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• W2969698508 abstract "The plasma serine protease inhibitor α2-antiplasmin (α2-AP, also known as plasmin inhibitor) plays a key role in controlling fibrinolysis. Congenital deficiency of α2-AP is extremely rare, with fewer than 18 cases reported worldwide (Pozzi et al, 2019) and causes a significant bleeding disorder due to uninhibited hyperfibrinolysis. A recent review highlighted that only three women have been described with homozygous α2-AP deficiency, with limited published experience of management (Saes et al, 2018). We report a family with a novel germline variant in SERPINF2 causing α2-AP deficiency and discuss some of the challenges faced in the management of this rare bleeding disorder. An eight-year-old girl of Bengali origin was referred to our centre with a spontaneous haemarthrosis of the knee. From a young age she had complained of intermittent severe joint and bone pain, which significantly limited her mobility. She also had widespread superficial bruising and a long history of iron deficiency. Aged 4 years, she was reviewed in paediatric clinic and underwent extensive workup with numerous radiological investigations; however no diagnosis was made. Her parents were first cousins. Her mother had a history of easy bruising and iron deficiency, and her 12-year-old brother had a history of easy bruising, bone pain and epistaxis. Her father and 4-year-old sister had no history of bleeding problems. Initial workup revealed a normal prothrombin time, activated partial thromboplastin time, fibrinogen and platelet count with normal platelet morphology. Assays for factors II, V, VII, VIII, IX, X, XI, XIII, Von Willebrand factor antigen and ristocetin cofactor activity were all within normal limits. Platelet function by light transmission aggregometry and nucleotides measured by luminometry demonstrated no reproducible platelet function defect. Magnetic resonance imaging demonstrated diffuse marrow signal abnormality in the long bones with multiple focal areas of hypo-intensity on T1 weighted sequences, most notably in the proximal shaft of the right femur (Fig 1A). Hypo-intense lesions were also seen in the proximal shaft of the tibia in the patient's brother (Fig 1B). The history of severe bleeding and consanguinity prompted further workup for rarer disorders. α2-AP activity was measured by chromogenic assay [Siemens Berichrom α2-antiplasmin (Siemens Healthcare Ltd., Camberley, Surrey, UK), assayed using standard protocol on a CS-2100i analyser (Sysmex, Milton Keynes, UK)] revealing severe deficiency with levels below the assay detection limit of 6·8 μ/dl (normal 68–136 μ/dl). Her brother also had reduced α2-AP levels (15·3 μ/dl), while her parents and sister had low-normal values. Targeted next generation sequencing of all family members was performed using the Thrombogenomics platform (Sivaparalatnam et al, 2017). This revealed a variant in SERPINF2 (17:1650851 GGGCAA>G) with homozygous inheritance of the affected siblings and heterozygous parents (Fig 2). This variant is rare (not present in the known datasets at time of reporting) and causes a change from lysine to arginine initially, with a subsequent premature stop codon arginine. Since diagnosis, the patient has had numerous presentations with bleeding episodes either spontaneously or secondary to minor injuries. On one occasion, she presented with right hip pain due to an atraumatic psoas muscle haematoma despite tranexamic acid prophylaxis. This was managed with admission, bed rest and 15 ml/kg fresh frozen plasma (FFP) once daily for 8 days followed by graded rehabilitation. There were no episodes of fluid overload secondary to FFP and resolution was achieved after 9 days. Subsequently, tranexamic acid prophylaxis was increased to a higher than licensed dose of 60 mg/kg three times daily. Chronic bone pain is an on-going issue, probably secondary to intramedullary haematoma. These are rarely seen in other bleeding disorders but are a well described feature of α2-AP deficiency (Takahashi et al, 1991; Miyauchi et al, 1996). Miyauchi et al (1996) described three cases managed with intramedullary injection of fibrin glue mixed with tranexamic acid resulting in therapeutic benefit and reduction of acute and chronic pain. These operations were managed with intravenous tranexamic acid alone. Given the bleeding phenotype of the index patient, our view is that current available therapy is insufficient to mitigate the potential bleeding risk associated with this orthopaedic intervention. Management has therefore been limited to analgesia alone and the patient is jointly managed with a pain specialist. Prophylaxis for invasive procedures has proved challenging. A single dental extraction under local anaesthetic was covered with high dose tranexamic acid alone. This resulted in re-presentation 3 days later with intractable bleeding necessitating 15 ml/kg/day FFP for 3 days to achieve resolution. Rotational thromboelastometry (ROTEM) was used to measure clot lysis time before and after tranexamic acid. Maximal lysis (ML) measured at 60 min describes the degree of fibrinolysis relative to maximum clot firmness (MCF), expressed as percentage of clot firmness lost. In this case, ML prior to tranexamic acid was 0% (normal range 0–15%); however, following tranexamic acid, ML increased to 22%. The lack of clinical response to tranexamic acid and the changes seen in clot lysis using viscoelastic testing is surprising and contrary to all other reports which describe single agent tranexamic acid to be sufficient prophylaxis for invasive procedures (Morimoto et al, 2004; Carpenter & Matthew, 2008; Pozzi et al, 2019). This requires further evaluation. There are only two other cases of heavy menstrual bleeding associated with homozygous α2-AP deficiency described in the literature (Miles et al, 1982; Pozzi et al, 2019) thus guidance for management is limited. We had planned for pre-menstrual counselling in clinic; however, the patient's menarche preceded this appointment and when aged 12 years she experienced heavy menstrual bleeding requiring admission. No additional haemostatic intervention beyond tranexamic acid was required, nevertheless norethisterone was used to halt menstruation and was continued for several weeks. Since then, menstruation has been regulated with the combined oral contraceptive pill used back-to-back to limit bleeding to every 2–3 months. She continues to have regular follow-up in a joint haematology and gynaecology clinic. This case illustrates the importance of considering α2-AP deficiency in the differential diagnosis of a severe bleeding phenotype with normal screening assays. To the best of our knowledge, it is the first reported case in the United Kingdom since 1985 (Kettle & Maybe, 1985). Our experience and the challenges we have faced highlight how current therapy remains unsatisfactory, and how anti-fibrinolytic agents alone are insufficient for prophylaxis of severe bleeding or to cover invasive procedures. Given there is limited worldwide experience and evidence to guide management, it is imperative that we continue to report cases and share our experience in managing this rare and debilitating disease. MA, AZ: Co-wrote initial draft manuscript. SP: Reviewed manuscript and contributed to analysis of all laboratory data. SS: Reviewed manuscript and provided data on specific genomics. SV: Reviewed manuscript and description of radiological findings. AT, DH, JP: Reviewed manuscript. LB: Supervising, senior author." @default.
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• W2969698508 date "2019-08-22" @default.
• W2969698508 modified "2023-10-13" @default.
• W2969698508 title "A novel variant causing α2 antiplasmin deficiency: case report and experience in a UK centre" @default.
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• W2969698508 doi "https://doi.org/10.1111/bjh.16165" @default.
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