Potential Risk Factors For Thrombosis Research Articles

Impaired fibrinolysis and increased clot strength are potential risk factors for thrombosis in lymphoma

AbstractThrombosis and bleeding are significant contributors to morbidity and mortality in patients with hematological cancer, and the impact of altered fibrinolysis on bleeding and thrombosis risk is poorly understood. In this prospective cohort study, we investigated the dynamics of fibrinolysis in patients with hematological cancer. Fibrinolysis was investigated before treatment and 3 months after treatment initiation. A dynamic clot formation and lysis assay was performed beyond the measurement of plasminogen activator inhibitor 1, tissue- and urokinase-type plasminogen activators (tPA and uPA), plasmin-antiplasmin complexes (PAP), α-2-antiplasmin activity, and plasminogen activity. Clot initiation, clot propagation, and clot strength were assessed using rotational thromboelastometry. A total of 79 patients were enrolled. Patients with lymphoma displayed impaired fibrinolysis with prolonged 50% clot lysis time compared with healthy controls (P = .048). They also displayed decreased clot strength at follow-up compared with at diagnosis (P = .001). A patient with amyloid light-chain amyloidosis having overt bleeding at diagnosis displayed hyperfibrinolysis, indicated by a reduced 50% clot lysis time, α-2-antiplasmin activity, and plasminogen activity, and elevated tPA and uPA. A patient with acute promyelocytic leukemia also displayed marked hyperfibrinolysis with very high PAP, indicating extreme plasmin generation, and clot formation was not measurable, probably because of the extremely fast fibrinolysis. Fibrinolysis returned to normal after treatment in both patients. In conclusion, patients with lymphoma showed signs of impaired fibrinolysis and increased clot strength, whereas hyperfibrinolysis was seen in patients with acute promyelocytic leukemia and light-chain amyloidosis. Thus, investigating fibrinolysis in patients with hematological cancer could have diagnostic value.

Assessing the Relationship between Thrombosis and Immune-Related Adverse Events in Patients with Lung Cancer Treated with Immune Checkpoint Inhibitors

Introduction: Venous thromboembolisms (VTE) frequently occur in cancer patients, and the role of immune checkpoint inhibitors on thrombotic risk has been a rising concern for clinicians. Identifying pro-thrombotic risk factors could guide primary prophylaxis strategies in patients receiving immunotherapy. Immune checkpoint blockade can induce inflammatory side effects known as immune-related Adverse Events (irAE). Inflammatory states are known to be associated with a hypercoagulable state. It is not established whether patients treated with immunotherapy experience a higher risk of thrombotic events during periods of increased inflammation surrounding irAE occurrence. Similarly, while immune checkpoint inhibitors have been shown to be associated with increased bleeding events, it is not clear whether irAE occurrence affects incidence of hemorrhage. Our primary objective was to determine the association between irAE and thrombosis in patients with non-small cell lung cancer treated with immune checkpoint inhibitors in order to better elucidate potential risk factors for thrombosis in patients on immunotherapy. Our secondary objective was to evaluate the association between irAE and clinically significant bleeding events. Methods: We identified all patients with non-small cell lung cancer treated with pembrolizumab at an academic medical center between 2016 and 2021. Outcomes of interest were VTE and clinically relevant bleeding (a composite of major bleeding and clinically-relevant non-major bleeds). We collected information regarding concurrent chemotherapy use with immunotherapy, frequency and type of irAE, steroid use for treatment for irAE, and use of anticoagulation or antiplatelet agents. We used logistic regression to calculate the odds ratios (OR) and 95% confidence intervals (CI) of VTE and clinically-relevant bleeding among patients who had an irAE prior to the outcome of interest compared to those who did not. We calculated the odds of VTE associated with use of concurrent chemotherapy (vs. no concurrent chemotherapy). Results: Of 102 patients included, 46.1% were female, and average age at diagnosis was 66.8 ± 10.5 years. Thirty-four patients were treated with pembrolizumab alone, with the remainder receiving concurrent chemotherapy and/or targeted therapy with pembrolizumab. Overall, 21 patients experienced thrombotic events (20.6%), 7 (6.9%) experienced clinically-relevant bleeding events, and 28 (27%) experienced an irAE. (Table 1). Overall, occurrence of irAE was not associated with increased odds of VTE (OR: 1.07, 95% CI: 0.37-3.11, P=0.90). (Figure 1). Similarly, among those with an irAE, steroid treatment was not associated with increased odds of VTE (OR: 1.14, 95% CI: 0.17-7.69, P=0.89). The combination of chemotherapy with pembrolizumab did not result in a statistically significant increase in odds of VTE (OR: 1.37, 95% CI: 0.52-3.60, P=0.53). The odds of clinically-relevant bleeding was not statistically higher among those with an irAE (OR: 2.10, 95% CI: 0.44-10.0, P=0.35). Conclusions: The development of irAE in patients with NSCLC treated with pembrolizumab does not appear to predict the development of VTE. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Incidence, risk factors, and evolution of venous thromboembolic events in patients diagnosed with pancreatic carcinoma and treated with chemotherapy on an outpatient basis

BackgroundPancreatic carcinoma is one of the tumors associated with a higher risk for thromboembolic events, with incidence rates ranging from 5% to 41% in previous retrospective series. Patients and methodsWe conducted a retrospective study in eleven Spanish hospitals that included 666 patients diagnosed with pancreatic carcinoma (any stage) between 2008 and 2011 and treated with chemotherapy. The main objective was to evaluate the incidence of venous thromboembolic events (VTE) in this population, as well as potential risk factors for thrombosis. The impact of VTE on mortality was also assessed. ResultsWith a median follow-up of 9.3 months, the incidence of VTE was 22.1%; 52% were diagnosed incidentally. Our study was unable to confirm the ability of the Khorana score to discriminate between patients in the intermediate or high risk category for thrombosis. The presence of VTE proved to be an independent prognostic factor associated with increased risk of death (HR 2.39, 95% CI 1.96–2.92). Symptomatic events correlated with higher mortality than asymptomatic events (HR 1.72; 95% CI, 1.21–2.45; p = 0.002), but incidental VTE, including visceral vein thrombosis (VVT), negatively affected survival compared to patients without VTE. Subjects who developed VTE within the first 3 months of diagnosis of pancreatic carcinoma had lower survival rates than those with VTE after 3 months (HR 1.92, 95% CI 1.30–2.84; p<0.001). ConclusionsPancreatic carcinoma is associated with a high incidence of VTE, which, when present, correlates with worse survival, even when thrombosis is incidental. Early onset VTE has a particularly negative impact.

Chest radiotherapy after left upper lobectomy may be a risk factor for thrombosis in the pulmonary vein stump

BackgroundThrombosis in the pulmonary vein stump (PVS) is not a well-known complication after pulmonary lobectomy, but it has the potential to cause embolism to vital organs. The aim of this study was to evaluate the risk factors for thrombosis in the PVS after pulmonary lobectomy.MethodsA total of 439 patients who underwent pulmonary lobectomy from 2008 to 2017 were retrospectively reviewed, and 412 patients were further analyzed. The state of the PVS was evaluated by chest contrast-enhanced computed tomography (CECT). Univariate analysis was performed to evaluate the potential risk factors for thrombosis in the PVS.ResultsThrombosis in the PVS was detected in 6 of 412 (1.5%) patients, and 5 of them underwent left upper lobectomy (LUL) (5/100, 5.0%) (P = 0.004). In the analyses of the LUL group, postoperative chest radiotherapy was identified as a risk factor for thrombosis in the PVS (P = 0.024), and postoperative atrial fibrillation showed a tendency to be a risk factor for thrombosis (P = 0.058).ConclusionsChest radiotherapy after LUL is a possible risk factor for thrombosis in the PVS. Periodic chest CECT is recommended after postoperative chest radiotherapy for patients after LUL.

Thromboembolic events during neoadjuvant chemotherapy in muscle invasive bladder cancer – any correlation to the central venous access? A clinical practice article

Patients with muscle invasive bladder cancer have a generally known 5-year overall survival of approximately 58% with neoadjuvant chemotherapy (NAC). During the last decades, addition of Cisplatinum-based NAC in fit patients prior to radical cystectomy (RC), has significantly improved OS, compared to RC only. However, some published studies following NAC addition, describe an intermediate risk increase of thromboembolic events (TEEs). Placement of central venous access (CVA) before NAC has also been suggested as being a potential risk factor for thrombosis. We present a combination of images and cases from the Northern Swedish health region where three patients developed venous TEE after CVA placement for NAC-administration and found that the time until curable RC was prolonged circa one month each, with an addition of one RC cancelled. These are serious events and to our knowledge, there are no current guidelines on prevention of TEE before RC. The aim with this report was to provide examples of these events and conclude that further prospective trials are warranted on prevention and future guidelines regarding venous anticoagulant treatment for TEE that occur pre-RC in NAC-patients.

Thromboembolism in COVID-19: the unsolved problem.

The recent Sars-CoV-2 pandemic (COVID-19) has led to growing research to explain the poor clinical prognosis in some patients. While early observational studies highlighted the role of the virus in lung failure, in a second moment thrombosis emerged as a possible explanation of the worse clinical course in some patients. Despite initial difficulties in management of such patients, the constant increase of literature in the field is to date clarifying some questions from clinicians. However, several other questions need answer. We performed systematic research using Embase and PubMed, inserting the keywords and mesh terms relative to the new coronavirus and to VTE: "COVID-19," "SARS," "MERS," "coronavirus," "2019 n-CoV," venous thromboembolism," "pulmonary embolism," "deep vein thrombosis," "thromboembolism," "thrombosis." Boolean operators "AND," "OR," "NOT" were used where appropriate. We found 133 articles of interest but only 20 were selected, providing the most representative information. A novel disease (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (Sars-CoV-2) infection was responsible for thousands of hospitalizations for severe acute respiratory syndrome, with several cases of thrombotic complications due to excessive inflammation, platelet activation, endothelial dysfunction, and stasis. COVID-19 and hospitalizations for COVID-19 may carry several potential risk factors for thrombosis. Severe coagulation abnormalities may occur in almost all the severe and critical ill COVID-19 cases. Despite a strong pathophysiological rationale, the evidence in literature is not enough to recommend an aggressive antithrombotic therapy in COVID-19. However, it is our opinion that an early use, even at home at the beginning of the disease, could improve the clinical course.

Thrombosis risk factors in PIK3CA-related overgrowth spectrum and Proteus syndrome.

Increased risk of thromboembolism has been recognized in individuals with mosaic overgrowth disorders, Proteus syndrome (PS) and PIK3CA-related overgrowth spectrum (PROS), including Klippel-Trenaunay syndrome and CLOVES syndrome. PS and PROS have distinct, yet overlapping clinical findings and are caused by somatic pathogenic variants in the PI3K/AKT gene signaling pathway. PS is caused by a single somatic activating AKT1 c.49G > A p.E17K variant while PROS can be caused one of multiple variants in PIK3CA. The role of prothrombotic factors, endothelial cell adhesion molecules, and vascular malformations in both PS and PROS have not been previously investigated. A pilot study of prospective clinical and laboratory evaluations with the purposes of identifying potential risk factors for thrombosis was conducted. Doppler ultrasounds and magnetic resonance angiogram/ venography (MRA/MRV) scans identified vascular malformations in PS and PROS that were not appreciated on physical examination. Abnormal D-dimers (0.60-2.0 mcg/ml) occurred in half of individuals, many having vascular malformations, but no thromboses. Soluble vascular endothelial markers, including thrombomodulin, soluble vascular adhesion molecule (sVCAM), soluble intercellular adhesion molecule (sICAM), E-selectin, and P-selectin were significantly higher in PS and PROS compared to controls. However, no single attribute was identified that explained the risk of thrombosis. Predisposition to thrombosis is likely multifactorial with risk factors including chronic stasis within vascular malformations, stasis from impaired mobility (e.g., following surgery), decreased anticoagulant proteins, and effects of AKT1 and PIK3CA variants on vascular endothelium. Based on our findings, we propose clinical recommendations for surveillance of thrombosis in PS and PROS.

Study on the Patency of the Contralateral Iliac Vein After Stenting Across the Iliocaval Confluence With an Experimental In Vivo Model.

Stenting is the preferred treatment for iliac vein lesions. For the treatment of occlusions in the junction of the iliac vein and the inferior vena cava (IVC), the stent needs to be positioned in the IVC to cover the lesion. However, the pathological changes in the contralateral iliac vein due to stent coverage on its ostium remain unclear. We observed the patency of the contralateral iliac vein via animal experiments. The stents were placed in the left iliac vein and extended into the IVC in 8 beagle dogs. Doppler ultrasonography, angiography, and histopathological examination were used to assess the patency and histopathological changes in the contralateral iliac vein. Angiography showed patency of the contralateral iliac vein and no sign of thrombosis or stenosis. Twelve months after stenting, Doppler ultrasonography showed a stenotic change in the ostium of the contralateral iliac vein. The histopathological examination showed that the stent strut at the ostium of the contralateral iliac vein was mostly covered by the intima, and the cross-sectional stenosis rate was greater than 60%. The coverage of the iliac vein stent on the ostium of the contralateral iliac vein does not cause complete occlusion of the contralateral vein but can cause significant stenosis at the ostium of the contralateral iliac vein, which is considered to be a potential risk factor for thrombosis.

Characterization of thrombosis in patients with Proteus syndrome.

Patients with overgrowth and complex vascular malformation syndromes, including Proteus syndrome have an increased risk of thromboembolism. Proteus syndrome is a mosaic, progressive overgrowth disorder involving vasculature, skin, and skeleton, and caused by a somatic activating mutation in AKT1. We conducted a comprehensive review of the medical histories and hematologic evaluations of 57 patients with Proteus syndrome to identify potential risk factors for thrombosis. We found that six of ten patients, who were deceased, died secondary to deep venous thrombosis and/or pulmonary embolism. Of the remaining 47 living patients, six had thromboembolic events that all occurred postoperatively and in an affected limb. Eleven of 21 patients had an abnormal hypercoagulable panel including Factor V Leiden heterozygotes, antithrombin III deficiency, positive lupus anticoagulant, or Protein C or S deficiencies. We observed that eight of 17 patients had an abnormal D-dimer level >0.5 mcg/dl, but deep venous thromboses occurred in only four of those with D-dimer >1.0 mcg/dl. We conclude that the predisposition to thrombosis is likely to be multifaceted with risk factors including vascular malformations, immobility, surgery, additional prothrombotic factors, and possible pathophysiologic effects of the somatic AKT1 mutation on platelet function or the vascular endothelium. The D-dimer test is useful as a screen for thromboembolism, although the screening threshold may need to be adjusted for patients with this disorder. We propose developing a registry to collect D-dimer and outcome data to facilitate adjustment of the D-dimer threshold for Proteus syndrome and related disorders, including PIK3CA-Related Overgrowth Spectrum.

Thrombocytopenia as a thrombotic risk factor in patients with antiphospholipid antibodies without disease criteria

IntroductionThe antiphospholipid syndrome (APS) is an acquired immune disorder defined by the presence of thrombosis (arterial and/or venous) and/or pregnancy morbidity along with the presence of positive antiphospholipid antibodies (aPL). There is a clear relationship between aPL and some events not included in the clinical criteria, including haematologic. Objectives(a) to study the probability of developing clinical APS in patients with positive aPL and thrombopenia; (b) to identify potential risk factors for thrombosis, and (c) to study the association between thrombocytopenia and aPL. MethodsA retrospective study of 138 patients with positive aPL without fulfilling clinical criteria for APS. Thrombocytopenia was defined as a platelet count ≤100,000/μl. Patients with other causes of thrombocytopenia were excluded. ResultsSeventeen of the 138 (12%) patients in the study had thrombocytopenia. The mean platelet count was 60,000/μl. The risk of developing thrombocytopenia was higher in smokers (OR 2.8; p=0.044), in those with lupus anticoagulant (OR 13.5; p<0.001) and those with higher burden of aPL (OR 50.8; p<0.001). After a mean follow-up of 146±60.3 months, 5 patients with thrombocytopenia (29.4%) developed thrombosis. ConclusionsIn our series, the incidence of thrombocytopenia is 12%. aPL-positive patients who develop thrombocytopenia have a potential risk of developing thrombosis. Tobacco could be a risk factor for thrombocytopenia. Autoantibodies load is a risk factor for the development of thrombocytopenia.

Trombocitopenia como factor de riesgo trombótico en pacientes con anticuerpos antifosfolipídicos sin criterios de enfermedad

IntroductionThe antiphospholipid syndrome (APS) is an acquired immune disorder defined by the presence of thrombosis (arterial and/or venous) and/or pregnancy morbidity along with the presence of positive antiphospholipid antibodies (aPL). There is a clear relationship between aPL and some events not included in the clinical criteria, including haematologic. Objectivesa) to study the probability of developing clinical APS in patients with positive aPL and thrombopenia; b) to identify potential risk factors for thrombosis, and c) to study the association between thrombocytopenia and aPL. MethodsA retrospective study of 138 patients with positive aPL without fulfilling clinical criteria for APS. Thrombocytopenia was defined as a platelet count≤100,000/μl. Patients with other causes of thrombocytopenia were excluded. ResultsSeventeen of the 138 (12%) patients in the study had thrombocytopenia. The mean platelet count was 60,000/μl. The risk of developing thrombocytopenia was higher in smokers (OR 2.8; P=.044), in those with lupus anticoagulant (OR 13.5; P<.001) and those with higher burden of aPL (OR 50.8; P<.001). After a mean follow-up of 146±60.3 months, 5 patients with thrombocytopenia (29.4%) developed thrombosis. ConclusionsIn our series, the incidence of thrombocytopenia is 12%. aPL-positive patients who develop thrombocytopenia have a potential risk of developing thrombosis. Tobacco could be a risk factor for thrombocytopenia. Autoantibodies load is a risk factor for the development of thrombocytopenia.

Biomarkers and Clinical Prediction Rules in the Diagnosis of Suspected Deep Vein Thrombosis: A Comparison of Cancer and Non-Cancer Patients

Introduction: Despite efforts toward prevention, thousands of patients suffer from venous thromboembolic disease (VTE), consisting of deep vein thrombosis (DVT) and pulmonary embolism (PE), each year; this results in significant morbidity and mortality. Clinical prediction rules, such as the Wells score, in conjunction with biomarkers like the D-dimer, are suggested by national guidelines to aide in evaluating for DVT. Substantial interest exists in developing improved diagnostic testing strategies and algorithms to limit the need for more costly, time consuming, and/or invasive testing. Novel biomarkers, like the soluble P selectin (sP-Sel), a cell adhesion molecule that functions to mediate thrombus formation and amplification, have shown promise in this area.While cancer patients suffer from a high burden of VTE, the D-dimer and Wells score are less helpful in this group. This is due to non-specific D-dimer elevations in these patients, and cancer being part of the Wells risk stratification schema. We sought to identify a more specific combination of biomarkers and Wells score, for the diagnosis of DVT that would apply to cancer patients as well.Methods: We previously performed a prospective cohort study of adults presenting with symptoms of DVT afflicting the upper or lower extremities (Vandy et al. J Vasc Surg Venous Lymphat Disord., 2013). Patients were enrolled from December 2008 to July 2013. Those with isolated calf DVT, superficial venous thrombosis, pregnant or breastfeeding, on therapeutic anticoagulation, or with symptoms of simultaneous upper and lower DVT were excluded. After informed consent was obtained, clinical characteristics and biomarkers (D-dimer, C-reactive protein (CRP), Von Willebrand Factor activity (VWF), and sP-Sel) were collected, and duplex ultrasonography was performed to determine if DVT was present. In this subset analysis, cancer patients were compared to non-cancer patients with regards to thrombotic risk factors, biomarker values, and to assess the test characteristics of various combinations of biomarkers and Wells score.Results: A total of 373 patients were enrolled, 151 (40%) in the cancer group, compared to 222 (60%) in the non-cancer group. Cancer patients were more likely to have a DVT on confirmatory testing (58.9% vs. 43.2%). Cancer patients tended to be older, male, have a lower BMI, more recent acute illness, and more central lines, relative to the non-cancer group. Non-cancer patients were more likely to have other potential risk factors for thrombosis, i.e. recent surgery, oral contraceptive use, and a family history of thrombosis. Biomarker values for CRP and sP-Sel were similar, however VWF and D-dimer values were significantly higher in the cancer patients (see table).D-Dimer > 500 with Wells score ≥ 2 was less specific for the diagnosis of DVT among cancer patients compared to non-cancer patients (p=0.003). However, D-Dimer ≥ 500 with sP-Sel ≥ 90 showed not only high specificity, but that specificity was not different between the cancer and non-cancer populations (p=0.88). sP-Sel ≥ 90 and Wells ≥ 2 had similar performance characteristics in both groups as well (p=0.54 for specificity, p=0.14 for positive predictive value (PPV)).Conclusion: Co-morbid risk factors for thrombosis among cancer patients included an older age, male gender, and an increased use of central lines. This group was less likely to have other potential thrombotic risk factors like family history or recent surgery.Our results concur with the finding that the D-dimer, combined with a clinical prediction rule, is not as helpful for DVT in cancer patients. Moreover, this study further supports sP-Sel as a specific test for DVT, that can be combined with clinical information (Wells score) or other laboratory data (D-dimer) to reflect the presence of DVT and potentially rule in clot; the test seems equally useful for both cancer and non-cancer populations. This could potentially be used to guide initial patient management in scenarios where imaging or further testing is not immediately available, such as in an outpatient clinic or rural area. Further exploration of the optimal strategy for utilizing biomarkers and clinical prediction rules in the diagnosis of DVT in cancer is needed. [Display omitted] DisclosuresSood:Bayer: Research Funding.

Risk factors for central venous catheter-related thrombosis in children: a retrospective analysis.

Central venous catheter (CVC) placement is associated with increased risk of thrombosis in the paediatric population, particularly in relation to the type of catheter and the manner of its insertion. Here, we investigate risk factors associated with CVC-related thrombosis in children, with particular emphasis on positioning of the catheter tip. Patients aged 0-18 who underwent at least one CVC placement from 2008 to 2013 at a single centre with a subsequent follow-up echocardiogram were included for a total of 104 patients and 147 lines. Data on clinical and catheter-related risk factors were collected from patient charts. Statistical analysis using Pearson's χ tests, independent samples t-test, and odds ratios were used to assess potential risk factors for thrombosis. Neither insertion site (subclavian vein or otherwise), left- vs. right-sided insertion, nor catheter type were significant risk factors for thrombosis. There were no thrombotic events reported at the superior vena cava (SVC)-right atrium junction and no significant differences in thrombotic risk with initial tip placement in the SVC-right atrium junction vs. the SVC, right atrium, or inferior vena cava. Acute lymphoblastic leukaemia was a major clinical risk factor for thrombosis. Tip movement was common and may have been an important factor in the development of CVC-related thrombi. Prospective studies can yield insight into the role of follow-up imaging in the prevention of catheter-related thrombosis in children.

Pediatric Anti-Phospholipid Syndrome: Thromboses Outcomes, Mayo Clinic Children’s Center Experience

▪Background: Pediatric Anti-Phospholipid Syndrome (APS) is the most commonly acquired state of hypercoagulability in children, and is defined by venous and/or arterial thrombosis in the presence of circulating anti-phospholipid antibodies (aPLs) (most commonly lupus anticoagulant (LA), anticardiolipin antibody (aCL) and anti-β2-glycoprotein antibody (aβ2GP)). Catastrophic APS (CAPS) is a rare manifestation of APS, with thrombosis of multiple vessels that can lead to multi-system organ failure.Purpose: To determine the thromboses outcomes and factors predisposing to the risk of thrombotic recurrence in pediatric patients with a diagnosis of APS.Methods: Retrospective review of patients between the ages of 0-21 years diagnosed and treated with APS from 1997-2013 at our institution. Clinical data and long-term outcomes of these patients were reviewed. Exclusion criteria included neonatal APS and thrombosis with fetal loss. Statistical tests were performed using JMP software (© 2014 SAS Institute Inc., North Carolina, US). Associations between categorical variables were tested using chi-square test or Fisher’s exact test when required. Differences were considered statistically significant if p<0.05.Results: The study identified 23 patients (12 female; 11 male). Three patients with CAPS were identified and excluded from the analysis (3 female). Gender distribution for primary and secondary APS was similar (5 female/6 male primary APS; 4 female/5 male secondary APS). The median follow up period was 3.2 years (range; 0.01 – 16.87 years ). Median age at diagnosis of first episode of thrombosis was 16.16 years (range; 6.05 – 20.6 years). Nine patients (45%) with secondary APS had underlying autoimmune disease or malignancy (7 systemic lupus erythematosus, 1 ulcerative colitis, 1 Non-Hodgkin Lymphoma) and the remaining 11 patients were diagnosed as primary APS. Arterial and venous thrombosis occurred as the first thrombotic event in 7 (35%) and 13 (65%) patients, respectively. Lower extremity deep vein thrombosis (DVT) was the most frequent thrombotic event 11/20 (55%), followed by pulmonary embolism 7/20 (35%), ischemic stroke 4/20 (20%), lower extremity arterial thrombosis 3/20 (15%), upper extremity DVT 2/20 (10%), and IVC thrombosis 2/20 (10%).Recurrent or progressive thrombotic events occurred in 12/20 patients (60%). Of those, 7 were venous (58%), 5 were arterial (42%). At the time of recurrence, 3 patients were fully anticoagulated, (INR 2.5-3.5) versus 9 who were subtherapeutic (INR<2.0). Recurrent/progression thrombotic events occurred at the original site of thrombosis in 8 patients (3 arterial, 5 venous) while the remaining 4 recurrent thrombotic events occurred at other sites than the primary site. Overall venous and arterial thrombotic events were no different among primary or secondary APS (p=0.88). Thrombosis recurrence/progression risk at the original site or distant site was no different among primary or secondary APS (p=0.22 and p=0.30 respectively). Risk of recurrence/progression was not associated with subtherapeutic levels of anticoagulation (p=0.08), or presence of residual thrombosis at primary site at the time of recurrence (p=0.48).Conclusion: Recurrence and/or progression of thrombosis in APS occurred in 60% of the patients in our cohort, with 25% of the thrombosis recurrences occurring despite documented therapeutic anticoagulation in these patients. In contrast to other studies, our APS cohort demonstrated a higher rate of recurrence with other groups reporting thrombosis rates of recurrence such as 19-25%. Our cohort demonstrated similar rates of primary and secondary APS among female patients, in contrast to other studies suggesting higher rates of secondary APS in females. Potential risk factors such as primary versus secondary APS, subtherapeutic anticoagulation, and residual thrombosis from primary thrombotic event were not found as significant risk factors for thrombosis recurrence. Larger pediatric APS studies are needed in order to address other potential risk factors for thrombosis (ie obesity, inherited thrombophilia, intensity of anticoagulation, immune suppression approach for secondary APS), in order to establish treatment strategies for the prevention of recurrent thrombosis. DisclosuresNo relevant conflicts of interest to declare.

Biological variation in tPA-induced plasma clot lysis time

Hypofibrinolysis is a risk factor for venous and arterial thrombosis, and can be assessed by using a turbidimetric tPA-induced clot lysis time (CLT) assay. Biological variation in clot lysis time may affect the interpretation and usefulness of CLT as a risk factor for thrombosis. Sufficient information about assay variation and biological variation in CLT is not yet available. Thus, this study aimed to determine the analytical, within-subject and between-subject variation in CLT. We collected blood samples from 40 healthy individuals throughout a period of one year (average 11.8 visits) and determined the CLT of each plasma sample in duplicate. The mean (± SD) CLT was 83.8 (± 11.1) minutes. The coefficients of variation for total variation, analytical variation, within-subject variation and between-subject variation were 13.4%, 2.6%, 8.2% and 10.2%, respectively. One measurement can estimate the CLT that does not deviate more than 20% from its true value. The contribution of analytical variation to the within-subject variation was 5.0%, the index of individuality was 0.84 and the reference change value was 23.8%. The CLT was longer in the morning compared to the afternoon and was slightly longer in older individuals (> 40 years) compared to younger (≤40 years) individuals. There was no seasonal variation in CLT and no association with air pollution. CLT correlated weakly with fibrinogen, C-reactive protein, prothrombin time and thrombin generation. This study provides insight into the biological variation of CLT, which can be used in future studies testing CLT as a potential risk factor for thrombosis.

Quantification of the 5-Year Incidence of Thromboembolic Events in U.S. Air Force Academy Cadets in Comparison to the U.S. Naval and Military Academies

The medical literature is replete with case reports of thromboembolic events related to high altitude exposure. Studies have shown an increased risk of thromboembolic events at high and very high altitudes. Most of these case reports and studies have been documented at altitudes between 3,000 m and 8,000 m (9,843-26,247 ft). The U.S. Air Force Academy (USAFA) rests at moderate altitude of 7,250 ft (2,210 m). This study was designed to quantify the incidence of thromboembolic events in USAFA cadets over a 5-year period and then compare the incidence of events to those in the age-matched, similarly screened midshipmen and cadet populations of the U.S. Naval and U.S. Military Academies living at sea level. Our study showed an increased incidence of thromboemoblic events in USAFA cadet outpatients compared with that in the U.S. Military Academy cadets and U.S. Naval Academy midshipmen. This implicates moderate altitude as a potential risk factor for thrombosis.

Ornithine Transcarbamylase Deficiency: A Possible Risk Factor for Thrombosis

We describe four infants with ornithine transcarbamylase (OTC) deficiency, who developed arterial and venous thromboses prior to undergoing liver transplantation. These patients prompted a retrospective chart review of children with inborn errors of metabolism associated with hyperammonemia seen at our institution between 1998 and 2008; no additional cases with thrombosis were detected. Data abstracted from medical records include patient demographics, details about thrombus, treatment, associated risk factors and metabolic abnormalities. OTC deficiency was diagnosed during the first week of life in all patients (median age – 4 days; age range 1–7 days). Thrombotic complications developed prior to liver transplant in all patients (median age - 63 days; age range 6–71 days). One patient had arterial thrombus; the rest developed venous thromboses. Possible risk factors for thrombosis are summarized in the table below.Risk factorsPatient 1Patient 2Patient 3Patient 4Indwelling catheter at the site of thrombusYesYesYesYesHyperammonemia (>94 mmol/L)YesNoYesYesLow plasma arginine (<42 mmol/L)YesYesYesYesHypercoagulable risk factorsNoneElevated factor 8, fibrinogenElevated fibrinogen, low AT III*DysfibrinogenemiaInfection (positive blood culture)NoneC albicansCoag neg StaphNoneTable 1. Patient characteristics that are potential risk factors for thrombosis * AT III - Anti-thrombin IIIMultiple pro-thrombotic risk factors were present. Hyperammonemia was seen in 3 patients and low plasma arginine level was present in all patients around the time of thrombosis. As L-arginine is a substrate for nitric oxide synthesis, arginine deficiency leads to low nitric oxide levels. Recent studies have linked nitric oxide insufficiency to platelet hyperaggregability, thrombosis and endothelial damage. Infants with OTC deficiency, indwelling vascular catheters, hyperammonemia and low plasma arginine may be at increased risk for thrombosis. Further studies in patients with OTC deficiency, to evaluate the role of hyperammonemia and low plasma arginine in thrombogenesis are warranted.

Thrombosis in Myeloproliferative Disorders: Prevalence, Prognostic Factors, and the Role of Leukocytes and JAK2V617F

An underlying myeloproliferative disorder (MPD), especially polycythemia vera (PV) or essential thrombocythemia (ET), is a risk factor for thrombosis. Considering large selected studies, prevalence rates for major thrombosis, at time of diagnosis, range from approximately 34 to 39% for PV and 10 to 29% for ET; the corresponding figures for thrombosis at follow-up are approximately 8 to 19% for PV and 8 to 31% for ET. In all instances, arterial events were more frequent than venous events. In both PV and ET, advanced age and history of thrombosis are independent predictors of recurrent thrombosis. In addition, leukocytosis, but not thrombocytosis, has been identified as a potential risk factor for thrombosis in both diseases. The particular observation is consistent with the laboratory demonstration, in these disorders, of increased number of activated granulocytes and granulocyte-platelet aggregates, upregulation of platelet P-selectin and tissue factor expression by granulocytes, and the antithrombotic value of hydroxyurea therapy. Most recently, a JAK2 gain-of-function mutation ( JAK2V617F) was described in virtually all patients with PV and approximately 50% of those with ET. Whether the presence of this specific mutation or its allele burden modifies the risk of thrombosis in patients with MPDs currently is under investigation.

Thrombocytosis and Thrombosis

The aim of this review is to discuss current diagnostic approaches to, and classification of, patients presenting with thrombocytosis, in light of novel information derived from the discovery of specific molecular abnormalities in chronic myeloproliferative disorders (CMPD), which represent the most common cause of primary thrombocytosis. The JAK2V617F and the MPLW515L/K mutations have been found in patients with essential thrombocythemia, polycythemia vera, and primary myelofibrosis, and less frequently in other myeloproliferative disorders complicated by thrombocytosis. However, neither mutation is disease specific nor is it universally present in patients with elevated platelet counts due to a CMPD; therefore, distinguishing between reactive and primary forms of thrombocytosis, as well as among the different clinical entities that constitute the CMPD, still requires a multifaceted diagnostic approach that includes as a key step the accurate evaluation of bone marrow histology. The role of elevated platelet counts in thrombosis, which represent the predominant complication of CMPD,significantly affecting prognosis and quality of life as well as, paradoxically, in the pathogenesis of the hemorrhagic manifestations, will be discussed. Established and novel potential risk factors for thrombosis, including the clinical relevance of the JAK2V617F mutation, and current management strategies for thrombocytosis are also briefly discussed.

Internal jugular vein thrombosis associated with hemodialysis catheters.

To determine the prevalence of internal jugular vein thrombosis among patients undergoing hemodialysis in whom tunneled dialysis catheters were placed by interventional radiologists and to evaluate potential risk factors for thrombosis, such as the number of catheters inserted per patient through the right internal jugular vein, catheter type and material, total catheter days, and catheter-associated infection. Ultrasonographic (US) evaluation of the right internal jugular vein was performed by interventional radiologists in 143 patients with a history of dialysis catheter placement. The examination focused on the detection of right internal jugular vein thrombosis, with or without occlusion. Total catheter days, catheter type, and catheter-related complications, most notably infection, were evaluated with database analysis for possible association with subsequent development of thrombosis. Statistical analysis of potential risk factors was performed with logistic regression models and chi2 tests. Evidence of right internal jugular vein thrombosis was present in 25.9% of the patients enrolled in the study. Among the veins with thrombosis, 62% were occluded. Only the mean number of catheters placed in the right internal jugular vein per patient was significant below the level of P =.20; therefore, a multivariate logistic regression model was not used. Prevalence of internal jugular thrombosis, both complete and incomplete, was higher in the study population than previously reported. The risk factors that were analyzed demonstrated no statistically significant association with development of thrombosis.