Search

Anti-PP1P K alloimmunization is rare given ubiquitous P1PK expression. Prevention of recurrent miscarriages and hemolytic disease of the fetus and newborn (HDFN) in pregnant individuals with anti-PP1P K antibodies has relied upon individual reports. Here, we demonstrate the successful management of maternal anti-PP1P K alloimmunization in a 23-year-old, G2P0010, with therapeutic plasma exchange (TPE), intravenous immunoglobulin (IVIG), and monitoring of anti-PP1P k titers. Twice-weekly TPE (1.5 plasma volume [PV], 5% albumin replacement) with weekly titers and IVIG (1 g/kg) was initiated at 9 weeks of gestation (WG). The threshold titer was ≥16. Weekly middle cerebral artery-peak systolic velocities (MCA-PSV) for fetal anemia monitoring was initiated at 16 WG. PVs were adjusted throughout pregnancy based on treatment schedule, titers, and available albumin. Antigen-negative, ABO-compatible RBCs were obtained through the rare donor program and directed donation. An autologous blood autotransfusion system was reserved for delivery. Titers decreased from 128 to 8 by 10 WG. MCA-PSV remained stable. At 24 WG, TPE decreased to once weekly. After titers increased to 32, twice-weekly TPE resumed at 27 WG. Induction of labor was scheduled at 38 WG. Vaginal delivery of a 2950 g neonate (APGAR score: 9, 9) occurred without complication (Cord blood: 1+ IgG DAT; Anti-PP1P k eluted). Newborn hemoglobin and bilirubin were unremarkable. Discharge occurred postpartum day 2. Anti-PP1P k alloimmunization is rare but associated with recurrent miscarriages and HDFN. With multidisciplinary care, a successful pregnancy is possible with IVIG and TPE adjusted to PV and titers. We also propose a patient registry and comprehensive management plan., (© 2024 Wiley Periodicals LLC.)

Background: Consensus guidelines recommend that therapeutic plasma exchange (TPE) should be started within 4 to 8 hours after the diagnosis of suspected acquired thrombotic thrombocytopenic purpura (aTTP). This study aimed to audit the steps from diagnosis to initiation of plasma exchange at a centralized apheresis service., Methods: A retrospective review of the electronic medical record and laboratory information systems from January 1, 2014 to August 31, 2017 was conducted to identify all patients with suspected aTTP undergoing TPE. Demographics, comorbidities, pertinent laboratory tests, and temporal TPE procedural data were collected., Results: The median (5th-95th percentile) time from request to initiation of TPE was 5.4 (3.2-10.6) hours. TPE was initiated within 8 hours in 94 of the 108 patients (87.0%). The median (5th-95th percentile) time from request to central venous access was 2.5 (0.5-6.9) hours and from request to plasma product issuance from the blood bank was 3.4 (1.6-8.1) hours. aTTP patients in whom TPE was initiated greater than 6 hours from request did not have worse outcomes compared to those with TPE initiation within 6 hours: in-hospital mortality (2/14 [14.3%] vs 2/21 [9.5%], P = 0.66), median length of stay (9.0 [4.7-44.1] vs 8.3 [3.9-27.0] days, P = 0.76), and median number of days to durable platelet count recovery (4.5 [2.0-9.0] vs 4.0 [2.0-18.0] days, P = 0.66)., Conclusions: The 4 to 8-hour target window from TPE request to initiation appears feasible for a centralized apheresis program servicing a large healthcare system., (© 2021 Wiley Periodicals LLC.)

Sickle cell disease (SCD) patients require urgent red cell exchange (RCE) procedures for acute chest syndrome (ACS), demanding a coordinated effort of multiple clinical services. Execution of RCE is a multistep process from the time the procedure is requested to the time the procedure is initiated. A retrospective review of patients with SCD requiring urgent RCE for ACS and stroke from 2012 to 2017 was performed at a centralized hemapheresis service covering a multihospital healthcare system. A total of 30 urgent RCE procedures performed on 28 patients were evaluated. The time required for red blood cell (RBC) preparation was the longest step in the process (median 3.8 hours). Furthermore, RBC preparation time was longer for sickle cell patients with RBC alloimmunization compared with nonalloimmunized patients (8.6 vs 3.8 hours, P = .03). One mortality event occurred in Ab- group. This study identified potentially modifiable factors, which impact the time to implementation of RCE in one service area. It highlights the importance of a structured and coordinated approach for the efficient and timely delivery of this vital treatment modality., (© 2020 Wiley Periodicals LLC.)

Germline mutations in checkpoint kinase 2 (CHEK2), a multiple cancer-predisposing gene, increase breast cancer (BC) risk; however, risk estimates differ substantially in published studies. We analyzed germline CHEK2 variants in 1,928 high-risk Czech breast/ovarian cancer (BC/OC) patients and 3,360 population-matched controls (PMCs). For a functional classification of VUS, we developed a complementation assay in human nontransformed RPE1-CHEK2-knockout cells quantifying CHK2-specific phosphorylation of endogenous protein KAP1. We identified 10 truncations in 46 (2.39%) patients and in 11 (0.33%) PMC (p = 1.1 × 10 -14 ). Two types of large intragenic rearrangements (LGR) were found in 20/46 mutation carriers. Truncations significantly increased unilateral BC risk (OR = 7.94; 95%CI 3.90-17.47; p = 1.1 × 10 -14 ) and were more frequent in patients with bilateral BC (4/149; 2.68%; p = 0.003), double primary BC/OC (3/79; 3.80%; p = 0.004), male BC (3/48; 6.25%; p = 8.6 × 10 -4 ), but not with OC (3/354; 0.85%; p = 0.14). Additionally, we found 26 missense VUS in 88 (4.56%) patients and 131 (3.90%) PMC (p = 0.22). Using our functional assay, 11 variants identified in 15 (0.78%) patients and 6 (0.18%) PMC were scored deleterious (p = 0.002). Frequencies of functionally intermediate and neutral variants did not differ between patients and PMC. Functionally deleterious CHEK2 missense variants significantly increased BC risk (OR = 3.90; 95%CI 1.24-13.35; p = 0.009) and marginally OC risk (OR = 4.77; 95%CI 0.77-22.47; p = 0.047); however, carriers low frequency will require evaluation in larger studies. Our study highlights importance of LGR detection for CHEK2 analysis, careful consideration of ethnicity in both cases and controls for risk estimates, and demonstrates promising potential of newly developed human nontransformed cell line assay for functional CHEK2 VUS classification., (© 2019 UICC.)

Background: Currently, low titer A plasma is used on a routine basis in bleeding trauma patients of unknown AB type. Three AB non-bleeding apheresis patients are presented here who safely received a combination of AB and low titer A plasma during therapeutic plasma exchange (TPE). One control AB patient received AB plasma only., Methods: Data was obtained retrospectively on number of procedures, volume replaced, total plasma, and A plasma volumes including hemolysis laboratory data. Average A plasma volume and % of A plasma out of total plasma volume used were calculated., Results: Two female AB patients were treated for thrombotic thrombocytopenic purpura (TTP) with TPE and a third female AB patient was treated for microangiopathic hemolytic anemia. Patient 1 received a total of 12 procedures, 10/12 with AB+A plasma (average 916.3 ±84.6 mL). Patient 2 received a total of 12 procedures, 4/12 with AB+A plasma (average 1210.5 ±27.9 mL). Patient 3 received a total of six procedures, four out of six procedures with AB+A plasma (average 1009.8 ±80.3 mL). Patient 4, control, received AB plasma only. Percent of A plasma volume exchanged ranged between 23.8% and 47.8%. Haptoglobin, LDH, hemoglobin, and total bilirubin were monitored and trends were comparable with the control patient. The patients had a negative follow up direct antiglobulin test, adequate platelet recovery and a favorable clinical outcome with treatments., Conclusions: TPE was effectively performed without evidence of increased hemolysis using up to 47.8% of low titer A plasma. This approach can reduce strains on limited supplies of AB plasma whereas providing a vital treatment alternative for AB patients undergoing TPE with plasma replacement., (© 2018 Wiley Periodicals, Inc.)

The widespread use of next generation sequencing for clinical testing is detecting an escalating number of variants in noncoding regions of the genome. The clinical significance of the majority of these variants is currently unknown, which presents a significant clinical challenge. We have screened over 6,000 early-onset and/or familial breast cancer (BC) cases collected by the ENIGMA consortium for sequence variants in the 5' noncoding regions of BC susceptibility genes BRCA1 and BRCA2, and identified 141 rare variants with global minor allele frequency < 0.01, 76 of which have not been reported previously. Bioinformatic analysis identified a set of 21 variants most likely to impact transcriptional regulation, and luciferase reporter assays detected altered promoter activity for four of these variants. Electrophoretic mobility shift assays demonstrated that three of these altered the binding of proteins to the respective BRCA1 or BRCA2 promoter regions, including NFYA binding to BRCA1:c.-287C>T and PAX5 binding to BRCA2:c.-296C>T. Clinical classification of variants affecting promoter activity, using existing prediction models, found no evidence to suggest that these variants confer a high risk of disease. Further studies are required to determine if such variation may be associated with a moderate or low risk of BC., (© 2018 The Authors. Human Mutation published by Wiley Periodicals, Inc.)