It's in the blood: a review of the hematological system in SARS-CoV-2-associated COVID-19.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to an unprecedented global healthcare crisis. While SARS-CoV-2-associated COVID-19 affects primarily the respiratory system, patients with COVID-19 frequently develop extrapulmonary manifestations. Notably, changes in the hematological system, including lymphocytopenia, neutrophilia and significant abnormalities of hemostatic markers, were observed early in the pandemic. Hematological manifestations have since been recognized as important parameters in the pathophysiology of SARS-CoV-2 and in the management of patients with COVID-19. In this narrative review, we summarize the state-of-the-art regarding the hematological and hemostatic abnormalities observed in patients with SARS-CoV-2-associated COVID-19, as well as the current understanding of the hematological system in the pathophysiology of acute and chronic SARS-CoV-2-associated COVID-19.

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.

Differing coagulation profiles of patients with monoclonal gammopathy of undetermined significance and multiple myeloma.

The link between myeloma and thrombosis is well established. Monoclonal gammopathy of undetermined significance (MGUS) has also been associated with an increased risk of thrombosis. It was recently demonstrated that patients with myeloma display changes in thromboelastometry that may indicate a prothrombotic state. There is little data with regard to changes in thromboelastography in patients with myeloma or MGUS. The aim of this study was to investigate the differing coagulation profiles of patients of patients with myeloma and MGUS by means of conventional coagulation tests and thromboelastography. Blood was taken by direct venepuncture from patients with myeloma, MGUS and normal controls. Routine coagulation tests were performed in an accredited hospital laboratory. Thromboelastography (TEG(®)) was performed as per the manufacturer's protocol. Eight patients were recruited in each group. Patients with myeloma had a significantly lower mean haemoglobin level than patients with MGUS or normal controls (p < 0.001). Patients with myeloma had a significantly more prolonged mean prothrombin time than normal controls (p = 0.018) but not patients with MGUS. Patients with myeloma had significantly higher median D-dimer levels than normal controls (p = 0.025), as did patients with MGUS (p = 0.017). Patients with myeloma had a significantly higher mean factor VIII level than normal controls (p = 0.009) and there was a non-significant trend towards patients with MGUS having higher factor VIII levels than normal controls (p = 0.059). There was no significant difference in thromboelastographic parameters between the three groups. Patients with MGUS appear to have a distinct coagulation profile which is intermediate between patients with myeloma and normal controls.

VTE risk assessment, prevention and diagnosis in pregnancy.

Venous thromboembolism (VTE) is still reported as the leading cause of direct maternal death in pregnancy in serial international reports in developed countries. VTE risk is higher during pregnancy but is further increased by additional well-characterized risk factors. International guidelines recommend that formal VTE risk assessment should be conducted at least in early pregnancy, at delivery and when risk factors change. High quality data supporting optimal VTE prevention strategies are lacking, outside the setting of prevention of VTE recurrence. Moreover, recent high-quality studies have provided much-needed data on diagnostic strategies for pulmonary embolism (PE) in pregnancy. In this review, we summarize knowledge gaps and recently published data in the prevention and diagnosis of VTE in pregnancy. Moreover, we describe ongoing high-quality randomised trials and prospective clinical management studies in this area. High quality clinical studies and trials in pregnancy can be done and must be prioritised, through international network efforts and national funding advocacy. Ultimately, translation of study results to impact upon guidelines and policy will deliver better care to and will protect the lives and health of pregnant people and those contemplating pregnancy throughout the world.

Removing direct oral factor Xa inhibitor interferences from routine and specialised coagulation assays using a raw activated charcoal product.

BACKGROUND: Direct oral anticoagulants (DOACs) are increasingly prescribed for the prevention and treatment of thrombosis. However, DOACs are associated with extensive interference in coagulation assays. Herein, we evaluate raw activated charcoal (AC) as an adsorbent material, to minimise DOAC-associated interferences in routine and specialised coagulation parameters on CS-series analysers (Sysmex, Kobe, Japan). METHODS: Commercial human-derived non-anticoagulated plasma materials, with or without increasing concentrations of anticoagulant, were assayed for routine and specialised coagulation parameters before and after treatment with AC. RESULTS: Treatment of non-anticoagulated plasma with raw AC had minimal impact on routine and specialised coagulation parameters available on the CS-series; however, clinically relevant prolongations of certain activated partial thromboplastin time (APTT)-based assays were observed after treatment. Furthermore, in apixaban- and rivaroxaban-containing plasma material, AC efficiently adsorbed therapeutic and supratherapeutic DOAC concentrations; and, treatment with raw AC resolved DOAC-associated interferences on all affected routine and specialised coagulation parameters. CONCLUSIONS: Overall, raw AC efficiently adsorbed apixaban and rivaroxaban from human-derived plasma, without significantly affecting the majority of underlying routine and specialised coagulation parameters available on CS-series analysers.

Heterogeneity in the half-life of factor VIII concentrate in patients with hemophilia A is due to variability in the clearance of endogenous von Willebrand factor.

BACKGROUND: Previous studies have reported marked interindividual variation in factor VIII (FVIII) clearance in patients with hemophilia (PWH) and proposed a number of factors that influence this heterogeneity. OBJECTIVES: To investigate the importance of the clearance rates of endogenous von Willebrand factor (VWF) compared with those of other FVIII half-life modifiers in adult PWH. METHODS: The half-life of recombinant FVIII was determined in a cohort of 61 adult PWH. A range of reported modifiers of FVIII clearance was assessed (including plasma VWF:antigen and VWF propeptide levels; VWF-FVIII binding capacity; ABO blood group; and nonneutralizing anti-FVIII antibodies). The FVIII-binding region of the VWF gene was sequenced. Finally, the effects of variation in FVIII half-life on clinical phenotype were investigated. RESULTS: We demonstrated that heterogeneity in the clearance of endogenous plasma VWF is a key determinant of variable FVIII half-life in PWH. Both ABO blood group and age significantly impact FVIII clearance. The effect of ABO blood group on FVIII half-life in PWH is modulated entirely through its effect on the clearance rates of endogenous VWF. In contrast, the age-related effect on FVIII clearance is, at least in part, VWF independent. In contrast to previous studies, no major effects of variation in VWF-FVIII binding affinity on FVIII clearance were observed. Although high-titer immunoglobulin G antibodies (≥1:80) were observed in 26% of PWH, these did not impact FVIII half-life. Importantly, the annual FVIII usage (IU/kg/y) was significantly (p = .0035) increased in patients with an FVIII half-life of <12 hours. CONCLUSION: Our data demonstrate that heterogeneity in the half-life of FVIII concentrates in patients with hemophilia A is primarily attributable to variability in the clearance of endogenous VWF.

A novel algorithm to reduce VTE in peri-operative patients on tamoxifen.

INTRODUCTION: Venous thromboembolism (VTE) is a serious adverse event associated with tamoxifen use, with a 2 to 3-fold increase incidence in users. We aimed to reduce the incidence of venous thromboembolism in patients undergoing breast related surgery by implementing a risk stratifying algorithm for the perioperative management of tamoxifen. METHODS: A retrospective control cohort was compared to a prospective interventional cohort to validate the algorithm which was created by a multidisciplinary team. The algorithm classed patients as low, moderate, high, or very high risk, based on patient factors, and then managed their tamoxifen accordingly during the perioperative period. Each case was then analysed for the presence of a symptomatic, diagnosed venous thromboembolic event up to 60 days post operatively. RESULTS: A total of 446 (n = 446) consecutive patients were analysed between May 2015 and July 2018 with a 3.36% (15/446) incidence of venous thromboembolism. The retrospective arm consisting of 306 cases, not subjected to the algorithm, showed a 4.58% (14/306) event rate while the prospective arm of 140 cases, managed with the algorithm, showed an event rate of 0.71% (1/140). Analysis with Fisher's exact test showed a significant reduction in VTE using the algorithm (p = 0.0447, CI = 0.95). The cessation of tamoxifen was more rationalised (no algorithm-18.1 days, low risk-0.125 days, moderate risk-14.988 days, high risk-29.6 days, very high risk-32.5 days) and stopped for 11.6% fewer days when using the algorithm. CONCLUSION: The use of this algorithm significantly reduces the risk of venous thromboembolism in this population while reducing the number of omitted tamoxifen doses.

Direct Oral Anticoagulant Concentrations in Obese and High Body Weight Patients: A Cohort Study.

BACKGROUND: Direct oral anticoagulants (DOACs) are prescribed for atrial fibrillation (AF) and venous thromboembolism (VTE) and both occur more frequently in obese patients. Outcomes from DOAC trials included few individuals ≥ 120 kg leading to uncertainty whether high body weight (BW) reduces DOAC concentrations. OBJECTIVES: This article investigates the relationship between factor Xa (FXa) inhibitor concentrations, BW, and renal function, and compares them in high BW patients with unselected populations. METHODS: Consecutive patients in two United Kingdom centers, weighing ≥ 120 kg receiving 5 mg twice daily apixaban or 20 mg once daily rivaroxaban for AF or VTE were prospectively included. Peak or trough concentrations were measured using specific chromogenic assays, expressed in mean or median (5th-95th percentiles). On-therapy range was the interval from the 5th percentile trough concentration to the 95th percentile peak concentration. RESULTS: One hundred patients were included; age range: 23 to 78 years, 31% were women, 58% had AF, creatinine clearance range: 67 to 474 mL/min. Median BW was 139 kg, and 84% had body mass index (BMI) ≥ 40 kg/m2. DOAC peak and trough concentrations varied from 44 to 727 and 14 to 299 ng/mL, respectively. There was no linear relationship between FXa inhibitor concentrations at peak or trough and BW or BMI, and creatinine clearance. Apixaban troughs in AF and rivaroxaban peaks in VTE were lower than in unselected populations. However, only two trough concentrations were below the expected range, and 109/116 were within the on-therapy range. CONCLUSION: These data indicated that obese or high BW patients generally achieve therapeutic FXa inhibitor concentrations. However, further investigations assessing clinical outcomes are required.

Mental healthcare interfaces in a regional Irish prison.

PURPOSE: The purpose of this paper is to study the demographic, clinical characteristics and outcomes for those prisoners referred to secondary mental healthcare in a regional Irish prison and the proportion of individuals diverted subsequently from prison to psychiatric settings. DESIGN/METHODOLOGY/APPROACH: The authors conducted a retrospective review of 130 successive psychiatric assessment case records at a regional mixed gender prison serving six southern Irish counties. The authors analysed demographics, clinical characteristics and outcomes. Where diversion out of prison was undertaken, Dangerousness, Understanding, Recovery and Urgency Manual (DUNDRUM) scores were retrospectively completed to assess security need. FINDINGS: In total, 8.6 per cent of all committals from liberty were referred by a general practitioner and 8.1 per cent subsequently assessed by the visiting psychiatrist. Predominantly, these were young males charged with a violent offence. In all, 42.2 per cent of those assessed by secondary care were diagnosed with a substance misuse disorder and 21.1 per cent with a personality disorder. In total, 20.3 per cent suffered from a psychotic disorder and 10.6 per cent with an affective disorder. Of those seen by psychiatric services, 51.2 per cent required psychotropic medication, 29.2 per cent required psychological input and 59.3 per cent required addiction counselling. In all, 10.6 per cent of those assessed were diverted from prison, the majority to approved centres. Mean DUNDRUM-1 scores suggested that those referred to high and medium secure hospitals were appropriately placed, whereas those diverted to open wards would have benefited from a low secure/intensive care setting. ORIGINALITY/VALUE: The multifaceted need set of those referred strengthens the argument for the provision of multidisciplinary mental healthcare into prisons. The analysis of security needs for those diverted from prisons supports the need for Intensive Care Regional Units in Ireland.

Incidence of Contrast-Induced Nephropathy in Patients with Multiple Myeloma Undergoing Contrast-Enhanced Procedures.

Multiple myeloma (MM) is a malignant disorder characterized by clonal proliferation of plasma cells. Renal impairment is a common complication. Contrast-induced nephropathy (CIN) is a form of acute renal failure that can occur in the setting of IV contrast administration. It is more commonly seen in patients with pre-existing renal impairment. Patients with MM commonly require contrast enhanced procedures. The literature regarding the safety of IV contrast in this cohort is lacking. A retrospective review was carried out in a university hospital to identify the incidence of CIN in patients with MM and to look for associated risk factors. 94 patients and 165 procedures were included in the analysis. 10% of procedures resulted in CIN. 59% (10/17) of creatinines had normalized within one month of the procedure. The only factor found to be significant for the development of CIN was the timing of the procedure (<18mths verses >18mths post diagnosis of MM; p = 0.045). CIN appears to occur at an increased rate in patients with MM. However this may be an over-estimation given the common occurrence of renal impairment in this cohort and the close temporal relationship which often exists between systemic illness and contrast-enhanced procedures.