Spontaneous Venous Thromboembolism Research Articles

The Prevalence of Behçet's Disease in a Thrombosis Clinic.

the prevalence of venous thromboembolism (VTE) in Behcet's disease (BD) is around 40%, though recognition of BD in a thrombosis clinic has been poorly addressed. to evaluate the prevalence of signs and symptoms leading to the diagnosis of BD in a thrombosis clinic compared to patients attending a general haematology clinic and to healthy controls. Design: cross-sectional case-double control anonymous questionnaire survey. Participants: consecutive patients with spontaneous VTE (n=97) attending a thrombosis clinic, consecutive patients from a general haematology (GH) clinic (n=89) and controls (CTR). BD was diagnosed in 1.03% of VTE participants, in 2.2% of GH participants and in 1.2% of healthy CTR. Exhaustion was more common reported in participants from the VTE group (15.6%) than in those from the GH group (10.3%) and from the healthy CTR (3%) (p=0.06); the sum of signs and symptoms of BD clustered in the VTE group (89.5%) compared to the GH (72.4%) and the CTR (59.7%) (p<0.0001). BD may be diagnosed in 1 every 100 patients with VTE attending a thrombosis clinic and in 2 every 100 patients attending a GH clinic: awareness must be raised not to under-diagnose or misdiagnose BD in these settings as management of VTE in BD deviates from the norm.

Comparison of the Efficacy of Aspirin with Rivaroxaban in Postoperative DVT Prophylaxis after Hip Arthroplasty

Background: Patients suffering from severe hip arthritis and osteonecrosis are increasingly turning to total hip arthroplasty (THA) as a treatment option, according to recent research. If deep vein thrombosis (DVT) is not treated properly, it can result in a life-threatening pulmonary embolism as well as other potentially life-threatening consequences (PE). Aim: To compare the efficacy of aspirin with rivaroxaban in postoperative dvt prophylaxis after hip arthroplasty in patients at tertiary care hospital, Karachi Methodology: The College of Physicians and Surgeons of Pakistan approved this study prior to its completion. The Department of Orthopedics at JPMC, Karachi, chose those who had complete hip arthroplasty for the study. The school's ethical committee approved the study before it could begin. Before participating in the trial, all patients signed an informed consent form granting them permission to do so. Results: Patients from JPMC Karachi's Department of Orthopedics were included in the study. They were aged 49 to 75. Travel time to the hospital was an average of 58.878.19 years. They were aged 49 to 75. For every month, hour, and day spent in hospital, there are 14.416.14. Eighty people used aspirin, 32(40%) were 40-60 and 48(60%) were 61-75. In the rivaroxaban group, 40 patients (50%) were 40-60, and (61-75). The aspirin group had 80 patients, 38 male (47%) and 42 female (42%) (52.5%). One hundred and twenty-five patients (68.8%) were on rivaroxaban (31.2%). Conclusions: People who have a spontaneous venous thromboembolism should not be given long-term thromboprophylaxis after taking oral anticoagulants until more research is done. It is very important to figure out what DVY risk factors are in order to come up with preventative measures that are both safe and affordable. People can live longer if they get an early diagnosis and get treatment quickly, so they can live longer. High-quality, large-scale studies must be done before a conclusion can be drawn. Keywords: DVY risk, thromboembolism, thromboprophylaxis, arthroplasty

Real-world experience with limited screening for occult malignancy in patients presenting with spontaneous venous thromboembolism: a single-centre, retrospective cohort study.

Spontaneous venous thromboembolism (VTE) may represent the first manifestation of previously undiagnosed malignancy; however, contemporary international guidelines call for a limited approach to screening for malignancy in such patients. This retrospective cohort study of 328 patients presenting to the Auckland City Hospital Thrombosis Unit identified 17 patients who were subsequently diagnosed with some form of malignancy within 12 months of their presentation. Review of their history, physical examination and limited age and gender-appropriate cancer screening investigations as described by the National Institute for Clinical Excellence and International Society of Thrombosis and Haemostasis guidelines revealed that all 17 would have been safely diagnosed by the 'limited' screening approach endorsed by these guidelines, thus presenting a 'real-world' basis for clinicians to pursue 'limited' screening for malignancy in their everyday practice in patients with spontaneous VTE.

Sequential first-line treatment with nab-paclitaxel/gemcitabine and FOLFIRINOX in metastatic pancreatic adenocarcinoma: GABRINOX phase Ib-II controlled clinical trial

BackgroundNab-paclitaxel/gemcitabine (AG) and FOLFIRINOX (FFX) are promising drugs in metastatic pancreatic cancer (MPC). This study evaluated a new first-line sequential treatment (AG followed by FFX) in MPC that might overcome resistance to primary therapy and delay tumor progression.Patients and methodsPatients with histologically/cytologically confirmed MPC were included in a multicentric trial receiving AG (day 1, 8 and 15) followed by FFX (day 29 and 43). In phase Ib, three dose-levels were tested for maximum tolerated dose (MTD) and recommended phase II dose. In phase II, the main outcome was the objective response rate (ORR) and secondarily safety, progression-free survival (PFS) and overall survival (OS).ResultsIn phase Ib, we included 33 patients (31 assessable) of median age 61.0 years (range 42-75 years) and represented by 54.8% males. Five dose-limiting toxicities were reported without any death. The main grade 3/4 toxicities were neutropenia with spontaneous resolution (35.5%/32.3%), venous thromboembolism (grade 3: 22.6%) and thrombopenia (grade 3: 29.0%), while the MTD was not reached. In phase II, we included 58 patients of median age 60 years (range 34-72 years), 50% males and with Eastern Cooperative Oncology Group stage score 0 and 1 of 37.9% and 62.1%, respectively. They received a median of 4 (1-9) cycles in 8.5 months (0.5-19.8 months). The ORR was 64.9% [95% confidence interval (CI) 51.1% to 77.1%], and neurotoxicity was remarkably low. The main grade 3-4 toxicities were venous thromboembolism, thrombopenia, neutropenia/febrile neutropenia, nausea, diarrhea, weight loss and asthenia without any death. Tumor response was complete in 3.5% and partial in 61.4%, while disease was stable in 19.3% and progressive in 15.8% of patients. The median PFS was 10.5 months (95% CI 6.0-12.5 months) and median OS was 15.1 months (95% CI 10.6-20.1 months).ConclusionSequential AG and FFX showed acceptable toxicity as first-line treatment with no limiting neurotoxicity, while high response rate and survival justify randomized trials.

Impact of double heterozygosity for Factor V Leiden and Prothrombin G20210A on the thrombotic phenotype

IntroductionBecause of the rarity of double heterozygosity for Factor V Leiden (FVL) and Prothrombin (FII) G20210A, little is known about the thrombotic phenotype in double heterozygotes. Material and methodsIn a retrospective cohort study of patients referred for a thrombophilia work-up, we investigated whether double heterozygotes (n = 138) exhibit a more severe thrombotic phenotype compared with single FVL or FIIG20210A heterozygotes, single FVL homozygotes, or wildtype carriers. ResultsThe risk of venous thromboembolism (VTE) was higher for female but not male double heterozygotes compared with single heterozygotes (FVL: 2.51, 95%CI 1.55–4.08, FIIG20210A: 1.75, 95%CI 1.14–2.68) and wildtype carriers (HR 2.53, 95%CI 1.58–4.05) but not compared with FVL homozygotes (HR 1.31, 95%CI 0.94–1.83). Female double heterozygotes developed VTE nearly a decade earlier than wildtype carriers and FVL heterozygotes (mean 44.2 vs. 52.6 and 52.2 years), most often in association with oral contraceptives. Spontaneous VTE and arterial thromboembolic events were not more frequent in double heterozygotes compared with the other genotype groups.Deep vein thrombosis (DVT) of the lower limb was the predominant VTE location in double heterozygotes, atypical vein thrombosis was rare. A phenomenon that has been described as the FVL paradox, a higher proportion of isolated DVT than pulmonary embolism, was also found for double heterozygotes. ConclusionThe thrombotic phenotype in double heterozygotes resembles the appearance of the thrombotic phenotype in FVL carriers but the thrombotic risk is aggravated by women-specific risk factors.

The Incidence of Venous Thromboembolism in Asymptomatic Carriers of a Deficiency of Antithrombin, Protein C, or Protein S: A Prospective Cohort Study

AbstractDeficiencies of antithrombin, protein C, and protein S are associated with an increased risk of venous thromboembolism. The objective of this study was to prospectively assess the incidence of venous thromboembolism in nontreated asymptomatic subjects with such a deficiency. We conducted a prospective cohort study in asymptomatic family members of unselected patients who presented with a venous thromboembolic event and who were found to have a deficiency of antithrombin, protein C, or protein S. No anticoagulant prophylaxis was given to the study participants, except during risk periods for venous thromboembolism. All venous thromboembolic events were diagnosed by objective diagnostic tests. A total of 208 individuals with a mean age of 37 years (range, 15 to 79) were included in the study. A total of 611 patient observation years was obtained. Nine venous thromboembolic events occurred, resulting in an annual incidence of 1.5% (95% confidence interval [CI], 0.7 to 2.8) for the 3 deficiencies combined. Five of these events occurred spontaneously, resulting in an annual incidence of spontaneous venous thromboembolism of 0.8% (95% CI, 0.3 to 1.9). For antithrombin, protein C, and protein S deficiencies separately, this figure was 1.6%, 1.0%, and 0.4%, respectively. Thirty-four subjects experienced a total of 40 risk periods during which 4 venous thromboembolic events occurred (10% per risk period). We conclude that the use of continuous anticoagulant prophylaxis seems not warranted in asymptomatic individuals with a deficiency of antithrombin, protein C, or protein S. During risk periods for venous thromboembolism, adequate anticoagulant prophylaxis is necessary.

Cerebral paradoxical embolism associated with patent foramen ovale and idiopathic venous thromboembolism in a 31-year-old patient.

ABSTRACTParadoxical embolism is the passage of venous thrombi into the arterial circulation through a pulmonary or intracardiac shunt. We report the management of a 31-year-old patient who initially presented with chest pain and right brachiofacial paresis. A diagnosis of paradoxical cerebral embolism associated with a spontaneous venous thromboembolism and a patent foramen ovale was made. The patient benefited from thrombolytic therapy and lifelong anticoagulation with good recovery. This case showed that percutaneous closure of a patent foramen ovale needs to be discussed individually.

Pulmonary embolism as the presenting symptom and a confounder in ACTH-secreting bronchial carcinoid

SummaryEctopic ACTH-secreting pulmonary neuroendocrine tumors are rare and account for less than 5% of endogenous Cushing’s syndrome cases. We describe an unusual case of metastatic bronchial carcinoid tumor in a young woman presenting with unprovoked pulmonary emboli, which initially prevented the detection of the primary tumor on imaging. The source of ectopic ACTH was ultimately localized by a Gallium-DOTATATE scan, which demonstrated increased tracer uptake in a right middle lobe lung nodule and multiple liver nodules. The histological diagnosis was established based on a core biopsy of a hepatic lesion and the patient was started on a glucocorticoid receptor antagonist and a somatostatin analog. This case illustrates that hypercogulability can further aggravate the diagnostic challenges in ectopic ACTH syndrome. We discuss the literature on the current diagnosis and management strategies for ectopic ACTH syndrome.Learning points:In a young patient with concurrent hypokalemia and uncontrolled hypertension on multiple antihypertensive agents, secondary causes of hypertension should be evaluated.Patients with Cushing’s syndrome can develop an acquired hypercoagulable state leading to spontaneous and postoperative venous thromboembolism.Pulmonary emboli may complicate the imaging of the bronchial carcinoid tumor in ectopic ACTH syndrome.Imaging with Gallium-68 DOTATATE PET/CT scan has the highest sensitivity and specificity in detecting ectopic ACTH-secreting tumors.A combination of various noninvasive biochemical tests can enhance the diagnostic accuracy in differentiating Cushing’s disease from ectopic ACTH syndrome provided they have concordant results. Bilateral inferior petrosal sinus sampling remains the gold standard.

PB2426 CLINICAL MANIFESTATION OF HEREDITARY THROMBOPHILIA IN CHILDREN

Background:Venous thromboembolism (VTE) in children is becoming a more frequent problem. The pathogenesis of thrombosis is complex: thrombophilia, background disease, trigger factor. Special attention should be deserved to hereditary thrombophilia (HT), which from childhood can be accompanied by persistent disorders in the hemostasis system and significantly increase the risk of thrombosis.Aims:To assess the influence of HT on the development of venous thromboembolic complications in children.Methods:We have examined 24 patients aged from 1 day to 18 years, who had various types of thrombotic manifestations (n = 20) or the threat thereof taking into account the family history (n = 4). The average age of children was 5.6 years, the ratio of girls to boys was 1.4 / 1.0. All patients underwent a full laboratory examination aimed at the diagnosis of HT and antiphospholipid syndrome (APS): levels of antithrombin III (ATIII), protein C and S, antibodies to β2‐glycoprotein and cardiolipin, lupus anticoagulant, homocysteine level. Molecular genetic testing included thrombogenic mutations and polymorphisms.Results:In half of the cases of VTE, the lower extremity deep vein thrombosis of was diagnosed. Venous sinus thrombosis ‐ in 20% of the examined (n = 4); pulmonary artery thromboembolism in one case; thrombosis in the pool of the portal and superior vena cava ‐ in 35%. VTE recurrences were observed in 20% of cases. The diagnosis of HT is verified in 62.5% of all examined children and in 55% of children with thrombosis. The HT variants were distributed in the following way: 33.3% ‐ mutation in the FV Leiden (het) gene; 20% ‐ in the prothrombin G20210A (het) gene; AT III deficiency was diagnosed in three patients (20%); combined mutations in MTHFRC‐677T (T/T) and PAI‐1 (4G/4G) genes‐ 26.7%. MTHFRC‐677T (T/T) mutations in two cases were accompanied by moderate hyperhomocysteinemia. Trigger factors for VTE not associated with HT were background diseases and its associated complications: acute lymphoblastic leukemia (n = 4); parenteral nutrition (n = 1); operative interventions (n = 2); autoimmune diseases (n = 2) and APS (n = 1). Clinical manifestation of HT in 63.3% of cases was observed in patients over 10 years old. In 72.7% of cases, VTE occurred spontaneously. The earliest spontaneous VTE was detected in a child at the age of 1 day (portal vein thrombosis). In 75% of cases of recurrent VTE, HT has occurred.Summary/Conclusion:Hereditary thrombophilia is a sign of the potential risk of thrombosis in children. Clinical manifestation of VTE occurs at any location, at any age, but significantly more often in children older than 10 years. The presence of HT is a high risk factor for recurrent and spontaneous VTE. Diagnosis of HT is reasonable to carry out in all cases of VTE in children, which is important not only for assessment of the risk of repeated thrombotic episodes, but also for selecting the antithrombotic therapy regimen and optimizing preventive measures.

Do investigations for cancer in patients with spontaneous venous thromboembolism (VTE) (deep vein thrombosis [DVT] or pulmonary embolism [PE]) improve patient outcomes (morbidity and mortality)?

Category: Research

The Relationship between Leukocyte Counts and Venous Thromboembolism: Results from RETROVE Study

Introduction: Different studies have shown a possible increased risk of venous thromboembolism (VTE) and arterial thrombosis in patients with an increased leukocyte count. The underlying mechanisms are not completely understood, but they could partly be explained by the role that white blood cells play in inflammation. Our objective is to investigate investigated the relationship between leukocyte counts and VTE. Material and methods: Analyses were performed in 400 patients and 400 control subjects of the RETROVE (Riesgo de Enfermedad TROmboembolica VEnosa) Study. To evaluate the odds ratio (OR) for VTE of leukocyte counts we used an unconditional logistic regression analysis taking into account the confounders. Results: We observed more spontaneous (273, 68.3%) than non–spontaneous (127, 31.8%) VTE. Monocyte counts showed a strong association with thrombosis risk: For the 90th percentile in the controls (>0.7 × 109/L), the OR of VTE and its 95% confidence intervals are 2.1 (1.4-3.3). A highly significant relation between high monocyte counts and spontaneous VTE was found. Conclusion: We confirmed a strong association between high monocyte counts and past VTE. High monocyte counts (even within the clinical reference range) could constitute a risk factor for VTE.

A rare case of unprovoked venous thromboembolism manifestation in a young patient with antithrombin Type IIB deficiency combined with inferior vena cava anomaly from Lithuania.

A 12-year-old previously healthy boy of Romani origin presented with a swollen, painful left leg and fever. Imaging revealed signs of inferior vena cava (IVC) thrombosis, the presence of interrupted intrahepatic IVC with azygos continuation and bilateral iliofemoral thrombosis with enlargement of the azygous and hemiazygos venous system. In addition, right pleural effusion and signs of bilateral renal pericortical cysts, possibly caused by retroperitoneal lymphangiectasia, were disclosed. Thrombophilia screening involving protein C, Protein S, Antithrombin (chromogenic assays based on the inhibition of FIIa and FXa, antigen concentration), APC resistance, prothrombin mutation and Lupus anticoagulants was performed using standard laboratory methods. Genetic analysis of the SERPINC1 gene was done by direct sequencing. Thrombophilia screening showed isolated decreased AT activity at 21% (RR 80-120%). AT levels were retested and remained decreased (33-36%) on two consecutive occasions. SERPINC1 gene analysis revealed a previously described homozygous mutation (Budapest III) causing type IIB deficiency (c.391C>T; p.Leu131Phe). A family study confirmed the same mutation in both parents and three siblings. The patient improved significantly following warfarin therapy and over the past 2.5 years did not experience new thromboembolism. This case represents a rare combination of two risk factors provoking manifestation of spontaneous venous thromboembolism at a young age requiring permanent anticoagulant therapy.

TROUSSEAU'S SYNDROME PRESENTING WITH CARDIAC TAMPONADE AND MIGRATORY ATRIAL THROMBUS

Malignant disease may present with spontaneous venous or arterial thromboembolism, described as Trousseau's Syndrome. A 51 year old female presented with cough and exertional fatigue. Examination revealed basal crepitations with a leucocytosis. Her chest x-ray was consistent with pneumonia and

Risk factors and clinical features of acute pulmonary embolism in children from the community

Background and aimsCurrent clinical decision rules for pulmonary embolism are based on adult populations and have not been validated in children. The objective was to identify and evaluate clinical features for a first lifetime episode of pulmonary embolism in children presenting to the emergency department. Materials and methodsWe present a case–control study of children (≤18years) presenting to the emergency department of the Royal Children's Hospital, Melbourne between November 2007 and February 2015. Children with radiologically proven pulmonary embolism formed the case group, whilst children in whom there was a clinical suspicion of pulmonary embolism but negative diagnostic imaging formed the control group. Charts, electronic medical and imaging records of both cases and controls were reviewed and analysed. ResultsThere were a total of 50 patients in this study (11 cases and 39 controls). Current or recent (within three months) use of the oral contraceptive pill was the most significant risk factor in our study (odds ratio 14.667, 95% confidence interval 3.001–71.678, P<0.001). Most other features failed to discriminate between cases and controls, although there was a trend towards increased heart rate in cases. ConclusionsPulmonary embolism is perhaps the most common presenting spontaneous venous thromboembolism in the community and teenage girls on the oral contraceptive pill are most at-risk amongst children. The clinical signs and symptoms are often non-specific. Additional larger studies are required to determine the significance and magnitude of potential clinical predictors identified in this study. This may lead to derivation of a paediatric-specific pre-test probability tool.

Incidence of Unprovoked Venous Thromboembolic Events in Patients with Chronic Lymphocytic Leukemia (CLL)

While lymphoma is a known risk factor for venous thromboembolism (VTE), the thrombogenicity of chronic lymphocytic leukemia (CLL) has not been investigated. One study reported a ten-fold increased risk in VTE compared to the general population, but this included both provoked and unprovoked events, making it difficult to discern the independent contribution of CLL to the thrombogenic predisposition (Whittle A et al. Leuk Res 2011; 35:419-21). Since we found no studies examining only unprovoked VTE in CLL, we sought to estimate the risk of spontaneous VTE occurring in patients with CLL in the absence of known thrombogenic risk factors. The study was approved by the institutional human subjects committee. We examined patients diagnosed with CLL between 1997-2014 by the persistent presence of ≥ 5,000 circulating small, mature, monoclonal, CD5+, CD23+ B lymphocytes (per diagnostic criteria in: Halleck M et al. Blood 2008;111:5446-56) and listed in the Minneapolis VA Tumor Registry. Clinical and laboratory data were obtained from the electronic medical record. Each patient's chart was reviewed individually for VTE, either pulmonary embolism (PE) or deep vein thrombosis (DVT), and the report of a confirmatory imaging study was examined to confirm the diagnosis.We followed patients (n = 308, 99% males, mean age 70 years) starting at the date of CLL diagnosis or the date after CLL diagnosis when the patient began follow-up at the VA and ending at last patient contact or death (122/308 [39.6%] patients died during the observation period). Each patient made at least annual contact with the VA between the start and end dates, with a mean VA follow-up time of 4.6 +/- 2.9 years; 90% patients were followed continuously at the VA since after the diagnosis of CLL. Patients were excluded if there was a preceding period of immobility, serious illness requiring hospitalization, diagnosed hypercoagulable state, or recent chemotherapy known to be associated with increased thrombotic risk. The total follow-up time was 1408 patient-years, during which 10 unprovoked VTE occurred, for an estimated incidence rate of unprovoked VTE of 0.71 per 100 patient-years, 95% CI [0.38, 1.32]. Eight VTE were originally diagnosed at our institution. Confirmatory imaging was available for the 2 VTE diagnosed elsewhere. All 10 patients were males between the ages of 55 to 95 years at the time of CLL diagnosis. Six had DVT, three had PE, and one had both DVT and bilateral PE. Nine patients had symptoms that prompted diagnostic imaging, while one PE was diagnosed incidentally on a chest CT scan. Nine patients had bulky lymphadenopathy at the time of VTE, but these did not compress the relevant vein in any patient. Small, stable monoclonal paraproteinemia was identified in 2/5 VTE patients tested (one patient at 0.39 and 0.35 g/dL, one patient at 0.32 and 0.27 g/dL). At time of development of VTE, 4, 1, 1 and 3 patients had Rai stage I, II, III or IV CLL, respectively. Thus, while there were relatively few events, there did not appear to be any clear relationship of VTE with advanced CLL stage. Recurrence of unprovoked VTE occurred in only 1 of 10 (10%) patients.In a study of the general population in our region of the US (Olmsted County, MN), the overall incidence of VTE in 70-74 year old males was 0.65 per 100 patient-years (Silverstein M et al. Arch Internal Med 1998;158:585-93). Since 17-47% of all VTEs were unprovoked in various population series (Cushman M et al. Thromb Haemost 2001;86[suppl 1]:OC2349, Heit JA et al. Arch Intern Med 2002;162:1245-8, Spencer FA et al. J Thromb Thrombolysis 2009;28:401-9, White RH Circulation 2003;107:I-4-8), the incidence rate of unprovoked VTEs observed in CLL patients in the current series (0.71; 95% CI: 0.38, 1.32) approximates the expected incidence of unprovoked VTEs in the general population. Further, the development of unprovoked VTE would have been expected to be skewed towards patients with advanced stage (Rai stages III/IV), and/or have been associated with more frequent recurrences, if CLL was an independently thrombogenic condition.Conclusion: This is the first long-term study of unprovoked VTE in patients with CLL, with >1400 patient-years of follow-up. The low incidence of unprovoked VTEs observed in our study suggests that primary thromboprophylaxis may not be required in patients with CLL who do not have additional risk factors for thromboembolism. DisclosuresNo relevant conflicts of interest to declare.

Aspirin and venous thromboses

The pharmacological prevention of venous thromboembolism (VTE) has so far been carried out mainly with classic (low-molecular-weight heparins, coumarins) or new direct oral anticoagulants (DOACs). The role of antiplatelet treatment with aspirin is controversial. New data, however, suggest a paradigm shift with the reassessment of aspirin as part of a multimodal antithrombotic approach. The article provides an up-to-date overview of the role of antiplatelet treatment with aspirin in the primary and secondary prevention of VTE. Primary prevention of surgery-related VTE with anticoagulants is effective but apparently not superior to a multimodal approach with aspirin, pneumatic compression, and early mobilization. Against this background, aspirin is now also included in the VTE prevention guidelines in the US (ACCP, AAOS) but not in the UK (NICE) and Germany (AMWF). A final evaluation of aspirin as compared to classic anticoagulants and DOACs in primary prophylaxis requires further randomized controlled, prospective trials. These should also consider the iatrogenic risk of bleeding as well as possible postoperative complications, such as retarded wound healing that might require prolonged hospitalization. After ending guideline-conforming anticoagulant treatment in patients with idiopathic VTE, administration of aspirin reduces the risk of recurrent VTE by about 40% without increasing the risk of severe bleeding (standardized INSPIRE evaluation of ASPIRE and WARFASA data). These data add to the current use of aspirin in the prevention of arterial thrombosis the new option of preventing spontaneous VTE. On the basis of new data from recent studies, an indication can be made for the use of aspirin, combined with other preventive measures, in the prevention of primary and secondary venous thromboses.

Aspirin for prophylaxis of venous thromboembolism

Cessation of vitamin K antagonists (VKA) after a primary incidence of spontaneous venous thromboembolism (VTE) has been associated with recurrent events in about one-fifth of patients. Although long-term continuation of VKA prophylaxis has been suggested as a means to prevent recurrent VTE, concerns remain over issues of high bleeding risk, patient non-compliance as well as dosage irregularities. Antiplatelet therapy has been proposed as a safer, cheaper and more convenient alternative for long-term prophylaxis after initial treatment with VKA following VTE. Here we compare two major randomized trials that were conducted back-to-back – the WARFASA trial and the ASPIRE trial – to determine the role of aspirin as a long-term treatment option to reduce the incidence of recurrent VTE. Despite the encouraging results of these trials, suggesting that aspirin may have a beneficial effect on secondary prevention of VTE, it must be emphasized that both trials only started aspirin after 6-18 months of treatment with VKA, which remain a cornerstone of management for a first unprovoked VTE.

Thrombophilia Testing in Hospitalized Children: Waste Not, Want Not?

AbstractAbstract 1150 IntroductionThe incidence of venous thromboembolism (VTE) in children is rising. Our institutional experience has shown VTE incidence in hospitalized children rose from 0.3 to 71/10,000 admissions over a 13 year span. Many of these children had multiple acquired risk factors, e.g. central venous line (CVL), and many of these children underwent extensive thrombophilia testing. Hypothesis: Thrombophilia testing in hospitalized children with VTE is unnecessary and adds cost burden to patient (pt) care. MethodsWe evaluated thrombophilia testing performed in children aged 0–20 admitted to Riley Hospital for Children from Jan 2005-Apr 2012. Eligibility criteria included admission for > 48 hours with no clinical suspicion of VTE on admit and subsequent VTE confirmed by ultrasound, CT or MRI. We evaluated for presence of 8 acquired risk factors identified a priori and known to be significant at our hospital: BMI > 85th %ile for age/gender, length of stay > 7 days, mechanical ventilation, direct ICU admit, bacteremia, immobilization > 72 hours, estrogen therapy, and CVL presence (Sharathkumar et al J Thromb Haemost 2012). Thrombophilia testing included Protein C, Protein S, and Antithrombin activities, antiphospholipid antibody panel (APLA, including anti-phosphatidylserine, anti-cardiolipin and lupus anticoagulant), β2 glycoprotein 1 (β2GP1) Ab, presence of Factor V Leiden (FVL) and prothrombin 20210A gene (PTm) mutations, PAI-1 and MTHFR gene (A1298C & C677T) polymorphisms. A thrombophilic condition was diagnosed if a low Protein C, Protein S, or Antithrombin activity was found initially and confirmed after VTE resolution, if APLA or β2GP1 Ab was positive at diagnosis and again after > 12 weeks, hetero- or homozygosity for FVL or PTm, 4G/5G or 4G/4G PAI-1 status with elevated PAI-1 serum level, or MTHFR mutation with elevated fasting AM homocysteinelevel. Cost of thrombophilia testing was evaluated with hospital charges and Medicaid reimbursement rates. ResultsVTE was diagnosed in 239 patients. At least 1 risk factor was found in 232 (97%) patients and 7 (3%) had no risk factors. These 7 patients with no risk factors had thrombophilia tests done and none had a positive test. Presence of a CVL was significantly associated with nothaving any tests done (p<0.0022).At least 1 thrombophilia test was ordered on 157/239 patients (66%). There were 940 total tests ordered (6 tests/pt) and only 16 positive results (1.7%). Eleven patients were FVL heterozygous and 1 patient was FVL homozygous yielding FVL prevalence of 7.6%. Four patients were PTm heterozygous yielding PTm prevalence of 2.5%. This is similar to prevalence of FVL (5–7%) and PTm (3%) in healthy populations (Martinelli J Thromb Haemost2001).Table 1 shows thrombophilia testing distribution. Cost analysis shows average Medicaid reimbursement of 32.7% of charges billed. Medicaid cost savings of up to $365.25/ptcan be attained by eliminating routine thrombophilia testing in hospitalized children who develop VTE.Table 1Initial Thrombophilia Tests & Costs in 157 ptsTest# of testsHospital Charge ($)Medicaid reimbursement ($)*Prot. C Activity131109.1319.59Prot. S Activity13169.5021.70AT activity135104.1216.79APLA54131.2036.96β2GP1 Ab30409.24FVL PCR144103.5740.78PTm PCR12513091PAI-1 PCR3626740.78MTHFR PCR108119.7464.52Homocysteine4672.6823.89Total9401146.94365.25*Apr ‘12 rates. DiscussionThe incidence of VTE in hospitalized children is increasing. Many hospitalized children who develop VTE undergo thrombophilia testing. With increased survival of children with chronic diseases and increased prevalence of acquired VTE risk factors, thrombophilia testing in hospitalized children is not necessary and adds cost burden. Thrombophilia testing in children may best be limited to spontaneous VTE. This evaluation is somewhat limited by the low number of subjects with APLA, PAI-1 serum activity or homocysteine labs. Also, we did not include other risk factors, e.g. family history. However, recent ACCP guidelines recommend anticoagulation duration not be adjusted for presence of thrombophilia. There is also concern Medicaid may not reimburse for inpatient VTE in children in the future. Considering we found no difference between hospitalized children with VTE and healthy populations along with current and future financial concerns, we support not testing for thrombophilia in hospitalized children who develop VTE. Disclosures:No relevant conflicts of interest to declare.

Identification of Patients At High Risk for Recurrent Venous Thromboembolism by Whole Blood Gene Expression Analysis

Abstract 2305 Background.Recurrent venous thromboembolism (VTE) occurs in ∼30% of patients with spontaneous VTE after completion of a standard course of anticoagulant therapy. D-dimer levels and selected clinical parameters have been used to identify patients at low risk for recurrent VTE, who may safely discontinue antithrombotic therapy. We have used gene expression profiles to distinguish patients with a single VTE from patients with recurrent VTE. The purpose of this study was to extend this initial report and identify unique gene expression patterns from whole blood that correlate with different risk profiles for VTE recurrence. Methods.Patients with ≥1 prior VTE, with the first event occurring at age 18 years or older and >3 months from the most recent event were recruited for this study. Patients were allocated into 4 groups: (1) ‘low-risk' patients had sustained ≥1 provoked VTE; (2) ‘moderate-risk' patients had sustained 1 unprovoked VTE (with or without provoked VTE); (3) ‘high-risk' patients had sustained ≥2 unprovoked VTE and had no evidence for antiphospholipid antibodies; and (4) antiphospholipid syndrome (APS) patients met established consensus criteria for APS. A similar number of individuals with no prior history of VTE were enrolled as a control population. Citrated plasma, serum and PAXgene RNA tubes were collected, processed and stored at −80°C until shipped to the CDC for analysis. Antiphospholipid testing was performed on all participants to confirm correct group distribution. Total RNA was isolated from whole blood drawn into PAXgene tubes. Following sample labeling and normalization, cRNA samples were hybridized to Illumina HT-12 Beadchips to assay whole genome gene expression with over 47,000 probes against human transcripts. Two hundred and twenty six unique samples passed initial quality control measures. Quality assessment of raw data was done using GenomeStudio. The raw data files were converted to a text file using the IlluminaExpression FileCreator in GenePattern and then log transformed, normalized and median-centered using Cluster. Both unsupervised (hierarchical clustering using Cluster) and supervised analyses (SAM) were used to identify genes that were differentially expressed between the groups. GATHER was used to help understand the biological processes and gene ontology of the gene lists generated by Cluster and SAM. Results.A total of 226 participants were enrolled into the study. Characteristics of the patient groups are summarized in the Table. Demographically, the groups were similar except that patients in the high-risk group tended to be older and were more likely male. The number of events per patient, and the proportion on anticoagulant therapy, increased with the risk group.GroupAge, yrSex, F (%)Race, W (%)Time since last VTE, yrPE, N (%)VTE/Patient N (n; %)AC therapy?Low-risk (n=44)49 (25–90)25 (57%)37 (84%)4 (1–15)15 (34%)1 (37; 84%); 2 (7; 16%)31 (70%)Moderate-risk (n=45)53 (22–86)23 (51%)37 (82%)3 (1–9)34 (76%)1 (28; 62%); 2 (15; 33%); 3 (2; 4%)41 (91%)High-risk (n=46)58 (28–82)15 (33%)37 (80%)6 (1–22)25 (54%)2 (29; 63%); 3 (9; 20%) ≥4 (7; 15%)46 (100%)APS (n=47)48 (20–83)24 (51%)43 (91%)7 (1–26)25 (53%)1 (22; 47%); 2 (19; 40%); ≥3 (3; 6%)44 (94%)Normals (n=44)48 (21–75)26 (59%)39 (89%)–0–2 (5%)Antiphospholipid antibodies were detected in several patients in each of the 3 non-APS VTE patient groups, but in most cases this was a single test positive; antiphospholipid antibodies were present in the majority of patients with APS, typically with more than one test positive (37 of 45 with complete testing, 82%). Preliminary analysis of the gene expression profiles using an unsupervised clustering by gene on the high-risk and low-risk groups identified multiple genes that distinguished the two groups, including 18 immune response genes identified by GATHER. These two patient groups were also distinguished by SAM analysis, and multiple genes in the MAPK signaling pathway that separated the two groups were identified by the KEGG pathways in GATHER. Additional analyses are being performed on all of the groups. Conclusions.Whole blood gene expression profiling can be used to develop profiles that distinguish patients with VTE who differ based on their risk of recurrent events. Individual genes identified in these profiles may provide biological insights into the molecular basis for recurrent VTE. Disclosures:Heit:Daiichi Sankyo: Honoraria; Ortho-McNeil Janssen: Honoraria; Covidien: Honoraria. Manco-Johnson:Octapharma AG: Consultancy; Bayer: Research Funding.

Whole blood gene expression analyses in patients with single versus recurrent venous thromboembolism

Introduction Venous thromboembolism may recur in up to 30% of patients with a spontaneous venous thromboembolism after a standard course of anticoagulation. Identification of patients at risk for recurrent venous thromboembolism would facilitate decisions concerning the duration of anticoagulant therapy. Objectives In this exploratory study, we investigated whether whole blood gene expression data could distinguish subjects with single venous thromboembolism from subjects with recurrent venous thromboembolism. Methods 40 adults with venous thromboembolism (23 with single event and 17 with recurrent events) on warfarin were recruited. Individuals with antiphospholipid syndrome or cancer were excluded. Plasma and serum samples were collected for biomarker testing, and PAXgene tubes were used to collect whole blood RNA samples. Results D-dimer levels were significantly higher in patients with recurrent venous thromboembolism, but P-selectin and thrombin-antithrombin complex levels were similar in the two groups. Comparison of gene expression data from the two groups provided us with a 50 gene probe model that distinguished these two groups with good receiver operating curve characteristics (AUC 0.75). This model includes genes involved in mRNA splicing and platelet aggregation. Pathway analysis between subjects with single and recurrent venous thromboembolism revealed that the Akt pathway was up-regulated in the recurrent venous thromboembolism group compared to the single venous thromboembolism group. Conclusions In this exploratory study, gene expression profiles of whole blood appear to be a useful strategy to distinguish subjects with single venous thromboembolism from those with recurrent venous thromboembolism. Prospective studies with additional patients are needed to validate these results.