Management of Antithrombotic Drugs in Patients with Isolated Traumatic Brain Injury: An Intersociety Consensus Document.

BACKGROUND: All available recommendations about the management of antithrombotic therapies (ATs) in patients who experienced traumatic brain injury (TBI) are mainly based on expert opinion because of the lack of strength in the available evidence-based medicine. Currently, the withdrawal and the resumption of AT in these patients is empirical, widely variable, and based on the individual assessment of the attending physician. The main difficulty is to balance the thrombotic and hemorrhagic risks to improve patient outcome. METHODS: Under the endorsement of the Neurotraumatology Section of Italian Society of Neurosurgery, the Italian Society for the Study about Haemostasis and Thrombosis, the Italian Society of Anaesthesia, Analgesia, Resuscitation, and Intensive Care, and the European Association of Neurosurgical Societies, a working group (WG) of clinicians completed two rounds of questionnaires, using the Delphi method, in a multidisciplinary setting. A table for thrombotic and bleeding risk, with a dichotomization in high risk and low risk, was established before questionnaire administration. In this table, the risk is calculated by matching different isolated TBI (iTBI) scenarios such as acute and chronic subdural hematomas, extradural hematoma, brain contusion (intracerebral hemorrhage), and traumatic subarachnoid hemorrhage with patients under active AT treatment. The registered indication could include AT primary prevention, cardiac valve prosthesis, vascular stents, venous thromboembolism, and atrial fibrillation. RESULTS: The WG proposed a total of 28 statements encompassing the most common clinical scenarios about the withdrawal of antiplatelets, vitamin K antagonists, and direct oral anticoagulants in patients who experienced blunt iTBI. The WG voted on the grade of appropriateness of seven recommended interventions. Overall, the panel reached an agreement for 20 of 28 (71%) questions, deeming 11 of 28 (39%) as appropriate and 9 of 28 (32%) as inappropriate interventions. The appropriateness of intervention was rated as uncertain for 8 of 28 (28%) questions. CONCLUSIONS: The initial establishment of a thrombotic and/or bleeding risk scoring system can provide a vital theoretical basis for the evaluation of effective management in individuals under AT who sustained an iTBI. The listed recommendations can be implemented into local protocols for a more homogeneous strategy. Validation using large cohorts of patients needs to be developed. This is the first part of a project to update the management of AT in patients with iTBI.

A new progestin-only pill (POP): the impact of drospirenone-only pill 4 mg 24 + 4 on coagulation markers and bleeding patterns.

PURPOSE: Progestin-only pills (POPs), compared to combined, are not associated with an increased risk of venous thromboembolism, but are associated with a poor cycle control. The aim of this study was to evaluate the impact of a new POP [4 mg drospirenone (DRSP) for 24 days with a 4-day hormone-free interval] on some coagulation markers (both procoagulant and fibrinolytic) and to describe its impact on bleeding patterns. MATERIALS AND METHODS: This is a prospective trial, based on serum evaluation of following coagulation markers and tests: Factor (F) X, F VIII, F V, INR, aPTT, Protein S and antithrombin III. A 'bleeding diary' was used to categorise women as having (1) unscheduled bleeding, (2) scheduled bleeding and (3) amenorrhoea. Thirty patients were followed for six 28-day intake cycles, with a follow-up at the end of the 3rd and 6th cycles. RESULTS: There was a significant decrease of F X (p = 0.03) (-5.7% at cycle 6). No significant changes have been observed for F VII, F V and INR. A significant increase in aPTT (p = 0.01 at 3 cycles), Protein S (p = 0.0006 at 3 cycles) and antithrombin III (p < 0.0001 at 3 cycles) was recorded. This non-deteriorating coagulation impact was associated with a significant and progressive reduction of days of scheduled and unscheduled bleeding in users between cycles 4 and 6 (from 1.3 ± 0.2 days at cycle 4 to 0.8 ± 0.1 days at cycle 6 and from 2.6 ± 0.4 days at cycle 4 to 0.6 ± 0.2 days at cycle 6, respectively, p < 0.0001). CONCLUSIONS: DRSP 24 + 4 use was associated with a non-deteriorating effect on coagulation markers and a significant progressive reduction of days of scheduled and unscheduled bleeding.

Contraception with DRSP 24 + 4 was associated with a non-deteriorating effect on coagulation markers and a significant progressive reduction of days of scheduled and unscheduled bleeding.

Fibrinogen Depletion Coagulopathy Predicts Major Bleeding After Thrombolysis for Ischemic Stroke: A Multicenter Study.

BACKGROUND: Symptomatic intracerebral hemorrhage (sICH) and major bleeding can be fatal complications of intravenous thrombolysis (IVT) for acute ischemic stroke. We investigated the impact of early fibrinogen depletion after IVT on major bleeding events. METHODS: This multicenter observational prospective cohort study enrolled 1678 consecutive patients receiving IVT for acute ischemic stroke at 6 Italian centers, undergoing fibrinogen concentration assessment at baseline, 2 hours and 6 hours after IVT. Fibrinogen depletion was defined as a reduction below 200 mg/dL after 2 hours from IVT, or as a reduction below 50% of baseline fibrinogen levels after 2 hours from IVT. Main outcomes were (1) sICH (National Institute of Neurological Disorders and Stroke criteria) and (2) major bleeding defined as fatal bleeding, decrease in the hemoglobin level>2 g/dL/>1 unit transfusion, or bleeding at critical site. Additional outcomes were (1) any ICH, (2) any bleeding, (3) fatal ICH, and (4) sICH according to ECASSII definition. Good functional recovery was defined as modified Rankin Scale score 0 to 2 at 3 months. RESULTS: Overall, 1678 patients were included (mean age 72 years, 46% female). sICH (n=116) and major bleeding (n=297) were associated with lower rate of good functional recovery (P<0.001). Despite similar fibrinogen levels at admission, fibrinogen depletion after 2 hours from IVT was more common in people with sICH, major bleeding and all additional bleeding outcomes. In the backward stepwise multivariable logistic regression model, fibrinogen depletion remained a significant predictor of sICH (OR, 1.55 [95% CI, 1.04-2.32]) and major bleeding (OR, 1.36 [95% CI, 1.03-1.8]). Thirty-one percent of sICH could be attributable to fibrinogen depletion. The association between fibrinogen depletion and worse clinical outcome at 3 months after stroke (P=0.012) was attributable to the higher risk of major bleeding/sICH. CONCLUSIONS: Fibrinogen depletion significantly increases the risk of sICH and major bleeding after IVT for acute ischemic stroke. Fibrinogen depletion represents an independent risk factor for bleeding, and routine assessment could be considered to stratify the risk of ICH. Trials on early fibrinogen repletion are needed to investigate mitigation of bleeding risk.

Direct oral anticoagulants for atrial fibrillation in patients with congenital factor VII deficiency.

The management of anticoagulant therapy (OAT) in patients with factor VII (FVII) deficiency is a very challenging clinical issue, as warfarin further reduces FVII levels, thus potentially increasing bleeding risk. On the other hand, the International Normalized Ratio test is misleading in such patients, as they do not reflect the actual level of global inhibition of the coagulation system. We report here three cases of patients with a moderate FVII deficiency and receiving direct oral anticoagulants (DOAC) for prevention of cardioembolism in atrial fibrillation. Of note, two of them experienced a treatment failure while on warfarin, while DOAC treatment was not associated with thrombotic or hemorrhagic adverse events. DOAC are very attractive for the management of OAT in FVII deficient patients, because they do not require monitoring by tests affected by the inherited defect, and their mechanism of action is FVII-independent.

The introduction of biosimilars of low molecular weight heparins in Europe: a critical review and reappraisal endorsed by the Italian Society for Haemostasis and Thrombosis (SISET) and the Italian Society for Angiology and Vascular Medicine (SIAPAV).

Recently, the European Medicines Agency (EMA) authorized the introduction and marketing of Thorinane® and Inhixa®, biosimilars of the Low Molecular Weight Heparin (LMWH) enoxaparin. The authorization path is considerably different from the guidelines published by the EMA in 2009, as well as from the recommendations from the International Society on Thrombosis and Haemostasis published in 2013. Indeed, both of them recommended that LMWHs biosimilars therapeutic equivalence should be demonstrated in at least one adequately designed clinical trial. Shortly after enoxaparin biosimilars approval, EMA published a revised version of its guideline, no longer requiring the execution of a clinical study in patients at risk of venous thromboembolism. Also the assessment of safety shows some relevant flaws, as it relies only on a 20 healthy volunteers study, clearly underpowered to draw any conclusions about the safety profile of the drug. In our opinion, the approach taken by EMA for approval of enoxaparin biosimilars raises serious concerns about their actual, clinical "similarity". On these grounds, with the endorsement of the Italian Society for Haemostasis and Thrombosis (SISET) and the Italian Society for Angiology and Vascular Medicine (SIAPAV), we elaborated the present document aimed at reviewing and reappraising some critical points regarding the introduction of biosimilars of LMWH in Europe. Moreover, we would strongly advise the Italian National Health Authorities not to entrust safety assessment to the post-marketing surveillance only, but to promote well designed and powered studies aimed at establish the actual efficacy and safety of LMWH biosimilars.

Fibrinogen decrease after intravenous thrombolysis in ischemic stroke patients is a risk factor for intracerebral hemorrhage.

BACKGROUND: Intravenous thrombolysis is an effective treatment in acute stroke patients, but it increases the risk of intracerebral hemorrhages. Our aim is to establish if fibrinogen depletion increases the risk of intracerebral hemorrhage after intravenous thrombolysis for acute ischemic stroke. METHODS: In 104 ischemic stroke patients, treated with intravenous thrombolysis, we assessed the rate of intracerebral hemorrhages documented by computed tomographic scan at 24 hours and within 7 days post-treatment. Fibrinogen levels were determined at 2 hours after therapy: patients were classified as belonging to "low fibrinogen group" if levels decreased to less than 2 g/L and/or by 25% or more. Fibrinogen levels and other known hemorrhagic risk factors were studied using univariate and multivariate analyses. RESULTS: During the first 7 days, an intracerebral hemorrhage was detected in 24 patients (23.1%), and only 6 of these (5.8%) experienced symptomatic bleeding; 41 patients were included in the low fibrinogen group. Among the 24 hemorrhages, 18 occurred in the low fibrinogen group and 6 in the "normal fibrinogen group": the bleeding rate in the low fibrinogen group was significantly higher (43.9%) than that in the normal fibrinogen group (9.5%; odds ratio [OR] 7.43, P < .001). Univariate and multivariate analyses revealed that only clinical severity (OR 1.15, P < .001) and hypofibrinogenemia (OR 7.47, P < .001) were significantly associated with brain bleeding at 7 days and at 24 hours (P = .008). CONCLUSIONS: An early fibrinogen reduction seems to increase the risk of intracerebral hemorrhage after rtPA treatment in ischemic stroke. Fibrinogen assessment could be a rapid, inexpensive, and widely available tool to help the identification of patients at higher risk of bleeding.

Perceived challenges and attitudes to regimen and product selection from Italian haemophilia treaters: the 2013 AICE survey.

Despite great advances in haemophilia care in the last 20 years, a number of questions on haemophilia therapy remain unanswered. These debated issues primarily involve the choice of the product type (plasma-derived vs. recombinant) for patients with different characteristics: specifically, if they were infected by blood-borne virus infections, and if they bear high or low risk of inhibitor development. In addition, the most appropriate treatment regimen in non-inhibitor and inhibitor patients compel physicians operating at the haemophilia treatment centres (HTCs) to take important therapeutic decisions, which are often based on their personal clinical experience rather than on evidence-based recommendations from published literature data. To know the opinion on the most controversial aspects in haemophilia care of Italian expert physicians, who are responsible for common clinical practice and therapeutic decisions, we have conducted a survey among the Directors of HTCs affiliated to the Italian Association of Haemophilia Centres (AICE). A questionnaire, consisting of 19 questions covering the most important topics related to haemophilia treatment, was sent to the Directors of all 52 Italian HTCs. Forty Directors out of 52 (76.9%) responded, accounting for the large majority of HTCs affiliated to the AICE throughout Italy. The results of this survey provide for the first time a picture of the attitudes towards clotting factor concentrate use and product selection of clinicians working at Italian HTCs.

[Novel oral anticoagulants: more opportunities or more risks? And for which patients?]. / I nuovi anticoagulanti orali nella prevenzione del cardioembolismo nei pazienti con fibrillazione atriale non valvolare: più opportunità o più rischi? E per chi?

Novel direct oral anticoagulants (NAO) represent an innovative and potentially relevant option for the prevention of cardiac embolism in patients with atrial fibrillation. Their recent introduction has been followed by a wide debate on their appropriate use, considering that they do not require regular monitoring of INR values as Vitamin K Antagonists (VKA) do, but that are much less tested in everyday clinical practice and much more expensive than VKA. Starting from the quite favourable results of the available RCTs - showing that NAO are at least non-inferior to VKA and that may be even better for some outcomes - this article discusses the clinical relevance of these results, their transferability into clinical practice looking at the methods of those RCTs and potential risks related to their widespread introduction. Final considerations on possible strategies for their appropriate and progressive introduction are also provided, using the experience developing in the Emilia-Romagna region.

Gynecological Cancer and Venous Thromboembolism: A Narrative Review to Increase Awareness and Improve Risk Assessment and Prevention.

The prevention and appropriate management of venous thromboembolism in cancer patients is of paramount importance. However, the literature data report an underestimation of this major problem in patients with gynecological cancers, with an inconsistent venous thromboembolism risk assessment and prophylaxis in this patient setting. This narrative review provides a comprehensive overview of the available evidence regarding the management of venous thromboembolism in cancer patients, focusing on the specific context of gynecological tumors, exploring the literature discussing risk factors, risk assessment, and pharmacological prophylaxis. We found that the current understanding and management of venous thromboembolism in gynecological malignancy is largely based on studies on solid cancers in general. Hence, further, larger, and well-designed research in this area is needed.

Low-molecular-weight heparin for the prevention of clinical worsening in severe non-critically ill COVID-19 patients: a joint analysis of two randomized controlled trials.

Coronavirus disease 2019 (COVID-19) carries a high risk of vascular thrombosis. However, whether a specific anticoagulation intensity strategy may prevent clinical worsening in severe COVID-19 patients is still debated. We conducted a joint analysis of two randomized controlled trials, COVID-19 HD (NCT044082359) and EMOS-COVID (NCT04646655), to assess the efficacy and safety of two anticoagulant regimens in hospitalized severe COVID-19 patients. Subjects with COVID-19-associated respiratory compromise and/or coagulopathy were randomly assigned to low (4000 IU qd) or high (70 IU Kg-1 every 12 h) enoxaparin dose. The primary efficacy endpoint was clinical worsening within 30 days, defined as the occurrence of at least one of the following events, whichever came first: in-hospital death, evidence of arterial or venous thromboembolism, acute myocardial infarction, need for either continuous positive airway pressure (CPAP) or non-invasive ventilation (NIV) in patients receiving standard oxygen therapy or none at randomization, and need for mechanical ventilation in any patient. The safety endpoint was major bleeding. We estimated the relative risk (RR) and its 95% confidence interval (CI) for the outcomes. Among 283 patients included in the study (144 in the low-dose and 139 in the high-dose group), 118 (41.7%) were on NIV or CPAP at randomization. 23/139 (16.5%) patients in the high-dose group reached the primary endpoint compared to 33/144 (22.9%) in the low-dose group (RR 0.72, 95% CI 0.45-1.17). No major bleeding was observed. No significant differences were found in the clinical worsening of hospitalized COVID-19 patients treated with high versus low doses of enoxaparin.

Thrombotic events associated with low baseline direct oral anticoagulant levels in atrial fibrillation: the MAS study.

ABSTRACT: Although effective and safe, treatment with direct oral anticoagulants (DOAC) in atrial fibrillation (AF) is still associated with thrombotic complications. Whether the measurement of DOAC levels may improve treatment efficacy is an open issue. We carried out the observational, prospective, multicenter Measure and See (MAS) study. Blood was collected 15 to 30 days after starting DOAC treatment in patients with AF who were followed-up for 1 year. Plasma samples were centralized for DOAC level measurement. Patients' DOAC levels were converted into drug/dosage standardized values to allow a pooled analysis in a time-dependent, competitive-risk model. The measured values were transformed into standardized values (representing the distance of each value from the overall mean) by subtracting the DOAC-specific mean value from the original values and dividing by the standard deviation. Trough and peak DOAC levels were assessed in 1657 and 1303 patients, respectively. In total, 21 thrombotic complications were recorded during 1606 years of follow-up (incidence of 1.31% of patients per year). Of 21 thrombotic events, 17 occurred in patients whose standardized activity levels were below the mean of each DOAC (0); the incidence was the highest (4.82% of patients per year) in patients whose standardized values were in the lowest class (-1.00 or less). Early measurement of DOAC levels in patients with AF allowed us to identify most of the patients who, having low baseline DOAC levels, subsequently developed thrombotic complications. Further studies are warranted to assess whether thrombotic complications may be reduced by measuring baseline DOAC levels and modifying treatment when indicated. This trial was registered at www.ClinicalTrials.gov as #NCT03803579.

MORE EARLY BLEEDS ASSOCIATED WITH HIGH BASELINE DIRECT ORAL ANTICOAGULANT LEVELS IN ATRIAL FIBRILLATION: THE MAS STUDY.

Treatment with direct oral anticoagulants (DOAC) in atrial fibrillation (AF) patients is effective and safe. However, bleeding complications still occur. Whether the measurement of DOAC levels may further improve treatment efficacy and safety is still an open issue. In the "Measure and See" (MAS) Study (#NCT03803579) venous blood was collected 15-30 days after DOAC initiation in AF patients who were then followed for one year to record the occurrence of major and clinically relevant non-major bleeding. DOAC plasma levels were measured in one laboratory, and results were kept blind to patients and treating doctors. Trough DOAC levels were assessed in 1657 patients [957 (57.7%) and 700 treated with standard and low-dose, respectively]. Fifty bleeding events were recorded during 1606 years of follow-up (3.11% pt/yrs). Fifteen bleeding events (4.97% pt/yrs) occurred in patients with C-trough standardized values in the highest activity class (> 0.50); whereas 35 events (2.69% pt/yrs) occurred in those with values in the two lower classes ( 0.50, p= 0.0401). Increasing DOAC levels and low-dose DOAC use were associated with increased bleeding risk in the first three months of treatment. 19% of patients receiving low doses had standardized activity values in the highest class. More bleeding occurred in patients treated with low (4.3% pt/yrs) than standard (2.2% pt/yrs; p= 0.0160) dose DOAC. Early measurement of DOAC levels in AF patients identified many subjects with high activity levels despite the low doses use and had more bleeding risk during the first 3 months of treatment.

Hemostasis in acute liver and kidney failure: nothing is as it seems.

Very little is known about the behavior of the hemostatic system in patients with acute kidney injury (AKI) associated with acute liver failure (ALF). Agarwal and colleagues show that patients who suffer from both ALF and AKI exhibit a higher degree of hemostasis impairment than those with normal renal function. Both anticoagulant and procoagulant factors were impaired. The development of AKI appears to displace the hemostatic equilibrium toward a more prothrombotic pattern.

Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis.

BACKGROUND & AIMS: We performed a randomized controlled trial to evaluate the safety and efficacy of enoxaparin, a low-molecular-weight heparin, in preventing portal vein thrombosis (PVT) in patients with advanced cirrhosis. METHODS: In a nonblinded, single-center study, 70 outpatients with cirrhosis (Child-Pugh classes B7-C10) with demonstrated patent portal veins and without hepatocellular carcinoma were assigned randomly to groups that were given enoxaparin (4000 IU/day, subcutaneously for 48 weeks; n = 34) or no treatment (controls, n = 36). Ultrasonography (every 3 months) and computed tomography (every 6 months) were performed to check the portal vein axis. The primary outcome was prevention of PVT. Radiologists and hepatologists that assessed outcomes were blinded to group assignments. Analysis was by intention to treat. RESULTS: At 48 weeks, none of the patients in the enoxaparin group had developed PVT, compared with 6 of 36 (16.6%) controls (P = .025). At 96 weeks, no patient developed PVT in the enoxaparin group, compared with 10 of 36 (27.7%) controls (P = .001). At the end of the follow-up period, 8.8% of patients in the enoxaparin group and 27.7% of controls developed PVT (P = .048). The actuarial probability of PVT was lower in the enoxaparin group (P = .006). Liver decompensation was less frequent among patients given enoxaparin (11.7%) than controls (59.4%) (P < .0001); overall values were 38.2% vs 83.0%, respectively (P < .0001). The actuarial probability of liver decompensation was lower in the enoxaparin group (P < .0001). Eight patients in the enoxaparin group and 13 controls died. The actuarial probability of survival was higher in the enoxaparin group (P = .020). No relevant side effects or hemorrhagic events were reported. CONCLUSIONS: In a small randomized controlled trial, a 12-month course of enoxaparin was safe and effective in preventing PVT in patients with cirrhosis and a Child-Pugh score of 7-10. Enoxaparin appeared to delay the occurrence of hepatic decompensation and to improve survival.

Successful liver transplantation in a patient with splanchnic vein thrombosis and pulmonary embolism due to polycythemia vera with Jak2v617f mutation and heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is a rare complication of heparin treatment resulting in a severe acquired thrombophilic condition with an associated mortality of about 10 %. We report the first case of successful urgent liver transplantation (LT) in a patient with end-stage liver disease due to a Budd-Chiari syndrome, portal vein thrombosis and pulmonary embolism due to acquired thrombophilia associated to polycythemia vera carrying JAK2V617F gene mutation and HIT in the acute phase. Lepirudin was used to provide anticoagulation in the LT perioperative period that was performed without haemorrhagic and thrombotic complications despite the donor received heparin during liver explantation.

Risk and Management of Bleeding Complications with Direct Oral Anticoagulants in Patients with Atrial Fibrillation and Venous Thromboembolism: a Narrative Review.

Atrial fibrillation (AF) and venous thromboembolism (VTE) are highly prevalent conditions with a significant healthcare burden, and represent the main indications for anticoagulation. Direct oral anticoagulants (DOACs) are the first choice treatment of AF/VTE, and have become the most prescribed class of anticoagulants globally, overtaking vitamin K antagonists (VKAs). Compared to VKAs, DOACs have a similar or better efficacy/safety profile, with reduced risk of intracerebral hemorrhage (ICH), while the risk of major bleeding and other bleeding harms may vary depending on the type of DOAC. We have critically reviewed available evidence from randomized controlled trials and observational studies regarding the risk of bleeding complications of DOACs compared to VKAs in patients with AF and VTE. Special patient populations (e.g., elderly, extreme body weights, chronic kidney disease) have specifically been addressed. Management of bleeding complications and possible resumption of anticoagulation, in particular after ICH and gastrointestinal bleeding, are also discussed. Finally, some suggestions are provided to choose the optimal DOAC to minimize adverse events according to individual patient characteristics and bleeding risk.

[Home management of Covid-19 pneumonia in the early phases of the pandemic: analysis of real-life data of General Practitioners in the Province of Modena from the MAGMA study.] / Gestione domiciliare dei pazienti con polmonite da Covid-19 nelle fasi precoci della pandemia: analisi dei dati real-life della Medicina Generale della Provincia di Modena dallo studio MAGMA.

Primary care management of Covid-19 pneumonia in the Province of Modena in the early phases of the pandemic: data integration from MAGMA study. Retrospective study on patients affected of Covid-19 and followed by General Practitioner from March 2020 to April 2021. 5340 patients were studied, 27% of them developed pneumoniae. Among these, most of them were managed entirely at home with an elevated intensity of care. Daily remote monitoring and home visits, together with a personalized pharmacological treatment, especially for the most severe forms, appeared to be the most effective interventions in reducing hospitalizations.

Potential mechanisms of vaccine-induced thrombosis.

Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is a rare syndrome characterized by high-titer anti-platelet factor 4 (PF4) antibodies, thrombocytopenia and arterial and venous thrombosis in unusual sites, as cerebral venous sinuses and splanchnic veins. VITT has been described to occur almost exclusively after administration of ChAdOx1 nCoV-19 and Ad26.COV2.S adenovirus vector- based COVID-19 vaccines. Clinical and laboratory features of VITT resemble those of heparin-induced thrombocytopenia (HIT). It has been hypothesized that negatively charged polyadenylated hexone proteins of the AdV vectors could act as heparin to induce the conformational changes of PF4 molecule that lead to the formation of anti-PF4/polyanion antibodies. The anti-PF4 immune response in VITT is fostered by the presence of a proinflammatory milieu, elicited by some impurities found in ChAdOx1 nCoV-19 vaccine, as well as by soluble spike protein resulting from alternative splice events. Anti-PF4 antibodies bind PF4, forming immune complexes which activate platelets, monocytes and granulocytes, resulting in the VITT's immunothrombosis. The reason why only a tiny minority of patents receiving AdV-based COVID-19 vaccines develop VITT is still unknown. It has been hypothesized that individual intrinsic factors, either acquired (i.e., pre-priming of B cells to produce anti-PF4 antibodies by previous contacts with bacteria or viruses) or inherited (i.e., differences in platelet T-cell ubiquitin ligand-2 [TULA-2] expression) can predispose a few subjects to develop VITT. A better knowledge of the mechanistic basis of VITT is essential to improve the safety and the effectiveness of future vaccines and gene therapies using adenovirus vectors.