A survey on the implementation of Patient Blood Management programs in Italy.

BACKGROUND: Since 2012, in line with the World Health Organization (WHO) resolution WHA63.12 of 05/21/2010, the Italian National Blood Center has been promoting patient blood management (PBM). In order to verify the level of PBM implementation nationwide, we submitted a survey to all healthcare providers. MATERIAL AND METHODS: In line with what was proposed in the international scientific literature in the field, a series of indicators were used derived from the four main blocks related to PBM strategies: the management of patient anemia; the optimization of hemostasis; blood conservation strategies; patient-centred decision-making. We also added two blocks containing important information on general PBM management and other PBM-related aspects. RESULTS: The survey showed good implementation of anemia screening programs in accordance with the timelines established by national and international guidelines, and the single unit policy is used in line with national guideline recommendations. However, the survey also revealed limited auditing of PBM programs and reduced monitoring and reporting of clinical outcomes and indicators. DISCUSSION: The first national survey on the level of PBM implementation in Italy shows widespread adoption of diagnostic-therapeutic care pathways aimed at the diagnosis and treatment of anemia in the perioperative setting.

[Medico-legal and management issues in patient blood management era.] / Aspetti medico-legali e organizzativi nell'era del Patient blood management.

In recent decades, the approach to blood transfusion has changed radically around the world. In the past, transfusion represented the only solution for anemia, today the paradigm has changed: through the implementation of the Patient blood management (Pbm) program it is possible to manage the patient's own blood in order to reduce and, in many cases, eliminate the administration of blood components for transfusion. This approach increases patient safety by reducing clinical risks as well as costs. The implementation of the PBM program in Australia has demonstrated that the use of blood is not strictly necessary but, on the contrary, is largely avoidable. Through change management the traditional attitude of doctors and healthcare facilities can be modified. Law no. 24/2017 focuses on the safety of care by encouraging the necessary implementation of Pbm in hospital settings; the failure to adopt an organized Pbm program may constitute, in the event of an adverse transfusion event, a clear profile of health responsibility on the part of the management and clinicians.

Identification of a novel cord blood NK cell subpopulation expressing functional programmed death receptor-1.

Background: Natural Killer cells (NKs) represent the innate counterpart of TCRαß lymphocytes and are characterized by a high anti-tumor and an anti-viral cytotoxic activity. Recently, it has been demonstrated that NKs can express PD-1 as an additional inhibitory receptor. Specifically, PD-1 was identified on a subpopulation of terminally differentiated NKs from healthy adults with previous HCMV infection. So far it is unknown whether PD-1 appears during NK-cell development and whether this process is directly or indirectly related to HCMV infection. Methods: In this study, we analyzed the expression and function of PD-1 on Cord Blood derived NKs (CB-NKs) on a large cohort of newborns through multiparametric cytofluorimetric analysis. Results: We identified PD-1 on CB-NKs in more than of half the newborns analyzed. PD-1 was present on CD56dim NKs, and particularly abundant on CD56neg NKs, but only rarely present on CD56bright NKs. Importantly, unlike in adult healthy donors, in CB-NKs PD-1 is co-expressed not only with KIR, but also with NKG2A. PD-1 expression was independent of HCMV mother seropositivity and occurs in the absence of HCMV infection/reactivation during pregnancy. Notably, PD-1 expressed on CB-NKs was functional and mediated negative signals when triggered. Conclusion: To our understanding, this study is the first to report PD-1 expression on CB derived NKs and its features in perinatal conditions. These data may prove important in selecting the most suitable CB derived NK cell population for the development of different immunotherapeutic treatments.

Antifouling activity of isonitrosoacetanilides against microfouling and macrofouling.

Biofouling is responsible for structural and economic damage to man-made surfaces. Antifouling paints with biocides have been applied to structures to avoid organism adhesion; however, they have high toxicity and are not able to prevent all biofouling processes, necessitating the periodic mechanical removal of organisms and paint reapplication. Thus, there is an urgent demand for novel, effective, and environmentally friendly antifouling alternatives. As isonitrosoacetanilide is the precursor for many compounds with antibacterial activity, we believe that it could have antifouling activity against microfouling and, consequently, against macrofouling. The aim of this work was to investigate the antifouling potential of six isonitrosoacetanilide compounds and their toxicity. The compounds were employed at different concentrations (0.625-1.25-2.5-5-10 µg mL-1) in this study. The biofilm and planktonic bacteria inhibition and biofilm eradication potential were evaluated by crystal violet assay, while Amphibalus amphitrite barnacle settlement was evaluated by cyprid settlement assay. Toxicity evaluation (LC50 and EC50) was performed with A. amphitrite nauplii II and cyprid larvae. At least one of the tested concentrations of 4-Br-INA, 4-CH3-INA, and 2-Br-INA compounds showed nontoxic antifouling activity against microfouling (antibiofilm) and macrofouling (antisettlement). However, only 4-CH3-INA and 2-Br-INA also showed biofilm eradication potential. These compounds with antibiofilm activity and nontoxic effects could be combined with acrylic base paint resin or added directly into commercial paints in place of toxicant biocides to cover artificial structures as friendly antifouling agents.

Implementation of a patient blood management in an Italian City Hospital: is it effective in reducing the use of red blood cells?

To evaluate the effect of patient blood management (PBM) since its introduction, we analyzed the need for transfusion and the outcomes in patients undergoing abdominal surgery for different types of tumor pre- and post-PBM. Patients undergoing elective gastric, liver, pancreatic, and colorectal surgery between 2017 and 2020 were included. The implementation of the PBM program was completed on May 1, 2018. The patients were grouped as follows: those who underwent surgery before the implementation of the program (pre-PBM) versus after the implementation (post-PBM). A total of 1302 patients were included in the analysis (445 pre-PBM vs. 857 post-PBM). The number of transfused patients per year decreased significantly after the introduction of PBM. A strong tendency for a decreased incidence of transfusion was evident in gastric and pancreatic surgery and a similar decrease was statistically significant in liver surgery. With regard to gastric surgery, a single-unit transfusion scheme was used more frequently in the post-PBM group (7.7% vs. 55% after PBM; p = 0.049); this was similar in liver surgery (17.6% vs. 58.3% after PBM; p = 0.04). Within the subgroup of patients undergoing liver surgery, a significant reduction in the use of blood transfusion (20.5% vs. 6.7%; p = 0.002) and a decrease in the Hb trigger for transfusion (8.5, 8.2-9.5 vs. 8.2, 7.7-8.4 g/dl; p = 0.039) was reported after the PBM introduction. After the implementation of a PBM protocol, a significant reduction in the number of patients receiving blood transfusion was demonstrated, with a strong tendency to minimize the use of blood products for most types of oncologic surgery.

Biofouling initial succession on offshore artificial substrate under subtropical conditions.

This study presents the initial stages of the macrofouling community on artificial substrate exposed to the offshore subtropical marine environment, and the contribution of depth (3 and 22m), exposure time (1-2-4-7-10-13-weeks), UV-radiation, rainfall, temperature, pH, salinity, water chlorophyll-a, and zooplankton supply to organism establishment. Steel substrates were placed horizontally on the structure of a pipeline monobuoy off the southern shore of Brazil (Tramandaí beach), and the ecological succession was monitored by six random removals per depth during the summer-autumn of 2011. Approximately 88.5% of the quantified settled individuals comprised fouling fauna and 11.5% vagile and sedentary fauna, although the taxa richness was higher for non-sessile invertebrates. Species richness and organism density up to four weeks were significantly higher at 3m-depth. After this period, a higher density of organisms was found at 22m, while during the whole study the species richness and diversity remained higher at 3m-depth. Zooplankton composition did not show a simultaneous temporal relationship with invertebrate recruitment at any depth; however, increasing the exposure time, the similarity between the planktonic and benthic communities also increased. Meroplankton, tychoplankton, and holoplankton were recorded on the substrates. This study showed that the depth of available substrates affects the macrofouling establishment, which is mainly associated with UV-radiation, exposure time, and ecological interspecific interactions.

Characterizing Features of Human Circulating B Cells Carrying CLL-Like Stereotyped Immunoglobulin Rearrangements.

Chronic Lymphocytic Leukemia (CLL) is characterized by the accumulation of monoclonal CD5+ B cells with low surface immunoglobulins (IG). About 40% of CLL clones utilize quasi-identical B cell receptors, defined as stereotyped BCR. CLL-like stereotyped-IG rearrangements are present in normal B cells as a part of the public IG repertoire. In this study, we collected details on the representation and features of CLL-like stereotyped-IG in the IGH repertoire of B-cell subpopulations purified from the peripheral blood of nine healthy donors. The B-cell subpopulations were also fractioned according to the expression of surface CD5 molecules and IG light chain, IGκ and IGλ. IG rearrangements, obtained by high throughput sequencing, were scanned for the presence of CLL-like stereotyped-IG. CLL-like stereotyped-IG did not accumulate preferentially in the CD5+ B cells, nor in specific B-cell subpopulations or the CD5+ cell fraction thereof, and their distribution was not restricted to a single IG light chain type. CLL-like stereotyped-IG shared with the corresponding CLL stereotype rearrangements the IGHV mutational status. Instead, for other features such as IGHV genes and frequency, CLL stereotyped-IGs presented a CLL-like subset specific behavior which could, or could not, be consistent with CLL stereotyped-IGs. Therefore, as opposed to the immuno-phenotype, the features of the CLL stereotyped-IG repertoire suggest a CLL stereotyped subset-specific ontogeny. Overall, these findings suggest that the immune-genotype can provide essential details in tracking and defining the CLL cell of origin.

Salt marshes as the final watershed fate for meso- and microplastic contamination: A case study from Southern Brazil.

Plastics pose a major threat to aquatic ecosystems especially in smaller size fractions. Salt marshes play a crucial role in maintaining the coastal zone and aquatic food web, yet their contamination, including by plastic materials, is still poorly investigated. This work investigated meso- (MEP, 5-25 mm) and microplastic (MIP, 1 µm-5 mm) contamination of a salt marsh, which reached average levels of 279.63 ± 410.12 items kg-1, 366.92 ± 975.18 items kg-1, and 8.89 ± 8.75 items L-1 in surface sediment, sediment cores and water, respectively. Photomicrographs revealed a complex fouling community on plastics surface for both different salt marsh zones and plastic formats. Abundance of plastics in sediment was higher in the dryer, vegetated zones compared to flooded, unvegetated zones. This is consistent with the role of vegetation as a trap for solid litter and final fate of plastic deposition, but also with local hydrodynamics influencing deposition pattern. Plastics were detected up to 66 cm-depth, presenting higher levels at surface sediments. It was also possible to identify the main groups of microorganisms (1638 bacterial cells, 318 microalgae cells, and 20049.93 µm2 of filamentous fungi) composing the Plastisphere communities on all plastic items recorded in the different zones. These results are a pioneer contribution, highlighting that regional salt marshes participate in sequestration and longstanding accumulation of plastic particles in estuarine environments, before exportation to the ocean.

Variations and obstacles in the use of coagulation factor concentrates for major trauma bleeding across Europe: outcomes from a European expert meeting.

PURPOSE: Trauma is a leading cause of mortality, with major bleeding and trauma-induced coagulopathy (TIC) contributing to negative patient outcomes. Treatments for TIC include tranexamic acid (TXA), fresh frozen plasma (FFP), and coagulation factor concentrates (CFCs, e.g. prothrombin complex concentrates [PCCs] and fibrinogen concentrate [FCH]). Guidelines for TIC management vary across Europe and a clear definition of TIC is still lacking. METHODS: An advisory board involving European trauma experts was held on 02 February 2019, to discuss clinical experience in the management of trauma-related bleeding and recommendations from European guidelines, focusing on CFC use (mainly FCH). This review summarises the discussions, including TIC definitions, gaps in the guidelines that affect their implementation, and barriers to use of CFCs, with suggested solutions. RESULTS: A definition of TIC, which incorporates clinical (e.g. severe bleeding) and laboratory parameters (e.g. low fibrinogen) is suggested. TIC should be treated immediately with TXA and FCH/red blood cells; subsequently, if fibrinogen ≤ 1.5 g/L (or equivalent by viscoelastic testing), treatment with FCH, then PCC (if bleeding continues) is suggested. Fibrinogen concentrate, and not FFP, should be administered as first-line therapy for TIC. Several initiatives may improve TIC management, with improved medical education of major importance; generation of new and stronger data, simplified clinical practice guidance, and improved access to viscoelastic testing are also critical factors. CONCLUSIONS: Management of TIC is challenging. A standard definition of TIC, together with initiatives to facilitate effective CFC administration, may contribute to improved patient care and outcomes.

Therapeutic Use of Convalescent Plasma in COVID-19 Infected Patients with Concomitant Hematological Disorders.

The use of convalescent plasma (CP) from individuals recovered from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a promising therapeutic modality for the coronavirus disease 2019 (COVID-19). CP has been in use for at least a century to provide passive immunity against a number of diseases, and was recently proposed by the World Health Organization for human Ebola virus infection. Only a few small studies have so far been published on patients with COVID-19 and concomitant hematological malignancies (HM). The Italian Hematology Alliance on HM and COVID-19 has found that HM patients with COVID-19 clinically perform more poorly than those with either HM or COVID-19 alone. A COVID-19 infection in patients with B-cell lymphoma is associated with impaired generation of neutralizing antibody titers and lowered clearance of SARS-CoV-2. Treatment with CP was seen to increase antibody titers in all patients and to improve clinical response in 80% of patients examined. However, a recent study has reported impaired production of SARS-CoV-2-neutralizing antibodies in an immunosuppressed individual treated with CP, possibly supporting the notion of virus escape, particularly in immunocompromised individuals where prolonged viral replication occurs. This may limit the efficacy of CP treatment in at least some HM patients. More recently, it has been shown that CP may provide a neutralising effect against B.1.1.7 and other SARS-CoV-2 variants, thus expanding its application in clinical practice. More extensive studies are needed to further assess the use of CP in COVID-19-infected HM patients.

Post-Transplant Nivolumab Plus Unselected Autologous Lymphocytes in Refractory Hodgkin Lymphoma: A Feasible and Promising Salvage Therapy Associated With Expansion and Maturation of NK Cells.

Immune checkpoint inhibitors (CI) have demonstrated clinical activity in Hodgkin Lymphoma (HL) patients relapsing after autologous stem cell transplantation (ASCT), although only 20% complete response (CR) rate was observed. The efficacy of CI is strictly related to the host immune competence, which is impaired in heavily pre-treated HL patients. Here, we aimed to enhance the activity of early post-ASCT CI (nivolumab) administration with the infusion of autologous lymphocytes (ALI). Twelve patients with relapse/refractory (R/R) HL (median age 28.5 years; range 18-65), underwent lymphocyte apheresis after first line chemotherapy and then proceeded to salvage therapy. Subsequently, 9 patients with progressive disease at ASCT received early post-transplant CI supported with four ALI, whereas 3 responding patients received ALI alone, as a control cohort. No severe adverse events were recorded. HL-treated patients achieved negative PET scan CR and 8 are alive and disease-free after a median follow-up of 28 months. Four patients underwent subsequent allogeneic SCT. Phenotypic analysis of circulating cells showed a faster expansion of highly differentiated NK cells in ALI plus nivolumab-treated patients as compared to control patients. Our data show anti-tumor activity with good tolerability of ALI + CI for R/R HL and suggest that this setting may accelerate NK cell development/maturation and favor the expansion of the "adaptive" NK cell compartment in patients with HCMV seropositivity, in the absence of HCMV reactivation.

Litter contamination at a salt marsh: An ecological niche for biofouling in South Brazil.

The presence of solid litter and its consequences for coastal ecosystems is now being investigated around the world. Different types of material can be discarded in areas such as salt marshes, and various fouling organisms can associate with such items forming the Plastisphere. This study investigated the distribution of solid litter along zones (dry, middle, flooded) of a salt marsh environment in the Patos Lagoon Estuary (South Brazil) and the association of biofouling organisms with these items. Solid litter quantities were significantly higher in the dry zone when compared to the middle and flooded zones, showing an accumulation area where the water rarely reaches. Most items were made of plastic, as shown for many other coastal areas, and originated from food packaging, fishery and shipping activities and personal use. Although not statistically significant, there was a tendency of increased biofouling towards the flooded zone. Thirteen groups were found in association with solid litter items, mainly algae, amphipods, and gastropods. The preference for salt marsh zones, types of material and items' colour was highly variable among groups of organisms, which can be related to their varied physiological requirements. In summary, significant plastic contamination of salt marshes of the Patos Lagoon was associated with a heterogeneous distribution of fouling communities.

Acartia tonsa Dana 1849 as a Model Organism: Considerations on Acclimation in Ecotoxicological Assays.

The copepod Acartia tonsa was standardized as model organism in acute toxicity bioassays due to its key position in coastal food chains and high sensitivity. Once bioassays are performed according to a protocol their results may become tools for the protection of aquatic ecosystems. However, there are divergences in bioassays methods using A. tonsa. This study aimed to investigate: (i) the need for acclimation of A. tonsa collected from the environment for use in acute toxicological bioassays; and (ii) differences in sensitivity between copepods collected from the environment and laboratory-grown copepods. Laboratory-grown copepods are more sensitive to SDS than A. tonsa from the environment. The acclimation time of 30 h helped organisms to recover from stress of collection/handling and changing environment/conditions. Therefore, laboratory-grown copepods showed to be more sensitive than organisms from environment; and for ecotoxicological bioassays acclimating A. tonsa collected from the environment for 30 h can be adopted.

Practical approach to transfusion management of post-partum haemorrhage.

OBJECTIVES: To describe transfusion management during post-partum haemorrhage (PPH) and the usefulness of standard or point-of-care (POC) laboratory tests for guiding haemostatic management. BACKGROUND: PPH is the leading cause of maternal mortality and severe maternal morbidity worldwide. Despite the efforts made in recent years, PPH is often burdened by preventable death. Recent data from the active Italian Obstetric Surveillance System (ItOSS) highlighted the following main critical issues: inadequate communication between healthcare professionals, inability to correctly and promptly assess the severity of haemorrhage, delays in diagnosis and treatment, failure to request blood promptly and inappropriate monitoring post-partum. MATERIALS AND METHODS: Data in the literature have been compared with the rotational thromboelastometry (ROTEM)- and the thromboelastography (TEG)-guided algorithms applied in the authors' departments. RESULTS: PPH transfusion therapy may have an empirical approach based on the standard use of blood products or a targeted approach based on coagulation monitoring by laboratory or POC tests. Here, the authors describe how they manage PPH in their departments, according to the Italian guidelines, along with the addition of a ROTEM- and a TEG-guided algorithms developed by themselves. CONCLUSION: Although the proposed algorithms have not been validated by trials or observational studies conducted in our departments, we believe that these indications could be useful for supporting clinical practice. Furthermore, we deem it appropriate to emphasise the importance of a multidisciplinary approach and the need for standardised and shared protocols to support the decisions of healthcare professionals.

Bacteria-invertebrate interactions as an asset in developing new antifouling coatings for man-made aquatic surfaces.

Economic losses can result from biofouling establishment on man-made structures. Macrofouling causes damage to artificial substrates, which justifies the need for its control. However, the antifouling coatings employed nowadays are typically not safe for the environment. Microfouling can affect macrofouling colonization, and thus represents a potential target for alternative antifouling control. From both ecological and economical points of view, information on the ecology and interactions between micro- and macrofouling are crucial to develop successful and safe control strategies, which will prevent biofouling development on man-made structures while preserving water quality and the safety of non-target organisms. This study presents a metabarcoding analysis of biofilm-associated marine bacteria (16S-rRNA-gene) and fungi (ITS-region), with the aim to understand invertebrate settlement over time on hard substrates exposed to natural condition (Control) and two treatments (Antimicrobials and Antifouling Painted). Biofouling composition changed with exposure time (up to 12 days) and showed differences among Control and Antimicrobials and Painted treatments. Antimicrobial treatment influenced more the biofouling composition than traditional antifouling paint (Cu2O-based). Both treatments caused microbial resistance. Macrofouling establishment was strongly influenced by Gram-negative heterotrophic bacteria (mostly Proteobacteria and Bacteroidetes). Nevertheless, each macrofouling taxon settled in response to a specific biofilm bacterial composition, although other factors can also affect the biofouling community as the condition of the substrate. We suggest that proper friendly antifouling technologies should be focused on inhibiting bacterial biofilm adhesion.

The use of whole blood in traumatic bleeding: a systematic review.

Hemostatic resuscitation is currently considered a standard of care for the management of life-threatening hemorrhage, but in some critical settings the access to high quantities of blood components is problematic. Whole blood (WB) transfusion has been proposed as an alternative modality for hemostatic resuscitation of traumatic major bleeding. To assess the efficacy and safety of WB in trauma-associated massive bleeding, we performed a systematic review of the literature. We selected studies comparing WB transfusions to transfusion of blood components (COMP) in massive trauma bleeding; both randomized clinical trial (RCT) and observational studies were considered. The outcomes were mortality (30-day/in-hospital and 24-h mortality) and adverse events/transfusion reactions. The effect sizes were crude odds ratio (OR), adjusted OR and hazard ratio (HR). The methodological quality of studies was assessed using the Cochrane Risk of Bias tool for RCTs, and the ROBIN-1 tool for observational studies. The overall quality of the available evidence was assessed with the GRADE system. One RCT (2 reports) and 6 cohort studies were included (3642 adult patients; 675 receiving WB, 2967 receiving COMP). Three studies were conducted in military setting, and 4 in civilian setting. In the overall analysis, 30-day/in-hospital and 24-h mortality did not differ significantly between groups (very low quality of the evidence due to high risk of bias, imprecision and inconsistency). After adjustment for baseline covariates in three cohort studies, the OR for mortality was significantly lower in WB recipients compared to COMP (OR 0.22; 95% CIs 0.10/0.45) (moderate grade of evidence). Adverse events and transfusion reactions were overlooked and not consistently reported. The available evidence does not allow to draw definite conclusions on the short-term and long-term efficacy and safety of WB transfusion compared to COMP transfusion. Further well designed research is needed.

Viscoelastic testing in benign hematologic disorders: Clinical perspectives and future implications of point-of-care testing to assess hemostatic competence.

Viscoelastic tests (VETs) have been used routinely for liver transplantation, cardiac surgery, and trauma, but only recently have found clinical utility in benign hematologic disorders. Therefore, guidelines for diagnosis and treatment of these disorders based on viscoelastic variables have been adapted from the existing transplant, cardiothoracic surgery, and trauma resuscitation literature. As a result, diagnostic and therapeutic strategies for benign hematologic disorders utilizing VETs are not uniform. Accordingly, even though there has been a recent increase in the utilization of VET for the diagnosis and treatment of such disorders, the literature is still in its early stages. Analysis of point-of-care viscoelastic tracings from benign hematologic disorders has the potential to allow prompt recognition of disease and to guide patient-specific intervention. Here we present a review describing the application of VETs to benign hematologic disorders.

Viscoelastic testing in oncology patients (including for the diagnosis of fibrinolysis): Review of existing evidence, technology comparison, and clinical utility.

The quantification of the coagulopathic state associated with oncologic and hematologic diseases is imperfectly assessed by common coagulation tests such as prothrombin time, activated partial thromboplastin time, fibrinogen levels, and platelet count. These tests provide a static representation of a component of hemostatic integrity, presenting an incomplete picture of coagulation in these patients. Viscoelastic tests (VETs), such as rotational thromboelastometry (ROTEM) and thromboelastography (TEG), as whole blood analyses, provide data related to the cumulative effects of blood components and all stages of the coagulation and fibrinolytic processes. The utility of VETs has been demonstrated since the late 1960s in guiding blood component therapy for patients undergoing liver transplantation. Since then, the scope of viscoelastic testing has expanded to become routinely used for cardiac surgery, obstetrics, and trauma. In the past decade, VETs' expanded usage has been most significant in trauma resuscitation. However, use of VETs for patients with malignancy-associated coagulopathy (MAC) and hematologic malignancies is increasing. For the purposes of this narrative review, we discuss the similarities between trauma-induced coagulopathy (TIC) and MAC. These similarities center on the thrombomodulin-thrombin complex as it switches between the thrombin-activatable fibrinolysis inhibitor coagulation pathway and activating the protein C anticoagulation pathway. This produces a spectrum of coagulopathy and fibrinolytic alterations ranging from shutdown to hyperfibrinolysis that are common to TIC, MAC, and hematologic malignancies. There is expanding literature regarding the utility of TEG and ROTEM to describe the hemostatic integrity of patients with oncologic and hematologic conditions, which we review here.

The HLA Variant rs6903608 Is Associated with Disease Onset and Relapse of Immune-Mediated Thrombotic Thrombocytopenic Purpura in Caucasians.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening thrombotic microangiopathy caused by severe ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs 13) deficiency, recurring in 30-50% of patients. The common human leukocyte antigen (HLA) variant rs6903608 was found to be associated with prevalent iTTP, but whether this variant is associated with disease relapse is unknown. To estimate the impact of rs6903608 on iTTP onset and relapse, we performed a case-control and cohort study in 161 Italian patients with a first iTTP episode between 2002 and 2018, and in 456 Italian controls. Variation in rs6903608 was strongly associated with iTTP onset (homozygotes odds ratio (OR) 4.68 (95% confidence interval (CI) 2.67 to 8.23); heterozygotes OR 1.64 (95%CI 0.95 to 2.83)), which occurred over three years earlier for each extra risk allele (ß -3.34, 95%CI -6.69 to 0.02). Of 153 survivors (median follow-up 4.9 years (95%CI 3.7 to 6.1)), 44 (29%) relapsed. The risk allele homozygotes had a 46% (95%CI 36 to 57%) absolute risk of relapse by year 6, which was significantly higher than both heterozygotes (22% (95%CI 16 to 29%)) and reference allele homozygotes (30% (95%CI 23 to 39%)). In conclusion, HLA variant rs6903608 is a risk factor for both iTTP onset and relapse. This newly identified biomarker may help with recognizing patients at high risk of relapse, who would benefit from close monitoring or intensified immunosuppressive therapy.