How the Hemostasis Laboratory Can Help Clinicians to Manage Patients on Oral Anticoagulants.

Oral anticoagulants are widely used to treat or prevent cardiovascular diseases in millions of patients worldwide. They are the drugs of choice for stroke prevention and systemic embolism in patients with non-valvular atrial fibrillation and prosthetic heart valves, as well as for treatment/prevention of venous thromboembolism. Oral anticoagulants include vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs). The hemostasis laboratory plays a crucial role in the management of treated patients, spanning from dose adjustment based on laboratory testing that applies to VKAs to the measurement of drug concentrations in special situations that apply to DOACs. This article aims to overview how the hemostasis laboratory can help clinicians manage patients on oral anticoagulants. Special interest is devoted to the international normalized ratio, used to manage patients on VKAs and to the measurement of DOAC concentrations, for which the role of the laboratory is still not very well defined, and most interferences of DOACs with some of the most common hemostatic parameters are not widely appreciated.

Safety and efficacy of combined dual antiplatelet therapy and factor VIII prophylaxis in patients with haemophilia A after acute coronary syndrome.

INTRODUCTION: The increased life expectancy of patients with haemophilia A (HA) has led to a growing prevalence of cardiovascular risk factors and events. There is still scarce evidence on the safety and appropriate duration of dual antiplatelet therapy (DAPT) after acute coronary syndrome (ACS) in HA patients. AIM: We describe our experience on the clinical management of Italian HA patients after ACS. METHODS: Nine patients with congenital HA treated with DAPT after a revascularization procedure performed for ACS have been enrolled and followed at the Angelo Bianchi Bonomi Haemophilia and Thrombosis Center in Milan between 2005 and September 2022. The safety and efficacy of DAPT with or without FVIII prophylaxis were assessed. RESULTS: Ten ACS events occurred in the nine HA patients (four mild and five severe). All events were treated with percutaneous transluminal coronary angioplasty with deployment of 1 to 3 drug-eluting stents followed by DAPT for 1-12 months. All patients except one were treated with FVIII prophylaxis during DAPT aimed at achieving FVIII trough levels ≥20-30 IU/dL. DAPT was effective in all cases in preventing early ACS recurrence, with only a late recurrence. We observed two clinically relevant non-major bleeds (one in a patient without FVIII prophylaxis) and three minor bleeds. No venous thrombosis occurred. CONCLUSION: The long-term secondary antithrombotic prevention consisting of DAPT and FVIII prophylaxis achieving a trough level of 20-30 IU/dL can be effective and safe in HA patients.

Open ADAMTS-13 conformation index predicts earlier relapse in immune-mediated thrombotic thrombocytopenic purpura.

BACKGROUND: ADAMTS-13 adopts an open conformation in patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP) in acute phase while being closed in healthy donors. We reported that a substantial number of patients with iTTP in remission with restored ADAMTS-13 activity (>50%) still had an open ADAMTS-13 conformation, although a closed conformation is expected given the extent of remission. OBJECTIVES: To investigate whether open ADAMTS-13, represented by a conformation index >0.5, is associated with a risk of earlier ADAMTS-13 and/or clinical relapse. METHODS: We collected follow-up data (ADAMTS-13 parameters, ADAMTS-13 and clinical relapse, and treatment) from 81 patients with iTTP in remission with ADAMTS-13 activity >50%. RESULTS: During follow-up, 19 ADAMTS-13 and 10 clinical relapses were reported (median follow-up period, 20 months). First, open or closed ADAMTS-13 conformation was dichotomized based on the 0.5 conformation index cutoff. Open ADAMTS-13 (conformation index, >0.5) was not identified as a risk factor for ADAMTS-13 and clinical relapse (log-rank test and Cox regression model). In contrast, by identifying the optimal conformation index cutoff for relapse prediction, using classification and regression tree analysis, a conformation index >0.645 and >0.835 was shown to be a risk factor for ADAMTS-13 relapse (hazard ratio, 3.3; 95% CI, 1.3-8.3; P = .01) and clinical relapse (hazard ratio, 4.4; 95% CI, 1.3-15.3; P = .02), respectively. CONCLUSION: Patients with open ADAMTS-13 with a conformation index >0.645 and >0.835 have a >3- and >4-fold higher risk of earlier ADAMTS-13 and clinical relapse, respectively. Hence, ADAMTS-13 conformation index could be used to complement ADAMTS-13 activity monitoring to timely notice ADAMTS-13 relapse and prevent clinical relapse.

Development and validation of the Medical Attitudes Towards Deprescribing Questionnaire.

Polypharmacy and inappropriate prescriptions in the elderly are widely discussed themes in scientific literature. Although more and more studies showed the safety and feasibility of deprescribing strategies, these are not implemented in clinical practice. In order to measure the attitudes of Italian doctors towards deprescribing and address their awareness, experiences, difficulties in applying these strategies and potential suggestions, we aimed to develop and validate a questionnaire, the Medical Attitudes Towards Deprescribing Questionnaire (MATD-Q). Between November 2017 and October 2018 an e-mail was sent to internists, geriatricians and general practitioners, to invite them to connect to a platform and answer to the questionnaire, consisting in 38 items (with a five level score) and five questions. After 2-3 weeks, a second e-mail was sent for a second completion of the questionnaire. Test-retest reliability was assessed by means of the intraclass correlation coefficient (ICC). The correlations between items were assessed by means of Pearson linear correlation coefficients and Cronbach Alpha was used to assess internal consistency. A total of 77 questionnaires completed twice were collected. By a principal component analysis we defined a smaller set of variables (n = 12), which resulted to be representative of the 38-item questionnaire.The final version of the questionnaire we developed (MATDQ-12), after validation in other cohorts, could be a useful tool to measure the efficacy of educational interventions aimed at improving the attitude of physicians towards deprescribing strategies with the final goal to allow their implementation in clinical practice.

Minimum factor VIII levels to prevent joint bleeding in mild hemophilia A.

The severity of the bleeding phenotype in patients with hemophilia A (HA) broadly correlates with the degree of coagulation factor VIII (FVIII) deficiency in plasma. However, the FVIII level necessary to achieve the goal of zero joint bleeds remains unclear. This study aimed to identify the minimum FVIII level necessary to prevent joint bleeds in patients with HA. In this retrospective study, patients with congenital mild HA treated on demand, aged ≥16 years, with no history of FVIII inhibitors, followed at the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center in Milan, were enrolled. We investigated 270 male patients with a median age of 45 years (16-88) and median lifelong FVIII of 21 IU/dL. One hundred patients (37%) had a lifelong history of at least 1 joint bleed. The mean annualized joint bleeding rate (AJBR) and spontaneous AJBR were 0.016 (standard deviation [SD], 0.032) and 0.001 (SD, 0.010), respectively. After adjusting for age, for each IU/dL increase in FVIII, there was a 6% reduction in AJBR and an 11% reduction in spontaneous AJBR. The minimum FVIII levels needed to prevent lifelong any joint bleeds and spontaneous joint bleeds resulted to be 19.2 IU/dL and 17.7 IU/dL, respectively. In this large cohort of persons with mild HA, we identified the minimum FVIII levels needed to prevent total and spontaneous joint bleeds (19.2 IU/dL and 17.7 IU/dL, respectively). These findings could suggest important implications for the accurate design of prophylactic therapies for persons with moderate and severe HA, including gene therapy.

Caplacizumab use for immune thrombotic thrombocytopenic purpura: the Milan thrombotic thrombocytopenic purpura registry.

•Data on caplacizumab use for thrombotic thrombocytopenic purpura (TTP) in Italy are missing.•Twenty-six Italian patients were treated with caplacizumab for an acute immune TTP episode.•Caplacizumab was effective in treating acute TTP in the Italian real-world clinical setting.•Two major bleeds leading to drug discontinuation were observed.

Effect of Physical Activity Intervention on Gait Speed by Frailty Condition: A Randomized Clinical Trial.

OBJECTIVES: There is uncertainty about effects of physical activity on physical performance, such as gait speed, among community-dwelling older adults according to their physical frailty status. We determined whether a long-term, moderate-intensity physical activity program was associated with different responses on gait speed over 4 m and 400 m based on physical frailty status. DESIGN: Post hoc analysis from the Lifestyle Interventions and Independence for Elders (LIFE) (NCT01072500), a single-blind randomized clinical trial testing the effect of physical activity intervention compared with health education program. SETTING AND PARTICIPANTS: We analyzed data on 1623 community-dwelling older adults (78.9 ± 5.2 years) at risk for mobility disability. METHODS: Physical frailty was assessed at baseline using the Study of Osteoporotic Fractures frailty index. Gait speed over 4 m and 400 m was measured at baseline, and 6, 12, and 24 months. RESULTS: We estimated significantly better 400-m gait speed at 6, 12, and 24 months for nonfrail older adults in the physical activity group, but not for frail participants. Among frail participants, physical activity showed a potentially clinically meaningful benefit on 400-m gait speed at 6 months (0.055; 95% CI 0.016-0.094; P = .005), compared with the healthy educational intervention, only in those who, at baseline, were able to rise from a chair 5 times without using their arms. CONCLUSIONS AND IMPLICATIONS: A well-structured physical activity program produced a faster 400-m gait speed potentially able to prevent mobility disability among physically frail individuals with preserved muscle strength in lower limbs.

Factor V Leiden but not the factor II 20210G>A mutation is a risk factor for premature coronary artery disease: a case-control study in Iran.

Background: Factor V Leiden (FVL) and factor II c.∗97G>A (rs1799963) are genetic risk factors for venous thromboembolism. Their contribution to coronary artery disease (CAD) is less clear. Objectives: This study aimed to investigate the association between FVL, rs1799963, and premature CAD in Iranians. Methods: We performed a genetic case-control study of 944 cases and 1081 controls from the premature CAD Milano-Iran study, including patients aged 18-55 (female) and 18-45 years (male) who underwent coronary angiography at the Tehran Heart Centre (Iran) in 2004-2011. Cases had luminal stenosis ≥50% in at least 1 main coronary artery or branch. Controls were age- and sex-matched with no CAD history. FVL and rs1799963 were genotyped using TaqMan SNP genotyping assays. Association was tested by logistic regression adjusted for matching factors and ethnicity. Effect modification by sex and cardiovascular risk factors (metabolic [obesity, hypertension, hyperlipidemia, and diabetes], and smoking) was assessed. Results: The risk of premature CAD was increased by 50% in FVL carriers (adjusted odds ratio [adjOR] 1.54 [95% CI, 0.95-2.48]) and slightly reduced in rs1799963 carriers (adjOR 0.71 [95% CI, 0.40-1.27]). These effects were more pronounced in women than men (FVL, adjOR 1.66 vs 1.25; rs1799963, adjOR 0.60 vs 1.07). The risk of premature CAD was substantially increased in carriers of FVL with at least 1 metabolic risk factor compared with noncarriers without metabolic risk factors (adjOR 25.14 [95% CI, 12.51-50.52]). Conclusion: FVL but not FII rs1799963 was associated with an increased risk of CAD in young Iranians. This risk increased considerably when combined with metabolic cardiovascular risk factors.

Underdiagnosis and undertreatment of osteoporotic patients admitted in internal medicine wards in Italy between 2010 and 2016 (the REPOSI Register).

PURPOSE: To evaluate clinical features, treatments, and outcomes of osteoporotic patients admitted to internal medicine and geriatric wards compared with non-osteoporotic patients (REPOSI registry). METHODS: We studied 4714 patients hospitalized between 2010 and 2016. We reported age, sex, educational level, living status, comorbidities and drugs taken, Cumulative Illness Rating Scale (CIRS), Barthel Index, Short-Blessed Test, 4-item Geriatric Depression Scale, serum hemoglobin, creatinine, and clinical outcomes. Osteoporosis was defined based on the diagnoses recorded at admission, according to the following ICD9: 733, 805-813, 820-823. RESULTS: Twelve percent of the patients had a preadmission diagnosis of osteoporosis. Only 20% of these had been prescribed oral bisphosphonates; 34% were taking vitamin D supplements. Osteoporotic patients were significantly older, with lower BMI, higher CIRS, and taking more drugs. They were significantly more depressed, less independent, with a higher severity of cognitive impairment compared with non-osteoporotic patients. At discharge, the number of patients receiving treatment for osteoporosis did not change. Length of stay and inhospital mortality did not differ between groups. Osteoporotic patients were more frequently nonhome discharged compared with those without osteoporosis (14.8 vs. 7.9%, p = 0.0007), mostly discharged to physical therapy or rehabilitation (8.8 vs. 2.5% of patients, p < 0.0001). Among osteoporotic patients deceased 3 months after discharge, the number of those treated with vitamin D, with or without calcium supplements, was significantly lower compared with survivors (12 vs. 32%, p = 0.0168). CONCLUSIONS: The diagnosis of osteoporosis is poorly considered both during hospital stay and at discharge; osteoporotic patients are frailer compared to non-osteoporotic patients.

Anti-atherogenic Modification of Serum Lipoprotein Function in Patients with Rheumatoid Arthritis after Tocilizumab Treatment, a Pilot Study.

Lipid metabolism derangement contributes to increased cardiovascular risk in Rheumatoid Arthritis (RA). It is still debated whether and how tocilizumab, an interleukin-6 receptor inhibitor used in active RA, impacts cardiovascular risk. We studied the effect of tocilizumab on the regulation of macrophage cholesterol homeostasis, measuring patient serum ability to respectively load (cholesterol loading capacity, CLC) and discharge (cholesterol efflux capacity, CEC) cells with cholesterol. Patients with RA (n = 8) were studied before and after 4 and 12 weeks of tocilizumab treatment. CLC was measured by a fluorimetric assay of intracellular cholesterol content in human macrophages and CEC was measured for the three main pathways, mediated by the transporters Scavenger Receptor class B-type I (SR-BI), ATP binding cassette-G1 (ABCG1) and -A1 (ABCA1) in specific cell models. After 12 weeks of tocilizumab treatment, serum LDL cholesterol levels were increased, while CLC was reduced. HDL cholesterol levels were unchanged, but CEC was significantly ameliorated for the SR-BI and ABCG1 pathways with respect to baseline. Tocilizumab reduces LDL pro-atherogenic potential despite increasing their serum levels and increases HDL protective activity in RA. The data of our pilot study suggest that tocilizumab regulates lipoprotein function in selected patient populations and lay the groundwork for future larger studies.

Prevalence of the age-related diseases in older patients with acquired thrombotic thrombocytopenic purpura.

BACKGROUND: The prevalence of older patients with acquired thrombotic thrombocytopenic purpura (TTP) is increasing. There is scarce information on the prevalence of multimorbidity, polypharmacy and age-related diseases in aging TTP patients. This study aimed to evaluate the prevalence of multimorbidity and polypharmacy in a population of acquired TTP patients aged 65 years or more compared with a group of age-matched controls. METHODS: Acquired TTP patients enrolled in the Milan TTP registry from December 1st 1999 to March 31th 2018 and aged 65 years or more at the date of last follow-up were evaluated. Controls were Italian healthy individuals recruited from 2006 to March 31th 2018 among friends and non-consanguineous relatives of patients tested for thrombophilia screening at the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center of Milan. RESULTS: 36 TTP patients and 127 age-matched controls were included. Compared with controls, TTP patients had a higher prevalence of multimorbidity and polypharmacy. They also showed a higher prevalence of autoimmune diseases, osteoporosis and arterial hypertension and were more chronically treated with corticosteroids and antiplatelets for primary cardiovascular prevention. All these results were confirmed after adjusting for sex. Compared with the general elderly population, TTP patients showed a higher prevalence of ischemic heart disease and stroke. CONCLUSIONS: Our findings suggest that a careful comprehensive geriatric assessment of acquired TTP patients is necessary. It is important to look for other autoimmune diseases and such age-related comorbidities as osteoporosis, arterial hypertension, ischemic heart disease and cerebrovascular disease.

Views of medical practitioners about deprescribing in older adults: Findings from an Italian qualitative study.

BACKGROUND: Even though increasing attention is given to deprescribing owing to the risks related to polypharmacy in older adults, deprescribing is not yet part of clinical culture. METHODS: We conducted three focus groups with 25 internists, geriatricians and general practitioners to explore the factors influencing the implementation of deprescribing in the Italian context, and more specifically: i. to investigate the barriers to deprescribing; ii. to define strategies and actions to address these barriers; and iii. to identify skills and tools that may assist in implementing deprescribing in clinical practice. Thematic analysis was used. RESULTS: Six themes were identified: Good reasons for deprescribing, Difficulties and doubts about deprescribing, System factors affecting polypharmacy and deprescribing, Perspectives on how to practically approach polypharmacy, Need for effective communication with patients and caregivers, Taking responsibility and starting action. Participants reported a willingness to challenge themselves by addressing the barriers to deprescribing through regular review of prescriptions and collaboration with colleagues and patients. CONCLUSIONS: Italian internists, geriatricians and general practitioners reported many system-level barriers to deprescribing as well as some doubts about its necessity. Strategies to address the barriers to deprescribing include regular medication review and enhancing collaboration with colleagues and patients. Additionally, participants were willing to challenge themselves and use uncertainty as an impetus for deprescribing.

Long-term neuropsychological sequelae, emotional wellbeing and quality of life in patients with acquired thrombotic thrombocytopenic purpura.

Neurological symptoms related to microthrombosis are the hallmark of acute manifestations of acquired thrombotic thrombocytopenic purpura (TTP). Despite the achievement of hematological remission, patients may report persisting neurological impairment that affects their quality of life. To assess the long-term neuropsychological consequences of acute TTP, we recruited 35 acquired TTP patients (77% females, median age at onset 41 years, interquartile range: 35-48) regularly followed at our out-patient clinic of thrombotic microangiopathies in Milan (Italy) from December 2015 to October 2016. Patients underwent a psychological evaluation of memory and attentional functions, emotional wellbeing and health-related quality of life at least three months after their last acute TTP event (median 36 months, interquartile range: 17-54). During the psychological consultation, 17 patients (49%) referred persisting subjective neurological impairment in the frame of a remission phase, with at least one symptom as disorientation, loss of concentration, dizziness, lack of balance, headache and diplopia. Neuropsychological assessment revealed lower scores than the Italian general population pertaining to direct, indirect and deferred memory. A higher degree of impairment of memory domains was found in patients with neurological involvement at the time of presentation of the first acute TTP episode. Anxiety and depression were detected in seven (20%) and 15 (43%) patients, respectively. Health-related quality of life was lower than the Italian general population, with mental domains more impacted than physical domains (mean difference 58.43, 95% confidence interval: 71.49-45.37). Our study demonstrates compromised memory and attention functions, persisting anxiety/depression symptoms and a generally reduced quality of life in patients recovering from acute acquired TTP. New clinical strategies should be considered to improve these symptoms.

The features of acquired thrombotic thrombocytopenic purpura occurring at advanced age.

INTRODUCTION: Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare life-threatening thrombotic microangiopathy (TMA) affecting more frequently women of 30-50 years of age. There is scarce information on the clinical features of aTTP occurring in the elderly. Our goal was to evaluate the impact of an elderly-onset disease on the expression, severity and management of aTTP. MATERIALS AND METHODS: We performed a cross-sectional study of patients enrolled in the Milan TTP Registry (www.ttpdatabase.org) after a first acute episode of aTTP from January 2002 to March 2018. The aTTP diagnosis was suspected on the basis of the presence of thrombocytopenia and microangiopathic hemolytic anemia with no alternative causes, and was confirmed centrally by a severe plasma deficiency of ADAMTS13 activity (<10%). Triggers, clinical manifestations, laboratory parameters, management and outcome of the first acute events of elderly-onset aTTP patients (≥65 years) were compared with those of younger patients. RESULTS: Among 143 eligible patients, 16 (11%) were elderly at onset. In comparison with younger cases they showed a lower rate of bleeding symptoms and severe anemia (30% and 18%), with a trend towards a higher rate of neurological and renal signs and symptoms. These patients were less frequently treated with plasma exchange and corticosteroids and more often with plasma infusion. No difference for gender, triggers and episode outcomes was observed. CONCLUSIONS: Older patients with aTTP differed from younger patients mainly for being treated less frequently with plasma exchange and corticosteroids, perhaps for the perceived risks associated with these treatments in the elderly.