Erythrocytosis has a diverse background. While polycythaemia vera has well defined criteria, the diagnostic approach and management of other types of erythrocytosis are more challenging. The aim of study was to retrospectively analyse the aetiology and management of non-clonal erythrocytosis patients referred to a haematology outpatient clinic in an 8-year period using a 3-step algorithm. The first step was inclusion of patients with Hb > 185 g/L and/or Hct > 0.52 in men and Hb > 165 g/L and/or Hct > 0.48 in women on two visits ≥ two months apart, thus confirming true erythrocytosis. Secondly, polycythaemia vera was excluded and secondary causes of erythrocytosis (SE) identified. Thirdly, idiopathic erythrocytosis patients (IE) were referred to next-generation sequencing for possible genetic background evaluation. Of the 116 patients, 75 (65%) are men and 41 (35%) women, with non-clonal erythrocytosis 34/116 (29%) had SE, 15/116 (13%) IE and 67/116 (58%) stayed incompletely characterized (ICE). Patients with SE were significantly older and had significantly higher Hb and Hct compared to patients with IE. Most frequently, SE was attributed to obstructive sleep apnoea and smoking. Phlebotomies were performed in 56, 53 and 40% of patients in the SE, IE, and ICE group, respectively. Approx. 70% of patients in each group received aspirin. Thrombotic events were registered in 12, 20 and 15% of SE, IE and ICE patients, respectively. Congenital erythrocytosis type 4 (ECYT4) was diagnosed in one patient. The study demonstrates real-life management of non-clonal erythrocytosis which could be optimized using a 3-step diagnostic algorithm.

CALR mutations are a revolutionary discovery and represent an important hallmark of myeloproliferative neoplasms (MPN), especially essential thrombocythemia and primary myelofibrosis. To date, several CALR mutations were identified, with only frameshift mutations linked to the diseased phenotype. It is of diagnostic and prognostic importance to properly define the type of CALR mutation and subclassify it according to its structural similarities to the classical mutations, a 52-bp deletion (type 1 mutation) and a 5-bp insertion (type 2 mutation), using a statistical approximation algorithm (AGADIR). Today, the knowledge on the pathogenesis of CALR-positive MPN is expanding and several cellular mechanisms have been recognized that finally cause a clonal hematopoietic expansion. In this review, we discuss the current basis of the cellular effects of CALR mutants and the understanding of its implementation in the current diagnostic laboratorial and medical practice. Different methods of CALR detection are explained and a diagnostic algorithm is shown that aids in the approach to CALR-positive MPN. Finally, contemporary methods joining artificial intelligence in accordance with molecular-genetic biomarkers in the approach to MPN are presented.

Background: Anticoagulant-related nephropathy (ARN) is a form of acute kidney injury that mainly occurs in patients with previously unrecognized glomerular disease in addition to excessive anticoagulation. Since a renal biopsy is not performed in most cases, the diagnosis is often presumptive. Methods: Here, we present the characteristics of a national Slovenian patient cohort with histologically verified ARN, from the first case in 2014 to December 2020, and a review of the current literature (Pubmed database). Results: In Slovenia, ARN has been detected in 13 patients, seven of whom were treated with coumarins, and others with direct oral anticoagulants. In seven patients, ARN appeared after excessive anticoagulation. As many as 11 patients had underlying IgA nephropathy. Similar to the global data presented here, the pathohistological impairment associated with pre-existing glomerulopathy was mild and disproportionate to the degree of functional renal impairment. The majority of our patients with ARN experienced severe deterioration of renal function associated with histological signs of accompanying acute tubular injury, interstitial edema, and occlusive red blood cell casts. These patients were treated with corticosteroids, which (in addition to supportive treatment and discontinuation of the anticoagulant drug) led to a further improvement in renal function. Conclusions: Anticoagulant therapy combined with a pre-existing glomerular injury may lead to ARN. In addition to discontinuation of the anticoagulant and supportive care, corticosteroids, which are currently listed in only a few cases in the world literature, may have a positive influence on the course of treatment. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections.

Suspicion of myeloproliferative neoplasms (MPNs) and especially essential thrombocythemia (ET) in primary care is often based solely on blood counts, with patients referred to a haematologist without a thorough evaluation. We retrospectively assessed the role of calreticulin gene (CALR) mutations in the diagnosis of MPN in this population. We studied CALR mutations in 524 JAK2 V617F-negative patients with suspected MPN. Uncommon CALR mutations were confirmed by Sanger sequencing and searched for in the COSMIC or HGMD database. Mutations were defined as frameshift or non-frameshift mutations. CALR mutations were detected in 23 patients (23/524 = 4.4%). Four mutations detected in our study were newly identified mutations. Non-frameshift mutations were detected in two patients. Most patients (380/524 = 72.5%) were diagnosed with secondary conditions leading to blood count abnormalities such as iron deficiency, inflammatory and infectious diseases, malignancy and hyposplenism. Nine patients (9/23 = 39%) were retrospectively diagnosed with ET based on CALR mutation confirmation. Two patients with non-frameshift CALR mutations were diagnosed with reactive thrombocytosis and MPN unclassifiable, respectively. Our study showed that CALR mutations are important, non-invasive diagnostic indicators of ET and can aid in its diagnosis. Moreover, the type of CALR mutation must be accurately defined, as non-frameshift mutations may not be associated with ET. Finally, CALR mutation detection should be reserved for patients with high suspicion of clonal haematological disease.

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Background and Aims Anticoagulant-related nephropathy is a recently recognized form of acute kidney injury associated with previously underdiagnosed kidney damage in addition to (usually) excessive anticoagulation. It occurs in patients receiving warfarin as well as those receiving direct oral anticoagulants. Method We collected and analyzed cases of Slovenian patients with pathohistologically documented anticoagulant-related nephropathy associated with all types of anticoagulant treatment from the first case in 2014 to 2020. We also performed an analysis of previously documented cases of anticoagulant-related nephropathy in the global literature (PubMed) in the period from their first mention until recently. Results In Slovenia, 13 patients with anticoagulant-related nephropathy have been histologically verified so far. All patients were diagnosed with concomitant underlying renal disease, and 80% had IgA nephropathy, which was disproportionately mild according to the degree of renal function impairment. After supportive measures and reversal of excessive anticoagulation, 8 of 13 patients were further treated with corticosteroids, resulting in significant improvement in renal function. During the follow-up period, a total of one steroid-treated patient died due to infectious complications and one patient progressed to end-stage renal failure. In the worldwide literature, we found 46 case reports or case series of patients with anticoagulant-related nephropathy. Failure of restitution of renal function with the need for maintenance dialysis was reported much more frequently compared to the results of our cohort (up to 67% vs. 8.3%) Conclusion To our knowledge, the Slovenian cohort of patients with histologically established anticoagulant-related nephropathy is the largest reported series to date that received corticosteroid therapy in addition to conservative measures. Our results indicate that steroids have a beneficial effect, likely exerted via suppression of hemoglobin-associated oxidative stress and inflammation. However, considering the polimorbidity of these patients, the benefit of additional steroid therapy must be weighed against the potential risks of side effects, especially life-threatening infections.

JAK2, MPL, and CALR mutations define clonal thrombocytosis in about 90% of patients with sustained isolated thrombocytosis. In the remainder of patients (triple-negative patients) diagnosing clonal thrombocytosis is especially difficult due to the different underlying conditions and possible inconclusive bone marrow biopsy results. The ability to predict patients with sustained isolated thrombocytosis with a potential clonal origin has a prognostic value and warrants further examination. The aim of our study was to define a non-invasive clinical or blood parameter that could help predict clonal thrombocytosis in triple-negative patients. We studied 237 JAK2 V617-negative patients who were diagnosed with isolated thrombocytosis and referred to the haematology service. Sixteen routine clinical and blood parameters were included in the logistic regression model which was used to predict the type of thrombocytosis (reactive/clonal). Platelet count and lactate dehydrogenase (LDH) were the only statistically significant predictors of clonal thrombocytosis. The platelet count threshold for the most accurate prediction of clonal or reactive thrombocytosis was 449 × 109/L. Other tested clinical and blood parameters were not statistically significant predictors of clonal thrombocytosis. The level of LDH was significantly higher in CALR-positive patients compared to CALR-negative patients. We did not identify any new clinical or blood parameters that could distinguish clonal from reactive thrombocytosis. When diagnosing clonal thrombocytosis triple-negative patients are most likely to be misdiagnosed. Treatment in patients with suspected triple negative clonal thrombocytosis should not be delayed if cardiovascular risk factors or pregnancy coexist, even in the absence of firm diagnostic criteria. In those cases the approach “better treat more than less” should be followed.

We present two cases of transmission of a pancreatic adenocarcinoma from a single donor to two kidney transplant recipients. Autopsy of the donor revealed a pancreatic adenocarcinoma that had already spread locally to the regional lymph nodes and had not been detected at the time of organ procurement. Both recipients were carefully monitored, as neither consented to graft nephrectomy. In one patient, the tumor was discovered on surveillance biopsy of the graft approximately 14 months after transplantation, and in the second patient, ultrasound-guided aspiration needle biopsy of a growing formation in the lower pole of the graft revealed poorly differentiated metastatic adenocarcinoma. Both patients were successfully treated with graft nephrectomy and complete discontinuation of immunosuppression. None of the follow-up imaging showed persistent or recurrent malignancy, and both patients were candidates for re-transplantation. These exceptional cases of donor-derived pancreatic adenocarcinoma suggest that removal of the donor organ and restoration of immunity may lead to complete recovery.