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.

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.

Mechanical methods of venous thromboembolism prevention: from guidelines to clinical practice.

The paper discusses guidelines for the prevention of venous thromboembolism (VTE), with particular emphasis on the use of mechanical methods. Mechanical prophylaxis of VTE does not involve the risk of bleeding, which may be life­threatening. Mechanical methods are particularly recommended in patients at high risk of bleeding while on pharmacological thromboprophylaxis. Although antithrombotic prophylaxis is safe and cost­effective, there is evidence that the majority of preventive measures are applied too rarely in clinical practice, and that only a small proportion of patients receive complete and appropriate prophylaxis in the real­world clinical setting.

Genetic characterization of antithrombin, protein C, and protein S deficiencies in Polish patients.

INTRODUCTION    Inherited deficiencies of natural anticoagulants such as antithrombin (AT; gene: SERPINC1), protein C (PC; PROC), and protein S (PS; PROS1), with the prevalence in the general European population of 0.02% to 0.17%, 0.2% to 0.3%, and 0.5%, respectively, are associated with increased risk of thromboembolic events. Only a few case reports of Polish deficient patients with known causal mutations have been published so far. OBJECTIVES    The aim of the study was to characterize the frequency of SERPINC1, PROC, and PROS1 mutations and their thromboembolic manifestations in patients with AT, PC, or PS deficiencies, inhabiting southern Poland. PATIENTS AND METHODS     Ninety unrelated patients (mean [SD] age, 40.1 [13.2] years) with AT (n = 35), PC (n = 28), or PS (n = 27) deficiencies, with a history of venous 73 (81%) or arterial 17 (19%) thromboembolism, were screened for mutations using the Sanger sequencing or multiplex ligation­dependent probe amplification. RESULTS    Twenty mutations (29%) described here were new, mostly in the SERPINC1 and PROC genes. Missense mutations accounted for 84% of all mutations in the PROC gene and approximately 50% of those in the SERPINC1 and PROS1 genes. In all 3 genes, the ratio of nonsense and splice-site mutations was 8% to 31% and 8% to 23%, respectively. The mutation detection rate was 90% for AT or PC when anticoagulant activity was below 70%, while for the PROS1 gene, the rate reached 80% at the free PS levels below 40%. CONCLUSIONS    To our knowledge, this is the largest cohort of Polish patients deficient in natural anticoagulants and evaluated for the causal genetic background. Several new Polish detrimental mutations were detected, mostly in AT- and PC­deficient patients.

Efficacy, safety and pharmacokinetic profiles of a plasma-derived VWF/FVIII concentrate (VONCENTO®) in subjects with haemophilia A (SWIFT-HA study).

INTRODUCTION: VONCENTO® (CSL Behring) is a plasma-derived, high-concentration, low-volume, high-purity concentrate,which contains a high level of von Willebrand factor (VWF) high-molecular-weight multimers and aVWF/factor VIII (FVIII) ratio of ~2.4:1, similar to Haemate® P (CSL Behring). METHODS: The pharmacokinetic, efficacy and safety profiles of VONCENTO® were investigated in this multicentre,double-blind, randomised study. Subjects aged ≥ 12 years with haemophilia A who required treatment of nonsurgical bleeds, treatment during surgical events or who were receiving prophylaxis were included. Pharmacokinetics were investigated with a single dose of 50 IU FVIII/kg body weight of either VONCENTO® or BIOSTATE® reference product (Biostate-RP) (Day 1; Day 8 [n= 16], repeated on Day 180 [VONCENTO® only; n=15]). Efficacy and safety analyses were performed either during on-demand treatment (n=52) or prophylaxis (n=29)for ≥ 6 months and ≥ 50 exposure days, respectively. RESULTS: Besides the confirmation of bioequivalence between VONCENTO® and Biostate-RP, which displayed comparable PK profiles, haemostatic efficacy was rated by the investigators as either 'excellent' or 'good' in 96.4% of all bleeding events (96.5% spontaneous, 96.6% traumatic, 96.9% joint bleeds) as well as in 80% of major and 100% of minor surgical procedures at discharge. The median number of annualised bleeding events per subject [range] was significantly lower in the prophylaxis group (2.0 [0.0-34.6]) than in the on-demand group (14.0 [0.0-87.8], p = 0.0013).VONCENTO® was well tolerated and no inhibitory antibodies were identified during the study period. CONCLUSIONS: This study demonstrated the bioequivalence of VONCENTO® to Biostate-RP, and its excellent efficacy and safety profile in haemophilia A subjects.

[Hemoptysis during concomitant treatment with rivaroxaban and amiodarone in a patient with a history of pulmonary disease]. / Krwioplucie w trakcie jednoczesnego leczenia rywaroksabanem i amiodaronem u chorego z obciazonym wywiadem plucnym.

UNLABELLED: Rivaroxaban, a selective inhibitor of active factor X, is metabolized by cytochrom P450 3A4 (CYP3A4) and is a substrate for transporter protein--P-glycoprotein (P-gp). Amiodarone, an antiarrhytmic agent, is classified as moderate CYP3A4 and P-gp inhibitor. A CASE REPORT: A 75-year-old male, who underwent lobectomy for bronchiectasis many years ago, is presented. For one year the patient was treated with rivaroxaban (20 mg/d) due to venous thromboembolism and recurrent episodes of atrial fibrillation. Two weeks after amiodarone initiation (200 mg/d) hemoptysis occurred and computed tomography revealed unilateral pulmonary infiltrates with ground-glass opacities limited to the lower lobe of the left lung. The symptoms disappeared following discontinuation of the two medications and did not recur while rivaroxaban was reintroduced in a dose of 15 mg/d; measurement of anti-Xa activity confirmed it as a therapeutic dose. Amiodarone, that had been used for a short time and well tolerated a few years before, was definitely withdrawn. CONCLUSIONS: The authors suggest, that the concomitant use of rivaroxaban and amiodarone should be very careful in patients with a history of pulmonary disease.

Intracranial bleedings in patients on long-term anticoagulant treatment: Benefits from oral thrombin and factor Xa inhibitors in clinical practice.

Dabigatran, a direct thrombin inhibitor and activated factor X inhibitors, rivaroxaban and apixaban, used in the prevention of stroke or systemic embolism in patients with nonvalvular atrial fibrillation (AF), have several advantages over vitamin K antagonists (VKAs). The non-vitamin K oral anticoagulants (NOACs) have been shown to reduce the risk of intracranial bleedings by 50%. The current review summarizes the available data on the epidemiology, mechanisms and treatment of intracranial bleedings observed on oral anticoagulation with the focus on the specificity of NOACs in this context.

Long-term results of the Polish Adult Leukemia Group PALG-CLL2 phase III randomized study comparing cladribine-based combinations in chronic lymphocytic leukemia.

Long-term outcomes following newer therapies for chronic lymphocytic leukemia (CLL) have rarely been reported. This article presents the results of the final analysis of the Polish Adult Leukemia Group PALG-CLL2 study performed 10 years from final patient enrollment. With the extended follow-up time, it was found that cladribine (2-CdA)-based combinations CMC (2-CdA, cyclophosphamide, mitoxantrone) and CC (2-CdA, cyclophosphamide) administered as first-line treatment of progressive CLL resulted in significantly longer progression-free survival, but similar overall survival compared to 2-CdA monotherapy. Furthermore, the risk of potentially fatal late adverse events including infections, autoimmune complications and, particularly, secondary neoplasms was comparable among patients treated with CMC, CC or 2-CdA. The results of our analysis support the importance of long-term outcome monitoring of randomized trials in CLL.

Immune thrombocytopenia in patients with chronic lymphocytic leukemia treated with cladribine-based regiments or chlorambucil--follow-up of PALG-CLL randomized trials.

OBJECTIVES: The relationship between treatments of chronic lymphocytic leukemia (CLL) with cladribine (2-CdA) or chlorambucil and immune thrombocytopenia (IT) has not been yet determined. METHODS: The records of 777 patients in two randomized Polish Adult Leukemia Group (PALG)-CLL programs treated with these agents were retrospectively analyzed. RESULTS: Immune thrombocytopenia occurred in 55 of 777 (7.1%) patients. No significant differences in IT prevalence were seen between patients on chlorambucil or 2-CdA-based regiments (P = 0.33). IT developed at a median time of 0.499 yr (0.06-4.8) from the start of CLL therapy. This time was significantly longer in patients treated with chlorambucil (2.03 yr, 95% CI: 0.06-4.22) in relation to patients treated with 2-CdA-based regiments (0.52 yr, 95%CI: 0.34-0.69, P = 0.049). Overall survival (OS) of patients with IT and those without IT were similar (2.65 yr vs. 3.2 yr P = 0.23) but the severity of bleeding was more pronounced in the 2-CdA group. The responses to IT therapy were 35%, 54% and 75% for steroids, chemotherapy and splenectomy, respectively. CONCLUSIONS: In this study, an unexpectedly high percentage of IT incidence was demonstrated in patients with CLL requiring chemotherapy. Although no marked differences were seen in IT frequency in patients treated with 2-CdA-based regiments compared to chlorambucil regimen, the clinical course of hemorrhagic diathesis was more severe in 2-CdA group. Also, the time elapsed from study screening to IT diagnosis was significantly shorter in the 2-CdA group than in the chlorambucil group suggesting a causative relationship. The appearance of IT did not influence the median time of OS.

Therapeutic problems in elderly patients with hemophilia.

Since the introduction of clotting factor concentrates, the life expectancy of patients with hemophilia has increased from 40 years in the 1960s to 60 or even 70 years today. In Poland, almost all elderly patients with hemophilia have arthropathy, the majority are infected with hepatitis C virus (HCV), and some even with hepatitis B or human immunodeficiency virus. Liver cirrhosis associated with HCV infection develops within 15 to 20 years in 20% to 30% of these patients. Coexistent diseases related to aging and affecting the heart, kidneys, and other organs constitute another challenge. To prevent ischemic heart disease, cardiovascular risk factors should be carefully monitored. The present paper describes the current recommendations for the use of antithrombotic therapy for acute coronary syndromes and atrial fibrillation in patients with hemophilia. Changes in the urinary system in hemophiliacs develop with age, often leading to dialysis. There is an urgent need for intensive physiotherapy and improved access to orthopedic treatment for patients with arthropathy. High­risk surgical procedures in these patients should be performed in specialized centers with an experienced team and a coagulation laboratory. Older patients with mild hemophilia are at an increased risk for inhibitor development following intensive factor replacement therapy for surgical or invasive procedures. Pain control is a particular challenge due to contraindications to the use of many effective analgesics; another concern is the quality of life of these patients. An increasing number of older patients with hemophilia requires a comprehensive diagnostic and therapeutic approach, preferably at hematological centers.

Cladribine, but not fludarabine, added to daunorubicin and cytarabine during induction prolongs survival of patients with acute myeloid leukemia: a multicenter, randomized phase III study.

PURPOSE: The goal of this study was to evaluate whether the addition of a purine analog, cladribine or fludarabine, to the standard induction regimen affects the outcome of adult patients with acute myeloid leukemia (AML). PATIENTS AND METHODS: A cohort of 652 untreated AML patients with median age 47 years (range, 17 to 60 years) were randomly assigned to receive one of three induction regimens: DA (daunorubicin plus cytarabine), DAC (DA plus cladribine), or DAF (DA plus fludarabine). Postremission treatment was the same for all arms. RESULTS: Complete remission rate in the DAC arm was higher compared with the DA arm (67.5% v 56%; P = .01) as a consequence of reduced incidence of resistant disease (21% v 34%; P = .004). There was no significant difference in early outcome between the DAF and DA arms. The probability of overall survival was improved for the DAC arm (45% ± 4% at 3 years) compared with the DA arm (33% ± 4%; P = .02), and leukemia-free survival was comparable. Long-term outcome did not differ significantly for the comparison of the DAF and DA arms. A survival advantage of the DAC arm over the DA arm was observed among patients age 50 years or older (P = .005), those with initial leukocyte count above 50 × 10(9)/L (P = .03), and those with unfavorable karyotype (P = .03). DAF revealed a significant advantage over DA in patients with adverse karyotype (P = .02). CONCLUSION: The addition of cladribine to the standard induction regimen is associated with increased rate of complete remission and improved survival of adult patients with AML.

[Polish guidelines for the prevention and treatment of venous thromboembolism. 2012 update]. / Polskie wytyczne profilaktyki i leczenia zylnej choroby zakrzepowo-zatorowej. Aktualizacja 2012.

The overall objective of the Polish guidelines for the prevention and treatment of venous thromboembolism is to increase patient benefit and safety by appropriate prevention and treatment of deep vein thrombosis and pulmonary embolism as well as proper management of the complications associated with antithrombotic and thrombolytic therapy. These guidelines apply to adult trauma, cancer, surgical, and medical patients as well as those at increased risk of venous thromboembolism. Specific recommendations have been formulated for pregnant women, patients requiring surgery while receiving long-term oral anticoagulant treatment, and patients undergoing regional anesthesia and/or analgesia. We chose to update the existing Polish guidelines with the use of the most recent high-quality international guidelines that we identified and adjusted the final product to Polish cultural and organizational setting. We based our recommendations primarily on the 9th edition of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines on Antithrombotic Therapy and Prevention of Thrombosis, the European Society of Cardiology Guidelines on the Diagnosis and Management of Acute Pulmonary Embolism, the 3rd edition of the American Society of Regional Anesthesia and Pain Medicine Evidence-Based Guidelines on Regional Anesthesia in the Patient Receiving Antithrombotic or Thrombolytic Therapy, the ACOG practice bulletin on thromboembolism in pregnancy (Number 123), and Guidance from the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis on the Duration of Anticoagulant Therapy after a First Episode of Unprovoked Pulmonary Embolus or Deep Vein Thrombosis, as well as two other Polish practice guidelines on the prophylaxis and treatment of venous thromboembolism and the management of patients treated with oral direct inhibitors of factor X or factor II. To make recommendations regarding specific management issues that had not been addressed in other guidelines, or whenever the panel members felt they needed additional information to reach the decision, we also consulted the authors of guidelines developed by other professional societies and organizations as well as additional sources of evidence. For each adapted recommendation, we explicitly assessed its relevance and applicability in the context of the healthcare system in Poland. When necessary, we explicitly stated the rationale for modification of the previously published recommendations and judgements about the values and preferences we assumed. The information regarding reimbursement of drugs mentioned in the recommendations was added in chapters 6-9 and 13 and approved by the National Health Fund. The final version of the practice guidelines was officially approved by the scientific societies and institutions listed at the beginning of the document.  

[Severe pulmonary embolism in a young marijuana smoker]. / Ciezka zatorowosc plucna u mlodego mezczyzny palacego regularnie marihuane.

It is a popular belief, that marijuana smoking is not harmful to health. Some publications, however, suggest its possible association with mental, respiratory and cardiovascular complications, but not with venous thromboembolism. The authors describe a case of severe pulmonary embolism in a mildly obese, 22 year-old marijuana and tobacco smoker. After thrombolysis, rapid haemodynamic improvement was observed, contrary to slow regression of concomitant deep vein thrombosis during anticoagulation with warfarin. Toxycologic assessment of urine cannabinols was positive for two months. In trombophilia screening only moderate hyperhomocysteinaemia (not related to MTHFR C667T polymorphism) was found.

[Depression, its therapy and venous thromboembolism: three cases of pulmonary embolism]. / Depresja i jej leczenie a zylna choroba zakrzepowo-zatorowa: trzy przypadki zatorowosci plucnej.

The associations between depression and coronary heart disease, especially via platelet hyperactivity, have been widely described. The relationships between depression and venous thromboembolism are less clear. We present three cases of pulmonary embolism (PE) in patients with previously diagnosed depression and discuss possible, depression-related prothrombotic factors, including the impact of psychotropic drugs. A 69 year-old woman, treated with different antidepressants and also antipsychotics, died two months after recurrent PE. Another woman, at the same age, on mirtazapine therapy, developed segmental PE. In a 39 year-old man, taking paroxetine, severe PE required thrombolysis.

[Venous thromboembolism triggered by spinning in a young woman with thrombophilia]. / Zylna choroba zakrzepowo-zatorowa sprowokowana przez spinning u mlodej kobiety z trombofilia.

Although regular sports activities decrease the risk of venous thromboembolism (VTE), VTE cases have been observed among professional and amateur athletes practicing various disciplines. The authors describe a case of a 25-year-old-woman in whom calf pain, as popliteal vein thrombosis manifestation--preceding pulmonary embolism, occurred after she took up spinning, a popular form of indoor cycling. There was no history of leg injury. In hemostasis work up, factor V Leiden mutation and acquired low antithrombin activity-related to oral contraceptives use, were found. Strenuous exercise in an untrained woman might augment prothrombotic hemostasis profile. Vigorous cycling in standing position in the last phase of spinning, seems to be most unfavorable for patients with high VTE risk.