Systematic pulmonary embolism follow-up increases diagnostic rates of chronic thromboembolic pulmonary hypertension and identifies less severe disease: results from the ASPIRE Registry.

BACKGROUND: Diagnostic rates and risk factors for the subsequent development of chronic thromboembolic pulmonary hypertension (CTEPH) following pulmonary embolism (PE) are not well defined. METHODS: Over a 10-year period (2010-2020), consecutive patients attending a PE follow-up clinic in Sheffield, UK (population 554 600) and all patients diagnosed with CTEPH at a pulmonary hypertension (PH) referral centre in Sheffield (referral population estimated 15-20 million) were included. RESULTS: Of 1956 patients attending the Sheffield PE clinic 3 months following a diagnosis of acute PE, 41 were diagnosed with CTEPH with a cumulative incidence of 2.10%, with 1.89% diagnosed within 2 years. Of 809 patients presenting with pulmonary hypertension (PH) and diagnosed with CTEPH, 32 were Sheffield residents and 777 were non-Sheffield residents. Patients diagnosed with CTEPH at the PE follow-up clinic had shorter symptom duration (p<0.01), better exercise capacity (p<0.05) and less severe pulmonary haemodynamics (p<0.01) compared with patients referred with suspected PH. Patients with no major transient risk factors present at the time of acute PE had a significantly higher risk of CTEPH compared with patients with major transient risk factors (OR 3.6, 95% CI 1.11-11.91; p=0.03). The presence of three computed tomography (CT) features of PH in combination with two or more out of four features of chronic thromboembolic pulmonary disease at the index PE was found in 19% of patients who developed CTEPH and in 0% of patients who did not. Diagnostic rates and pulmonary endarterectomy (PEA) rates were higher at 13.2 and 3.6 per million per year, respectively, for Sheffield residents compared with 3.9-5.2 and 1.7-2.3 per million per year, respectively, for non-Sheffield residents. CONCLUSIONS: In the real-world setting a dedicated PE follow-up pathway identifies patients with less severe CTEPH and increases population-based CTEPH diagnostic and PEA rates. At the time of acute PE diagnosis the absence of major transient risk factors, CT features of PH and chronic thromboembolism are risk factors for a subsequent diagnosis of CTEPH.

Agreement between one stage and chromogenic assays in samples from patients receiving recombinant porcine FVIII (Obizur, Susoctocog-alfa).

INTRODUCTION: Recombinant porcine FVIII (rpFVIII) (Obizur, Susoctcog-alfa, Takeda, Japan) is licensed for the treatment of bleeding in acquired Haemophilia A (AHA). The summary of product characteristics state that monitoring should be by one stage assay (OSA) rather than chromogenic assay (CSA). CSA have been shown to underestimate activity when rpFVIII is added to plasma in vitro. METHODS: Samples from three AHA patients (n = 21) (pre- and post rpFVIII) were assessed using FVIII:C assays; OSA methods: Actin, Actin FS, Actin FSL and Pathromtin SL performed on CS5100i (Sysmex, Kobe, Japan); APTT-SP, SynthASil and SynthAFax performed on ACL TOP (Werfen, Barcelona, Spain). CSA methods on CS5100i: Siemens Chromogenic Assay, Biophen FVIII:C, Technochrom FVIII:C; on ACL TOP: Rox Factor VIII, Coamatic Factor VIII and CRYOcheck Factor VIII. RESULTS: OSA and CSA varied according to reagent used median OSA 61 IU/dL (range 41.5-81 IU/dL (ANOVA p < 0.0001)) median CSA 46.5 IU/dL (range of method specific medians 36.5-84 IU/dL (ANOVA p < 0.0001)). Amongst OSA, Actin FS was associated with the highest FVIII:C, APTT-SP was associated with the lowest. Variation in CSA results by different methods was also seen with highest FVIII:C levels obtained using the Technochrom FVIII:C and the lowest levels obtained with Siemens Assay. CONCLUSION: The relationship between OSA and CSA was not consistent between method or patient. Previously there has been reports of underestimation by CSA in in vitro spiked samples. Investigation into concentration of phospholipids in the APTT reagents may explain some of these variations.

An expert consensus to define how higher standards of equitable care for von Willebrand disease can be achieved in the UK and Republic of Ireland.

INTRODUCTION: Von Willebrand Disease (VWD) is the most common inherited bleeding disorder. However, recognition of the disease by both the public and healthcare professionals lags behind that of other bleeding disorders, leading to delays in diagnosis and treatment for patients. Updated national guidelines are needed to highlight an appropriate pathway for managing VWD patients in a timelier manner. AIM: To identify ways in which care for VWD can be achieved on a more equitable basis. METHODS: Using a modified Delphi approach, a panel of VWD experts developed 29 statements across five key themes. These were used to form an online survey that was distributed to healthcare professionals involved in VWD care across the UK and Republic of Ireland (ROI). Stopping criteria comprised 50 responses received, a 3-month window for response (February-April 2022) and 90% of statements passing consensus threshold. Threshold for consensus for each statement was agreed at 75%. RESULTS: A total of 66 responses were analysed with 29/29 statements achieving consensus of which 27 attained ≥90% agreement. From the high degree of consensus, eight recommendations were derived regarding how detection and management of VWD can be improved to provide equity of care between men and women. CONCLUSION: Implementation of these eight recommendations across the VWD pathway has the potential to raise the standard of care for patients in the UK and ROI by reducing delays to diagnosis and treatment initiation.

The combination of emicizumab and recombinant factor VIII in plasma: Which assays can we use for accurate measurement?

INTRODUCTION: The bispecific antibody, emicizumab, is a prophylactic therapy used for the treatment of haemophilia A (HA). Patients may require additional replacement factor VIII (FVIII) to ensure adequate haemostasis. This study investigated the laboratory measurement of severe HA (SHA) plasma spiked with 36 combinations of emicizumab plus recombinant (r) FVIII concentrates. METHOD: FVIII assays were performed by one stage assay (OSA) using eight APTT reagents from three manufacturers and chromogenic assays (CSA) using seven kits. CSA kits comprised a range of bovine FX/FIXa, bovine FX/human FIXa or human FX/FIXa. Thrombin generation (TG) was assessed by CAT and ST-Genesia. RESULTS: Emicizumab-calibrated modified OSA and human FX CSA both overestimated rFVIII in the presence of emicizumab; median FVIII:C of up to 89% higher was observed in plasma spiked with both drugs compared to just rFVIII. In bovine FX CSA assays, there was a FVIII:C increase of up to 11% in plasmas spiked with both drugs compared to rFVIII alone. TG parameters were not all normalized by the presence of emicizumab however addition of rFVIII increased TG. ETP and peak thrombin were normalized at 50 µg/ml emicizumab using ST-Genesia but were still reduced at 75 µg/ml with CAT. Addition of rFVIII further normalized results. CONCLUSION: Modified OSA and human FX CSA could not distinguish between rFVIII or emicizumab. The presence of both emicizumab and rFVIII increased thrombin generation to normal levels compared to each drug alone. Bovine FX CSA can be used to accurately determine FVIII activity of rFVIII in plasma which also contains emicizumab.

Von Willebrand factor assays in patients with acquired immune thrombotic thrombocytopenia purpura treated with caplacizumab.

Acquired immune thrombotic thrombocytopenic purpura (iTTP) is a rare disease with a poor prognosis if undiagnosed. It is caused by autoantibody production to the von Willebrand factor (VWF) cleaving protease, A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13). Caplacizumab, an immunoglobulin directed to the platelet glycoprotein Ibα receptor of VWF, has been reported to induce quicker resolution of iTTP compared to placebo. The laboratory measurement of VWF activity was significantly reduced in clinical trials of caplacizumab. Several VWF assays are available in the UK and this study investigated whether differences in VWF parameters were present in 11 patients diagnosed with iTTP and treated with daily caplacizumab. Chromogenic factor VIII activity, VWF antigen, collagen binding activity, VWF multimers and six VWF activity assays were measured prior to caplacizumab therapy and on several occasions during treatment. VWF antigen and collagen binding activity levels were normal or borderline normal in all patients. Ultra-large molecular weight multimers were present in all patients following treatment. VWF activity assays were normal or reduced during treatment, but this was reagent and patient dependant. In the unusual scenario of a caplacizumab-treated patient requiring measurement of VWF activity, it is important that laboratories understand how their local reagents perform as results cannot be predicted.

Caution in Using the Activated Partial Thromboplastin Time to Monitor Argatroban in COVID-19 and Vaccine-Induced Immune Thrombocytopenia and Thrombosis (VITT).

INTRODUCTION: Argatroban is licensed for patients with heparin-induced thrombocytopenia and is conventionally monitored by activated partial thromboplastin time (APTT) ratio. The target range is 1.5 to 3.0 times the patients' baseline APTT and not exceeding 100 s, however this baseline is not always known. APTT is known to plateau at higher levels of argatroban, and is influenced by coagulopathies, lupus anticoagulant and raised FVIII levels. It has been used as a treatment for COVID-19 and Vaccine-induced Immune Thrombocytopenia and Thrombosis (VITT). Some recent publications have favored the use of anti-IIa methods to determine the plasma drug concentration of argatroban. METHODS: Plasma of 60 samples from 3 COVID-19 patients and 54 samples from 5 VITT patients were tested by APTT ratio and anti-IIa method (dilute thrombin time dTT). Actin FS APTT ratios were derived from the baseline APTT of the patient and the mean normal APTT. RESULTS: Mean APTT ratio derived from baseline was 1.71 (COVID-19), 1.33 (VITT) compared to APTT ratio by mean normal 1.65 (COVID-19), 1.48 (VITT). dTT mean concentration was 0.64 µg/ml (COVID-19) 0.53 µg/ml (VITT) with poor correlations to COVID-19 baseline APTT ratio r2 = 0.1526 p <0.0001, mean normal r2 = 0.2188 p < 0.0001; VITT baseline APTT ratio r2 = 0.04 p < 0.001, VITT mean normal r2 = 0.0064 p < 0.001. CONCLUSIONS: We believe that dTT is a superior method to monitor the concentration of argatroban, we have demonstrated significant differences between APTT ratios and dTT levels, which could have clinical impact. This is especially so in COVID-19 and VITT.

Cross-reacting recombinant porcine FVIII inhibitors in patients with acquired haemophilia A.

INTRODUCTION: Acquired haemophilia A (AHA) is a rare bleeding disorder caused by the development of autoantibodies to endogenous human factor VIII (hFVIII). If treatment of bleeding is required, one option is recombinant porcine FVIII (rpFVIII). Cross-reactivity between factor VIII inhibitors and rpFVIII has previously been described. AIM: The aim of this study was to retrospectively assess the incidence of cross-reacting anti-porcine inhibitors in patients diagnosed with AHA in two UK centres. METHODS: The plasma of fifty-one patients diagnosed with AHA via reduced FVIII:C and positive FVIII inhibitor titre as detected with a Nijmegen-Bethesda assay (NBA) was also tested by a porcine Bethesda assay (PBA). The NBA was modified by replacement of human FVIII with rpFVIII in the PBA, with determination of residual FVIII by one-stage clotting assay. RESULTS: The median FVIII inhibitor titre by NBA was 22.8 BU/mL (range: 0.8-1000 BU/mL). 37% of samples exhibited linear, type 1 kinetics in the NBA. Negative PBA was observed in 26 patients, and 25 were positive (median PBA: 3.5 BU/mL; range: 0.8-120 BU/mL). Type 1 kinetics were observed in 40% of PBA-positive patients. At NBA tires of greater than 100 BU/mL, the positive predictive value for the presence of porcine cross-reactivity was 100%. At NBA below 5 BU/mL, the negative predictive value for the presence of porcine cross-reactivity was 71%. CONCLUSION: Cross-reactivity between FVIII inhibitors and rpFVIII was observed in 49% of patients. The presence of inhibitors to rpFVIII may influence the treatment choice for patients with acquired haemophilia A.

Effects of emicizumab on APTT, one-stage and chromogenic assays of factor VIII in artificially spiked plasma and in samples from haemophilia A patients with inhibitors.

INTRODUCTION: Emicizumab (Hemlibra, Roche-Chugai) is a recombinant humanized bispecific IgG4 antibody which mimics some of the actions of activated factor VIII (FVIIIa) by binding to factor X (FX) and activated factor IX (FIXa) to activate FX. AIM: To evaluate the effect of emicizumab on the APTT, standard one-stage APTT-based FVIII activity assay (sOSA) using plasma calibrators, modified OSA (mOSA) using r2 Diagnostics emicizumab specific calibrator and chromogenic FVIII assays. Tests were performed on plasma artificially spiked with emicizumab and from four severe haemophilia A (SHA) patients treated with emicizumab. METHOD: APTT in spiked plasma was performed with 13 APTT reagents and in SHA patients with 5 reagents. OSA in spiked plasma was performed with 9 APTT reagents, 7 APTT reagents were used for OSA in SHA patients and six chromogenic substrate assays (CSA) were performed. RESULTS: In SHA, APTTs normalized after the first dose of emicizumab. At weeks 32/36 of treatment, the mean sOSA FVIII:C ranged from 2.47 IU/mL (Synthasil) to greater than 7.00 IU/mL with all other reagents. mOSA ranged from 59.8 µg/mL (Synthasil) to 74.5 µg/mL (APTT SP). Bovine CSA did not recover any FVIII:C activity. Hyphen Biomed human CSA, demonstrated FVIII activity when calibrated against a plasma calibrator. CONCLUSION: The APTT was significantly shortened in the presence of emicizumab. sOSA FVIII:C levels were erroneously high, and it is not recommended that these be performed. Quantification of emicizumab concentration was possible by mOSA. Human CSA was sensitive to emicizumab and surrogate FVIII:C activity could be determined. Bovine CSA were insensitive to emicizumab and could not be used to quantify emicizumab concentration.

A three-year prospective study of the presentation and clinical outcomes of major bleeding episodes associated with oral anticoagulant use in the UK (ORANGE study).

The outcomes of patients developing major bleeding while on oral anticoagulants remain largely unquantified. The objectives of this study were to: (i) describe the burden of major hemorrhage associated with all available oral anticoagulants in terms of proportion of bleeds which are intracranial hemorrhages, in-hospital mortality and duration of hospitalization following major bleeding; (ii) identify risk factors for mortality; and (iii) compare the characteristics of major hemorrhage between cases treated with warfarin and direct oral anticoagulants for the subgroups of patients with atrial fibrillation or venous thromboembolism. This was a multicenter, 3-year prospective cohort study of patients aged ≥18 years on oral anticoagulants who developed major hemorrhage leading to hospitalization. The patients were followed up for 30 days or until discharge or death, whichever occurred first. In total 2,192 patients (47% female, 81% on warfarin, median age 80 years) were reported between October 2013 and August 2016 from 32 hospitals in the UK. Bleeding sites were intracranial (44%), gastrointestinal (33%), and other (24%). The in-hospital mortality was 21% (95% CI: 19%-23%) overall, and 33% (95% CI: 30%-36%) for patients with intracranial hemorrhage. Intracranial hemorrhage, advanced age, spontaneous bleeding, liver failure and cancer were risk factors for death. Compared to warfarin-treated patients, patients treated with direct oral anticoagulants were older and had lower odds of subdural/epidural, subarachnoid and intracerebral bleeding. The mortality rate due to major bleeding was not different between patients being treated with warfarin or direct oral anticoagulants. Major bleeding while on oral anticoagulant therapy leads to considerable hospital stays and short-term mortality.

Thrombotic thrombocytopenic purpura and pregnancy: presentation, management, and subsequent pregnancy outcomes.

Pregnancy can precipitate thrombotic thrombocytopenic purpura (TTP). We present a prospective study of TTP cases from the United Kingdom Thrombotic Thrombocytopenic Purpura (UK TTP) Registry with clinical and laboratory data from the largest cohort of pregnancy-associated TTP and describe management through pregnancy, averting fetal loss and maternal complications. Thirty-five women presented with a first TTP episode during pregnancy: 23/47 with their first congenital TTP (cTTP) episode and 12/47 with acute acquired TTP in pregnancy. TTP presented primarily in the third trimester/postpartum, but fetal loss was highest in the second trimester. Fetal loss occurred in 16/38 pregnancies before cTTP was diagnosed, but in none of the 15 subsequent managed pregnancies. Seventeen of 23 congenital cases had a missense mutation, C3178T, within exon 24 (R1060W). There were 8 novel mutations. In acquired TTP presentations, fetal loss occurred in 5/18 pregnancies and 2 terminations because of disease. We also present data on 12 women with a history of nonpregnancy-associated TTP: 18 subsequent pregnancies have been successfully managed, guided by ADAMTS13 levels. cTTP presents more frequently than acquired TTP during pregnancy and must be differentiated by ADAMTS13 analysis. Careful diagnosis, monitoring, and treatment in congenital and acquired TTP have assisted in excellent pregnancy outcomes.

Management dilemmas in acute pulmonary embolism.

BACKGROUND: Physicians treating acute pulmonary embolism (PE) are faced with difficult management decisions while specific guidance from recent guidelines may be absent. METHODS: Fourteen clinical dilemmas were identified by physicians and haematologists with specific interests in acute and chronic PE. Current evidence was reviewed and a practical approach suggested. RESULTS: Management dilemmas discussed include: sub-massive PE, PE following recent stroke or surgery, thrombolysis dosing and use in cardiac arrest, surgical or catheter-based therapy, failure to respond to initial thrombolysis, PE in pregnancy, right atrial thrombus, role of caval filter insertion, incidental and sub-segmental PE, differentiating acute from chronic PE, early discharge and novel oral anticoagulants. CONCLUSION: The suggested approaches are based on a review of the available evidence and guidelines and on our clinical experience. Management in an individual patient requires clinical assessment of risks and benefits and also depends on local availability of therapeutic interventions.

Real world usage of PCC to "rapidly" correct warfarin induced coagulopathy.

BACKGROUND: Life threatening bleeding and emergency procedures in patients on vitamin K antagonists are indications for urgent reversal with prothrombin complex concentrate and vitamin K. Rapid reversal in these situations is emphasized in the literature and guidelines, but only very limited information is available on its real life use, especially on the timing of treatment in relation to presentation. MATERIALS AND METHODS: We retrospectively audited emergency warfarin reversal in 131 consecutive patients. We studied the indication, use of vitamin K, time between presentation and administration of vitamin K and PCC, effectiveness in INR reduction and clinical outcome. RESULTS: The median PCC dose was 26.8 IU/kg. The median INR was reduced from 3.1 to 1.2. Vitamin K (5 mg) was given in 91.6% of evaluable patients. We found significant delays in administration of PCC and vitamin K. The median time between presentation and administration of vitamin K/PCC was 3.6 and 5.2 hours respectively. The times in intracranial haemorrhage were 2.7 and 3.0 hours and in emergency procedures 17.4 and 15.9 hours respectively. Mortality related to bleeding was 7.6% overall but in patients with intracranial haemorrhage 22.8%. The thrombotic rate within 7 days of reversal was 1.5%. DISCUSSION: The local protocol for reversal with PCC and vitamin K was adhered to well but the delay in pre-procedural patients, suggests that intravenous vitamin K alone may be sufficient in many cases and PCC administration can be avoided by better planning. Intracranial haemorrhage in warfarinised patients carries a high mortality. Treatment delays should be avoided by making PCC stocks available within emergency departments, simple dosing structures independent of INR and administering PCC without waiting for INR and CT scan results in those with strong suspicion of intracranial haemorrhage and clear trauma. Future reports and studies should always include the time from presentation to PCC treatment.

Protamine reversal of low molecular weight heparin: clinically effective?

Low molecular weight heparins (LMWHs) are frequently used in the prophylaxis or treatment of venous thrombosis, acute coronary syndromes and peri-operative bridging. Major bleeding occurs in 1-4% depending on dose and underlying condition. Protamine is recommended for reversal but only partially reverses the anti-Xa activity and there are very limited data on clinical effectiveness. We retrospectively studied the effect of emergency reversal of LMWH with protamine in actively bleeding patients and patients requiring emergency surgery in our institution. Eighteen patients were identified through haematology referral/pharmacy records of protamine prescriptions between 1998 and 2009. Case notes were checked for the reversal indication, type/dose of LMWH, dose and clinical response to protamine, timing in relation to the last dose of LMWH and anti-Xa levels before and after protamine. All but one patient received enoxaparin. Fourteen were actively bleeding, three required emergency surgery without active bleeding and one had an accidental overdose without bleeding. The three patients requiring surgery had an uneventful procedure. In 12 of 14 patients with active bleeding, protamine could be evaluated. Bleeding stopped in eight. In the four with continuing bleeding, one had an additional coagulopathy. Protamine only partially affected anti-Xa levels. Protamine may be of use in reversing bleeding associated with LMWH but not in all patients. Anti-Xa levels were useful to assess the amount of anticoagulation before protamine administration but unhelpful in assessing its effect. Better reversal agents and methods to monitor LMWH therapy are required.

Incidence of factor VIII inhibitors throughout life in severe hemophilia A in the United Kingdom.

The age-adjusted incidence of new factor VIII inhibitors was analyzed in all United Kingdom patients with severe hemophilia A between 1990 and 2009. Three hundred fifteen new inhibitors were reported to the National Hemophilia Database in 2528 patients with severe hemophilia who were followed up for a median (interquartile range) of 12 (4-19) years. One hundred sixty (51%) of these arose in patients ≥ 5 years of age after a median (interquartile range) of 6 (4-11) years' follow-up. The incidence of new inhibitors was 64.29 per 1000 treatment-years in patients < 5 years of age and 5.31 per 1000 treatment-years at age 10-49 years, rising significantly (P = .01) to 10.49 per 1000 treatment-years in patients more than 60 years of age. Factor VIII inhibitors arise in patients with hemophilia A throughout life with a bimodal risk, being greatest in early childhood and in old age. HIV was associated with significantly fewer new inhibitors. The inhibitor incidence rate ratio in HIV-seropositive patients was 0.32 times that observed in HIV-seronegative patients (P < .001). Further study is required to explore the natural history of later-onset factor VIII inhibitors and to investigate other potential risk factors for inhibitor development in previously treated patients.

Guidelines for supportive care in multiple myeloma 2011.

Supportive care plays an increasingly important role in the modern management of multiple myeloma. While modern treatments have significantly prolonged overall and progression free survival through improved disease control, the vast majority of patients remain incurable, and live with the burden of the disease itself and the cumulative side effects of treatments. Maintenance of quality of life presents challenges at all stages of the disease from diagnosis through the multiple phases of active treatment to the end of life. Written on behalf of the British Committee for Standards in Haematology (BCSH) and the UK Myeloma Forum (UKMF), these evidence based guidelines summarize the current national consensus for supportive and symptomatic care in multiple myeloma in the following areas; pain management, peripheral neuropathy, skeletal complications, infection, anaemia, haemostasis and thrombosis, sedation, fatigue, nausea, vomiting, anorexia, constipation, diarrhoea, mucositis, bisphosphonate-induced osteonecrosis of the jaw, complementary therapies, holistic needs assessment and end of life care. Although most aspects of supportive care can be supervised by haematology teams primarily responsible for patients with multiple myeloma, multidisciplinary collaboration involving specialists in palliative medicine, pain management, radiotherapy and surgical specialities is essential, and guidance is provided for appropriate interdisciplinary referral. These guidelines should be read in conjunction with the BCSH/UKMF Guidelines for the Diagnosis and Management of Multiple Myeloma 2011.