Afibrinogenemia caused by a novel homozygous missense mutation, FGB p.Cys241Tyr, in a male patient with recurrent intracranial bleeding: case report and review of literature.

INTRODUCTION: Congenital afibrinogenemia is a severe bleeding disorder, sometimes manifesting as thrombosis and/or pregnancy complications. Intracranial haemorrhage (ICH) constitutes the major cause of death in this disease. METHODS: We present the case of a male patient with congenital afibrinogenemia, who presented with recurrent intracranial hemorrhages, despite prophylactic fibrinogen substitution. We also review the literature for the risk of intracranial hemorrhages in afibrinogenemia. RESULT: Molecular analysis revealed a novel homozygous missense mutation in FGB exon 5, p.Cys241 Tyr, that was named "Fibrinogen Krakow V". DISCUSSION AND CONCLUSION: Intracranial hemorrhage is a severe manifestation of afibrinogenemia, also in children. The clinical presentation of afibrinogenemia is variable. Fibrinogen substitution carries a risk of thrombotic complications.

Immune Thrombocytopenia: Characteristics of the Population and Treatment Methods-One-Center Experience.

BACKGROUND: Immune thrombocytopenia (ITP) is a disease with variable clinical presentation, requiring different treatment lines. AIM: The study aimed to characterize a group of ITP patients in terms of clinical picture and disease treatment, as well as to present the current standard of care of ITP in Poland, in the context of local and international guidelines. MATERIALS AND METHODS: The study included adult patients diagnosed with ITP, treated at the Department of Haematology of the Jagiellonian University Hospital in Krakow from January 2006 to January 2021. Patient characteristics, clinical manifestation of ITP, and treatment methods were analyzed. RESULTS: A total of 245 ITP patients were included. 57.1% of them were asymptomatic at diagnosis. Most common symptoms were thrombocytopenic purpura (68.2%), followed by epistaxis (34.7%) and gum bleeds (19.2%). Life-threatening bleedings were noted in three cases (1.2%). 23.2% of patients did not require treatment. Prednisone was the most commonly used first-line therapy (75.5% of patients). Treatment with eltrombopag and romiplostim was used in 40.4 and 8.5% of patients requiring second-line therapy, respectively. 14.3% of all patients ultimately underwent splenectomy, including 51.5% of those who needed second-line treatment. The initial response rate was 74.3%; however, post-splenectomy relapses occurred in 22.9% of patients. CONCLUSIONS: ITP is a disease of mild clinical course, often asymptomatic. Chronic disease often requires multiple treatment lines and balancing between bleeding risk and treatment toxicity, based on individual risk-benefit assessment. Local access restrictions to thrombopoietin receptor agonists determined the treatment strategy.

Avatrombopag increased platelet count in a patient with chronic immune thrombocytopenia refractory to multiple lines of treatment.

We present a case of a 30-year-old man suffering from chronic refractory immune thrombocytopenia (ITP) from early childhood. The patient was treated with all the therapeutic methods available in Poland, without platelet response: corticosteroids, intravenous immunoglobulins, splenectomy, cyclophosphamide, vinblastine, azathioprine, mycophenolate mofetil, rituximab, ciclosporin A, romiplostim, and eltrombopag. He continued to function persistently with deep thrombocytopenia, symptoms of hemorrhagic diathesis, and one episode of spontaneous subarachnoid bleeding. In April 2022, at the age of 29, the patient received avatrombopag. Within 4 weeks of starting avatrombopag 20 mg daily for 2 weeks and then 40 mg daily, he reached a platelet (PLT) count of 67 x 10 9 /l. In the next month, platelets fell below 30 x 10 9 /l, but subsequently the count increased to 47 x 10 9 /l, then to 52 x 10 9 /l, and remained stable. The symptoms of cutaneous hemorrhage diathesis have resolved completely since avatrombopag was introduced and did not reappear despite the decrease in PLT count.

Autoimmune cytopenias in patients with malignant lymphoma: A multicenter report by the Polish Lymphoma Research Group.

BACKGROUND: Autoimmune cytopenias (ACs), including immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA) and autoimmune granulocytopenia, are rare complications observed in lymphoma patients. They may appear before, during or after lymphoma diagnosis, whether the patients had disease progression or not. OBJECTIVES: This study aims to correlate ACs with lymphoma type, disease course and prognosis. We performed a multicenter retrospective analysis of adult patients with malignant lymphoma and ACs coexistence diagnosed and treated in centers aligned with the Polish Lymphoma Research Group (PLRG). MATERIAL AND METHODS: The analysis covers the years 2016-2022 and included 51 patients comprised of 23 women and 28 men. Of these, 35 patients were diagnosed with AIHA, 15 patients with ITP and 1 patient with both AIHA and ITP. RESULTS: The most common type of lymphoma was Hodgkin lymphoma (HL) (12 patients) and diffuse large B-cell lymphoma (DLBCL) (14 patients). At the time of diagnosis, 31 (61%) of patients had stage 4 of HL or DLBCL, according to Ann Arbor classification. In total, the response to treatment was evaluated in 50 patients, with 25 being in complete remission and 6 in partial remission. We observed that B cell symptoms (p = 0.036), bone marrow involvement (p = 0.073), splenomegaly (p = 0.025), and more than 2 lines of treatment were more common in AIHA compared to ITP patients. Conversely, eucopenia (p = 0.056) and ACs without lymphoma progression (p = 0.002) were more often diagnosed in ITP patients. CONCLUSIONS: In the study group, relapsed and refractory disease was observed more often, and shorter overall survival (OS) was noted in patients with DLBCL. We found that AC is associated with a worse prognosis in comparison to the general population of lymphoma patients. There were no differences in response to AC therapy. To have more accurate data, a larger group, as part of a multicenter study, should be evaluated.

Eculizumab treatment in pregnant women with paroxysmal nocturnal hemoglobinuria: A Polish experience.

BACKGROUND: Eculizumab is an antibody targeting the C5 complement protein. Clinical trials suggest that eculizumab significantly reduces transfusion requirements and prevents disease complications in patients with paroxysmal nocturnal hemoglobinuria (PNH). OBJECTIVES: To analyze the outcome of pregnancies among Polish women with PNH treated with eculizumab as a part of the Polish National Health Fund program. MATERIAL AND METHODS: We report the outcomes of 3 pregnancies among women treated with eculizumab between 2017 and 2020. For 1 of these woman, it was the 1st pregnancy, while the remaining 2 patients had previously had 1 previous successful pregnancy each. RESULTS: All 3 mothers survived pregnancy, and all children were born alive. One of the patients had a vaginal delivery. Another required cesarean delivery at the 34th week due to a decreasing platelet count. In 1 case, premature rupture of the fetal membranes occurred at week 36, followed by artificial labor induction. All children were born without any inborn defects. The 2 prematurely born babies required a prolonged hospital stay. CONCLUSION: Treatment with eculizumab seems to reduce the risk to a mother and a child associated with PNH. However, more data are necessary to confirm this notion.

Adherence to prophylactic treatment in adult patients with severe hemophilia in Poland.

INTRODUCTION: Patient adherence to a prophylactic regimen is important for optimal benefit of hemophilia treatment. Despite a growing number of adults with hemophilia in Poland receiving secondary prophylaxis, data on adherence to the regimen are limited. OBJECTIVES: The aim of the study was to assess adherence to secondary prophylaxis in Polish adults with severe hemophilia. PATIENTS AND METHODS: Patients were recruited in 18 hemophilia treatment centers in Poland. Adherence to prophylaxis was assessed with the Validated Hemophilia Regimen Treatment Adherence Scale Prophylaxis (VERITAS­Pro) questionnaire. RESULTS: Data on 270 men on the prophylactic regimen (median [interquartile range, IQR] age, 37 [18-75] years; mean [SD], 38.2 [13.3] years) were analyzed. Median (IQR) VERITAS­Pro score for the study population was 36 (24-76) years; mean (SD), 37.7 (9.9) years, indicating general adherence to the prophylactic regimen. The median subscale scores ranged from 4 for Dosing to 8 for Planning (means, 5.6 and 7.7, respectively). The most pronounced difference in the subscale scores between adherent and nonadherent patients was recorded for Dosing (median, 4 vs 10; mean, 5.3 vs 9.3) and Remembering (median, 5 vs 11; mean, 5.7 vs 10.7). The overall adherence rate was 94%. CONCLUSIONS: Our results show a high rate of adherence to hemophilia prophylaxis by Polish adults. Problems with the management of clotting factor stocks and remembering about the injection of the clotting factor were identified as potential barriers to adherence in adults with hemophilia in Poland.

Unexplained hemorrhagic syndrome? Consider acquired hemophilia A or B.

There is a dire need to develop an algorithm to improve the recognition of acquired hemophilia A and B (AHA and AHB) in clinical practice. Initial and intensive care unit (ICU) management of the disorder is particular and represents a challenge for the internist/hematologist and the ICU physician. A delay in the proper treatment of bleeding episodes can lead to a life-threatening event. Expert advice should be sought as soon as possible. Succesful resolution involves accurate diagnosis, bleeding control with hemostatic and immunotherapy, and eradication of the autoantibodies to improve overall survival. Current treatment guidelines are based on the literature in the form of cases and observational studies due to a lack of randomized controlled trials. AH can be triggered by many pathologies, presenting as a paraneoplastic syndrome in case of malignancies or as surgical associated acquired hemophilia (SAHA). We have reviewed the literature from 2015 to 2021 regarding the new case reports to further assess if there is an improvement in the clinical approach.

Congenital dysfibrinogenemia as a rare cause of recurrent gastrointestinal bleeding.

<b>Introduction: </b>Gastrointestinal bleeding is a common disease that surgeons encounter in everyday clinical practice. It is most often easy to diagnose and treat. However, rare causes of bleeding can lead to delayed diagnosis and ineffective treatment. Dysfibrinogenemia is a qualitative fibrinogen disorder in which functional fibrinogen level is reduced with normal antigenic level. <br><b> Case report:</b> Herein we present the case of a 59-year-old female with recurrent gastrointestinal bleeds, that turned out to be an unusual manifestation of congenital dysfibrinogenemia. Detailed imaging and endoscopic diagnostics revealed portal hypertension with a non-bleeding 1-cm gastrointestinal stromal tumor and multiple angiodysplastic lesions in close proximity.

Six molecular patterns leading to hemophilia A phenotype in 18 females from Poland.

INTRODUCTION: Female hemophilia is an intriguing rare disorder and few larger reports on its genetic etiology are available. While historically the diagnosis was satisfactorily reached by factor VIII activity assays, the clinical and potentially therapeutic heterogeneity of female hemophilia calls for comprehensive molecular diagnosis in each case. Currently, the genetic investigations are not a part of routine, state-funded, diagnostics in Poland, and thus molecular epidemiological data are missing. AIM: We set out to perform a comprehensive genetic analysis of Polish females with hemophilia A. PATIENTS/METHODS: Eighteen females with hemophilia A (including 2 with severe and 5 with moderate hemophilia phenotype) consented for genetic diagnostics. To establish F8 mutations, we used next-generation sequencing of a panel of genes associated with hematological disorders, standard assays for recurrent intragenic F8 inversions and MLPA when deletions were suspected. When appropriate we also used karyotyping, genomic microarrays and X chromosome inactivation assays. RESULTS: While abnormally skewed X-chromosome inactivation combined with a F8 variant on the active allele was, as expected, the most common genetic etiology, a number of other genetic scenarios were unraveled. This included: misdiagnosis (molecular diagnosis of vWd), Turner syndrome, compound heterozygosity and androgen insensitivity syndrome (a phenotypical 46,XY female with a novel androgen receptor gene mutation). We report 3 novel F8 mutations. CONCLUSION: Every case of female hemophilia warrants full genomic diagnostics, as this may change the diagnosis or reveal broader morbidity than a coagulation disorder (Turner syndrome, androgen insensitivity, or cardiovascular morbidity that we described previously in a SHAM syndrome carrier).

Avatrombopag for the treatment of immune thrombocytopenia.

INTRODUCTION: Thrombopoietin-receptor agonists (TPO-RAs) are the only American Society of Hematology (ASH) guideline-advocated, second-line treatment for immune thrombocytopenia (ITP) that have been validated by randomized, controlled trials with a placebo comparator. Avatrombopag is a new candidate in this class that has been investigated as a treatment option for the treatment of ITP. Areas covered: In this Drug Profile, we provide a review of the clinical data of avatrombopag, which was approved in May 2018 by the United States Food and Drug Administration (FDA) for the treatment of thrombocytopenia in patients with chronic liver disease undergoing an invasive procedure, and an opinion of its potential place in the current evidence-based ITP treatment landscape. Expert commentary: Avatrombopag induces doubling of platelet counts, increasing them to above 50 X 109/L, and prevents the need for platelet transfusions while minimizing the need for rescue medications. Treatment-emergent adverse events (TEAEs) are comparable to placebo. Oral delivery, a 5-day dosing schedule and good tolerability (<1% discontinuation rate) with no clinically significant hepatoxicity make it a promising entrant as a potential second-line treatment for ITP. Further, data from a phase 3 study in patients with ITP supports its utility in the treatment of patients with ITP.

A Retrospective Analysis of Clinical and Laboratory Data of Patients with Factor VII Deficiency: A Single Centre Experience.

Bleeding phenotype in patients with congenital factor VII (FVII) deficiency is highly variable. No direct correlation between FVII activity and bleeding tendency is noted. The aim of this study was to analyse clinical and laboratory phenotype of patients with FVII deficiency treated in one haemophilia treatment centre in Little Poland. Clinical and laboratory data of 106 patients were collected retrospectively. Bleeding symptoms were evaluated according to the Bleeding Assessment Tool. The mean FVII activity was 19.5% (range: 1.0-49.2) and the mean prothrombin time (PT) was 29.7 seconds (range: 13.2-64.8), comparable in both sexes. Activity was lower than 1% in 6.6% of individuals. The average age at diagnosis (31.2 years; range: 1-76) did not correlate with FVII activity. Half of the patients were diagnosed incidentally, mostly due to routine PT measurement. The most frequently reported symptoms were gum, nose and tooth extraction bleeds. A total of 22.6% of patients remained asymptomatic and 60.4% never required replacement therapy. Thrombotic episodes were diagnosed in five women (4.7%). In conclusion, the clinical picture of the analysed group is similar to the previously described. It should be stressed that a significant risk of bleeds, including joint haemorrhages, can be expected in patients with mildest FVII deficiency (>26%) as well. The rate of thrombosis (4.7%) was similar to other reports, with all affected patients having strong prothrombotic risk factors or being intensively treated with FVII concentrate.

Acquired Haemophilia A Associated with Subsequent Hepatocellular Carcinoma.

Acquired haemophilia A (AHA) is a rare autoimmune disease caused by antibodies directed against clotting factor VIII. About half of cases are idiopathic, but AHA may also be secondary to autoimmune, dermatologic, or oncologic diseases. In approximately 10% of non-idiopathic cases, the disease occurs after or with the diagnosis of cancer as an extremely rare paraneoplastic syndrome. We describe the case of a 73-year-old male patient diagnosed with AHA and successfully treated with recombinant human activated factor VIIa and immunosuppression. Two and a half years later, however, the disease relapsed and a routine ultrasound revealed a liver tumour that was then diagnosed as hepatocellular carcinoma. We present this case to increase awareness that this life-threatening condition may develop years prior to the diagnosis of cancer.

Genetic and clinical characterization of congenital fibrinogen disorders in Polish patients: Identification of three novel fibrinogen gamma chain mutations.

INTRODUCTION: Congenital fibrinogen disorders are poorly explored in Slavic populations. The aim of this study was to characterize the genetic background and clinical manifestations of fibrinogen disorders in the Polish case series. MATERIALS AND METHODS: In 27 unrelated patients (mean [SD] age, 30.4 [19.2] years, 30% men) with fibrinogen concentration (von Clauss method) < 1.8 g/L, exons and intron-exon junctions of the fibrinogen alpha chain (FGA), fibrinogen beta chain (FGB), and fibrinogen gamma chain (FGG) genes were analyzed using polymerase chain reaction (PCR) amplification followed by sequencing. RESULTS: At enrollment, 15 (55.6%) and 2 (7.4%) of patients experienced bleeding and thrombotic events, respectively, and the remainder were asymptomatic. The following congenital fibrinogen disorders were identified: 1A. afibrinogenemia, n = 1; 2A. severe hypofibrinogenemia, n = 2; 2B. moderate hypofibrinogenemia, n = 4; 2C. mild hypofibrinogenemia, n = 6; 3A. dysfibrinogenemia, n = 12; 3B. thrombotic related-dysfibrinogenemia, n = 1; 4C. mild hypodysfibrinogenemia, n = 1. Eight dysfibrinogenemic patients (62%) were carriers of hotspot mutations. Fifteen patients were heterozygous and one (afibrinogenemia) homozygous for known causative mutations. Three new heterozygous mutations were detected, all affecting splicing in FGG: fibrinogen Poznan II, a 177 bp deletion eliminating parts of intron 6 and exon 7 in a dysfibrinogenemic woman with recurrent bleeding; fibrinogen Zakopane, (intron 2 acceptor splice site) and fibrinogen Belchatow (intron 1 donor splice site), found in hypofibrinogenemic patients. During follow-up (median 60, interquartile range 10-60 months), bleeding episodes, mainly menorrhagia and easy bruising were reported in 15 (55.6%) patients. One thromboembolic event was observed. CONCLUSION: This study of the largest cohort of Slavic patients with congenital fibrinogen disorders has enabled the identification of 3 new FGG mutations and shows a high prevalence of bleeding manifestations with recurrences.

Elbow Arthroplasty in Patients with Bleeding Disorders. Preliminary Report of a Single-centre Experience.

Spontaneous or traumatic hemorrhages into joints that occur in the course of congenital bleeding disorders due to deficiencies of plasma clotting factors lead to early and extensive damage to joints. Arthropathy in those patients most commonly affects the knee, elbow and ankle. Replacement surgery of the damaged joint is the only effective way to treat such advanced changes. Although arthritis of the elbow is quite common, surgery is rarely undertaken; hence relevant reports in the literature are limited to individual or small groups of cases. The paper presents two patients with severe haemophilia A who underwent elbow arthroplasty at the Cracow Center of Rehabilitation and Orthopaedics.

Acquired hemophilia A: an underdiagnosed, severe bleeding disorder.

Acquired hemophilia is a rare bleeding disorder caused by autoantibodies that inhibit coagulation factor VIII. In most cases, it manifests with severe, often life­threatening bleeds. Acquired hemophilia may be idiopathic or secondary to another condition, most commonly other autoimmune disease or cancer. Treatment is directed to stop bleeding and eradicate inhibitory autoantibodies. Like in most life­threatening conditions, early diagnosis and treatment are essential for good prognosis. Prompt diagnosis and treatment of acquired hemophilia are constantly improving owing to the increasing availability of laboratory diagnostic tests and growing awareness of physicians of various specialties.

Decreased von Willebrand factor ristocetin cofactor activity and increased ADAMTS13 antigen increase postoperative drainage after coronary artery bypass grafting.

OBJECTIVES: Routine coagulation tests and bleed-scores fail to identify patients at risk of excessive postoperative drainage following coronary artery bypass grafting (CABG). We sought to investigate whether lower von Willebrand factor (VWF) and higher ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) are associated with a high postoperative drainage after CABG. METHODS: In the prospective cohort study, VWF antigen (VWF:Ag), VWF ristocetin cofactor (VWF:RCO), VWF collagen-binding (VWF:CB), ADAMTS13 antigen (ADAMTS13:Ag) and ADAMTS13 activity were measured on the day of elective on-pump CABG in 232 consecutive patients without a prior history of haemorrhagic diathesis, including von Willebrand disease (95% discontinued aspirin preoperatively). Postoperative drainage and blood product use were recorded. RESULTS: A comparison of extreme drainage quartiles (n=56) showed that individuals with the highest drainage volumes have mean VWF:RCO lower by 19% (P<0.0001), median VWF:Ag lower by 19% (P<0.0001), ADAMTS13:Ag higher by 8% (P=0.0002), ADAMTS13 activity higher by 9% (P=0.01) and fibrinogen lower by 14% (P=0.03) than those with the lowest drainage. Linear regression analysis showed that preoperative VWF:RCO (b=-4.83, P=0.002) and fibrinogen (b=-61.52, P=0.04) are the only independent predictors of postoperative drainage. Multivariate logistic regression demonstrated that preoperative VWF:RCO in the lowest quartile and ADAMTS13:Ag levels in the highest quartile increased the risk of high (≥1000 ml) drainage (odds ratio [95% confidence interval]=4.88 [1.83-13.02], P=0.001 and 3.77 [1.49-9.52], P=0.005; respectively). CONCLUSIONS: Patients undergoing elective CABG with lower preoperative VWF:RCO are at risk of having larger postoperative drainage, which suggests a novel contributor to increased perioperative bleeding in cardiac surgery.