Patterns in anticoagulant utilization in the Czech Republic during 2007-2017.

Direct oral anticoagulants (DOACs) have gradually entered the Czech market as alternatives to vitamin K antagonists and parenteral anticoagulants since 2008. Considering the eventual changes, the aim was to evaluate drug use and expenditure patterns on anticoagulants in the Czech Republic. A retrospective utilization study was conducted retrieving data from the State Institute for Drug Control database, including reports on drug supplies from distributors with anatomical therapeutic chemical classification (ATC) codes B01AA, B01AB, B01AE, B01AF, and B01AX. The utilization on national level was expressed as the ratio of the number of defined daily doses per 1000 inhabitants per day (DDD/TID). Expenditures on all anticoagulants were also assessed. Data was analyzed using PASW (version 18.0). Between January 2007 and December 2017, the national anticoagulant utilization rate increased continuously from 14.15 to 27.67 DDD/TID. The use of DOACs was 0.002 DDD/TID in 2008, increased to 6.04 DDD/TID in 2017. Warfarin utilization, after a small decrease in 2008, has shown nearly stable levels in the recent years (70.9% of all anticoagulants; mean 11.55 DDD/TID over the last 5 years), while its increase was halted by the spread of DOACs utilization (p < 0.05). In 2017, over half of the expenditures (51.1%) were due to oral anticoagulants, whereof 47.6% was related to DOACs. The results reflected a growing utilization and increasing costs of all anticoagulants, especially in DOACs at the expense of warfarin. Still, additional information regarding patient persistence and prescribing patterns is needed for a better understanding of oral anticoagulant utilization.

Representative sample survey on factors determining the Czech physicians' awareness of generic drugs and substitution.

BACKGROUND: Generic drugs and generic substitution belong to the tools by which healthcare costs may be reduced. However, low awareness and reluctance among healthcare professionals towards generic drugs may negatively affect the rational use of generic substitution. METHODS: The study aimed to analyze opinions and attitudes towards generic drugs and generic substitution among Czech physicians including their understanding of generic substitution legislative rules and the physicians´ previous experience in this field. Using random allocation, 1551 physicians practicing in the Czech Republic were asked to participate in the sociological representative survey conducted from November to December 2016, through face-to-face structured interviews comprising 19 items. Factor analysis as well as reliability analysis of items focused on legal rules in the context of physicians' awareness were applied with p-value of < 0.05 as statistically significant. RESULTS: Of a total of 1237 (79.8%) physicians (43.7% males; mean age 47.5 ± 11.6 years, 46.3% general practitioners) 24.8% considered generic drugs to be less safe, especially those with specialized qualification (p < 0.01). However, only 4.4% of the physicians noticed any drug-related problems, including adverse drug reactions associated with generic substitution. The majority of physicians felt neutrally about performing generic substitution in pharmacies, nor they expressed any opinion on characteristics of generics, even though a better understanding of the legislation and higher need of accordance of substituted drugs were associated with more positive attitudes towards generic substitution (p < 0.05). Physicians showed low knowledge score of legislative rules (mean 3.9 ± 1.6 from maximum 9), nevertheless they overestimated the law, as they considered some rules valid, even if the law does not require them. Cronbach alpha of all legislative rules that regulate generic substitution increased from 0.318 to 0.553 if two optional rules (physician consent and strength equivalence) would be taken into account. CONCLUSIONS: There is no sufficient awareness of generic drugs and generic substitution related issues among Czech physicians, although a deeper knowledge of legislation improves their perception about providing generic substitution.

Prognostic relevance of angiopoietin-2, fibroblast growth factor-2 and endoglin mRNA expressions in chronic lymphocytic leukemia.

Elevated levels of circulating angiogenic cytokines and increased expression of genes encoding angiogenic factors have been reported in recent years in patients with chronic lymphocytic leukemia (CLL) but data regarding prognostic and predictive significance are still limited. Therefore, in the present study based upon our prior pilot results, we measured mRNA expressions of angiopoietin-2 (Ang-2), fibroblast growth factor-2 (FGF-2) and endoglin (CD105) by reverse transcription quantitative PCR in purified CD19+ cells from 70 untreated CLL patients (median age, 63 years; males, 64%; Rai III/IV stages, 29 %; unmutated IgVH genes, 60 %) and evaluated their possible association with established prognostic factors and clinical course of the disease. Higher expression of Ang-2 was significantly associated with unmutated IgVH genes (n = 55, p = 0.003). Higher CD105 expression was significantly associated with unmutated IgVH genes (n = 55, p < 0.001), high CD38 expression (n = 66, p = 0.022), high ZAP-70 expression (n = 66, p = 0.010), Rai stage I-IV (n = 70, p < 0.001), progressive clinical course of CLL (n = 70, p = 0.001) and shorter time to treatment (n = 70; p < 0.001). Expression of FGF-2 was not significantly associated with any of the prognostic markers. These results indicate that elevated expression of Ang-2 and in particular CD105 by CLL cells is associated with unfavorable prognostic features and clinical outcome; thus, both cytokines appear to play an important role in biology and progression of CLL and warrant further investigation.

Incidence and risk of central nervous system metastases as site of first recurrence in patients with HER2-positive breast cancer treated with adjuvant trastuzumab.

BACKGROUND: Central nervous system (CNS) disease as the site of first relapse after exposure to adjuvant trastuzumab has been reported. We carried out comprehensive meta-analysis to determine the risk of CNS metastases as the first site of recurrence in patients with HER2-positive breast cancer who received adjuvant trastuzumab. METHODS: Eligible studies include randomized trials of adjuvant trastuzumab administered for 1 year to patients with HER2-positive breast cancer who reported CNS metastases as first site of disease recurrence. Statistical analyses were conducted to calculate the incidence, relative risk (RR), and 95% confidence intervals (CIs) using fixed-effects inverse variance and random-effects models. RESULTS: A total of 9020 patients were included. The incidence of CNS metastases as first site of disease recurrence in HER2-positive patients receiving adjuvant trastuzumab was 2.56% (95% CI 2.07% to 3.01%) compared with 1.94% (95% CI 1.54% to 2.38%) in HER2-positive patients who did not receive adjuvant trastuzumab. The RR of the CNS as first site of relapse in trastuzumab-treated patients was 1.35 (95% CI 1.02-1.78, P = 0.038) compared with control arms without trastuzumab therapy. The ratio of CNS metastases to total number of recurrence events was 16.94% (95% CI 10.85% to 24.07%) and 8.33% (95% CI 6.49% to 10.86%) for the trastuzumab-treated and control groups, respectively. No statistically significant differences were found based on trastuzumab schedule or median follow-up time. No evidence of publication bias was observed. CONCLUSIONS: Adjuvant trastuzumab is associated with a significant increased risk of CNS metastases as the site of first recurrence in HER2-positive breast cancer patients.

Glycogen phosphorylase BB as a potential marker of cardiac toxicity in patients treated with anthracyclines for acute leukemia.

OBJECTIVES: The aim of the presented study was to assess plasma glycogen phosphorylase BB (GPBB) concentrations in acute leukemia patients treated with anthracycline containing chemotherapy. BACKGROUND: Anthracyclines represent the highest risk for development of cardiotoxicity. GPBB belongs to proposed biomarkers of cardiac injury with a very limited experience in this context. METHODS: Totally, 24 adult patients with acute leukemia were enrolled. Plasma GPBB concentrations were measured by ELISA at diagnosis (before chemotherapy), after first chemotherapy with anthracyclines and 6 months after the completion of treatment. The cut-off value for GPBB positivity was 10.00 µg/L as recommended by the manufacturer. RESULTS: Before chemotherapy, the mean plasma GPBB concentration was 5.25±3.81 µg/L, increased above the cut-off in 1 patient (4.2 %). After the first chemotherapy, the mean GPBB was 6.61±5.54 µg/L, positive in 7 (29.2 %) patients. Six months after treatment, the mean GPBB was 10.06±11.41 µg/L, positive in 8 (33.3 %) patients. Six months after treatment, we found a significant correlation between elevation in GPBB and diastolic left ventricular dysfunction on echocardiography (r=0.621; p<0.0001). The differences in plasma GPBB between healthy blood donors and patients treated for acute leukemia were statistically significant (p<0.01 in all cases). CONCLUSION: Our results suggested that GPBB could become a potential biomarker for detection of acute and chronic cardiotoxicity associated with anthracycline containing chemotherapy. The predictive value for development of treatment-related cardiomyopathy in future is not clear and will be evaluated during the follow-up. Further studies are needed to define the potential role of GPBB and other biomarkers in the assessment of chemotherapy-induced cardiotoxicity (Ref. 21). Text in PDF www.elis.sk.

[Our experience with the treatment of primary lymphomas of the central nervous system]. / Nase zkusenosti s lécbou primárních lymfomu centrálního nervového systému.

INTRODUCTION: The aim of this study was to assess treatment efficiency, overall survival (OS) and identify risk factors with the influence on patients prognosis in patients with primary central nervous system lymphomas (PCNSL) who were treated with intensive chemotherapy based on high-dose methotrexate and cytosin-arabinoside followed by whole-brain radiotherapy (MPV regimen). PATIENTS AND METHODS: From January 1998 to February 2011, 39 patients with PCNSL were diagnosed on our department. The median from the first clinical symptomatology to histological diagnosis was 4 weeks (range, 2-19). Thirty-seven patients were treated with MPV regimen. RESULTS: The therapeutic response was evaluated in 35 patients (2 patients died early during treatment). The overall response/complete remission rate was 63/60%. At the time of analysis (november 2011), the median of follow-up was 16,5 months; 31 patients died (the most often causes of death were poor treatment effect and treatment complications). The 2-year OS was 30% and median PFS and OS were 9 and 12 months. Patients with WHO performance status 0-1 and those with normal serum lactate dehydrogenase serum had significantly longer OS (p = 0.0495 and p = 0.0232). CONCLUSION: The treatment results of our patients appear to be inferior than data from literature. The reason is probably high occurrence of negative prognostic factors. Early diagnosis and intensive treatment are crucial for improvement of prognosis.

[Peripartal life-threatening hemorrhage - interdisciplinary consensus opinion]. / Peripartální zivot ohrozující krvácení - mezioborové konsenzuální stanovisko.

22 experts from the fields of gynecology and obstetrics, anesthesiology and resuscitation, intensive care, hematology and transfusion medicine has developed recommendations for diagnosis and procedure for life-threatening peripartum haemorrhage, which is still one of the most common causes of maternal mortality in childbirth. This guidelines, which is valid for the Czech Republic, supported by a total of 10 professional medical societies. There are based on new knowledge applicable at this time and is focused mainly on eliminating the most common causes of bleeding during delivery and prevention of haemorrhagic shock.

Plant extracellular vesicles and their potential in human health research, the practical approach.

Extracellular vesicles are small membrane particles (30-1000 nm) released by Bacteria, Eukaryotes and Archaea. They have been shown to play an important role in intracellular and intercellular communication, within and between kingdoms via transport of bioactive molecules. Thus, they can be involved in altering gene expression and regulation of physiological and pathological processes of the recipient. Their unique properties make extracellular vesicles a perfect candidate vector for targeted drug delivery or a biomarker. For a long time, animal and mainly mammal extracellular vesicles have been used in research. But for plants, there had been speculations about the existence of nanovesicles due to the presence of a cell wall. Today, awareness of plant extracellular vesicles is on the rise and their research has proved they have various functions, such as protein secretion, transport of bioactive molecules or defense against pathogens. Further potential of plant extracellular vesicles is stressed in this review.

Use of ultra high performance liquid chromatography-tandem mass spectrometry to demonstrate decreased serum statin levels after extracorporeal LDL-cholesterol elimination.

BACKGROUND: Using our statin analysis method, it was possible to uncover a significant drop in statin levels (atorvastatin, simvastatin, and metabolites) after extracorporeal LDL-cholesterol elimination (EE) in severe familial hypercholesterolemia (FH). The purpose of this work was to identify the mechanism underlying this drop and its clinical significance as well as to propose measures to optimize a pharmacotherapeutical regimen that can prevent the loss of statins. METHODS: Ultra High Performance Liquid Chromatography (UHPLC) connected to the triple quadrupole MS/MS system was used. Patients. A group of long-term treated patients (3-12 years of treatment) with severe FH (12 patients) and treated regularly by LDL-apheresis (immunoadsorption) or haemorheopheresis (cascade filtration) were included in this study. RESULTS: After EE, the level of statins and their metabolites decreased (atorvastatin before/after LDL-apheresis: 8.83/3.46 nmol/l; before/after haemorheopheresis: 37.02/18.94 nmol/l). A specific loss was found (concentration of atorvastatin for LDL-apheresis/haemorheopheresis: 0.28/3.04 nmol/l in washing fluids; 11.07 nmol/l in filters). To prevent substantial loss of statin concentrations, a pharmacotherapeutic regimen with a longer time interval between the dose of statins and EE is recommended (15 hours). CONCLUSIONS: A specific loss of statins was found in adsorbent columns and filters. The decrease can be prevented by the suggested dosage scheme.

Quantification of ZAP-70 expression in chronic lymphocytic leukemia: T/B-cell ratio of mean fluorescence intensity provides stronger prognostic value than percentage of positive cells.

Expression of ZAP-70 measured by flow cytometry belongs to the most powerful prognostic parameters in chronic lymphocytic leukemia (CLL). However, many technical factors such as setting of the positivity threshold may significantly influence results.. Quantification using mean fluorescent intensity (MFI) may eliminate the subjective error which is inevitable in the isotype control method. The aim of the present project was therefore to assess the prognostic significance of ZAP-70 using three different methods. Between 2005 and 2010 we measured ZAP-70 expression in 157 patients with CLL (108 males, 49 females, median age 60 years [range, 31-82]; low/intermediate/high Rai risk in 41/48/11%). Expression of ZAP-70 was determined by flow cytometry using phycoerythrin (PE)-conjugated monoclonal antibody, clone 1E7.2. Evaluation was performed by 1) percentage of positive cells compared to isotype control (cut-off 20%), 2) MFI ratio of T-cells/CLL cells (cut-off 3.0); 3) MFI ratio of ZAP-70/isotype control on CLL cells (cut-off 2.5). MFI method with T-cells/CLL cells ratio was the best in the identification of patients with unfavourable outcome: ZAP-70 positive patients had significantly shorter time to treatment (TTT, median 24 vs. 55 months, p=0.0001) and overall survival (OS, median 97 vs 174 months, p=0.0074). The differences in TTT a OS were not significant with the use of isotype percentage and MFI isotype methods. Combined analysis of ZAP-70 with CD38 expression or IgVH mutation status lead to identification of a subgroup with the longest TTT and OS (ZAP-70 and CD38 negative, p<0.0001 and p=0.012; ZAP-70 negative and mutated IgVH genes, p<0.0001 and p=0.0019). In conclusion, our results suggest that measurement of ZAP-70 expression in CLL by MFI using T-cells/CLL cells ratio might be the optimal method for accurate prediction of clinical course. Combined analysis of ZAP-70 with CD38 or IgVH mutation status further refined individual patient´s prognosis.

[New antithrombotics in the prevention of venous thromboembolia and new anti-platelet drugs]. / Nová antitrombotika v prevenci zilní tromboembolie a nové protidestickové léky.

We first present a brief overview of new antithrombotic agents that are assumed to replace coumarines and heparin in many indications; this overview provides information on pentasaccharides, direct thrombin inhibitors and direct factorXa inhibitors. Secondly, since the new drugs with antiplatelet effect act through blockade of the reactions involved in blood platelet activation, we review and discuss the substances that interfere with this process. The current antiplatelet therapy focuses mainly on an inhibition of platelet aggregation stimulated by ADP, reducing the risk of arterial occlusions.

[Prognostic markers in chronic lymphocytic leukemia]. / Prognostické faktory u chronické lymfocytární leukemie.

Chronic lymphocytic leukemia is the most common leukemia type in Western countries. Even incidence of chronic lymphocytic leukemia is high, this disease remained beyond interest for a very long time. However, in the last few years the view of this disease fundamentally changed and due to intensive study, new knowledge especially on pathogenesis, prognostic factors and therapy based on intensive therapeutic procedures were made. Today we know that usage of classical prognostic factors is insufficient for prognosis evaluation in the individuals. However modern (IgVH mutation status, cytogenetic abberations) and new markers (LPL/ADAM29 ratio, microRNA, markers of angiogenesis etc) have potential to distinguish patients in early stages to groups with significantly different prognosis and predict clinical course of the disease.

[Technique of implantation and experience with temporary mechanical cardiac support in right ventricular failure]. / Technika implantace a zkusenosti s docasnou mechanickou srdecní podporou pri selhání pravé komory.

AIM: Severe right heart failure remains unfrequent but fatal complication of cardiac surgical procedures. Implantation of temporary right ventricular assist device may be life-saving procedure in various situations of right heart failure as: heart transplantation, LVAD therapy and post-cardiotomy failure. The aim of the study is an introduction of the implantation technique and retrospective review of current experience with the method. MATERIAL AND METHODS: Since January 2007 isolated right ventricular assist device Levitronix CentriMag has been implanted in 16 patients. Patients were divided into 3 groups: post transplantation (post-Tx), post LVAD implantation (post-LVAD) and other cardiac procedures (OCP). Success rate of weaning from RVAD, 30-days mortality and major complications has been assessed. OUTCOMES: Distribution of implants in groups was: post-Tx 5 pts (31%), post-LVAD 6 pts (38%) and 5 in OCP group (31%). The mean support time was 12 days. Off-pump implantation was achieved in 9 pts. The device was successfully weaned in 13 (81%) patients. 30-days mortality occurred in 1 case only. CONCLUSION: Presented outcomes are encouraging for broader acceptance of the therapy. Excellent success rate has been reached in post-Tx and post-LVAD. This study emphasises decesive role of proactive approach in early indication of RVAD implantation for achieving satisfactory results.

[Cardiosurgical procedures in patients refusing blood transfusions: IKEM outcomes]. / Kardiochirurgické operace u pacientu odmítajících krevní transfuze: výsledky v IKEM.

INTRODUCTION: Jehovah's Witnesses who require cardiac operation represent a specific challenge to the physicians. Members of this faith will not accept blood or blood products under any circumstances on the basis of religious grounds. Nevertheless cardiac operations belong to surgical interventions with potential severe bleeding and necessity of blood transfusions. THE AIM OF THE STUDY: The aim of this retrospective study was to analyze clinical data, operative and postoperative courses of patients operated at IKEM who refused blood transfusions. METHODS AND RESULTS: From January 1995 to August 2010, 73 Jehovah's Witnesses ranging in age from 19 to 82 years underwent cardiac surgery at our institute. Aortocoronary bypass were performed in 34 patients, valve surgery in 25 patients, 6 patients underwent concomitant aortocoronary bypass and valve surgery, 2 patients underwent aortocoronary bypass and resection of the left ventricle aneurysm and 2 patients underwent atrial septal defect repair and tricuspid valve anuloplasty. Ventricular septal sefect repair, atrial septal defect repair, Cor Cap device implantation and left ventricular epicardial electrodes implantation were performed in the other patients. Early 30-days mortality was 2.8 % (2 patients). CONCLUSION: We can conclude that cardiac surgery in Jehovah's Witnesses can be performed safety without blood transfusion and belongs to standard operating procedures at our institution.

[Vascular complications in transcatheter aortic valve implantation in IKEM]. / Cévní komplikace pri transkatetrové implantaci aortální chlopne v IKEM.

AIM: Retrograde transfemoral arterial approach is the most common technique of transcatheter aortic valve implantation. Diameter of available catheters is the limiting factor for percutaneous usage. We currently use 18 French third generation Medtronic Core Valve system. We retrospectively analyzed procedure related complications in our patient cohort. MATERIAL AND METHODS: Transcatheter aortic vale implantation with 18 French Medtronic Core Valve was performed in 35 patients (23 females, 12 males) in between 12/2008 and 7/2010. RESULTS: Mean age was 81.4 +/- 6.1 years (range 69-92), mean logistics EuroSCORE was 19.3 +/- 8.9% (range 8-42), mean aortic valve gradient 59.8 +/- 19.8 mm Hg (range 30-86 mm Hg (mean indexed aortic valve area 0.37 +/- 0.11 cm.

Effects of Acute Pump Speed Changes on Cerebral Hemodynamics in Patients With an Implantable Continuous-Flow Left Ventricular Assist Devices.

Mechanical circulatory support (MCS) with an implantable left ventricular assist device (LVAD) is an established therapeutic option for advanced heart failure. Most of the currently used LVADs generate a continuous stream of blood that decreases arterial pulse pressure. This study investigated whether a change of the pulse pressure during different pump speed settings would affect cerebral autoregulation and thereby affect cerebral blood flow (CBF). The study included 21 haemodynamically stable outpatients with a continuous-flow LVAD (HeartMate II, Abbott, USA) implanted a median of 6 months before the study (interquartile range 3 to 14 months). Arterial blood pressure (measured by finger plethysmography) was recorded simultaneously with CBF (measured by transcranial Doppler ultrasound) during baseline pump speed (8900 rpm [IQR 8800; 9200]) and during minimum and maximum tolerated pump speeds (8000 rpm [IQR 8000; 8200] and 9800 rpm [IQR 9800; 10 000]). An increase in LVAD pump speed by 800 rpm [IQR 800; 1000] from the baseline lead to a significant decrease in arterial pulse pressure and cerebral blood flow pulsatility (relative change ?24% and ?32%, both p < 0.01), but it did not affect mean arterial pressure and mean CBF velocity (relative change 1% and ?1.7%, p = 0.1 and 0.7). In stable patients with a continuous-flow LVAD, changes of pump speed settings within a clinically used range did not impair static cerebral autoregulation and cerebral blood flow.

Extracorporeal immunoglobulin elimination for the treatment of severe myasthenia gravis.

Myasthenia gravis (MG) is a neuromuscular disorder leading to fluctuating muscle weakness and fatigue. Rarely, long-term stabilization is not possible through the use of thymectomy or any known drug therapy. We present our experience with extracorporeal immunoglobulin (Ig) elimination by immunoadsorption (adsorbers with human Ig antibodies). Acetylcholine receptor antibodies (AChRAs) were measured during long-term monitoring (4.7 +/- 2.9 years; range 1.1-8.0). A total of 474 samples (232 pairs) were analyzed, and a drop in AChRA levels was observed (P = .025). The clinical status of patients improved and stabilized. Roughly 6.8% of patients experienced clinically irrelevant side effects. The method of Ig elimination by extracorporeal immunoadsorption (IA) is a clinical application of the recent biotechnological advances. It offers an effective and safe therapy for severe MG even when the disease is resistant to standard therapy.

Late effect of early hypoxic disturbance in the rat heart: gender differences.

Perinatal hypoxemia may have serious long-term effects on the adult cardiovascular system and may lead to sex-dependent changes in cardiac tolerance to acute ischemia in adult life. The aim of the study was to answer the question whether gonadectomy of the male and female rats in the early phase of ontogenetic development affects the late effect of perinatal hypoxia. Pregnant Wistar rats were placed into a normobaric hypoxic chamber (12 % O(2)) 7 days before the expected date of delivery. Newborn pups were kept in the chamber with their mothers for another 5 days after birth. After hypoxic exposure all animals were kept for 3 months in room air. Some of the pups were gonadectomized right after removal from the hypoxic chamber. Ventricular arrhythmias were assessed on isolated perfused hearts. Castration did not influence arrhythmogenesis in the adult normoxic or perinatally hypoxic female hearts. Nevertheless, the number of arrhythmias was decreased in perinatally hypoxic gonadectomized males. In conclusion, we have shown that perinatal normobaric hypoxia increased cardiac tolerance to acute ischemia in adult male rats; however, it had no late effect in females. Gonadectomy did not affect arrhythmogenesis in both normoxic and hypoxic female hearts, whereas in males significantly decreased the number of arrhythmias.

[Diabetes mellitus and prothrombotic activity]. / Diabetes mellitus a protrombotická aktivita.

Diabetes mellitus (DM) is defined by significant hyperglycaemia representing a high risk of thrombosis in coronary as well as central and peripheral arteries. The risk of myocardial infarction in patients with type 2 diabetes is 3-5 times higher than in non-diabetics. This is consequent to changes in haemostasis in obese patients with type 2 diabetes, including changes to fibrinolysis, decreased fibrinolytic activity and increased thrombogenic risk, as part of the pluri-metabolic insulin resistance syndrome. The REACH study evaluated more than 67 thousands of patients with a risk of arterial thrombosis or with arterial thrombosis. The patients with diabetes were separated and the results subjected to multivariate analysis; differences were confirmed between intensity of treatment in patients with ischemic heart disease and diabetes and with diabetes only. Antithrombotic therapy in diabetic patients with no clinical signs of arterial thrombosis was less intensive.

[Cancer and deep vein thrombosis]. / Nádorová onemocnení a zilní tromboembolie.

Cancer patients with thrombosis and haemorrhagy are a particular problem. They have an increased risk of deep vein thrombosis and pulmonary embolism, and they're more prone to bleeding from anticoagulant therapy. So it really is a dilemma. Clinical research has shown that prevention and initial therapy can consist of subcutaneous low-molecular-weight heparin for an initial period, followed by long-term anticoagulant therapy.