Gian Marco Podda’s research while affiliated with Università degli Studi di Milano-Bicocca and other places

The natural history of chronic hepatitis C virus (HCV) infection has changed after the introduction of direct‐acting antiviral agents (DAAs). Screening programs have been ongoing to reach the World Health Organisation's goal of HCV elimination by 2030, and most infected people are eligible for treatment. Given the increased cardiovascular risk in people with HCV infection and the metabolic pathways of DAAs, it is not uncommon to face the issue of drug–drug interactions (DDIs) with antiplatelet or anticoagulant drugs. In the absence of clinical trials, we offer suggestions to deal with DDIs in case of treatment of patients with DAAs who are also receiving antiplatelet or anticoagulant drugs, based on the best available evidence from pharmacodynamics and pharmacokinetics studies in conjunction with clinical experience in the field of haemostasis and thrombosis.

The ongoing demographic, epidemiological and social changes are dramatically raising the clinical and care complexity of patients admitted to internal medicine (IM) departments. Collecting evidence for a better characterization of patients is crucial to tailor future interventions based on patient’s real needs. The aim of this prospective multicenter study was to describe the complexity of care of patients hospitalized in IM by calculating the complexity of care (ICC) score, through the combination of clinical instability (NEWS score) and care dependency scales (mICD). Furthermore, social frailty was assessed according to potential difficulty in discharge planning. 3912 patients were enrolled (median age 78 years); 71% had a Charlson Comorbidity Index ≥ 5. The ICC score was high in 14.7% of patients, while 15% exhibited a NEWS score at least moderate. One in four patients presented moderate to critical social frailty. The length of stay was correlated with social frailty, mICD and ICC scores, but not with NEWS. In-hospital mortality was correlated with the severity of all the considered scores. A relevant proportion of IM patients exhibited a high complexity of care. Our data support a model in which approximately 15% of IM beds are designated for clinically unstable patients managed in intermediate care sub-units. The substantial burden of social frailty highlights the urgency of national plans allowing at the same time to cover the needs of not self-sufficient and socially disadvantaged patients, and to efficiently address the issue of emergency department boarding.

Introduction. Liver cirrhosis (LC) is characterized by advanced damage to the hepatic architecture. Hemostasis is rebalanced in patients with LC because of the copresence of pro-thrombotic and pro-hemorrhagic pathomechanisms. With regards to primary hemostasis, thrombocytopenia, platelet function defects and low thrombopoietin (TPO) synthesis are counterbalanced by increased von Willebrand factor and low levels of ADAMTS13 in LC. Fewer data, however, are available regarding the platelet size, which is measured as mean platelet volume (MPV), in LC. MPV correlates with the degree of fibrosis and inflammation in patients with chronic liver disease (CLD). Moreover, MPV predicts the risk of death and thrombosis in healthy subjects and cardiovascular patients. We designed this study to investigate the MPV in patients with LC. Methods. For this case-control study we included adult patients with LC or CLD and control subjects. All patients (LC and CLD) were consecutively enrolled among the outpatients followed up at the Hepatology outpatient clinic of Ospedale San Paolo (Milan). Control subjects were enrolled among healthcare workers of Ospedale San Paolo. All subjects had at least one complete blood count (CBC) performed at the laboratory of Ospedale San Paolo between 2015 and 2020 (normal range for MPV: 9.3-12.6 fL). All CBCs were performed with the same instrument during this time. We retrieved the necessary data to calculate the prognostic scores Child-Pugh and MELD-Na for all LC patients. The primary outcome was the comparison of the MPV (median and proportion of subjects with a value above the upper limit of the normal range) in the three groups. Additionally, the MPV was evaluated in LC patients classified according to their Child-Pugh score at the time of blood withdrawal and history of previous decompensation (defined by any among ascites, portosystemic encephalopathy, variceal bleeding, spontaneous bacterial peritonitis and portal vein thrombosis). Finally, in patients with LC, we evaluated the correlations between platelet count and the MELD-Na score at the time of blood withdrawal with the MPV. Results. We enrolled 38 controls (21 females, median age 46 years, IQR 35-53), 120 patients with CLD (65 females, 60 years, 53-73) and 114 patients with LC (52 females, 67 years, 56-75). LC patients had significantly lower median platelet counts (124x109/L, IQR 80-184) compared to CLD patients (220x109/L, IQR 183-260) and controls (257x109/L, IQR 216-287) (p<0,0001). LC patients' Child-Pugh score was A for 59 subjects, B for 36 and C for 19 (with B and C scores indicating a greater severity of LC). Fifty-five LC patients (48%) had a history of previous decompensation. The median MPV was significantly higher both in LC patients (11.3 fL, IQR 10.4-12.3) and CLD patients (11.0 fL, IQR 10.2-11.8) compared to controls (10.7, IQR 10.0-11.1; p=0.0008 and p=0.005, respectively). The proportion of LC patients with a MPV higher than the upper limit of the reference range was 14.0% (95% CI, 8.2-21.8), significantly higher compared to controls (0%, 95% CI 0-9.3, p=0,0327), but non-significantly higher compared to CLD patients (8.3%, 95% CI 4.1-14.8%, p=0.2383). Neither the median MPV nor the proportion of patients with a MPV higher than the reference range significantly differed across Child-Pugh A, B and C LC patients. The proportion of LC patients with a MPV higher than the reference range was significantly higher in patients with previous decompensation (21.8%, 95% CI 11.8-35.0 vs 6.8%, 95% CI 1.9-16.5; p=0.04). There was an inverse correlation between the platelet count and the MPV (r=-0.37, p<0.0001) and a mild direct correlation between the MELD-Na score and the MPV (r=0.21, p=0.02) in LC patients. Conclusions. We found that 14.0% of LC patients have a MPV higher than the reference range and that such proportion increases to 21.8% in patients with previous decompensation, but not in patients with a higher Child-Pugh score. MPV inversely correlated with the platelet count, which could suggest that MPV is increased in LC because of compensatory platelet production in response to platelet consumption and/or sequestration. The fact that MPV does not increase with increasing disease severity could be explained by the copresence of pathomechanisms with opposite effects on platelet size (inflammation, hypersplenism, decline in TPO synthesis) in patients with more advanced disease.

Introduction. Immune thrombocytopenia (ITP) is caused by a complex interplay between increased platelet destruction and/or impaired platelet production. First-line treatment includes corticosteroids (CS) and intravenous immunoglobulin (IVIG). Up to 15-20% of patients are refractory to first-line treatment and require further lines of treatment. Currently, however, there are no clinical or laboratory predictors of failure of first-line treatment(s). The aim of our study was to identify potential platelet laboratory markers linked to the failure of first-line treatment(s) in ITP. Methods. All patients were identified from the Benign Hematology outpatient clinic of Ospedale San Paolo, Milan. We included adult patients with a diagnosis of ITP who had previously received CS and/or IVIG in accordance with clinical guidelines, with the latest course being the index. All patients underwent venous blood withdrawal at least 14 days after the start of CS and 3 days after the administration of IVIG. We evaluated reticulated platelets, markers of platelet activation [platelet-monocyte aggregates (PMAs) and platelet-granulocyte aggregates (PGAs)] and the degree of platelet desyalilation (assessed through platelet beta-galactose exposure) using flow cytometry. The cut-off for all evaluations was the 95th centile of 20 healthy subjects. Patients were categorized in three groups based on the quality of the platelet count response at the time of blood sampling after the index course of first-line treatment: poor (0-49x109/L), good (50-99x109/L), and optimal (100x109/L or more). Clinical records were screened up to 4 weeks post-sampling to assess first-line treatment failure (TF), which was defined as a platelet count below 25x109/L, active bleeding or need for subsequent treatment. Results. Twenty-eight patients were enrolled in this study. The median years since ITP diagnosis until study inclusion were 3 (IQR 1-13). Index first-line treatments included: CS (61% of patients), IVIG (7%) and CS+IVIG (32%). Nine patients had a poor response, 6 a good response, and 13 an optimal response to the index first-line treatment. In the poor response group, there was a lower proportion of females (44% vs 83% and 69% in the good and optimal response groups) and of secondary ITP (0% vs 17% and 31% in the good and optimal response groups) and the median age was higher (63 years, IQR 50-69, vs 40 years, IQR 37-55, and 55 years, IQR 41-65, in the good and optimal response groups). The proportion of patients with high reticulated platelets in the poor response group was 33% (3/9), which was non-significantly higher compared to the optimal response group (0/12, 0%, p=0.06) and the good response group (1/6, 17%, p=0.60). Similarly, the highest proportion of patients with elevated PMAs and PGAs was found in the poor response group (PMAs: 7/9, 78%; PGAs: 7/9, 78%) compared to the good response (PMAs: 2/6, 33%; PGAs: 3/6, 50%) and optimal response (PMAs, 3/13, 23%; PGAs, 5/13, 38%) groups. The proportion of ITP patients with increased PMAs was significantly higher in the poor response group compared to the optimal response group (p=0.03). Increased beta-galactose exposure was found in 50% of tested patients from the poor (3/6) and good (2/4) response groups, a proportion that was non-significantly higher compared to the optimal response group (2/10, 20%; p>0.10 for both comparisons). The 4-week follow-up post-blood sampling was complete for 25 patients. TF occurred in 5 patients, 3 in the poor response (3/8, 38%) and 2 (2/4, 50%) in the good response group. None of the TF patients had increased reticulated platelets (0/5, 0%). Increased PMAs and PGAs were found in 60% (3/5) of patients, and increased beta-galactose exposure in 67% of tested patients (2/3). Conclusions. Our results suggest that the quality of platelet count response following first-line treatment parallels the downregulation of diverse platelet laboratory markers. A higher proportion of patients with a poor response had increased reticulated platelets, markers of platelet activation and platelet desyalilation, which suggest a higher degree of ongoing Fc-dependent and -independent platelet clearance. However, none of the investigated markers was able to discriminate patients who underwent TF at 4 weeks post-sampling. Whether an inappropriately low reticulated platelet count signals the need for second-line treatment needs further investigation.

No risk factors have been identified for vaccine‐induced immune thrombotic thrombocytopenia (VITT) so far. The aim of this study was to identify human leucocyte antigen (HLA) alleles potentially associated with VITT susceptibility. Specific HLA class II alleles were detected with significantly higher frequency in VITT patients compared with Italian controls: DPB1*17:01, DQA1*05:01, and DRB1*11:04. In silico analysis revealed increased affinity of DRB1*11:04 for a platelet factor 4 (PF4)‐derived peptide, ITSLEVIKA, that contains two amino acids present in the specific binding site of anti‐PF4 antibodies from VITT patients. Our findings show for the first time a genetic predisposition to developing anti‐PF4 antibodies in response to Ad‐vector vaccines.

Anti-platelet factor 4 (PF4) disorders are a group of platelet-consumptive disorders characterized by platelet-activating antibodies against PF4, thrombocytopenia and an increased risk of thrombosis. PF4 is a chemokine released by platelet alpha granules upon activation, which can form immune complexes with negatively charged substances, such as heparin, cartilage components, nucleic acids, and viral and bacterial agents. Antibodies formed in response to PF4-polyanion complexes may display platelet-activating properties and cause pan-cellular activation, leading to the marked prothrombotic state of anti-PF4 disorders. In recent years, the landscape of anti-PF4 disorders has evolved to include classic heparin-induced thrombocytopenia (cHIT), autoimmune HIT (aHIT), spontaneous HIT (SpHIT), vaccine-induced immune thrombotic thrombocytopenia (VITT), and the newly recognized spontaneous VITT (SpVITT). These disorders have garnered increased attention due to their association with severe clinical outcomes. Recent discoveries have expanded the understanding of these conditions, highlighting the role of various triggers, such as upper respiratory tract infections and monoclonal gammopathy of undetermined significance, in their development. Compared to cHIT, the less common anti-PF4 disorders VITT, aHIT, SpHIT and SpVITT generally appear more severe, with aggressive disease courses, more severe thrombocytopenia and a higher frequency of bleeding, thrombosis at unusual sites, involvement of the central nervous system and of multiple vascular beds. Clinical suspicion and knowledge of the less well-known triggers of anti-PF4 disorders are pivotal to ordering the appropriate laboratory tests and initiating the necessary treatments. Herein, we will review cHIT, aHIT, SpHIT and VITT, focusing on their clinical presentation and therapeutic management.

Acquired disorders of platelet function are an underdiagnosed cause of bleeding tendency. A 14-year-old girl developed moderate mucocutaneous bleeding two weeks after a Mycoplasma pneumoniae infection successfully treated with clarithromycin. The patient was referred to us 7 months later for laboratory investigation of the persisting bleeding diathesis. The patient’s personal and family histories were negative for bleeding disorders. Complete blood count, von Willebrand Factor levels and coagulation tests were normal; platelet aggregation, ATP secretion, δ-granules content and serum thromboxane B2 levels were defective. At follow-up visits, laboratory parameters and the bleeding diathesis progressively normalized within 2 years. The patient’s condition is compatible with a diagnosis of acquired Storage Pool Deficiency (SPD), associated with defective thromboxane A2 production. To our knowledge, this is the first case of acquired, transient SPD with spontaneous remission. The pathogenic role of Mycoplasma pneumoniae infection or clarithromycin is possible, albeit uncertain.

Background: Patients with acute venous thromboembolism (VTE) need anticoagulation (AC) therapy for at least 3/6 months (primary treatment); after that period, they should receive a decision on the duration of therapy. Methods: This study examined the complications occurring during two years of follow-up (FU) in patients with a first VTE who were recruited in 20 clinical centers and had discontinued or prolonged AC. They were included in the START2-POST-VTE prospective observational study. Results: A total of 720 patients (53.5% males) who, after the completion of primary treatment, had received the decision to continue (n = 281, 39%; 76.1% with a DOAC) or discontinue (n = 439, 61%) AC were followed up for 2 years (total FU = 1318 years). The decision to prolong or suspend AC was made in similar proportions in patients with unprovoked or provoked index events. Courses of sulodexide treatment or Aspirin (100 mg daily) were prescribed to 20.3% and 4.5%, respectively, of the patients who discontinued AC. The bleeding rate was significantly higher in patients who extended AC (1.6% pt/y) than in those who stopped AC (0.1% pt/y; p = 0.001) and was higher in patients using standard-dose DOACs (3.1% pt/y) than in those using reduced-dose DOACs (0.4% pt/y). The recurrent VTE rates were similar between the two groups (2.2% pt/y during AC vs. 3% pt/y off AC). Conclusion: Physicians' decisions about AC duration were independent of the unprovoked/provoked nature of the index event. The bleeding rate was higher in patients who continued AC using standard-dose DOACs. Surprisingly, the rate of thrombotic recurrence was not different between those who continued or discontinued AC. Randomized studies comparing different procedures to decide on the duration of AC after a first VTE are needed.