Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare thrombomicroangiopathy caused by an inherited deficiency of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13). There are limited data on genotype-phenotype correlation; there is no consensus on treatment. We reviewed the largest cohort of cTTP cases, diagnosed in the United Kingdom, over the past 15 years. Seventy-three cases of cTTP were diagnosed, confirmed by genetic analysis. Ninety-three percent were alive at the time of review. Thirty-six percent had homozygous mutations; 64% had compound heterozygous mutations. Two presentation peaks were seen: childhood (median diagnosis age, 3.5 years) and adulthood, typically related to pregnancy (median diagnosis age, 31 years). Genetic mutations differed by age of onset with prespacer mutations more likely to be associated with childhood onset (P = .0011). Sixty-nine percent of adult presentations were associated with pregnancy. Fresh-frozen plasma (FFP) and intermediate purity factor VIII concentrate were used as treatment. Eighty-eight percent of patients with normal blood counts, but with headaches, lethargy, or abdominal pain, reported symptom resolution with prophylactic therapy. The most common currently used regimen of 3-weekly FFP proved insufficient for 70% of patients and weekly or fortnightly infusions were required. Stroke incidence was significantly reduced in patients receiving prophylactic therapy (2% vs 17%; P = .04). Long-term, there is a risk of end-organ damage, seen in 75% of patients with late diagnosis of cTTP. In conclusion, prespacer mutations are associated with earlier development of cTTP symptoms. Prophylactic ADAMTS13 replacement decreases the risk of end-organ damage such as ischemic stroke and resolved previously unrecognized symptoms in patients with nonovert disease.

The cornerstone of life-saving therapy in immune mediated thrombotic thrombocytopenic purpura (iTTP) has been plasma exchange (PEX) combined with immunomodulatory strategies. Caplacizumab, a novel anti-von Willebrand factor nanobody, trialled in two multicentre, randomised-placebo-controlled trials leading to EU and FDA approval, has been available in the UK through a patient-access scheme. Data was collected retrospectively from 2018-2020 for 85 patients receiving caplacizumab, including 4 children, from 22 UK hospitals. Patient characteristics and outcomes in the real-world clinical setting were compared with caplacizumab trial endpoints and historical outcomes in the pre-caplacizumab era. 84/85 patients received steroid and rituximab alongside PEX; 26% required intubation. Median time to platelet count normalisation (3 days), duration of PEX (7 days) and hospital stay (12 days) was comparable with RCT data. Median duration of PEX and time from PEX initiation to platelet count normalisation was favourable compared with historical outcomes (p<0.05). TTP recurrence occurred in 5/85 patients; all with persistent ADAMTS13 activity <5iu/dL. Of 31 adverse events in 26 patients, 17/31 (55%) were bleeding episodes and 5/31 (16%) were thrombotic events (two unrelated to caplacizumab); mortality was 6% (5/85), with no deaths attributed to caplacizumab. In 4/5 deaths caplacizumab was introduced >48 hours after PEX initiation (3-21 days). This real-world evidence represents the first and largest series of TTP patients receiving caplacizumab outside clinical trials, including paediatric patients. Representative of true clinical practice, the findings provide valuable information for clinicians treating TTP globally.

Key Points• High anti-ADAMTS13 antibody and low ADAMTS13 antigen levels adversely affect outcome in immunemediated TTP with greater mortality seen.• A raised troponin at presentation confers a sixfold increase and reduced GCS a nine-fold increase in mortality in acute TTP.Immune-mediated thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder caused by antibodies against ADAMTS13. From the United Kingdom TTP registry, we undertook a prospective study investigating the impact of the presenting anti-ADAMTS13 IgG antibody and ADAMTS13 antigen on mortality. A total of 312 episodes involving 292 patients over 87 months were included; 68% were female, median age 46 (range, 11-88 years), and median presenting ADAMTS13 of <5% (range, <5%-18%). The mortality rate was 10.3% (n 5 32); 68% of patients had a raised troponin at presentation conferring a sixfold increase in mortality compared with those with normal troponin levels (12.1% vs 2.0%, P 5 .04). Twenty-four percent had a reduced Glasgow Coma Score (GCS) at presentation with a ninefold increase in mortality (20% vs 2.2% for normal GCS at presentation, P < .0001). Mortality increased with higher anti-ADAMTS13 antibody levels and lower ADAMTS13 antigen levels. Those with antibody levels in the upper quartile (antibody >77%) had a mortality of 16.9% compared with 5.0% for the lowest quartile (antibody <20%) (P 5 .004). Those with an antigen level in the lowest quartile (antigen <1.5%) had a mortality of 18% compared with 3.8% for the highest quartile (antigen >11%) (P 5 .005). The synergistic effect of anti-ADAMTS13 IgG antibody in the upper quartile and ADAMTS13 antigen in the lowest quartile had the highest mortality of 27.3%. We conclude that both anti-ADAMTS13 IgG antibody and ADAMTS13 antigen levels correlate with outcome in TTP with increased cardiac and neurological involvement and increased mortality. (Blood. 2017;130(4):466-471)

This guideline was compiled according to the British Society for Haematology (BSH) process at https://b-s-h.org.uk/med ia/16732/bsh-guidance-development-process-dec-5-18.pdf. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http:// www.gradeworkinggroup.org. The references to support the recommendations are listed in the preceding discussion. Literature review The information contained in this review was gathered from several sources. These included references from a search of MEDLINE, EMBASE and the Cochrane databases to identify studies and reviews relevant to prophylaxis in patients with haemophilia, abstracts from international meetings and references known to the authors (Appendix S1). Review of the manuscript The writing group produced the draft guideline, which was subsequently revised by consensus. Review of the manuscript was performed by the BSH Guidelines Committee Haemostasis and Thrombosis Taskforce, the BSH Guidelines Committee and the Haemostasis and Thrombosis sounding board of the BSH. It was also on the members section of the BSH website for comment. It has also been reviewed by members of the United Kingdom Haemophilia Centre Doctors' Organisation (UKHCDO) Advisory Board, Haemophilia Nurses Association (HNA), Haemophilia Chartered Physiotherapists Association (HCPA); these organisations do not necessarily approve or endorse the contents.

SummaryIt is estimated that up to 1% of the general population has a congenital bleeding disorder. With this level of disease burden, it is more likely than not that any practising surgeon or anaesthetist will, at one time or another, have occasion to manage one such patient. Congenital haemophilia, both A and B, von Willebrand's disease, and inherited qualitative platelet defects, constitute the bulk of these disorders, with the rest distributed between much rarer conditions. Although looking after such patients will continue to pose a challenge to anaesthetists, recent and continuing advances in haemostatic products, coupled with increasing awareness of haemostatic care, means that surgery in this challenging group of patients is safer now than ever before, and can now be undertaken with a degree of confidence not possible even two decades ago. Central to these recent successes has been the continuing evolution of specialised healthcare services; in particular, Haemophilia Comprehensive Care Centres. Of equal importance, at least in developed countries, has been the ease of access to highly purified, safe and effective haemostatic products. The key to successful surgical management of the patient with a bleeding disorder is a multidisciplinary approach involving not only surgeons, anaesthetists and haematologists, but also laboratory scientists, specialist physiotherapists and haemophilia nurses. With careful planning, most surgical and invasive procedures can be carried out safely in persons with haemophilia and other bleeding disorders.