Federica Melazzini

Thrombocytopenia during pregnancy is often thought to be associated with severe bleeding manifestations. Three are the main disorders associated with this condition: gestational thrombocytopenia (GT), immune thrombocytopenia (ITP), and inherited thrombocytopenias (ITs). Reaching the correct diagnosis of this condition has relevant therapeutic and outcome implications. We performed a retrospective, observational, monocentric study enrolling 59 consecutive women with isolated thrombocytopenia, attended to our referral center in the last 3 years. Together with personal and family history, platelet (PLT) count trend and mean platelet volume (MPV) in pregnancy are helpful for the diagnosis, with the highest PLT count in GT and lowest in ITs, with different timing of count decrease. MPV is significantly increased in both ITs and ITP. Misdiagnosis with ITP was responsible for unnecessary and unsuccessful therapy in some GT or ITs pregnant women, determining relevant side effects. Excluding inherited platelet function disorders (IPFDs), the bleeding risk for mother with thrombocytopenia and their newborns is similar to the general population. Vaginal delivery is associated with a lower risk of bleeding than cesarean section and therefore is preferable whenever obstetrical–gynecological conditions permit.

Correct interpretation of the pathogenicity of germline RUNX1 variants is essential for FPD/AML diagnosis, clinical management and leukaemia surveillance. We report two families with clear FPD/AML phenotypic features harbouring missense variants at RHD critical residue Gly168. Although classified as of unknown significance (VUS) by RUNX1 ‐specific curation guidelines, these variants should rather be considered likely pathogenic, as supported by computational tools, structural modelling and dysregulated platelet expression of RUNX1‐targets, adding Gly168 among amino acids currently recognised as mutational hotspots. Our data could help reduce the number of variants classified as VUS, providing evidence for updating RUNX1 guidelines, thus improving FPD/AML diagnosis.

Corrigendum: Diagnostic Delay of Pulmonary Embolism in COVID-19 Patients

Preliminary evidence supports the notion that COVID-19 patients may have an increased susceptibility to develop venous thromboembolism (VTE). However, the magnitude of this association still needs to be defined. Furthermore, clinical predictors of thrombogenesis, and the relationship with the inflammatory status are currently unknown. On this basis, we conducted a retrospective, observational study on 259 consecutive COVID-19 patients admitted to an academic tertiary referral hospital in Northern Italy between March 19th and April 6th, 2020. Records of COVID-19 patients with a definite VTE event were reviewed for demographic information, co-morbidities, risk factors for VTE, laboratory tests, and anticoagulation treatment. Twenty-five cases among 259 COVID-19 patients developed VTE (9.6%), all of them having a Padua score > 4, although being under standard anticoagulation prophylaxis since hospital admission. In the VTE subcohort, we found a significant positive correlation between platelet count (PLT) and either C reactive protein (CRP) (p < 0.0001) or lactate dehydrogenase (LDH) (p = 0.0013), while a significant inverse correlation was observed between PLT and mean platelet volume (p < 0.0001). Platelet-to-lymphocyte ratio significantly correlated with CRP (p < 0.0001). The majority of VTE patients was male and younger compared to non-VTE patients (p = 0.002 and p = 0.005, respectively). No significant difference was found in d-dimer levels between VTE and non VTE patients, while significantly higher levels of LDH (p = 0.04) and IL-6 (p = 0.04) were observed in VTE patients in comparison to non-VTE patients. In conclusion, our findings showed a quite high prevalence of VTE in COVID-19 patients. Raised inflammatory indexes and increased serum levels of pro-inflammatory cytokines should raise the clinical suspicion of VTE.

Summary: The inherited thrombocytopenias (IT) are a heterogeneous group of diseases resulting from mutations in more than 30 different genes. Among them, ACTN1‐related thrombocytopenia (ACTN1‐RT; Online Mendelian Inheritance in Man: 615193) is one of the most recently identified forms. It has been described as a mild autosomal dominant macrothrombocytopenia caused by mutations in ACTN1, a gene encoding for one of the two non‐muscle isoforms of α‐actinin. We recently identified seven new unrelated families with ACTN1‐RT caused by different mutations. Two of them are novel missense variants (p.Trp128Cys and p.Pro233Leu), whose pathogenic role has been confirmed by in vitro studies. Together with the 10 families we have previously described, our cohort of ACTN1‐RT now consists of 49 individuals carrying ACTN1 mutations. This is the largest case series ever collected and enabled a critical evaluation of the clinical aspects of the disease. We concluded that ACTN1‐RT is the fourth most frequent form of IT worldwide and it is characterized by platelet macrocytosis in all affected subjects and mild thrombocytopenia in less than 80% of cases. The risk of bleeding, either spontaneous or upon haemostatic challenge, is negligible and there are no other associated defects, either congenital or acquired. Therefore, ACTN1‐RT is a benign form of IT, whose diagnosis provides affected individuals and their families with a good prognosis.

Congenital amegakaryocytic thrombocytopenia (CAMT) is an inherited disorder characterized at birth by thrombocytopenia with reduced megakaryocytes, which evolves into generalized bone marrow aplasia during childhood. Although CAMT is genetically heterogeneous, mutations of MPL, the gene encoding for the receptor of thrombopoietin (THPO), are the only known disease‐causing alterations. We identified a family with three children affected with CAMT caused by a homozygous mutation (p.R119C) of the THPO gene. Functional studies showed that p.R119C affects not only ability of the cytokine to stimulate MPL but also its release, which is consistent with the relatively low serum THPO levels measured in patients. In all the three affected children, treatment with the THPO‐mimetic romiplostim induced trilineage hematological responses, remission of bleeding and infections, and transfusion independence, which were maintained after up to 6.5 years of observation. Recognizing patients with THPO mutations among those with juvenile bone marrow failure is essential to provide them with appropriate substitutive therapy and prevent the use of invasive and unnecessary treatments, such as hematopoietic stem cell transplantation or immunosuppression. Synopsis Congenital amegakaryocytic thrombocytopenia (CAMT) is a fatal inherited juvenile bone marrow failure syndrome, unless children are treated with hematopoietic stem cell transplantation (HSCT). The only known cause of CAMT is mutations in the MPL gene. A novel THPO mutation is here described. We identified a family affected with CAMT that is caused by a novel homozygous missense mutation (p.R119C) in THPO, the gene encoding for thrombopoietin (THPO). Functional studies in vitro showed that p.R119C significantly impairs secretion of THPO, consistent with the relatively low serum THPO levels measured in patients. The mutation also affects interaction of THPO with MPL, resulting in defective signalling downstream of the receptor, which is reduced by about 50% compared with wild‐type THPO. In three affected children, administration of the THPO‐mimetic romiplostim induced sustained trilineage improvement of blood counts and remission of bleeding and infections, maintained after an up to 6.5‐year follow‐up. THPO mutations must be considered in patients presenting with the phenotype of CAMT: recognition of this disorder (disease variant) is essential to avoid unnecessary HSCT and give appropriate substitutive therapy with MPL agonists.

Bleeding diathesis has been considered for a long time the main clinical issue impacting the lives of patients affected by inherited thrombocytopaenias. However, the number of known inherited thrombocytopaenias greatly increased in recent years, and careful evaluation of hundreds of patients affected by these ‘new’ disorders revealed that most of them are at risk of developing additional life‐threatening disorders during childhood or adult life. These additional disorders are usually more serious and dangerous than low platelet count. For instance, it is known that mutations in RUNX1, ANKRD26 and ETV6 cause congenital thrombocytopaenia, but we now know that they also predispose to haematological malignancies. Similarly, MYH9 mutations result in congenital thrombocytopaenia and increase the risk of developing kidney failure, cataracts and hearing loss at a later stage, while MPL mutations cause a congenital thrombocytopaenia that almost always evolves into deadly bone marrow failure. Thus, identification of patients with these disorders is essential for evaluation of their prognosis, enabling effective genetic counselling, personalizing follow‐up and giving appropriate treatments in case of development of additional diseases. Careful clinical evaluation and peripheral blood film examination are extremely useful tools in guiding the diagnostic process and identifying the candidate genes to be sequenced.