Mary Mathias

Guideline for the diagnosis and management of the rare coagulation disorders: a United Kingdom Haemophilia Centre Doctors' Organization guideline on behalf of the British Committee for Standards in Haematology.

PB 2.54-1. Bauduer, F., Guichandut, J.P. & Ducout, L. (2004) Successful use of fresh frozen plasma and desmopressin for transurethral prostatectomy in a French Basque with combined factors V + VIII deficiency. Journal of Thrombosis and Haemosta-

Rituximab and immune tolerance in severe hemophilia A: a consecutive national cohort

Summary.  Background and objectives: he management of patients with severe hemophilia A and inhibitors to factor VIII (FVIII) resistant to standard immune tolerance is challenging. There have been recent case reports of the successful use of rituximab in up to 57% of patients as part of rescue immune tolerance regimens. Because case reports and small series are prone to the potential bias of reporting good outcomes and relatively short follow up, a consecutive cohort of all patients treated in the UK with prolonged follow up was analyzed. Methods: A national survey of all Comprehensive Care Haemophilia Cente in the UK. Results: A total of 15 patients were reported of whom six (40%) achieved a negative inhibitor titer by Bethedsa assay. Durable responses were unusual, observed in only 14% of cases. Clinically significant responses with either a negative inhibitor or an inhibitor titer < 5 BU mL−1 and no spontaneous bleeding with FVIII replacement were observed in seven (47%) cases. Concomitant use of FVIII appeared to be important. Of the 12 patients treated with rituximab and FVIII, six (50%) achieved a negative inhibitor titer and seven (58%) had a clinically beneficial response. None of the three patients treated without FVIII responded. Conclusions: hese data suggest that the use of rituximab combined with FVIII is a potentially useful treatment for patients with inhibitors resistant to standard immune tolerance, although sustained inhibitor eradication is uncommon.

A gain-of-function variant in DIAPH1 causes dominant macrothrombocytopenia and hearing loss

Macrothrombocytopenia (MTP) is a heterogeneous group of disorders characterized by enlarged and reduced numbers of circulating platelets, sometimes resulting in abnormal bleeding. In most MTP, this phenotype arises because of altered regulation of platelet formation from megakaryocytes (MKs). We report the identification of DIAPH1, which encodes the Rho-effector diaphanous-related formin 1 (DIAPH1), as a candidate gene for MTP using exome sequencing, ontological phenotyping, and similarity regression. We describe 2 unrelated pedigrees with MTP and sensorineural hearing loss that segregate with a DIAPH1 R1213* variant predicting partial truncation of the DIAPH1 diaphanous autoregulatory domain. The R1213* variant was linked to reduced proplatelet formation from cultured MKs, cell clustering, and abnormal cortical filamentous actin. Similarly, in platelets, there was increased filamentous actin and stable microtubules, indicating constitutive activation of DIAPH1. Overexpression of DIAPH1 R1213* in cells reproduced the cytoskeletal alterations found in platelets. Our description of a novel disorder of platelet formation and hearing loss extends the repertoire of DIAPH1-related disease and provides new insight into the autoregulation of DIAPH1 activity.

Mechanical bridging to orthotopic heart transplantation in children weighing less than 10 kg: feasibility and limitations

OBJECTIVE Infants and young children are considered the most difficult group to bridge to orthotopic heart transplantation (OHT) and data regarding outcomes are scarce. METHODS We reviewed our patients ≤ 10 kg with those who were bridged to OHT using ventricular assist device (VAD) Berlin Heart (BH) Excor ± extracorporeal membrane oxygenation (ECMO) between 2004 and 2009. RESULTS Eleven children ≤ 10 kg with end-stage heart failure (cardiomyopathy or myocarditis) were treated with VAD as bridge to OHT: the median weight was 8.0 (range 3.9-10.0 kg)kg and median age was 12.3 (range 1.2-33.9 months) months. Five (45%) required ECMO support pre-BH and six were on mechanical ventilation and inotropes. In 9/11 (82%), the support mode was left ventricular assist device (L-VAD) (all alive): one of two patients needing Bi-VAD support died. On BH, the median support time was 27 days and time to extubation was 8 days. Two out of 11 (18%) suffered strokes confirmed on brain imaging; both recovered and one underwent resection of infarcted small bowel. Ten out of 11 (91%) were transplanted, one remains in hospital and nine are at home in good health. When compared to patients >10 kg bridged with BH (n = 15), the mortality (p = 0.51) and rates of neurological complications (p = 0.54) were similar. Post-transplant recovery (ventilation times and time to home discharge) was similar between the bridged children ≤ 10 kg and non-bridged children ≤ 10 kg who underwent OHT. CONCLUSIONS Mechanical bridging to transplantation is clinically feasible in children ≤ 10 kg, achieving excellent outcomes. Judicious use of VADs in smaller children will optimise the use of donor organs; however, the effect on overall OHT waiting times, if mechanical bridging was extended to a large number of small children, is unknown.

Subcutaneous protein C concentrate in the management of severe protein C deficiency--experience from 12 centres.

Since the first description of subcutaneous protein C concentrate as treatment for severe protein C deficiency in 1996, further cases have been reported but there is no uniform approach to this form of treatment. In order to assess the safety and effectiveness of subcutaneous protein C concentrate and suggest recommendations for future use, patients who had received subcutaneous protein C concentrate were identified from the literature, by contacting the manufacturers and by personal communication. Treatment details were available from 14 cases. Apart from one case where the infusion interval was inadvertently increased, no thrombotic events occurred even when doses were subsequently reduced. Initially, a trough protein C level of >0·25 iu/ml should be aimed for. Subsequently, a smaller dose of subcutaneous protein C concentrate, especially if taken with an oral anticoagulant, may be protective maintenance treatment. The treatment was well tolerated with few side effects. Subcutaneous protein C concentrate on its own or combined with an oral anticoagulant appears to be safe and effective as maintenance treatment of severe protein C deficiency. A major advantage is the avoidance of central venous access devices. The incidence of neurodevelopmental handicap was high with blindness affecting the majority of patients.

Prophylaxis with prothrombin complex concentrate in four children with severe congenital factor X deficiency

Dear Editor, We report the use of prothrombin complex concentrate (PCC, Beriplex ; CSL Behring, Marburg, Germany) as prophylaxis in four children with severe congenital factor X deficiency. Child 1, a Turkish boy born to consanguineous parents, presented at 14 weeks old with a left hemiparesis and oozing from venepuncture sites. A computerised tomography (CT) scan showed a large right-sided frontal haemorrhage. He had a grossly prolonged activated partial thromboplastin time (APTT) and prothrombin time (PT) and factor X was <1 IU dL. The clot was evacuated under the cover of PCC (Defix ; Scottish National Blood Transfusion Service, Edinburgh, UK) and he was commenced on prophylaxis with Defix via a Hickman line. On referral to our centre, his prophylaxis was changed to Beriplex , the dose being calculated based on factor XI units per kilogram and adjusted according to trough levels (as is the case for the three subsequent children). His Hickman line was replaced with a port-a-cath under the cover of Beriplex 15 units kg every 8–12 h in the perioperative period, whilst monitoring factor X levels to help guide replacement. There were no bleeding complications. His prophylaxis is currently Beriplex 375 units (20 units kg) every 72 h, with a trough level of >5 IU dL. He is now 3.5 years old and has suffered no further bleeds, but does have residual left arm weakness and developmental delay. Genetic studies show him to be homozygous for a G to A substitution at codon 222 of the factor X gene. Child 2, a Pakistani female born to consanguineous parents in Pakistan, presented soon after birth with bleeding from the umbilical stump and a haematoma on her back. The coagulation screen was reportedly abnormal with a prolonged APTT and PT and a factor X of <1 IU dL. She received fresh frozen plasma (FFP) and Vitamin K, after which the bleeding resolved. She represented at 25 days old with a right thigh haematoma and was given FFP without resolution of the bleeding, so was switched to PCC. At 6 weeks old she was referred to our centre. The diagnosis of severe factor X deficiency was confirmed and she was started on Beriplex 25 units kg every 72 h. A Hickman line was inserted which was changed to a port-a-cath at 25 weeks old. Both surgical procedures were carried out using Beriplex with no bleeding complications. Her current treatment is with Beriplex 375 units (28 units kg) every 72 h, with trough levels of >5 IU dL, which her parents administer at home. She is now 4 years old and has had no further bleeds and no complications from the port-a-cath. Genetic studies show her to be homozygous for an ATG to GTG substitution at the initiation codon, also known as Factor X Nice I. Child 3 is a female of consanguineous Irish decent, diagnosed with severe factor X deficiency at 6 days of life after presenting with umbilical stump and rectal bleeding. She had a family history of severe factor X deficiency, a brother having died at 8 weeks from an intracranial haemorrhage. She was given FFP daily until transfer to our centre at day 11. On arrival, the cord and rectal bleeding had resolved and her factor X level was 4 IU dL, 24 h after FFP. A Hickman line was inserted which was subsequently removed because of sepsis. A port-a-cath was inserted to facilitate home treatment. She has had two further port-a-cath infections, requiring removal and replacement. All procedures were performed using Beriplex perioperatively. Currently, she is on Correspondence: Dr R Liesner, The Haemophilia Centre, Great Ormond Street Hospital for Children NHS Trust, Great Ormond Street, London WC1N 3JH, UK. Tel.: +44 20 88298846; fax: +44 20 88298872; e-mail: liesnr@gosh.nhs.uk

Subcutaneous administration of protein C concentrate.

Children born with severe homozygous protein C deficiency do not survive beyond the neonatal period unless they receive protein C replacement. Protein C concentrate (Baxter Biosciences, Vienna) is usually given intravenously via a central venous catheter. The authors describe 2 children in whom protein C concentrate was successfully administered by subcutaneous infusion after they had had recurrent central line infections. Alternate daily doses of 250–350 IU/kg resulted in trough protein C levels of >25 IU/dL. In the follow-up period of 1–2 years neither child has had a thrombotic episode or purpuric skin lesions, and infusions are managed in the home by their parents.

Management of surgical procedures in children with severe FV deficiency: experience of 13 surgeries.

Homozygous severe factor V (FV) deficiency has a prevalence of around one per million. Even in patients with FV levels of <0.01 IU mL−1 there appears to be a variation in bleeding phenotype in that there is a subgroup of affected individuals who present in later childhood and have a relatively mild bleeding phenotype, but there are children who present as neonates with intracerebral bleeding events and who have a much more severe bleeding phenotype. The only available current FV replacement is in the form of fresh frozen plasma (FFP) or solvent detergent FFP. We present here our experience with surgical haemostatic cover for 13 surgeries in three children with severe FV deficiency.

Management of bleeding disorders in children.

Summary.  Haemophilia, if not properly managed, can lead to chronic disease and lifelong disabilities. The challenges and issues in infants/young children are different from those in older children and adults although episodes of bleeding still predominate as the diagnostic trigger. Awareness of clinical manifestations and treatment complications are crucial in instituting appropriate management and implementing preventive strategies. Currently, inhibitor development is a challenging complication of paediatric haemophilia and prophylaxis is emerging as the optimal preventive care strategy. In this section we will review some important aspects of haemophilia in children including early prophylaxis, current evidence relating to inhibitor development, including the aims of the SIPPET study which is already ongoing and involves boys <6 years, and the potential of immune tolerance therapy for eradicating the inhibitor and permitting a resumption of standard dosing schedules.

Prophylaxis in severe prothrombin deficiency.

Severe prothrombin (Factor II, FII) deficiency is an extremely rare autosomal recessive condition with an estimated incidence of 1:2 million and an increased prevalence in populations where consanguineous partnerships are more common. International registry data indicate that patients with a FII of <10 iu/dl have a significant risk of severe spontaneous bleeding including haemarthrosis and intracerebral haemorrhage. To our knowledge there is only one published case report of the use of prophylactic FII infusions in an individual with severe prothrombin deficiency. We describe the case of a boy with severe prothrombin deficiency who was treated with on demand prothrombin complex concentrate up to the age of 6 years, but in response to an increasing number of spontaneous bleeding episodes and increased levels of exercise was started on regular prophylaxis. Our patient was born by an induced vaginal delivery at term to Caucasian parents at that time residing overseas. He was given intramuscular vitamin K at birth with no adverse effects. At 4 d of age, he bled significantly from the umbilical stump requiring two attempts at suturing to control bleeding. No coagulation screen or factor assays were performed at this time. At 1 month he was investigated for fresh rectal bleeding which required a blood transfusion. At 4 months he was diagnosed with severe prothrombin deficiency when his FII level was found to be between 1–3 iu/dl. His parents were found to have FII levels of 68 and 54 iu/dl and further enquiry revealed that his maternal grandmother and his paternal grandfather were first cousins. Baseline thromboelastometry measurements were insensitive to his prothrombin deficiency but thrombin generation assay of platelet poor plasma was reduced. His family predominantly lived overseas until he was 6 years old and throughout this time he required on-demand treatment with prothrombin complex concentrate (Prothrombinex, Defix and Octaplex) for trauma-induced bleeding episodes. These tended to be soft-tissue and muscle bleeds although there were at least two haemarthroses when he was 5 years old. The family settled back in the UK when he was 6 years old and about to attend school. At this point he was having a number of soft tissue bleeding episodes with no clear traumatic trigger, so for this reason, and in order that his activities at school need not be circumscribed, he was started on prophylactic prothrombin complex concentrate (Octaplex, Octapharma) 40 iu/kg by Factor IX (FIX) content, administered once a week. He was initially treated at home by one of our haemophilia Clinical Nurse Specialists who then taught his mother to treat him. Aside from occasional gum bleeding associated with erupting adult teeth, which is managed with tranexamic acid mouth wash, he had no spontaneous or trauma-related bleeding episodes for 18 months whilst on prophylaxis. Within the last few weeks he has had one severe spontaneous knee bleed 6 d after treatment and, given that his FII level was 8 iu/dl at 5 d, it is reasonable to conclude that a level below this will not prevent bleeding episodes. We plan to increase the frequency of his prophylaxis to every 5 d to prevent further breakthrough bleeds. He is involved in football, athletics, tennis, cricket and swimming at school. He is now 9 years old and is likely to be able to treat himself within the next 12 months. Table I and Fig 1 show his FII, FIX and Factor X levels and Thrombogram parameters pre-infusion, and 1 and 4 h post-infusion.