Clinical Reasoning: A 25-Year-Old Woman With Eye Swelling and Headache.

Cerebral venous sinus thrombosis (CVST) is uncommon. Risk factors include inherited and acquired factors. Rapid diagnosis and treatment is essential and can help prevent complications, which can include seizures and visual disturbance. A 25-year-old woman with a background history of CVST and intermittent warfarin use presented to the hospital in 2021 with a 3-month history of progressive eye swelling and headache. Her headache was located in the right frontal region and worsened with movement. Her workup was consistent with recurrent CVST and dural arteriovenous fistula. IR-guided embolization of the fistulas and stenting of her sinuses was performed. She was treated with dual antiplatelet therapy and therapeutic tinzaparin. Her symptoms improved markedly over several days, with improvement in headache and visual acuity. This case illustrates the potential for severe complications including visual disturbance in untreated CVST, as well as the importance of a thorough history and examination in aiding the recognition of the condition.

Reference intervals for clinical biochemistry and haematology tests during normal pregnancy.

BACKGROUND: Pregnancy induces physiological changes which affect biochemical and haematological parameters. As the significance of laboratory test results change throughout pregnancy, the reference interval (RI) or key result interpretive guide should be specific to pregnancy. This study sought to establish trimester-specific-RIs for routine biochemical and haematological tests in healthy white European women with singleton pregnancies with comparison to RIs for non-pregnant European adults. METHODS: A retrospective analysis of a prospective longitudinal single-centre study of healthy pregnant women conducted between November 2018 and December 2020 in a tertiary academic hospital with approximately 3000 births annually. Inclusion criteria: signed informed consent, age ≥18 years, white European, body mass index (BMI) <25 kg/m2, blood pressure <140/90mmHg, non-smoker, no previous pathology or gestational diabetes. Trimester defined as T1: up to 13 weeks + 6 days, T2: 14-27 weeks + 6 days and T3: ≥28-41 weeks + 6 days. Baseline demographics, anthropometric and laboratory measurements were recorded. In total, 31 biochemical and 10 haematological ISO15189:2012 accredited tests were measured using Roche Cobas® and Sysmex XN-9100™ analysers, respectively. RIs were established according to the International Federation of Clinical Chemistry (IFCC) recommended method. RESULTS: Apparently healthy pregnant women (n = 124) with bio-banked serum samples in each trimester were recruited. At the booking visit, 49.2% (n = 61) of participants were nulliparous, with median age of 34.4 (IQR: 31.3-37.3) years, gestational age of 89 (IQR: 84-93) days, BMI of 22.5 (IQR: 21.0-23.7) kg/m2 and systolic and diastolic blood pressure of 116 (110-125) mmHg and 67 (61-75) mmHg, respectively. CONCLUSIONS: Normative trimester-specific biological intervals for routinely requested biochemical and haematological medical laboratory tests were established. These RIs will be invaluable to result interpretation and the management of pregnant women.

Recombinant factor IX-Fc fusion protein in severe hemophilia B: Patient-reported outcomes and health-related quality of life.

INTRODUCTION: In 2017, all people with severe hemophilia B in Ireland switched to recombinant factor IX Fc fusion protein concentrate (rFIXFc) prophylaxis. Patient-reported outcomes (PROs) and health-related quality of life (HRQoL) are important to evaluate with new treatments. AIMS: To assess HRQoL in people with severe hemophilia B and their experience after switching to rFIXFc prophylaxis. METHODS: Participants completed a Patient Reported Outcomes Burden and Experience (PROBE) questionnaire on initiation and following two years of rFIXFc prophylaxis. The PROBE questionnaire has four domains: demographics, general health, haemophilia-specific, and European Quality of Life 5-Dimensions (EQ-5D-5L) questionnaire. RESULTS: Twenty-three participants completed the questionnaire at both time points. The number of activities where chronic pain occurred and interfered with the activity was reduced by 25% and 33%, respectively (P < .001), following two years of rFIXFc prophylaxis. There was a 9% decrease in chronic pain during the second year of rFIXFc prophylaxis compared to baseline, but the rate remained high, at 74%. A 25% reduction in the number of affected activities of daily living (ADLs) was reported following 2 years of rFIXFc prophylaxis (P = .007). The most common health problems were arthritis, hypertension, anxiety/depression, and gingivitis. The median EQ-5D-5L score was similar following two years of rFIXFc prophylaxis, 0.76 (range, -0.01 to 0.95), compared to 0.77 (range, 0.36-1) at baseline. CONCLUSION: This study of real-world patient experience using PROs demonstrates a reduction in chronic pain and improvement in ADLs in participants after switching to rFIXFc prophylaxis. It provides important insights into patient-identified health care needs and living with severe hemophilia B.

Single centre, real-world experience of perioperative rFIXFc use in adult patients with haemophilia B undergoing major and minor surgery.

INTRODUCTION: Recombinant factor IX fusion protein concentrate (rFIXFc) is increasingly used for prophylaxis in people with haemophilia B (PWHB), but experience in the perioperative setting is limited. AIMS: To evaluate real-world perioperative factor usage, bleeding and complications in PWHB (≥18 years) who received rFIXFc for surgical haemostasis and to describe the treatment regimens used. METHODS: Single centre, retrospective review of all PWHB who underwent a major or minor surgical procedure between June 2017 and July 2020 and received rFIXFc perioperatively for maintenance of surgical haemostasis. RESULTS: A total of 56 PWHB (45 male and 11 female), including people with mild (n = 32), moderate (n = 4) and severe (n = 20) haemophilia B, underwent 11 major and 131 minor procedures with rFIXFc for surgical haemostasis. Haemostasis was rated as excellent (9/11) or good (2/11) in all major procedures. Median total rFIXFc consumption for orthopaedic surgeries was 972 IU/kg (range 812-1031 IU/kg) and for other major (non-orthopaedic) surgeries was 323 IU/kg (range 167-760 IU/kg). The median number of perioperative rFIXFc infusions was 19 (range 17-26) for orthopaedic surgery and 7 (range 5-17) for other major surgeries. The number of infusions in the postoperative period was determined by procedure and patient factors. Complications included bowel ileus and wound infection. Most minor procedures were managed with single infusion of rFIXFc, with no bleeding complications in 95% of minor procedures. There were no thromboembolic events or inhibitor formation. CONCLUSION: This unique data provides real-world evidence that rFIXFc is safe and effective in achieving haemostasis in PWHB undergoing surgery.

Real-world outcomes with recombinant factor IX Fc fusion protein (rFIXFc) prophylaxis: Longitudinal follow-up in a national adult cohort.

INTRODUCTION: In 2017, all people with severe haemophilia B (PWSHB) in Ireland switched from standard half-life (SHL) recombinant FIX (rFIX) to rFIX Fc fusion protein (rFIXFc) prophylaxis. AIMS: To evaluate prophylaxis regimens, bleeding rates and factor usage for two years of rFIXFc prophylaxis in a real-world setting. METHODS: Data collected retrospectively from electronic diaries and medical records of PWSHB for a two-year period on rFIXFc prophylaxis were compared with paired baseline data on SHL rFIX treatment. RESULTS: 28 PWSHB (≥18 years) were enrolled, and at switchover 79% were receiving prophylaxis and 21% episodic treatment with SHL rFIX. At 24 months following switchover, all remained on rFIXFc prophylaxis with reduced infusion frequency; median dose per infusion once weekly (55 IU/kg, 20/28), every 10 days (63 IU/kg, 2/28) or every 14 days (98 IU/kg, 6/28). Median annualised bleed rate improved significantly on rFIXFc prophylaxis (2.0 versus 3.3 on SHL FIX) (p = 0.01). Median FIX trough level with once-weekly infusions was 0.09 IU/ml (0.06-0.14 IU/ml). Management of bleeding episodes was similar with rFIXFc and SHL rFIX; one infusion was sufficient to treat 74% and 77% of bleeds, respectively, with similar total median treatment per bleeding episode. Factor consumption reduced by 28% with rFIXFc prophylaxis (57 IU/kg/week, range 40-86 IU/kg/week) compared with SHL rFIX (79 IU/kg/week, range 44-210 IU/kg/week) (p = 0.002). CONCLUSION: This study provides important insights into real-world experience of switching to rFIXFc prophylaxis in an adult population, demonstrating high rates of prophylaxis, with reduced infusion frequency, bleeding and FIX consumption.

Further observations on the clinical significance and inheritance of the low-frequency platelet antigen HPA-28bw.

BACKGROUND: Most recently described human platelet antigens (HPAs) have been low-frequency polymorphisms identified in cases of fetomaternal alloimmune thrombocytopenia (FMAIT). There is limited opportunity to study the clinical significance or different antenatal management strategies in cases involving low-frequency HPA antibodies because many are single pregnancies. We have previously described a low-frequency platelet (PLT) antigen, HPA-28bw, implicated in FMAIT in two of the three infants in the same family. This report describes the outcome of an additional two pregnancies in this family. STUDY DESIGN AND METHODS: The fourth and fifth pregnancies in a HPA-28bw-alloimmunized mother with a heterozygous partner were investigated to determine the risk of FMAIT. The presence of anti-HPA-28bw was assessed by paternal crossmatch studies. Prenatal HPA genotyping of amniocytes was performed to inform antenatal management. RESULTS: GPIIb/IIIa antibodies reactive only with paternal PLTs were detected. These antibodies had been previously identified as HPA-28bw specific using recombinant GPIIb glycoprotein mutated to contain the HPA-28bw (V740L) mutation. The fetus in the fourth pregnancy did not inherit the HPA-28bw mutation, no antenatal management was required, and the baby had a normal PLT count. The fetus in the fifth pregnancy did inherit the HPA-28bw mutation. The mother received IVIG (2 g/kg/week) and prednisolone during pregnancy, and the baby was born with a normal PLT count. CONCLUSION: Study of this family has provided a unique opportunity to assess the clinical significance of antibodies against the low-frequency PLT antigen (HPA-28bw) during five pregnancies and to compare the outcomes of different antenatal treatments.

A V740L mutation in glycoprotein IIb defines a novel epitope (War) associated with fetomaternal alloimmune thrombocytopenia.

BACKGROUND: Most recently described human platelet antigens (HPAs) have been detected in cases of fetomaternal alloimmune thrombocytopenia (FMAIT) where the mother has been immunized against a low-frequency antigen that the fetus has inherited from the father. Low-frequency antigens are not represented in normal panel platelets (PLTs) and antibody detection and identification in such cases requires incubation of maternal serum with paternal PLTs and definition of the causative mutation. STUDY DESIGN AND METHODS: A suspected case of FMAIT was investigated for PLT-specific antibodies using a panel of both HPA-typed and paternal PLTs. HPA typing was performed by polymerase chain reaction with sequence-specific primers and further DNA analysis was performed using direct sequencing of the coding regions of the ITGA2B and ITGB3 genes. RESULTS: Maternal antibodies reactive only with paternal PLTs were localized to glycoprotein (GP)IIb/IIIa using the monoclonal antibody immobilization of PLT antibody assay. A single-nucleotide polymorphism was detected in Exon 23 of ITGA2B in the father and affected child, which predicted a V740L substitution in the mature protein. Recombinant V740L mutated GPIIb expressed in HEK293 cells was specifically recognized by maternal antibodies. The polymorphism was not detected either in the mother or in a cohort of 100 donors. CONCLUSION: The V740L polymorphism defines a new low-frequency antigen implicated in two cases of FMAIT in a single family. Low-frequency HPAs are clinically important and their elucidation requires both crossmatch studies and gene sequencing in cases where there is strong clinical evidence of FMAIT but initial laboratory investigations do not support the diagnosis.

T-lymphoblastic leukemia/lymphoma: a single center retrospective study of outcome.

T-lymphoblastic leukemia/lymphoma (LBL and ALL) is a rare lymphoid malignancy typically presenting in adolescent and young adult males. Patients are traditionally treated with ALL-type protocols, with no consensus on the role of maintenance therapy, or allogeneic or autologous transplant. Outcome results are thus difficult to interpret. The successful use of intensified ALL protocols in patients <25 years with lymphoblastic malignancies without transplant prompted the Haematology Unit at St James's Hospital (SJH) to change practice in 2005 from transplanting in first complete remission (CR1) to treating patients <25 years with chemotherapy alone. We reviewed the outcome of patients treated before 2005 in order to compare the pre- and post-2005 management approaches in the future. This retrospective study included 31 patients with T-LBL treated from 1980 to 2004. The patients were divided into group A (16-25 years) and group B (>25 years). Twenty-one patients had an allograft in CR1 (group A, n = 12 and group B, n = 9). For the allografted patients the 5-year EFS and OS was 57%, with a treatment related mortality of 10%. In conclusion, this series confirms that allograft in CR1 has an acceptable cure rate, and we will use these results to benchmark outcomes using pediatric-type protocols in the future.

Abiotrophia defectiva endocarditis and associated hemophagocytic syndrome--a first case report and review of the literature.

In this manuscript we describe the first association in the literature between Abiotrophia defectiva endocarditis and the hemophagocytic syndrome. There are multiple important clinical points of information that must be highlighted from this case. A. defectiva is an aggressive organism with a high level of resistance to antibiotic pharmacotherapy with a high predilection for embolic complications and valvular destruction despite treatment with sensitive antibiotics. A. defectiva endocarditis has not been previously associated with the hemophagocytic syndrome. However, this case highlights the serious hematological complications that can occur with this dangerous bacterial pathogen.