Real-world use of thrombopoietin receptor agonists for the management of immune thrombocytopenia in adult patients in the United Kingdom: Results from the TRAIT study.

Few studies have reported the real-world use of both romiplostim and eltrombopag in immune thrombocytopenia (ITP). TRAIT was a retrospective observational study aimed to evaluate the platelet responses and adverse effects associated with the use of these thrombopoietin receptor agonists (TPO-RAs) in adult patients with ITP in the United Kingdom. Of 267 patients (median age at diagnosis, 48 years) with ITP (primary ITP [n = 218], secondary ITP [n = 49]) included in the study, 112 (42%) received eltrombopag and 155 (58%) received romiplostim as the first prescribed TPO-RA. A platelet count ≥30 × 109/L was achieved in 89% of patients with the first TPO-RA treatments, while 68% achieved a platelet count ≥100 × 109/L. Treatment-free response (TFR; platelet count ≥30 × 109/L, 3 months after discontinuing treatment) was achieved by 18% of the total patients. Overall, 61 patients (23%) switched TPO-RAs, most of whom achieved platelet counts ≥30 × 109/L with the second TPO-RA (23/25 who switched from eltrombopag to romiplostim [92%]; 28/36 who switched from romiplostim to eltrombopag [78%]). TFR was associated with secondary ITP, early TPO-RA initiation after diagnosis, the presence of comorbidity and no prior splenectomy or treatment with steroids or mycophenolate mofetil. Both TPO-RAs had similar efficacy and safety profiles to those reported in clinical studies.

Russell Viper Venom: A Journey from the Bedside to the Bench and Back to the Bedside.

Russell Viper Venom (RVV) is widely used as a diagnostic test for antiphospholipid syndrome (APS). But the history of how this venom came to be discovered is well known. Dr Patrick Russell is responsible for the identification of the venom during his work on snake bites in India while Dr Robert Macfarlane used it to staunch bleeding in persons with haemophilia. The ability to directly activate factor X led RVV to the laboratory diagnosis of APS. More recently, it has come back to clinical world with a potential for an engineered factor X activator from RVV to be used in the treatment of haemophilia.

Are Antiphospholipid Antibodies a Surrogate Risk Factor for Thrombosis in Sepsis?

Antiphospholipid syndrome (APS) is a hypercoagulable state caused by antiphospholipid antibodies (aPL). APS clinically manifests with arterial or venous or microvascular thrombi and/or pregnancy complications. It is well-known that the development of aPL can be a transient phenomenon and thus the current diagnostic criterion for APS requires repeat laboratory testing several weeks apart before a definitive diagnosis is made. However, transient presence of aPL may also be pathogenic. In this article, we attempt to give historical and clinical evidence for the importance of these antibodies, even when transient, and call for further research into mechanisms by which these antibodies may promote thrombosis and pregnancy morbidities.

Hemostasis Testing in the Emergency Department: A Narrative Review.

Routine laboratory screening is typically performed at initial evaluation of the vast majority of presentations to the emergency department (ED). These laboratory results are crucial to the diagnostic process, as they may influence up to 70% of clinical decisions. However, despite the usefulness of biological assessments, many tests performed are inappropriate or of doubtful clinical relevance. This overutilization rate of laboratory testing in hospitals, which represents a significant medical-economic burden, ranges from 20 to 67%, with coagulation tests at the top of the list. While reviews frequently focus on nonintensive care units, there are few published assessments of emergency-specific interventions or guidelines/guidance to date. The aim of this review is to highlight current recommendations for hemostasis evaluation in the emergency setting with a specific analysis of common situations leading to ED admissions, such as suspected venous thrombosis or severe bleeding. We revisit the evidence related to the assessment of patient's hemostatic capacity based on comprehensive history taking and physical examination as well as best practice recommendations for blood sample collection to ensure the reliability of results. This review also includes an examination of various currently available point of care tests and a comprehensive discussion on indications, limitations, and interpretation of these tests.

SARS-CoV-2 vaccination and ITP in patients with de novo or preexisting ITP.

Cases of de novo immune thrombocytopenia (ITP), including a fatality, following SARS-CoV-2 vaccination in previously healthy recipients led to studying its impact in preexisting ITP. In this study, 4 data sources were analyzed: the Vaccine Adverse Events Reporting System (VAERS) for cases of de novo ITP; a 10-center retrospective study of adults with preexisting ITP receiving SARS-CoV-2 vaccination; and surveys distributed by the Platelet Disorder Support Association (PDSA) and the United Kingdom (UK) ITP Support Association. Seventy-seven de novo ITP cases were identified in VAERS, presenting with median platelet count of 3 [1-9] ×109/L approximately 1 week postvaccination. Of 28 patients with available data, 26 responded to treatment with corticosteroids and/or intravenous immunoglobulin (IVIG), and/or platelet transfusions. Among 117 patients with preexisting ITP who received a SARS-CoV-2 vaccine, 19 experienced an ITP exacerbation (any of: ≥50% decline in platelet count, nadir platelet count <30 × 109/L with >20% decrease from baseline, and/or use of rescue therapy) following the first dose and 14 of 70 after a second dose. Splenectomized persons and those who received 5 or more prior lines of therapy were at highest risk of ITP exacerbation. Fifteen patients received and responded to rescue treatment. In surveys of both 57 PDSA and 43 UK patients with ITP, prior splenectomy was associated with worsened thrombocytopenia. ITP may worsen in preexisting ITP or be identified de novo post-SARS-CoV2 vaccination; both situations responded well to treatment. Proactive monitoring of patients with known ITP, especially those postsplenectomy and with more refractory disease, is indicated.

EFLM Task Force Preparation of Labs for Emergencies (TF-PLE) recommendations for reinforcing cyber-security and managing cyber-attacks in medical laboratories.

The healthcare systems are a prime target for cyber-attacks due to the sensitive nature of the information combined with the essential need for continuity of care. Medical laboratories are particularly vulnerable to cyber-attacks for a number of reasons, including the high level of information technology (IT), computerization and digitization. Based on reliable and widespread evidence that medical laboratories may be inadequately prepared for cyber-terrorism, a panel of experts of the Task Force Preparation of Labs for Emergencies (TF-PLE) of the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) has recognized the need to provide some general guidance that could help medical laboratories to be less vulnerable and better prepared for the dramatic circumstance of a disruptive cyber-attack, issuing a number of consensus recommendations, which are summarized and described in this opinion paper.

Venous thromboembolism in patients with acute myeloid leukemia: development of a predictive model.

BACKGROUND: Patients with acute myeloid leukemia (AML) are at increased risk of venous thromboembolic events (VTE). However, thromboprophylaxis is largely underused. OBJECTIVES: This study aimed to determine possible VTE development risk factors and to develop a novel predictive model. METHODS: We conducted a retrospective cohort study of adult patients with newly diagnosed AML. We used univariate and multivariable logistic regression to estimate binary outcomes and identify potential predictors. Based on our final model, a dynamic nomogram was constructed with the goal of facilitating VTE probability calculation. RESULTS: Out of 626 eligible patients with AML, 72 (11.5%) developed VTE during 6 months of follow-up. Six parameters were independent predictors: male sex (odds ratio [OR] 1.82, 95% confidence interval [CI]: 1.077-2.065), prior history of thrombotic events (OR 2.27, 95% CI: 1.4-4.96), international normalized ratio (OR 0.21, 95% CI: 0.05-0.95), Eastern Cooperative Oncology Group performance status (OR 0.71, 95% CI: 0.53-0.94), and intensive therapy (OR 2.05, 95% CI: 1.07-3.91). The C statistics for the model was 0.68. The model was adequately calibrated and internally validated. The decision-curve analysis suggested the use of thromboprophylaxis in patients with VTE risks between 8 and 20%. CONCLUSION: We developed a novel and convenient tool that may assist clinicians in identifying patients whose VTE risk is high enough to warrant thromboprophylaxis.

Management of patients on antithrombotic therapy with severe infections: a joint clinical consensus statement of the ESC Working Group on Thrombosis, the ESC Working Group on Atherosclerosis and Vascular Biology, and the International Society on Thrombosis and Haemostasis.

Patients with severe infections and a pre-existing indication for antithrombotic therapy, i.e. antiplatelet agents, anticoagulant drugs, or their combinations, require integrated clinical counselling among coagulation, infectious disease, and cardiology specialists, due to sepsis-induced coagulopathy that frequently occurs. Bacterial and viral pathogens constitute an increasing threat to global public health, especially for patients with ongoing antithrombotic treatment who have a high risk of thrombotic recurrences and high susceptibility to severe infections with increased morbidity and mortality. Similarly, sepsis survivors are at increased risk for major vascular events. Coagulopathy, which often complicates severe infections, is associated with a high mortality and obligates clinicians to adjust antithrombotic drug type and dosing to avoid bleeding while preventing thrombotic complications. This clinical consensus statement reviews the best available evidence to provide expert opinion and statements on the management of patients hospitalized for severe bacterial or viral infections with a pre-existing indication for antithrombotic therapy (single or combined), in whom sepsis-induced coagulopathy is often observed. Balancing the risk of thrombosis and bleeding in these patients and preventing infections with vaccines, if available, are crucial to prevent events or improve outcomes and prognosis.

Platelet kinetics in patients with chronic immune thrombocytopaenia treated with thrombopoietin receptor agonists.

INTRODUCTION: Thrombopoietin receptor agonists (TPO-RAs) increase platelet counts (PC) in the majority of patients with chronic immune thrombocytopaenia (ITP). Platelet kinetics study (PKS) might contribute to the understanding of mechanisms that lead to durable response. OBJECTIVES: To evaluate the effects of TPO-RAs on PKS parameters in chronic ITP patients. METHODS: Fifteen chronic ITP patients, aged 59 years [range: 22-84], female/male: 10/5, splenectomised 7/15, were treated with TPO-RAs (eltrombopag/romiplostim: 11/4). Durable response was defined as PC ≥30 × 109 /L at 6 months. Autologous 111 Indium-oxinate PKS was performed before and 5 months after TPO-RAs initiation. Accordingly, platelet survival (PS), platelet turnover, production ratio and sequestration site were assessed. RESULTS: Durable response was achieved in 13/15 of patients (eltrombopag/romiplostim: 10/3). Pre-treatment parameters were: PC 10 × 109 /L [range: 1-110], PS 0.5 days [range: 0.1-1.7 (normal values: 7-10)], platelet turnover 30 857 Plt/µL/day [range: 944-103 500] and platelet production ratio 0.64 [range: 0.01-3.2 (normal values: 1 ± 0.2)]. Post-treatment assessment showed significantly higher: PC 92.5 × 109 /L [range: 28-260, p = .001], PS 2.2 days [range: 0.1-3.6, p = .008], platelet turnover 70 213 Plt/µL/day [range: 2800-462 236, p = .02] and platelet production ratio 1.8 [range: 0.5-37.9, p = .011] compared to the pre-treatment values. Platelet sequestration site altered in 3/15 treated with TPO-RAs. CONCLUSIONS: TPO-RAs could increase PC by simultaneous increasing of platelet production and decreasing of platelet destruction.

International Survey of the Management of Disseminated Intravascular Coagulation Among Pediatric and Neonatal Health Care Practitioners.

The International Society of Thrombosis and Hemostasis (ISTH) provides objective disseminated intravascular coagulation (DIC) measurement through diagnostic criteria validated in adults. The applicability of these criteria in pediatric and neonatal DIC is controversial and unvalidated. Primary objective: to evaluate current practice in pediatric and neonatal DIC management among different specialties. Secondary objective: to understand the potential impact of developmental hemostasis on DIC laboratory evaluation. We performed a multicenter survey between January and September 2016. The questionnaire was distributed internationally through professional societies. In all, 211 responses were received, of which 160 were full responses and 51 were partial. Overall, 85% of respondents practiced in tertiary academic centers; 70% practiced in pediatric-only hospitals. The majority of respondents (42%) used their personal clinical experience in the management of DIC. Sixty percent of respondents treated DIC until the resolution of both clinical and laboratory parameters. Laboratory investigations were monitored in the majority of DIC cases without thrombosis or bleeding (80%); age-specific reference ranges for tests were lacking in 20% of pediatric-only hospitals and 35% of combined pediatric/adult hospitals. Adherence to standardized DIC guidelines was poor but varied by geographical location. This survey reveals variable practices among pediatricians in the management of DIC. Further studies are needed to validate the DIC diagnostic criteria in children.

UK prescribing practice of anticoagulants in patients with chronic kidney disease: a nephrology and haematology-based survey.

A survey to gain insight into anticoagulant prescribing practice in the setting of chronic kidney disease (CKD) across the UK was disseminated via renal and haematology networks. Areas of anticoagulant use included patients with venous thromboembolism (VTE), requiring thromboprophylaxis for VTE, Atrial Fibrillation (AF) and nephrotic syndrome.An online-survey was disseminated via British Haematology Society, UK Kidney Association, and Renal Pharmacy Group over a five month period. All responses were voluntary and anonymous.Among 117 responses there were 49 nephrology doctors, 47 renal pharmacists and 20 haematology clinicians. A specialist multidisciplinary team to discuss the specific anticoagulant management of these patients was only available to 3% (4/117) respondents. Renal function estimate used for anticoagulant dosing was mainly Cockcroft-Gault for pharmacists and haematology but lab-based estimates were used by nephrology doctors. Therapeutic dose of Low Molecular Weight Heparin was mostly likely to be reduced by one-third when used for VTE treatment, with the majority of units undertaking anti-Xa monitoring in CKD stage 5 and dialysis. Direct-acting Oral Anticoagulants are being used in patients with nephrotic syndrome, those with CKD stage 5 and on dialysis for VTE and AF in the absence of license in these indications.This survey highlighted the significant differences between anticoagulant prescribing in CKD between two professional specialties and marked variation between centres in anticoagulant management strategies employed for these patients. With gaps still existing in the evidence base and answers to these not expected within the next few years, development of a best-practice guideline would be warranted to support clinicians in this field.

Practical management of the haemorrhagic complications of myeloproliferative neoplasms.

Myeloproliferative neoplasms can be associated with bleeding manifestations which can cause significant morbidities. Although haematologists are aware of the likelihood of this complication in the setting of myeloproliferative neoplasms, it may often be overlooked especially in patients with no extreme elevation of blood counts and those with myelofibrosis. Acquired von Willebrand syndrome and platelet dysfunction are the two common diagnoses to be considered in this regard. In this review article, we discuss the mechanisms for the development of these rare bleeding disorders, their diagnosis and practical management.

Protamine-The Journey from DNA to Heparin Neutralization to Gene therapy.

Protamine is now well recognized as a key heparin neutralizing agent. However, protamine was discovered over a century ago, during experiments performed to uncover the secrets behind heritability. Although protamine was discovered as a highly charged protein, it did not receive the attention it deserved until the dawn of insulin era, when it was used to create the neutral protamine Hagedorn formulation. Based on the same principles, protamine was identified to neutralize heparin and has since been used successfully for many years in cardiothoracic surgery. More recently, its clinical applications have extended to gene therapy. In this historical sketch, the journey from the discovery of protamine, onwards to heparin neutralization, and up to its utilization in genetic modulatory treatments is detailed.

D-dimers-"Normal" Levels versus Elevated Levels Due to a Range of Conditions, Including "D-dimeritis," Inflammation, Thromboembolism, Disseminated Intravascular Coagulation, and COVID-19.

D-dimers reflect a breakdown product of fibrin. The current narrative review outlines how D-dimers can arise in normal individuals, as well as in patients suffering from a wide range of disease states. D-dimers in normal individuals without evident thrombosis can arise from background fibrinolytic activity in various tissues, including kidney, mammary and salivary glands, which ensures smooth flow of arising fluids where any blood contamination could be immediately lysed. In addition, healthy individuals can also regularly sustain minor injuries, often unbeknown to them, and wound healing follows clot formation in these situations. D-dimers can also arise in anxiety and following exercise, and are also markers of inflammation. Lung inflammation (triggered by microbes or foreign particles) is perhaps also particularly relevant, since the hemostasis system and fibrinolysis help to trap and remove such debris. Lung inflammation in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may contribute to D-dimer levels additive to thrombosis in patients with COVID-19 (coronavirus disease 2019). Indeed, severe COVID-19 can lead to multiple activation events, including inflammation, primary and secondary hemostasis, and fibrinolysis, all of which may contribute to cumulative D-dimer development. Finally, D-dimer testing has also found a role in the diagnosis and triaging of the so-called (COVID-19) vaccine-induced thrombotic thrombocytopenia.

Disseminated Intravascular Coagulation: The Past, Present, and Future Considerations.

Disseminated intravascular coagulation (DIC) has been understood as a consumptive coagulopathy. However, impaired hemostasis is a component of DIC that occurs in a progressive manner. The critical concept of DIC is systemic activation of coagulation with vascular endothelial damage. DIC is the dynamic coagulation/fibrinolysis disorder that can proceed from compensated to decompensated phases, and is not simply impaired hemostasis, a misunderstanding that continues to evoke confusion among clinicians. DIC is a critical step of disease progression that is important to monitor over time. Impaired microcirculation and subsequent organ failure due to pathologic microthrombi formation are the pathophysiologies in sepsis-associated DIC. Impaired hemostasis due to coagulation factor depletion from hemodilution, shock, and hyperfibrinolysis occurs in trauma-associated DIC. Overt-DIC diagnostic criteria have been used clinically for more than 20 years but may not be adequate to detect the compensated phase of DIC, and due to different underlying causes, there is no "one-size-fits-all criteria." Individualized criteria for heterogeneous conditions continue to be proposed to facilitate the diagnosis. We believe that future research will provide therapeutics using new diagnostic criteria. Finally, DIC is also classified as either acute or chronic, and acute DIC results from progressive coagulation activation over a short time and requires urgent management. In this review, we examine the advances in research for DIC.

Management of blood transfusion services in low-resource countries.

BACKGROUND AND OBJECTIVES: Enabling universal access to safe blood components should be a key component of every country's national healthcare strategy. This study aimed to assess the current status of infrastructure and resources of blood transfusion services (BTS) in low- and middle-income countries. MATERIALS AND METHODS: A cross-sectional survey was designed to gather information on blood donations, components, redistribution, testing resources and quality management systems (QMSs). The survey was distributed to the International Society of Blood Transfusion members between October 2021 and November 2021. RESULTS: A total of 54 respondents from 20 countries responded to the survey. This included hospital-based BTS/blood centres (46%), national blood centres (11%)and national and regional blood services (11%). Voluntary non-remunerated, replacement and paid donors accounted for 94.2%, 84.6% and 21.1% of donations, respectively. Apheresis donation was available in 59.6% of institutions. National/regional criteria for redistribution of blood components were reported by 75.9% of respondents. Blood components incurred payment charges in 81.5% of respondents' institutions, and payments were borne by patients in 50% of them. Testing methods, such as manual (83%), semi-automated (68%) or fully automated (36.2%), were used either alone or in combination. QMSs were reported in 17 institutions, while accreditation and haemovigilance were reported in 12 and 8 countries, respectively. CONCLUSION: QMS was implemented in most of the countries despite the common use of paid donations and the lack of advanced testing. Efforts to overcome persistent challenges and wider implementation of patient blood management programmes are required.

Deep Vein Thrombosis is Common After Cardiac Ablation and Pre-Procedural D-Dimer Could Predict Risk.

PURPOSE: Cardiac catheter ablations are an established treatment for supraventricular tachycardia (SVT) involving prolonged cannulation of the common femoral vein with multiple catheters. This study aimed to identify the risk of deep vein thrombosis (DVT) by studying the frequency of this complication after catheter ablation. METHODS: This was a prospective multi-centre cohort study of patients undergoing cardiac ablation for atrioventricular nodal re-entry tachycardia or right-sided accessory atrioventricular connection. Those taking anticoagulation or antiplatelet therapy prior to the procedure were excluded. Following the procedure, bilateral venous duplex ultrasonography from the popliteal vein to the inferior vena cava for DVT was undertaken at 24 hours and between 10 to 14 days. RESULTS: Eighty (80) patients (mean age 47.6 yrs [SD 13.4] with 67% female) underwent cardiac ablation (median duration 70 mins). Seven (7) patients developed acute DVT in either the femoral or external iliac vein of the intervention leg, giving a frequency of 8.8% (95% CI 3.6-17.2%). No thrombus was seen in the contralateral leg (p=0.023). An elevated D-dimer prior to the procedure was significantly more frequent in patients developing DVT (42.9% vs 4.1%, p=0.0081; OR 17.0). No other patient or procedural characteristics significantly influenced the risk of DVT. CONCLUSION: In patients without peri-procedural anticoagulation catheter ablation precipitated DVT in the catheterised femoral or iliac veins in 8.8% of patients. Peri-procedure prophylactic anticoagulation may be considered for all patients undergoing catheter ablation for SVT. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT03877770.

Thrombosis in immune thrombocytopenia - current status and future perspectives.

Immune thrombocytopenia (ITP) is an autoimmune disorder in which a combination of defective platelet production and enhanced clearance leads to thrombocytopenia. The primary aim for therapy in patients with this condition is the prevention of bleeding. However, more recently, increased rates of venous and arterial thrombotic events have been reported in ITP, even in the context of marked thrombocytopenia. In this review we discuss the epidemiology, aetiology and management of thrombotic events in these patients. We consider the impact of ITP therapies on the increased thrombotic risk, in particular the use of thrombopoietin-receptor agonists (TPO-RAs), as well as factors inherent to ITP itself. We also discuss the limited evidence available to guide clinicians in the treatment of these complex cases.

The relation between fibrinogen level, neutrophil activity and nucleosomes in the onset of disseminated intravascular coagulation in the critically ill.

BACKGROUND: Nucleosomes and neutrophil extracellular traps (NETs) are important in the pathophysiology of disseminated intravascular coagulation (DIC). Fibrinogen, as an acute phase reactant, may be protective by engaging neutrophils. We hypothesize that DIC can occur when NET formation becomes uncontrolled in relation to low fibrinogen levels. PATIENTS/METHOD: The ratio of both circulating nucleosomes and human neutrophil elastase alpha-1-antitrypsine complexes (HNE-a1ATc) to fibrinogen was correlated to thrombocytopenia, DIC and organ failure in 64 critically ill coagulopathic patients. RESULTS: A high nucleosome to fibrinogen ratio correlated with thrombocytopenia and organ failure (ρ -0.391, p 0.01 and ρ 0.556, p 0.01, respectively). A high HNE-a1ATc to fibrinogen ratio correlated with thrombocytopenia, DIC and organ failure (ρ -0.418, p 0.01, ρ 0.391, p 0.01 and ρ 0.477, p 0.01 respectively). CONCLUSION: These findings support the hypothesis that fibrinogen is protective against DIC by counterbalancing excessive neutrophil activation.

Can direct oral anticoagulants be used in kidney transplant recipients?

BACKGROUND: Kidney transplant recipients(KTRs) are at an increased risk of venous thromboembolism (VTE) and atrial fibrillation(AF). Direct oral anticoagulants (DOACs) have shown important advantages over vitamin K antagonists; however, in KTRs, concerns regarding interactions and use in severe kidney disease may limit their use. This evaluation describes a large UK kidney transplant center's experience of DOACs in KTRs with CrCl > 15 mL/min. METHODS: Electronic records were reviewed for all adult KTRs at Manchester University Foundation Trust Hospitals taking DOACs between January 2018 and October 2020 with VTE or AF. The primary outcome was trough and peak DOAC levels within the expected reference ranges and secondary outcomes included bleeding and thrombotic events. RESULTS: In 31 KTRs taking DOACS, eight patients had a CrCl < 30 mL/min. Overall, 94% (62/66) of DOAC levels were within the recommended ranges. There were no thrombotic events and four bleeding events (two major and two clinically relevant non-major bleeds). The overall bleeding rate was 6.9 per 100 patient-years at risk. CONCLUSIONS: There was no evidence of a significant interaction of apixaban or rivaroxaban with CNIs based on expected DOAC and CNI levels. Their use was found to be safe and effective with no VTE events and bleeding episodes similar to published trial data.