of therapeutic plasma exchange for pediatric neurological diseases.

Therapeutic plasma exchange is used to treat neurological diseases in the pediatric population. Since its first use in pediatric patients with hepatic coma in the form of manual whole blood exchange, therapeutic plasma exchange has been increasingly used to treat these disorders of the nervous system. This expansion is a result of improved techniques and apheresis instruments suitable for small children, as well as the recognition of its applicability to many diseases in the pediatric population. This review provides a historical overview of the use of therapeutic apheresis in children and highlights the most common applications for therapeutic plasma exchange to treat neurological disorders in children.

Therapeutic plasma exchange and intravenous immune globulin in the treatment of heparin-induced thrombocytopenia: A systematic review.

BACKGROUND: Immunomodulatory strategies in heparin-induced thrombocytopenia (HIT) include the use of intravenous immune globulin (IVIG) and therapeutic plasma exchange (TPE). The optimal application of these therapies is unknown and outcomes data are limited. We investigated treatment categories and laboratory and clinical outcomes of IVIG and/or TPE in HIT with a systematic literature review. STUDY DESIGN AND METHODS: We searched MEDLINE, Embase, and Web of Science through December 2019 for studies combining controlled vocabulary and keywords related to thrombocytopenia, heparin, TPE, and IVIG. The primary outcome was treatment indication. Secondary outcomes were platelet recovery, HIT laboratory parameters, heparin re-exposure, and post-treatment course. Case-level data were analyzed by qualitative synthesis. RESULTS: After 4241 references were screened, we identified 60 studies with four main categories of IVIG and/or TPE use as follows: (a) treatment of refractory HIT (n = 35; 31%); (b) initial therapy (n = 45; 40%); (c) cardiopulmonary bypass surgery (CPB; n = 30; 27%); and (d) other (n = 2; 2%). IVIG was most commonly used for the treatment of refractory HIT while TPE was primarily used to facilitate heparin exposure during CPB. Both IVIG and TPE were equally used as initial therapy. Heparin re-exposure occurred without thrombotic event in 29 TPE-treated patients and three IVIG-treated patients. CONCLUSION: In patients with HIT, both TPE and IVIG are used for initial therapy or treatment of refractory HIT. However, TPE is more commonly used in patients undergoing CPB. Prospective studies may help clarify which treatment is indicated in HIT population subsets.

Therapeutic plasma exchange for neuromyelitis optica spectrum disorder: A multicenter retrospective study by the ASFA neurologic diseases subcommittee.

IMPORTANCE: Neuromyelitis optica/neuromyelitis optica spectrum disorder patients' response to therapeutic plasma exchange (TPE) is currently incompletely characterized. OBJECTIVE: Our study aims to understand the clinical status improvement of neuromyelitis optica/neuromyelitis optica spectrum disorder patients treated with TPE. DESIGN, SETTING, AND PARTICIPANTS: This is a multicenter retrospective study conducted between 1 January 2003 and 31 July 2017 at 13 US hospitals performing apheresis procedures. Subjects studied were diagnosed with neuromyelitis optica/neuromyelitis optica spectrum disorder who received TPE during presentation with acute disease. MAIN OUTCOMES AND MEASURES: The primary outcome was clinical status improvement in patients treated with TPE. Secondary measures were procedural and patient characteristics associated with response to treatment. RESULTS: We evaluated 114 patients from 13 institutions. There was a female predilection. The largest ethnic group affected was non-Hispanic Caucasian. The average age of diagnosis was 43.1 years. The average time to diagnosis was 3.1 years. On average, five procedures were performed during each treatment series. The most commonly performed plasma volume exchange was 1.0 to 1.25 using 5% albumin as replacement fluid. Most patients (52%) did not require an additional course of TPE and noted "mild" to "moderate" clinical status improvement. Maximal symptom improvement appeared by the fourth or fifth TPE treatment. CONCLUSION AND RELEVANCE: TPE improved the clinical status of patients. Adults responded more favorably than children. Procedural characteristics, including number of TPEs, plasma volume exchanged, and replacement fluid used, were similar between institutions. TPE was well-tolerated and had a low severe adverse event profile.

Therapeutic plasma exchange for management of heparin-induced thrombocytopenia: Results of an international practice survey.

INTRODUCTION: Anti-heparin/platelet factor 4 antibody immune complexes resulting from heparin-induced thrombocytopenia (HIT) are removed by therapeutic plasma exchange (TPE). We sought to define TPE in HIT practice patterns using an international survey. METHODS: A 31-item online survey was disseminated through the American Society for Apheresis. After institutional duplicate responses were eliminated, a descriptive analysis was performed. RESULTS: The survey was completed by 94 respondents from 78 institutions in 18 countries. Twenty-nine institutions (37%) used TPE for HIT (YES cohort) and 49 (63%) did not (NO cohort). Most NO respondents (65%) cited "no requests received" as the most common reason for not using TPE. Of the 29 YES respondents, 10 (34%) gave incomplete information and were excluded from the final analysis, leaving 19 responses. Of these, 18 (95%) treated ≤10 HIT patients over a 2-year period. The most common indications were cardiovascular surgery (CS; 63%) and HIT-associated thrombosis (HT; 26%). The typical plasma volume processed was 1.0 (63% CS and 58% HT). For CS, the typical replacement fluid was plasma (42%) and for HT, it was determined on an individual basis (32%). For CS, patients were treated with a set number of TPE procedures (37%) or laboratory/clinical response (37%). For HT, the number of TPE procedures typically depended on laboratory/clinical response (42%). CONCLUSION: In a minority of responding institutions, TPE is most commonly used in HIT to prophylactically treat patients who will undergo heparin re-exposure during CS. Prospective studies are needed to more clearly define the role of TPE in HIT.

Superwarfarin Exposure: An Important Uncommon Cause of Painless Bleeding.

Painless bleeding in a patient presenting from the community with elevated coagulation studies rarely makes the physicians suspect superwarfarin or rodenticide poisoning. Although a significant number of superwarfarin exposure cases are diagnosed every year, we believe there appears to be delay in diagnosis and confusion in determining what is the ideal way to treat and monitor these patients during the management. This is the first thorough literature review of all the reported cases of superwarfarin poisoning which also studied the clinical presentation, management and follow-up patterns. We present a 70-year-old man who presented to the emergency room with epistaxis, melena, cola-colored urine with elevated prothrombin time (PT), activated partial thromboplastin time (aPTT) and international normalized ratio (INR). Mixing studies showed complete correction of coagulopathy indicative of factor deficiency. Additional history revealed that the patient had arguments with family member at home and made us suspect superwarfarin exposure. Qualitative brodifacoum testing was positive and was managed with fresh frozen plasma and high doses of vitamin K1 (phytomenadione) with serial monitoring of INR and clinical symptoms. Superwarfarin poisoning should be considered in the differential diagnosis of a patient who presents with above clinical and laboratory profile especially in the absence of any history of coagulopathy or anticoagulant use. We want to raise public and especially physician awareness that history taking, early diagnosis and managing in right clinical setting play a significant role in survival of these patients.

Hemostasis testing and therapeutic plasma exchange: Results of a practice survey.

INTRODUCTION: Performing therapeutic plasma exchange (TPE) with albumin replacement decreases coagulation factor and platelet levels. No defined guidelines exist regarding laboratory testing to assess hemostasis in patients undergoing TPE. MATERIALS AND METHODS: A survey to evaluate hemostasis testing with TPE was distributed using online survey software. One response per institution was analyzed based on a hierarchical algorithm, excluding membrane filtration users, resulting in a maximum of 120 respondents per question. Descriptive analysis was performed with results reported as the number and/or frequency (%) of respondents to each question. RESULTS: The practices represented vary by institution type, number of apheresis procedures per year, and performance of TPE on children. Prior to TPE planned with albumin replacement, many respondents obtain laboratory studies for almost all patients (54.9% outpatients and 68.7% inpatients); however, some do not routinely obtain laboratory studies (9.7% outpatients and 4.4% inpatients). Hemoglobin/hematocrit, platelet count, fibrinogen, partial thromboplastin time (aPTT), and international normalized ratio (INR) are obtained prior to all TPE by 62.5%, 53.4%, 31.0%, 18.1%, and 17.7% of respondents, respectively; however, 1.0%, 8.7%, 29.0%, 38.3%, and 35.4%, respectively, do not routinely obtain these studies. Variation was observed in laboratory threshold values for action; the most common reported were hemoglobin/hematocrit <7 g/dL or 21% (31.0%), platelet count <50 × 109 /L (24.1%), fibrinogen <100 mg/dL (65.3%), aPTT >reference range and >1.5 times reference range (tied, 28.1%), and INR >1.5 (20.7%). CONCLUSIONS: Practice variation exists in hemostasis laboratory testing and threshold values for action with TPE. Further studies are needed to determine optimal hemostasis testing strategies with TPE.

Hemostasis management and therapeutic plasma exchange: Results of a practice survey.

BACKGROUND: Patients undergoing therapeutic plasma exchange (TPE) may present with risks for hemorrhage or thrombosis. Use of replacement fluids devoid of coagulation factors will decrease factor levels and platelet levels. There are no established guidelines for hemostasis management in these situations. MATERIALS AND METHODS: A survey to evaluate current hemostasis management practice during TPE was conducted using online survey software. One response per institution was analyzed based on a hierarchical algorithm, excluding membrane filtration users, resulting in a maximum of 107 respondents. Descriptive analysis was performed with results reported as the number and frequency (%) of respondents to each question. RESULTS: Apheresis Medicine physicians, alone (59.4%) or jointly with the requesting provider (29.2%), choose the replacement fluid. Based on a theoretical patient case receiving five TPEs approximately every other day, the percent of respondents who would use albumin with or without normal saline was 94.7% with no history of a bleeding or clotting disorder, 1.1% with active bleeding, and 8.8% with hypofibrinogenemia (<100 mg/dL) due to recent TPE. More respondents would use albumin with or without normal saline for replacement fluid when a minor invasive procedure (49.5%) vs a major surgery (8.9%) was performed 1 day before TPE. Replacement fluid selection varied among respondents for several other clinical conditions. The most frequent use for cryoprecipitate by respondents (14.3%) was hypofibrinogenemia. CONCLUSIONS: These survey results demonstrate wide interinstitutional variation in replacement fluid selection to manage hemostasis in patients undergoing TPE. Further studies are needed to guide optimal hemostasis management with TPE.

High-dose intravenous immunoglobulin is strongly associated with hemolytic anemia in patients with Kawasaki disease.

BACKGROUND: Hemolysis is a reported side effect of intravenous immunoglobulin (IVIG) therapy in adults, but pediatric data are scarce. We determined the frequency of IVIG-associated hemolysis in patients with Kawasaki disease (KD) and characterized risk factors for hemolysis. We hypothesized that hemolysis is more common in children with KD than adults with other disorders, and hemolysis risk is related to IVIG dose and degree of inflammation. STUDY DESIGN AND METHODS: This was an 8-year, single-center, retrospective cohort study. A total of 419 KD patients were identified; 123 had pre- and post-treatment complete blood counts allowing for assessment of anemia. Hemolytic anemia was defined as decrease in hemoglobin after IVIG greater than 1 g/dL with immunohematologic or biochemical studies supporting hemolysis. RESULTS: 123 patients were stratified as having hemolysis (n = 18, 15%) or nonhemolysis (n = 105, 85%). Patients with hemolysis were more likely to have complete versus incomplete KD (65% vs. 39%, p = 0.04) and refractory versus nonrefractory course (78% vs. 16%, p < 0.001). Patients receiving 4 g/kg versus 2 g/kg IVIG were more likely to hemolyze (89% vs. 34%, p < 0.001). Patients with hemolysis had mostly non-O blood group (94%), positive direct antiglobulin tests (89%), and positive eluates (72%). Two-thirds of patients with hemolysis required RBC transfusion. CONCLUSIONS: Hemolysis occurred in 15% of KD patients evaluated for anemia and is strongly associated with high-dose (4 g/kg) IVIG. KD patients receiving high-dose IVIG should have close hematologic monitoring to identify hemolysis.

Severe Underestimation of Serum Na following IVIG Treatment.

Current chemistry analyzers measure ion concentration using ion- selective electrodes; however, may differ in the specific technology at the bedside versus the central laboratory. Instruments utilized for point-of-care testing (POCT) at the bedside use direct ion-selective electrodes, whereas central-laboratory analyzers use indirect ion-selective electrodes. Under most circumstances, these instruments will deliver the same result; however, various substances can cause interferences in one or the other. An 18-year-old Hispanic woman with a history of immune thrombocytopenic purpura (ITP) presented at Children's National Medical Center (CNMC) with a severe headache and required intravenous immunoglobulin (IVIG) therapy. Because a discrepancy developed between her point-of-care and central-laboratory sodium values, another instrument was used to retest the central-laboratory plasma specimens. The results were more in agreement with those from the point-of-care instrument and revealed a unique interference in sodium measurement related to IVIG use.

Parental versus non-parental-directed donation: an 11-year experience of infectious disease testing at a pediatric tertiary care blood donor center.

BACKGROUND: Directed donation is associated with a higher prevalence of donations that are positive for infectious disease markers; however, little is known about the positive rates among parental-directed, non-parental-directed, and allogeneic donations. STUDY DESIGN AND METHODS: We reviewed blood-collection records from January 1997 through December 2008, including infectious disease results, among parental, non-parental, and community donations. Infectious disease rates were compared by Mann-Whitney U test. RESULTS: In total, 1532 parental, 4910 non-parental, and 17,423 community donations were examined. Among parental donors, the median rate of positive infectious disease testing was 8.66% (interquartile range (IQR), 4.49%) for first-time donors and 1.26% (IQR, 5.86%) for repeat donors; among non-parental donors, the rate was 1.09% (IQR, 0.98%) for first-time donors and 0% (IQR, 0.83%) for repeat donors; and, among community donors, the rate was 2.95% (IQR, 1.50%) for first-time donors and 0.45% (IQR, 0.82%) for repeat donors. The mean rate of positive infectious disease testing for first-time parental donors was significantly higher (7.63%), whereas all repeat donors had similar rates. However, the rate of positive infectious disease testing among first-time non-parental donors was significantly lower than that in the other groups, especially for the period from 2001 through 2008. CONCLUSION: First-time non-parental and community donors had significantly higher infectious disease risk than the respective repeat donors. First-time parental donors had the highest rates of positive infectious disease testing. We suggest that first-time parental blood donation should be discouraged. Repeat community donors or first-time non-parental donors provide a safer alternative. These findings can foster better patient education, donor selection, and possibly a reduced risk of infectious disease.

Congenital Plasmodium falciparum Malaria in Washington, DC.

Congenital malaria is rare in the United States, but is an important diagnosis to consider when evaluating febrile infants. Herein, we describe a case of congenital Plasmodium falciparum malaria in a 2-week-old infant born in the United States to a mother who had emigrated from Nigeria 3 months before delivery.

Apheresis Medicine education in the United States of America: State of the discipline.

Apheresis Medicine is a medical discipline that involves a variety of procedures (based on the targeted component to be removed or collected), indications (therapeutic vs. donation), and personnel (operators, management, and medical oversight). Apheresis services are accredited and/or regulated by a number of agencies and organizations. Given the complexity and the heterogeneity of apheresis services, it has been particularly challenging to formulate educational goals and define curriculums that easily cover all aspects of Apheresis Medicine. This review summarizes the current state of the discipline in the United States of America, and some of the challenges, strategies, and resources that Apheresis Medicine educators have used to ensure that Apheresis Medicine educational programs meet the health care needs of the relevant population within regulatory and accrediting entity frameworks.

Report of the ASFA apheresis registry on muscle specific kinase antibody positive myasthenia gravis.

BACKGROUND: Anti-muscle specific kinase antibody positive (MuSK Ab) myasthenia gravis (MG) patients are known to have different clinical course compared to anti-acetylcholine receptor Ab positive MG patients. Therapeutic plasma exchange (TPE) has been reported to be effective; however, little is known of the response and of TPE procedural information. An ASFA Apheresis Registry was developed to analyze those data. METHODS: The study collected detailed de-identified patient data, TPE procedures, and treatment outcome/complications. Collected data was described in aggregate. RESULTS: A total of 15 MuSK Ab MG patients with exacerbation of MG symptoms, 13 females/2 males, median age 44, were investigated. Thirty TPE courses (median 5 procedures/course, total 145 procedures) were evaluated. All TPE procedures were performed with citrate anticoagulation, 1 - 1.25 plasma volume exchange in 100% fluid balance, and 90% of courses used only albumin as replacement. Calcium was added to albumin or given orally as needed. TPE was performed every other day in 55% of courses. Adverse events occurred in 3.4% of procedures. Ten patients (67%) experienced relapses within a median of 7 weeks. Objective symptoms were resolved in more than 75% of courses. Overall subjective improvement rates were 94.1%/93.3% after 3/4 TPE procedures, respectively. Thirty-one percent of patients responded poorly with minimal recovery. CONCLUSION: Overall subjective improvement was seen up to 94% of patients after one course of TPE. Some patients were poor-responders. Five TPE may be adequate for initial course with additional TPE as needed. Based upon this preliminary data, we will modify our future data collection. J. Clin. Apheresis 32:5-11, 2017. © 2016 Wiley Periodicals, Inc.

Thromboelastography in term neonates: an alternative approach to evaluating coagulopathy.

OBJECTIVE: To develop normative ranges for citrate-modified and heparinase-modified thromboelastography (TEG) in term neonates. DESIGN: Prospective observational study. SETTING: An outborn neonatal and cardiac intensive care unit in a free-standing academic children's hospital. PATIENTS: Thirty term neonates were enrolled as control subjects. Seventeen infants with clinically documented bleeding requiring blood transfusion were enrolled in the comparison group. MAIN OUTCOME MEASURES: Citrate-modified and heparinase-modified TEG parameters were calculated from blood specimens drawn via peripheral arterial stick or arterial line. RESULTS: TEG in neonates differs from older children and adults; clotting time (R) and clot kinetics (K) values are generally lower while fibrinolysis or rate of clot breakdown (LY30) and coagulation index (CI) are often higher in neonates. TEG values in term neonates calculated as median (Q1-Q3) are as follows: R 4.150 (3.200-6.200), K 1.550 (1.200-1.800), α angle (α) 70.100 (66.000-72.900), maximum amplitude (MA) 61.850 (59.400-66.000), LY30 1.050 (0.100-1.600) and CI 1.950 (0.100 to 2.900). Cut points selected for optimal predictive value for bleeding using receiver operating curve analyses were R>6.3 (sensitivity 82.4%, specificity 80%); K>2.5 (sensitivity 82.4%, specificity 96.7%); α<59 (sensitivity 82.4%, specificity 96.7%); MA<57 (sensitivity 82.4%, specificity 86.7%); CI<-0.15 (sensitivity 88.2%, specificity 83.3%). CONCLUSIONS: The reference ranges and cut points for citrate-modified and heparinase-modified TEG can be used to diagnose and evaluate coagulopathy in term neonates.

Role of C1q complement fixing antibody assay in therapeutic plasma exchange management of pediatric cardiac antibody mediated rejection.

Pediatric cardiac transplant patients with antibody-mediated rejection (AMR) often undergo therapeutic plasma exchange (TPE) to remove pathologic donor specific antibodies (DSA). In cases where DSA persist, it is unclear how long TPE should be continued. We report a case of a 17-year-old cardiac transplant patient with AMR where use of a C1q complement fixing antibody assay helped guide TPE cessation. This report adds to the existing literature that highlights the potential clinical significance of C1q antibodies in AMR management.