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.

Long-term risk of relapse in immune-mediated thrombotic thrombocytopenic purpura and the role of anti-CD20 therapy.

Disease relapse is recognized as a risk in immune-mediated thrombotic thrombocytopenic purpura (iTTP) after treatment of the acute presenting episode. Identification of patients at risk of relapse and its patterns are yet to be clearly established. We reviewed patients with iTTP having had >3 years of follow-up over 10 years in the United Kingdom to identify patient characteristics for relapse, assess relapse rates and patterns, and response to anti-CD20 therapy in those with a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) relapses (ADAMTS13 activity of <20% without thrombocytopenia). We identified 443 patients demonstrating relapse rates of 40% at 5-year follow-up. At 10-year follow-up, no difference in relapse was observed irrespective of whether rituximab was used at acute presentation (P = .39). Black Caribbean ethnicity increased the risk of disease relapse in the British population. There was a distinct population of patients (6%) that relapsed early with subsequent frequent relapses occurring on average within 2 years (average time to relapse in subgroup, 1.7 years). Overall, nearly 60% of relapses described were ADAMTS13 relapses, with subsequent treatment reducing the risk of progression to clinical relapses. We demonstrate that iTTP diagnosed in the latter part of the study period had lower rates of clinical relapses (22.6% vs 11.1%, P = .0004) with the advent of regular monitoring and preemptive rituximab. In ADAMTS13 relapses, 96% responded to anti-CD20 therapy, achieving ADAMTS13 activity of >20%. Anti-CD20 therapy was demonstrated to be an effective long-term treatment regardless of relapse pattern and there was no loss of this treatment response after subsequent treatment episodes.

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.

Laboratory methods for monitoring argatroban in heparin-induced thrombocytopenia.

INTRODUCTION: The Summary of Product Characteristics for the direct thrombin inhibitor argatroban states monitoring should be by activated partial thromboplastin time (APTT), with a target range of 1.5-3.0 times the patients' baseline APTT. APTT may be influenced by coagulopathies, lupus anticoagulant and raised FVIII levels. Previous studies have shown sensitivity differences of APTT reagents to argatroban. Some recent publications have favoured the use of anti-IIa methods to determine the plasma drug concentration of argatroban. This study aims to compare the anti-IIa assays: Hemoclot thrombin inhibitor assay (HTI) and Ecarin chromogenic assay (ECA) alongside the APTT. METHODS: Residual plasma of 25 samples from 8 patients (3 with COVID-19 and HIT: n = 18, 5 with HIT: n = 7) was tested at two sites: site A: Sysmex CS5100 by HTI and APTT (Actin FS and SynthASil), and also on Stago STA Compact Max: ECA and APTT (CK Prest); and site B: Stago STA R Max 2 by ECA and APTT (Cephascreen). RESULTS: Mean APTT ratio was 1.96 (Actin FS), 1.84 (SynthASil), 1.59 (CK Prest) and 2.48 (Cephascreen). Mean argatroban concentration by HTI was 0.60 µg/mL and by ECA was 0.65 µg/mL (site A) and 0.70 µg/mL (site B). There was a poor correlation to HTI in APTT ratios (range r2  = .0235-0.4181) with stronger correlations between ECA methods to HTI (r2  = .8998 site A, r2  = .8734 site B). CONCLUSION: This study confirms previous publications on the unsuitability of APTT and expands this by being multisited and included APTT reagents that use mechanical clot detection. Both anti-IIa methods are more suitable.

Real-world experience with caplacizumab in the management of acute TTP.

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 trialed in 2 multicenter randomized controlled trials (RCTs) leading to European Union and US Food and Drug Administration approval, has been available in the United Kingdom (UK) through a patient access scheme. Data were collected retrospectively from 2018 to 2020 for 85 patients (4 children) receiving caplacizumab from 22 UK hospitals. Patient characteristics and outcomes in the real-world clinical setting were compared with caplacizumab trial end points and historical outcomes in the precaplacizumab era. Eighty-four of 85 patients received steroid and rituximab alongside PEX; 26% required intubation. Median time to platelet count normalization (3 days), duration of PEX (7 days), and hospital stay (12 days) were comparable with RCT data. Median duration of PEX and time from PEX initiation to platelet count normalization were favorable compared with historical outcomes (P < .05). Thrombotic thrombocytopenic purpura (TTP) recurred in 5 of 85 patients; all had persistent ADAMTS13 activity < 5 IU/dL. Of 31 adverse events in 26 patients, 17 of 31 (55%) were bleeding episodes, and 5 of 31 (16%) were thrombotic events (2 unrelated to caplacizumab); mortality was 6% (5/85), with no deaths attributed to caplacizumab. In 4 of 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, including pediatric patients, receiving caplacizumab outside of clinical trials. Representative of true clinical practice, the findings provide valuable information for clinicians treating TTP globally.

Characterization and treatment of congenital thrombotic thrombocytopenic purpura.

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.

Use of platelet transfusions prior to lumbar punctures or epidural anaesthesia for the prevention of complications in people with thrombocytopenia.

BACKGROUND: People with a low platelet count (thrombocytopenia) often require lumbar punctures or an epidural anaesthetic. Lumbar punctures can be diagnostic (haematological malignancies, subarachnoid haematoma, meningitis) or therapeutic (spinal anaesthetic, administration of chemotherapy). Epidural catheters are placed for administration of epidural anaesthetic. Current practice in many countries is to correct thrombocytopenia with platelet transfusions prior to lumbar punctures and epidural anaesthesia, in order to mitigate the risk of serious procedure-related bleeding. However, the platelet count threshold recommended prior to these procedures varies significantly from country to country. This indicates significant uncertainty among clinicians regarding the correct management of these patients. The risk of bleeding appears to be low, but if bleeding occurs it can be very serious (spinal haematoma). Consequently, people may be exposed to the risks of a platelet transfusion without any obvious clinical benefit.This is an update of a Cochrane Review first published in 2016. OBJECTIVES: To assess the effects of different platelet transfusion thresholds prior to a lumbar puncture or epidural anaesthesia in people with thrombocytopenia (low platelet count). SEARCH METHODS: We searched for randomised controlled trials (RCTs), non-randomised controlled trials (nRCTs), controlled before-after studies (CBAs), interrupted time series studies (ITSs), and cohort studies in CENTRAL (the Cochrane Library 2018, Issue 1), MEDLINE (from 1946), Embase (from 1974), the Transfusion Evidence Library (from 1950), and ongoing trial databases to 13 February 2018. SELECTION CRITERIA: We included RCTs, nRCTs, CBAs, ITSs, and cohort studies involving transfusions of platelet concentrates, prepared either from individual units of whole blood or by apheresis, and given to prevent bleeding in people of any age with thrombocytopenia requiring insertion of a lumbar puncture needle or epidural catheter.The original review only included RCTs. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane for including RCTs, nRCTs, CBAs, and ITSs. Two review authors independently assessed studies for eligibility and risk of bias and extracted data. Results were only expressed narratively. MAIN RESULTS: We identified no completed or ongoing RCTs, nRCTs, CBAs, or ITSs. No studies included people undergoing an epidural procedure. No studies compared different platelet count thresholds prior to a procedure.In this update we identified three retrospective cohort studies that contained participants who did and did not receive platelet transfusions prior to lumbar puncture procedures. All three studies were carried out in people with cancer, most of whom had a haematological malignancy. Two studies were in children, and one was in adults.The number of participants receiving platelet transfusions prior to the lumbar puncture procedures was not reported in one study. We therefore only summarised in a narrative form the relevant outcomes from two studies (150 participants; 129 children and 21 adults), in which the number of participants who received the transfusion was given.We judged the overall risk of bias for all reported outcomes for both studies as 'serious' based on the ROBINS-I tool.No procedure-related major bleeding occurred in the two studies that reported this outcome (2 studies, 150 participants, no cases, very low-quality evidence).There was no evidence of a difference in the risk of minor bleeding (traumatic tap) in participants who received platelet transfusions before a lumbar puncture and those who did not receive a platelet transfusion before the procedure (2 studies, 150 participants, very low-quality evidence). One of the 14 adults who received a platelet transfusion experienced minor bleeding (traumatic tap; defined as at least 500 x 106/L red blood cells in the cerebrospinal fluid); none of the seven adults who did not receive a platelet transfusion experienced this event. Ten children experienced minor bleeding (traumatic taps; defined as at least 100 x 106/L red blood cells in the cerebrospinal fluid), six out of the 57 children who received a platelet transfusion and four out of the 72 children who did not receive a platelet transfusion.No serious adverse events occurred in the one study that reported this outcome (1 study, 21 participants, very low-quality evidence).We found no studies that evaluated all-cause mortality within 30 days from the lumbar puncture procedure, length of hospital stay, proportion of participants who received platelet transfusions, or quality of life. AUTHORS' CONCLUSIONS: We found no evidence from RCTs or non-randomised studies on which to base an assessment of the correct platelet transfusion threshold prior to insertion of a lumbar puncture needle or epidural catheter. There are no ongoing registered RCTs assessing the effects of different platelet transfusion thresholds prior to the insertion of a lumbar puncture or epidural anaesthesia in people with thrombocytopenia. Any future study would need to be very large to detect a difference in the risk of bleeding. A study would need to be designed with at least 47,030 participants to be able to detect an increase in the number of people who had major procedure-related bleeding from 1 in 1000 to 2 in 1000. The use of a central data collection register or routinely collected electronic records (big data) is likely to be the only method to systematically gather data relevant to this population.

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.

Specific and global coagulation assays in the diagnosis of discrepant mild hemophilia A.

The activity of the factor VIII coagulation protein can be measured by three methods: a one or two-stage clotting assay and a chromogenic assay. The factor VIII activity of most individuals with mild hemophilia A is the same regardless of which method is employed. However, approximately 30% of patients show marked discrepancies in factor VIII activity measured with the different methods. The objective of this study was to investigate the incidence of assay discrepancy in our center, assess the impact of alternative reagents on factor VIII activity assays and determine the usefulness of global assays of hemostasis in mild hemophilia A. Factor VIII activity was measured in 84 individuals with mild hemophilia A using different reagents. Assay discrepancy was defined as a two-fold or greater difference between the results of the one-stage and two-stage clotting assays. Rotational thromboelastometry and calibrated automated thrombography were performed. Assay discrepancy was observed in 31% of individuals; 12% with lower activity in the two-stage assay and 19% with lower activity in the one-stage assay. The phenotype could not always be predicted from the individual's genotype. Chromogenic assays were shown to be a suitable alternative to the two-stage clotting assay. Thromboelastometry was found to have poor sensitivity in hemophilia. Calibrated automated thrombography supported the results obtained by the two-stage and chromogenic assays. The current international guidelines do not define the type of assay to be used in the diagnosis of mild hemophilia A and some patients could be misclassified as normal. In our study, 4% of patients would not have been diagnosed on the basis of the one-stage factor VIII assay. Laboratories should use both one stage and chromogenic (or two-stage) assays in the diagnosis of patients with possible hemophilia A.

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.