HaemophiliaVolume 29, Issue 4 p. 1160-1162 LETTER TO THE EDITOR Mild FVII deficiency – Correlation between genotype and phenotype Craig Fraser, Craig Fraser Aberdeen Royal Infirmary, Foresterhill Health Campus, Foresterhill Road, Aberdeen, UKSearch for more papers by this authorHenry G. Watson, Henry G. Watson University of Aberdeen School of Medicine, Medical Sciences and Nutrition, Polwarth Building, Foresterhill, Aberdeen, UKSearch for more papers by this authorMohammed M. Khan, Corresponding Author Mohammed M. Khan [email protected] Aberdeen Royal Infirmary, Foresterhill Health Campus, Foresterhill Road, Aberdeen, UK Correspondence Mohammed Khan, Department of Haematology, Aberdeen Royal Infirmary, Foresterhill Health Campus, Foresterhill Road, Aberdeen AB25 2ZN, UK. Email: [email protected]Search for more papers by this author Craig Fraser, Craig Fraser Aberdeen Royal Infirmary, Foresterhill Health Campus, Foresterhill Road, Aberdeen, UKSearch for more papers by this authorHenry G. Watson, Henry G. Watson University of Aberdeen School of Medicine, Medical Sciences and Nutrition, Polwarth Building, Foresterhill, Aberdeen, UKSearch for more papers by this authorMohammed M. Khan, Corresponding Author Mohammed M. Khan [email protected] Aberdeen Royal Infirmary, Foresterhill Health Campus, Foresterhill Road, Aberdeen, UK Correspondence Mohammed Khan, Department of Haematology, Aberdeen Royal Infirmary, Foresterhill Health Campus, Foresterhill Road, Aberdeen AB25 2ZN, UK. Email: [email protected]Search for more papers by this author First published: 13 June 2023 https://doi.org/10.1111/hae.14817Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. REFERENCES 1Mumford AD, Ackroyd S, Alikhan R, et al. Guideline for the diagnosis and management of the rare coagulation disorders: a United Kingdom Haemophilia Centre Doctors’ Organisation guideline on behalf of the British Committee for Standards in Haematology. Br J Haematol. 2014; 167(3): 304-326. doi:10.1111/bjh.13058 2Herrmann FH, Wulff K, Auerswald G, et al. Factor VII deficiency: clinical manifestation of 717 subjects from Europe and Latin America with mutations in the factor 7 gene. Haemophilia. 2009; 15(1): 267-280. doi:10.1111/j.1365-2516.2008.01910.x 3Rodeghiero F, Tosetto A, Abshire T, et al. ISTH/SSC bleeding assessment tool: a standardized questionnaire and a proposal for a new bleeding score for inherited bleeding disorders. J Thromb Haemost. 2010; 8(9): 2063-2065. doi:10.1111/j.1538-7836.2010.03975.x 4Bowman R, Joosen AMCP, Welch AA, et al. Factor VII, blood lipids and fat intake: gene-nutrient interaction and risk of coronary heart disease with the factor VII R353Q polymorphism. Eur J Clin Nutr. 2009; 63: 771-777. doi:10.1038/ejcn.2008.28 5Bernardi F, Marchetti G, Pinotti M, et al. Factor VII gene polymorphisms contribute about one third of the factor VII level variation in plasma. Arterioscler Thromb Vasc Biol. 1996; 16(1): 72-76. doi:10.1161/ATVB.16v01.0072 6Mo X, Hao Y, Yang X, Chen S, Lu X, Gu D. Association between polymorphisms in the coagulation factor VII gene and coronary heart disease risk in different ethnicities: a meta-analysis. BMC Med Genet. 2011; 12: 107. doi:10.1186/1471-2350-12-107 7Hunault M, Arbini AA, Lopaciuk S, Carew JA, Bauer KA. The Arg353Gln polymorphism reduces the level of coagulation factor VII. In vivo and in vitro studies. Arterioscler Thromb Vasc Biol. 1997; 17(11): 2825-2829. doi:10.1161/01.atv.17.11.2825 PMID: 9409261 8Bozzini C, Girelli D, Bernardi F, et al. Influence of polymorphisms in the factor VII gene promoter on activated factor VII levels and on the risk of myocardial infarction in advanced coronary atherosclerosis. Thromb Haemost. 2004; 92(3): 541-549. doi:10.1160/TH04-02-0130 9Adler M, Kaufmann J, Alberio L, Nagler M. Diagnostic utility of the ISTH bleeding assessment tool in patients with suspected platelet function disorders. J Thromb Haemost. 2019; 17(7): 1104-1112. doi:10.1111/jth.14454 10Quintavalle G, Riccardi F, Rivolta GF, et al. F7 gene variants modulate protein levels in a large cohort of patients with factor VII deficiency. Results from a genotype-phenotype study. Thromb Haemost. 2017; 117(8): 1455-1464. doi:10.1160/TH17-02-0085. Epub 2017 Apr 27. PMID: 28447100 Volume29, Issue4July 2023Pages 1160-1162 ReferencesRelatedInformation

Background: Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is a rare syndrome associated with adenoviral vector vaccines for COVID-19. The syndrome is characterized by thrombosis, anti-platelet factor 4 (PF4) antibodies, thrombocytopenia, high D-dimer, and hypofibrinogenemia.Objectives: To investigate abnormalities in fibrinolysis that contribute to the clinical features of VITT.Methods: Plasma samples from 18 suspected VITT cases were tested for anti-PF4 by ELISA and characterized as meeting criteria for VITT (11/18) or deemed unlikely (7/18; non-VITT). Antigen levels of PAI-1, factor XIII (FXIII), plasmin-alpha 2antiplasmin (PAP), and inflammatory markers were quantified. Plasmin generation was quantified by chromogenic substrate. Western blotting was performed with antibodies to fibrinogen, FXIII-A, and plasminogen.Results: VITT patients 10/11 had scores indicative of overt disseminated intravascular coagulation, while 0/7 non-VITT patients met the criteria. VITT patients had significantly higher levels of inflammatory markers, IL-1 beta, IL-6, IL-8, TNF alpha, and C-reactive protein. In VITT patients, both fibrinogen and FXIII levels were significantly lower, while PAP and tPA-mediated plasmin generation were higher compared to non-VITT patients. Evidence of fibrinogenolysis was observed in 9/11 VITT patients but not in non-VITT patients or healthy controls. Fibrinogen degradation products were apparent, with obvious cleavage of the fibrinogen alpha-chain. PAP complex was evident in those VITT patients with fibrinogenolysis, but not in non-VITT patients or healthy donors.Conclusion: VITT patients show evidence of overt disseminated intravascular coagulation and fibrinogenolysis, mediated by dysregulated plasmin generation, as evidenced by increased PAP and plasmin generation. These observations are consistent with the clinical presentation of both thrombosis and bleeding in VITT.

Background Temporary lower limb immobilisation following injury is a risk factor for symptomatic venous thromboembolism (VTE). Pharmacological thromboprophylaxis can mitigate this risk but it is unclear which patients benefit from this intervention. The Aberdeen VTE risk tool was developed to tailor thromboprophylaxis decisions in these patients and this evaluation aimed to describe its performance in clinical practice. Secondarily, diagnostic metrics were compared with other risk assessment methods (RAMs). Methods A prospective cohort service evaluation was conducted. Adult patients (≥16 years) managed with lower limb immobilisation for injury who were evaluated with the Aberdeen VTE risk tool prior to discharge from the ED were identified contemporaneously between February 2014 and December 2020. Electronic patient records were scrutinised up to 3 months after removal of immobilisation for the development of symptomatic VTE or sudden death due to pulmonary embolism (PE). Other RAMs, including the Thrombosis Risk Prediction for Patients with cast immobilisation (TRiP(cast)) and Plymouth scores, were assimilated retrospectively and diagnostic performance compared. Results Of 1763 patients (mean age 46 (SD 18) years, 51% women), 15 (0.85%, 95% CI 0.52% to 1.40%) suffered a symptomatic VTE or death due to PE. The Aberdeen VTE tool identified 1053 (59.7%) patients for thromboprophylaxis with a sensitivity of 80.0% (95% CI 54.8% to 93.0%) and specificity of 40.4% (95% CI 38.1% to 42.6%) for the primary outcome. In 1695 patients, fewer were identified as high risk by the TRiP(cast) (33.3%) and Plymouth (24.4%) scores, but with greater specificity, 67.0% and 75.6%, respectively, than dichotomous RAMs, including the Aberdeen VTE tool. Conclusion Routine use of the Aberdeen VTE tool in our population resulted in an incidence of symptomatic VTE of less than 1%. Ordinal RAMs, such as the TRiP(cast) score, may more accurately reflect VTE risk and permit more individually tailored thromboprophylaxis decisions but prospective comparison is needed.

Hydroxycarbamide (HC) is used as a cytoreductive treatment in myeloproliferative neoplasms (MPN). Observational studies have raised the possibility that HC contributes to the development of secondary malignancies, including skin tumours in MPN patients. In this retrospective observational study, we report a single-centre experience of 324 HC-treated MPN patients with long-term follow-up, compared to 47 MPN patients not on HC. Thirty-three patients (10.2%) (HC) versus one patient (2.1%) (no HC) developed skin tumours during follow-up (Hazard ratios [HR] 5.70, 95% confidence intervals 0.66-48.09, p = 0.112). However, male gender, age at MPN diagnosis, type of MPN (polycythaemia rubra vera) and previous history of skin cancer were prognostic variables associated with development of skin cancer.

Polycythaemia vera (PV) is a clonal proliferative disorder of the bone marrow characterised by autonomous haematopoiesis, which results in a panmyelosis in the peripheral blood. It is typically characterised by an acquired mutation in JAK-2 V617F. Progression to myelofibrosis (MF), characterised by worsening cytopenias and the development of constitutional symptoms, is seen in up to 10% of cases. Extramedullary haematopoiesis (EMH) in the spleen is a common finding in myelofibrotic transformation, but elsewhere in the body it is extremely unusual. We report the case of a 69-year-old male whose PV progressed to secondary MF and who presented with compression of the thoracic spinal cord directly as a result of EMH. Cytogenetic and molecular findings in the bone marrow were in keeping with evolving myeloid disease. He was managed by surgical laminectomy with an excellent outcome. Extramedullary haematopoiesis may be seen in both PV and on transformation to MF. This very rare complication should be borne in mind when managing patients with myeloproliferative disorders.

BACKGROUND:Severe COVID-19 disease is associated with thrombotic complications and extensive fibrin deposition. This study investigates whether the hemostatic complications in COVID-19 disease arise due to dysregulation of the fibrinolytic system.METHODS:This prospective study analyzed fibrinolytic profiles of 113 patients hospitalized with COVID-19 disease with 24 patients with non-COVID-19 respiratory infection and healthy controls. Antigens were quantified by Ella system or ELISA, clot lysis by turbidimetric assay, and plasminogen activator inhibitor-1 (PAI-1)/plasmin activity using chromogenic substrates. Clot structure was visualized by confocal microscopy.RESULTS:PAI-1 and its cofactor, vitronectin, are significantly elevated in patients with COVID-19 disease compared with those with non-COVID-19 respiratory infection and healthy control groups. Thrombin activatable fibrinolysis inhibitor and tissue plasminogen activator were elevated in patients with COVID-19 disease relative to healthy controls. PAI-1 and tissue plasminogen activator (tPA) were associated with more severe COVID-19 disease severity. Clots formed from COVID-19 plasma demonstrate an altered fibrin network, with attenuated fiber length and increased branching. Functional studies reveal that plasmin generation and clot lysis were markedly attenuated in COVID-19 disease, while PAI-1 activity was elevated. Clot lysis time significantly correlated with PAI-1 levels. Stratification of COVID-19 samples according to PAI-1 levels reveals significantly faster lysis when using the PAI-1 resistant (tPA) variant, tenecteplase, over alteplase lysis.CONCLUSION:This study shows that the suboptimal fibrinolytic response in COVID-19 disease is directly attributable to elevated levels of PAI-1, which attenuate plasmin generation. These data highlight the important prognostic potential of PAI-1 and the possibility of using pre-existing drugs, such as tenecteplase, to treat COVID-19 disease and potentially other respiratory diseases.

International Journal of Laboratory HematologyVolume 43, Issue 5 p. e252-e253 LETTER TO THE EDITOR Outcomes in patients with nontriple antiphospholipid syndrome (APS) anticoagulated with rivaroxaban Thura Win Htut, Thura Win Htut orcid.org/0000-0002-5508-1472 Department Haematology, Aberdeen Royal Infirmary, Foresterhill Health Campus, Aberdeen, UKSearch for more papers by this authorDenis Milne, Denis Milne Department Haematology, Aberdeen Royal Infirmary, Foresterhill Health Campus, Aberdeen, UKSearch for more papers by this authorMohammed M. Khan, Mohammed M. Khan Department Haematology, Aberdeen Royal Infirmary, Foresterhill Health Campus, Aberdeen, UKSearch for more papers by this authorHenry G. Watson, Corresponding Author Henry G. Watson henry.watson@nhs.scot Department Haematology, Aberdeen Royal Infirmary, Foresterhill Health Campus, Aberdeen, UK Correspondence Henry G Watson, Consultant Haematologist and Honorary Professor of Medicine, Department of Haematology, Aberdeen Royal Infirmary, Foresterhill Health Campus, Aberdeen AB25 2ZN, UK. Email: henry.watson@nhs.scotSearch for more papers by this author Thura Win Htut, Thura Win Htut orcid.org/0000-0002-5508-1472 Department Haematology, Aberdeen Royal Infirmary, Foresterhill Health Campus, Aberdeen, UKSearch for more papers by this authorDenis Milne, Denis Milne Department Haematology, Aberdeen Royal Infirmary, Foresterhill Health Campus, Aberdeen, UKSearch for more papers by this authorMohammed M. Khan, Mohammed M. Khan Department Haematology, Aberdeen Royal Infirmary, Foresterhill Health Campus, Aberdeen, UKSearch for more papers by this authorHenry G. Watson, Corresponding Author Henry G. Watson henry.watson@nhs.scot Department Haematology, Aberdeen Royal Infirmary, Foresterhill Health Campus, Aberdeen, UK Correspondence Henry G Watson, Consultant Haematologist and Honorary Professor of Medicine, Department of Haematology, Aberdeen Royal Infirmary, Foresterhill Health Campus, Aberdeen AB25 2ZN, UK. Email: henry.watson@nhs.scotSearch for more papers by this author First published: 20 January 2021 https://doi.org/10.1111/ijlh.13464Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume43, Issue5October 2021Pages e252-e253 RelatedInformation

We our observations on a cohort of patients with cerebral vein sinus thrombosis. A notable finding we is the high proportion of individuals with antiphospholipid antibodies. Cerebral venous sinus thrombosis (CVST) is rare, accounting for 0 – 1% of all strokes. 1 The role of early diagnosis and anticoagulation is well established. 2,3 Less is known about the patho-genesis of CVST, its association with thrombophilic abnormalities and the optimal duration of anticoagulation in patients presenting with a first episode. Here we report the investigation, management and outcomes of patients diagnosed with CVST in our centre over 4 years.

Stable therapeutic anticoagulation protects patients with a predisposition to thrombosis while limiting the risk of bleeding. Therapeutic anticoagulation using vitamin K antagonists (VKAs) is most readily achieved in patients with consistent dietary vitamin K intake (Shearer, 1995). Poor dietary vitamin K intake enhances the pharmacodynamic effect of VKAs and confers increased risk of bleeding (Sconce et al., 2007; Rombouts et al., 2010), estimated to occur in 3–4% of patients taking warfarin (Hansen et al., 2018). Vitamin K supplementation has been proposed to improve control for patients on VKAs in whom conventional dosing algorithms have failed (Udall, 1968). This approach is not yet widely adopted in clinical practice, largely because patient studies have been unable to demonstrate any consistent benefit (Mahtani et al., 2014; Violi et al., 2016). The current dietary advice given to patients is to maintain a consistent vitamin K intake by avoiding changes in dietary habits and abstaining from foods perceived as being rich in vitamin K (Violi et al., 2016). The British Journal of Haematology guidelines on oral anticoagulation with warfarin (Keeling et al., 2011) state that fluctuations in international normalised ratio (INR) can be reduced for patients with unstable INRs by supplementing the diet with 100–150 µg vitamin K or altering the dietary intake of vitamin K. A 2017 survey by the UK NEQAS for Blood Coagulation found that the use of vitamin K supplementation in anticoagulation centres in the UK is uncommon. Of the 4438 centres surveyed in the UK, Ireland and New Zealand, 577 responded. One percent of respondents indicated that they use vitamin K supplementation routinely in all patients on VKAs and 11% indicated it is used in select patient groups (patients with low serum transthyretin concentrations/concern over dietary intake). To understand the reasons for the disparity between the guidelines and routine clinical practice we must consider the barriers to the use of supplements or dietary modifications. For supplements, there is insufficient regulation for clinical use (they are classed as a food rather than a drug). With no certified formulation designed for use in anticoagulation, clinicians are limited to advising the use of over-the-counter supplements. The vitamin K content of these supplements varies, and in the UK is typically 75 µg/tablet (UK RDI), although some do not include any vitamin K. There is also limited assurance in the accuracy of the stated vitamin K content (Bartle et al., 2013). Moreover, supplements often simply state ‘vitamin K’ on their nutritional information and, although most are likely to contain phylloquinone (vitamin K1), some are also available containing menaquinone-4 or menaquinone-7 (both from the vitamin K2 series), which have different pharmacological properties to vitamin K1. Some tablet formulations may have stability issues (depending on the excipient used), as vitamin K is known to be unstable in alkaline conditions. Multi-vitamin supplements often also contain vitamin E, and there is a known interaction between vitamins E and K, resulting in lowered vitamin K stores (Traber, 2008). When considering the challenges associated with modifying dietary habits, problems are related to the consistency of the intake of foods rich in vitamin K1 (kale, cabbage, spinach, etc.). Clinical trials of dietary modifications in anticoagulated patients showed that by increasing intake by ≥150 µg/day, the quality of anticoagulation was improved in patients with a history of instability (Sorano et al., 1993; Ferland et al., 2019). Here we provide the rationale for a simplified approach to dietary modification, with the objective of helping anticoagulation centres to trial this approach. Supermarkets in the UK commonly stock frozen spinach in pre-prepared portions, which makes it possible to maintain portion-control and ensure a consistent vitamin K1 intake. Spinach only contains vitamin K1 (rather than other forms of vitamin K) and very little vitamin E. The vitamin K1 content has been reliably estimated for raw spinach (498 µg/100 g, SD = 155), and boiled spinach (525 µg/100 g, SD = 72) (Kamao et al., 2007). A 750 g bag of frozen chopped spinach portions, costing £1.20, contained 25 individual portions weighing on average of 30g each (range = 26–32 g). After boiling for five minutes, the drained spinach weighed on average 26 g per portion. Applying published data on the vitamin K1 content of spinach, this equates to 110 µg/portion of frozen spinach. Vitamin K1 is heat stable, surviving the cooking process intact, and is insoluble in water used for cooking ‒ hence the higher content in boiled spinach (per weight) compared to raw. The bioavailability of vitamin K1 in spinach differs from that in supplements. The vitamin K1 absorption profiles are shown following dietary supplementation and an equivalent IV dose (Fig 1) (Garber et al., 1999) and (Fig 2) (Gijsbers et al., 1996). Oral supplementation and intravenous vitamin K1 result in highly elevated serum vitamin K1 concentrations, remaining above the upper limit of the reference range for many hours post-administration. In comparison, the equivalent dietary vitamin K1 intake results in a lowered peak serum concentration but is more constantly within the reference range. It is therefore likely that this regime is better suited for achieving consistent anticoagulation. It is also worth noting that dietary vitamin K1 absorption is improved by consuming it with oil to stimulate bile secretion. We suggest that a controlled daily portion of spinach is a feasible approach to enhanced anticoagulant control. One daily portion costs <5 pence per patient and provides a consistent dose of vitamin K1, giving stable serum vitamin K1 concentrations. No weighing or special preparation is required, which makes it suitable for integration into any dietary routine. We suggest that one or two portions should be consumed daily (depending on body mass) with an oil, or combined with other foods containing fat. In addition to the possibility of improved anticoagulation control, benefits for patients may include the concomitant increased intake of potassium, vitamin C and folate. Clinicians should also consider that the relatively high oxalate content of spinach may make this approach unsuitable for those at risk of developing kidney stones and there may also be a requirement to monitor iron stores since oxalate inhibits iron absorption.

Introduction It is known that D-dimer levels increase with age and several studies have evaluated the use of an age-adjusted (AA) cut-off in the initial assessment of suspected venous thromboembolism (VTE). We performed a retrospective study to assess the effect that using an AA D-dimer in the DASH score would have on the recommended duration of anticoagulant treatment for patients following a first unprovoked episode of VTE and then compared this with the advice that has been given to patients using a fixed cut-off D-dimer in the DASH score. Methods Data were collected for the period from April 2014 to October 2017. For each patient, the DASH score by a single cut-off D-dimer value (500 ng/mL) as well as an AA D-dimer cut-off value (D-dimer cut-off value equal to age in years x 10) was calculated for patients over 50 years. The Vienna prediction model was employed alongside this to compare the VTE recurrence risk using a well-established method. Results A total of 204 patients were eligible for analysis, 145 of whom were over the age of 50 years. In 24 of these patients, the use of the AA D-dimer made a significant impact on the predicted risk of recurrence using the DASH score and would have likely changed the recommendation to offer long-term anticoagulation. Conclusion As an age-adjusted D-dimer cut-off has been assessed in the diagnostic setting, it would be logical and appropriate to also consider this philosophy in the prediction of the risk of recurrence of VTE following a first unprovoked event.

Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare thrombomi-croangiopathy 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.

Background: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without previous cardiovascular disease (primary prevention). Methods: In CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), 4401 participants with type 2 diabetes mellitus and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care. Results: Primary prevention participants (n=2181, 49.6%) were younger (61 versus 65 years), were more often female (37% versus 31%), and had shorter duration of diabetes mellitus (15 years versus 16 years) compared with secondary prevention participants (n=2220, 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80 [95% CI, 0.67-0.95]; P=0.01), with consistent reductions in both the primary (HR, 0.68 [95% CI, 0.49-0.94]) and secondary (HR, 0.85 [95% CI, 0.69-1.06]) prevention groups (P for interaction=0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78 [95% CI, 0.61-1.00]), nonfatal myocardial infarction (HR, 0.81 [95% CI, 0.59-1.10]), and nonfatal stroke (HR, 0.80 [95% CI, 0.56-1.15]). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups (P for interaction >0.5 for each outcome). Conclusions: Canagliflozin significantly reduced major cardiovascular events and kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, including in participants who did not have previous cardiovascular disease.

The British Journal of Haematology publishes original research papers in clinical, laboratory and experimental haematology. The Journal also features annotations, reviews, short reports, images in haematology and Letters to the Editor.

Background and aims: Indiscriminate coagulation testing in emergency general surgical patients can lead to inappropriate delay in surgery, cause unnecessary concern and is associated with significant cost. The British Committee for Standards in Haematology recommends against coagulation testing to predict peri-operative bleeding risk in unselected patients. Our aim was to assess the appropriateness of coagulation tests performed in emergency general surgical patients and evaluate the effect of a series of educational interventions on clinical practice. Methods and results: Appropriate indications for performing coagulation testing included a positive bleeding history, the presence of liver disease/cholestasis, sepsis or use of anticoagulants. Initial data on 142 patients were collected over 2 weeks of receiving. Following analysis, indications for appropriate coagulation testing were highlighted and data were collected on a further 190 patients. Comparing the audit cycles, we observed a decrease in the proportion of patients who underwent routine testing (49.3% vs 32.6%; p = 0.002) and inappropriate testing (67% of tests vs 34% of tests; p < 0.001). Despite being highlighted, there was no evidence of improved documentation of bleeding histories on admission. Conclusions: This observational study suggests that simple educational messages can reduce the inappropriate use of coagulation screening tests in general surgical emergencies. This seems to result from clarification of the appropriate surgical indications for coagulation testing in this group.

Acquired factor XIII (FXIII) deficiency is a rare and life-threatening condition that is often misdiagnosed or missed completely. A 72-year-old woman presented with symptoms of major unprovoked bleeding but routine coagulation screening tests and platelet count were normal. Low activated FXIII (FXIIIa) activity levels and abnormal urea clot stability led to diagnosis of acquired FXIII deficiency. A modified Bethesda inhibitor titre of 1.6 Bethesda units/ml indicated the presence of a FXIII inhibitor. Bleeding responded to a single dose of FXIII concentrate and immunosuppression with prednisolone induced remission. A subsequent relapse was treated with combined prednisolone and Rituximab resulting in a prolonged, ongoing remission. Here we analyse the mechanisms underlying this idiopathic case of acquired FXIII deficiency. Prospective analysis of patient plasma revealed minimal FXIIIa activity and antigen in presentation and relapse samples. Thrombi formed from these samples lysed rapidly and showed an absence of cross-linked α2 AP. Western blotting revealed the presence of FXIII-B, indicating only FXIII-A and FXIII-A2 B2 were affected. FXIII activity and antigen levels normalised on remission. Our data suggest the presence of inhibitor-induced clearance of FXIII from plasma. As a consequence, reduced thrombus stability was evident due to defective α2 AP cross-linking, thereby explaining symptoms of excessive bleeding.

Congenital thrombotic thrombocytopenic purpura (cTTP) is a rare thrombomicroangiopathy in which there is an inherited deficiency of ADAMTS13. The prevalence of cTTP has been estimated at one per million per year and accounts for 5-10% of all TTP cases in international registries. Two main peaks of presentation are seen, in childhood and in pregnancy. The ADAMTS13 gene consists of 29 exons whilst the ADAMTS13 protein consists of 16 domains. Over 150 mutations spanning the entire length of ADAMTS13 have been discovered, but there is little evidence on their respective impact on the disease phenotype and evidence is lacking on the optimal management of patients.