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.

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.

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.

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.

[Central retinal artery occlusion in a 21-year-old male amateur bodybuilder]. / Zator tetnicy srodkowej siatkówki u 21-letniego mezczyzny uprawiajacego amatorsko kulturystyk.

The etiology of central retinal artery occlusion (CRAO) is usually associated with atherosclerotic risk factors and the presence of intravascular (carotid artery, aortic arch) or intracardiac embolic material. At young age, CRAO may be a manifestation of inherited or acquired thrombophilia. The authors present a case of CRAO in a 21-year-old, previously healthy, non-smoking male, with neither metabolic nor hemostatic abnormalities and with normal echocardiography. However, he had a positive family history of premature coronary heart disease and a history of anabolic-androgenic steroids (AAS) use during amateur bodybuilding. We have not found an example of CRAO in the literature on various, systemic thromboembolic complications following AAS use.

Comparison of cladribine plus cyclophosphamide with fludarabine plus cyclophosphamide as first-line therapy for chronic lymphocytic leukemia: a phase III randomized study by the Polish Adult Leukemia Group (PALG-CLL3 Study).

PURPOSE Little is known about comparison of the activity of different purine nucleoside analogs in chronic lymphocytic leukemia (CLL). We conducted a randomized phase III trial to compare efficacy and safety of cladribine and fludarabine, each combined with cyclophosphamide, in previously untreated progressive CLL. PATIENTS AND METHODS Patients received cladribine at 0.12 mg/kg combined with cyclophosphamide at 250 mg/m(2) for 3 days intravenously (CC regimen) or fludarabine at 25 mg/m(2) combined with cyclophosphamide at 250 mg/m(2) for 3 days intravenously (FC regimen), every 28 days for up to six cycles. The primary end point was complete response (CR) rate. Secondary end points included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and treatment-related toxicity. RESULTS Of 423 randomly assigned patients (211 to CC and 212 to FC), 395 were evaluated in the final analysis. The CR and ORR reached 47% and 88% in the CC arm and 46% and 82% in the FC arm (P = .25 and P = .11, respectively). The median PFS was 2.34 years with CC and 2.27 years with FC (P = .51). OS and grade 3/4 treatment-related toxicity were also comparable. Moreover, we did not observe any significant differences in CC and FC efficacy across different patient prognostic subgroups that included patients with 17p13 (TP53 gene) deletion who had poor survival in both study arms. CONCLUSION Cladribine and fludarabine in combination with cyclophosphamide are equally effective and safe first-line regimens for progressive CLL. Both combinations have unsatisfactory activity in patients with 17p13 (TP53 gene) deletion.

[Pulmonary embolism as a first manifestation of synchronous occurrence of two neoplasms]. / Zatorowosc plucna jako pierwszy objaw synchronicznego zachorowania na dwa nowotwory.

A case of 67-year-old man with a first episode of acute, unprovoked venous thromboembolism (VTE). Screening for cancer revealed coexistence of two neoplasms: colon sigmoid cancer (operated on 6 weeks after pulmonary embolism onset), and multiple myeloma (treated successfully with thalidomide and dexamethasone). Low molecular weight heparin use as VTE treatment was followed by thromboprophylaxis for myeloma therapy. During a 30-month follow-up period, neither new thromboembolic complications nor cancer recurrence were observed. Overlapping different prothrombotic mechanisms of double malignancy might result in detection of both neoplasms at early stage.

[Polish guidelines for the prevention and treatment of venous thromboembolism: 2009 update]. / Poliskie wytyczne profilaktyki i leczenia zylnej choroby zakrzepowo-zatorowej: aktualizacja 2009.

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 systematically identified all current clinical practice guidelines concerning the prevention and/or treatment of venous thromboembolism and assessed their methodological quality using the AGREE instrument. We chose to update existing Polish guidelines by adapting the most recent high quality guidelines that we identified to Polish cultural and organizational setting rather than develop all recommendations de novo. We based our recommendations primarily on the 8th edition of the American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines on Antithrombotic and Thrombolytic Therapy and on the European Society of Cardiology (ESC) Guidelines on the Diagnosis and Management of Acute Pulmonary Embolism. To make recommendations regarding specific management issues that had not been addressed in ACCP guidelines, or whenever panel members felt they needed additional information to reach the decision we also consulted guidelines developed by other professional societies and organizations as well as additional sources of evidence. For each recommendation we explicitly assessed its relevance and applicability in the context of health care system in Poland. We adapted recommendations when necessary, explicitly stating the rationale for modification and judgements about the values and preferences we assumed. We developed original recommendations on the use of new oral anticoagulants that have recently become available, following the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach.

Altered fibrin clot structure/function in patients with idiopathic venous thromboembolism and in their relatives.

We tested the hypothesis that fibrin structure/function is unfavorably altered in patients after idiopathic venous thromboembolism (VTE) and their relatives. Ex vivo plasma fibrin clot permeability, turbidimetry, and efficiency of fibrinolysis were investigated in 100 patients with first-ever VTE, including 34 with pulmonary embolism (PE), 100 first-degree relatives, and 100 asymptomatic controls with no history of thrombotic events. Known thrombophilia, cancer, trauma, and surgery were exclusion criteria. VTE patients and their relatives were characterized by lower clot permeability (P < .001), lower compaction (P < .001), higher maximum clot absorbancy (P < .001), and prolonged clot lysis time (P < .001) than controls, with more pronounced abnormalities, except maximum clot absorbance, in the patients versus relatives (all P < .01). Fibrin clots obtained for PE patients were more permeable, less compact, and were lysed more efficiently compared with deep-vein thrombosis patients (all P < .05) with no differences in their relatives. Being VTE relative, fibrinogen, and C-reactive protein were independent predictors of clot permeability and fibrinolysis time in combined analysis of controls and relatives. We conclude that altered fibrin clot features are associated with idiopathic VTE with a different profile of fibrin variables in PE. Similar features can be detected in VTE relatives. Fibrin properties might represent novel risk factors for thrombosis.

Altered fibrin clot structure/function in patients with cryptogenic ischemic stroke.

BACKGROUND AND PURPOSE: We tested the hypothesis that fibrin structure/function is unfavorably altered in patients with cryptogenic ischemic stroke. METHODS: Ex vivo plasma fibrin clot permeability, turbidimetry, and efficiency of fibrinolysis were determined in 89 patients with patent foramen ovale (PFO) and a history of first-ever stroke, 58 patients with first-ever stroke and no PFO, and 120 healthy controls. RESULTS: Stroke patients, evaluated 3 to 19 months after the event, and controls did not differ with regard to age, sex, smoking, and fibrinogen. Stroke patients with or without PFO had lower clot permeability (P<0.0001), faster fibrin polymerization (P<0.0001), prolonged clot lysis time (P<0.0001), higher maximum D-dimer levels released from clots (P<0.0001), and maximum rate of D-dimer release (P=0.02) than controls. Time from stroke occurrence showed no association with any clot variables. Scanning electron microscopy of fibrin clots showed increased fiber diameter and density in stroke patients. Clots from stroke patients with PFO were more permeable and showed shorter lysis time compared to those without PFO, and this was related to lower proportion of smokers in the former group. CONCLUSIONS: Altered fibrin clot structure and resistance to fibrinolysis are associated with cryptogenic stroke.

[Oral contraceptives use increases venous thromboembolic risk even for minor surgical procedure - a case report]. / Stosowanie doustnych srodków antykoncepcyjnych zwieksza ryzyko powiklan zakrzepowo-zatorowych nawet malego zabiegu chirurgicznego.

A case of a 25-year-old woman with life-threatening pulmonary embolism, which occurred on fourth day after appendectomy and was safely treated with alteplase infusion. Before surgery, oral contraceptive use history, as a sole venous thromboembolic risk factor has been missed and the patient did not receive perioperative, pharmacologic antithrombotic prophylaxis. Further screening for thrombophilia was negative. This case proves that contraceptives use may create, irrespectively of the woman age, a possibility of perioperative thromboembolic complications, even for such minor procedure as appendectomy.

Cladribine combined with high doses of arabinoside cytosine, mitoxantrone, and G-CSF (CLAG-M) is a highly effective salvage regimen in patients with refractory and relapsed acute myeloid leukemia of the poor risk: a final report of the Polish Adult Leukemia Group.

OBJECTIVES: Patients with primary refractory AML and with early relapses have unfavorable prognoses and require innovative therapeutic approaches. Purine analogs fludarabine (FA) and cladribine (2-CdA) increase cytotoxic effect of Ara-C in leukemic blasts and inhibit DNA repair mechanisms; therefore its association with Ara-C and mitoxantrone (MIT) results in a synergistic effect. In the current report, we present the final results of multi-center phase II study evaluating the efficacy and toxicity of CLAG-M salvage regimen in poor risk refractory/relapsed AML patients. METHODS: The induction chemotherapy consisted of 2-CdA 5 mg/m2, Ara-C 2 g/m2, MIT 10 mg/m2, and granulocyte-colony stimulating factor. In the case of PR, a second CLAG-M was administered. Patients in CR received consolidation courses based on high doses of Ara-C and MIT with or without 2-CdA. RESULTS: One hundred and eighteen patients from 11 centers were registered; 78 primary resistant and 40 relapsed. Sixty-six patients (58%) achieved CR after one or two courses of CLAG-M, 49 (35%) were refractory, and 8 (7%) died early. WBC >10 g/L and age >34 yr were factors associated with increased risk of treatment failure. Hematological toxicity was the most prominent toxicity of this regimen. The probability of OS at 4 yr was 14% (95% CI 4-23%). OS was influenced by age, WBC >10 g/L and poor karyotype in both univariate and multivariate analyses. The probability of 4 yr DFS was 30% for all 66 patients in CR (95% CI 11-49%). Poor karyotype was the only factor associated with decreased probability of DFS. CONCLUSIONS: We conclude that CLAG-M is a well-tolerated and highly effective salvage regimen in poor risk refractory/relapsed AML.

Resistance to acetylsalicylic acid in patients after ischemic stroke.

INTRODUCTION: Acetylsalicylic acid (ASA) due to its antiplatelet action is used in ischemic stroke therapy. The platelet response to ASA shows an interindividual variation. Decreased platelet sensitivity to ASA is termed as resistance to ASA. OBJECTIVES: The aim of the study was to assess the prevalence of resistance to ASA in stroke patients and discover dependence between resistance to ASA and stroke recurrence and certain genetic and environmental factors. PATIENTS AND METHODS: 59 patients aged 22-83 years (mean age: 53) who had ischemic stroke within the period of 1 month to 10 years prior to the study were analyzed. 51 patients received ASA in a daily dose of 75 mg, and 8 in a higher dose. ASA had been taken since the stroke episode. Resistance was analyzed using the PFA-100 and optical aggregometer, with adenosine diphosphate, collagen and arachidonic acid as platelet agonists. RESULTS: Resistance to ASA in patients after stroke is observed with frequency ranging from 9% in arachidonic acid-induced aggregometry to 65% in the PFA-100. There were correlations between platelet aggregation in response to various agonists (r = 0.37-0.77, p < or = 0.005), and between collagen-induced aggregation and the PFA-100 (r = -0.33, p = 0.016). Platelet aggregation induced by arachidonic acid (r = 0.39, p = 0.029) correlated with the stroke recurrence (n = 12). ASA resistance detected in aggregometry in response to collagen was more common in patients with 807CT genotype for Ia glycoprotein (p = 0.05), and in patients with diabetes (p = 0.039). CONCLUSIONS: In patients after ischemic stroke resistance to ASA is commonly observed. In patients with diabetes or C807Tglycoprotein Ia gene CT polymorphisms this phenomenon is more frequently detected.