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Main causes of venous thrombosis
Source publication
The key to understanding why certain individuals develop deep vein thrombosis at varying times, despite similar risk factors being present, is the realization of the importance of gene-gene and gene-environment interactions between risk factors. The discovery of factor V Leiden and several other coagulation abnormalities, which are now known to be...
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In haemostasis and thrombosis, platelet, coagulation and anticoagulation pathways act together to produce fibrin-containing thrombi. We developed a microspot-based technique, in which we assessed platelet adhesion, platelet activation, thrombus structure and fibrin clot formation in real time using flowing whole blood. Microspots were made from dis...
Citations
... The efficacy of bLf was also tested in pregnant and non-pregnant women suffering from hereditary thrombophilia (HT) and affected by AI Lepanto et al. 2018). HT is an inherited genetic condition, involving aberrant coagulation processes, predisposing the subjects to venous thrombus formation (Rosendaal 1999;Khan and Dickerman 2006). In pregnancy, this status is exacerbated by the increased activity of several coagulation factors, such as factor VII, VIII, X and the von Willebrand factor, as well as higher levels of fibrinogen (Szecsi et al. 2010) and thrombin generation markers, such as prothrombin F1 and F2 (Simcox et al. 2015). ...
Iron is by far the most widespread and essential transition metal, possessing crucial biological functions for living systems. Despite chemical advantages, iron biology has forced organisms to face with some issues: ferric iron insolubility and ferrous-driven formation of toxic radicals. For these reasons, acquisition and transport of iron constitutes a formidable challenge for cells and organisms, which need to maintain adequate iron concentrations within a narrow range, allowing biological processes without triggering toxic effects. Higher organisms have evolved extracellular carrier proteins to acquire, transport and manage iron. In recent years, a renewed interest in iron biology has highlighted the role of iron-proteins dysregulation in the onset and/or exacerbation of different pathological conditions. However, to date, no resolutive therapy for iron disorders has been found. In this review, we outline the efficacy of Lactoferrin, a member of the transferrin family mainly secreted by exocrine glands and neutrophils, as a new emerging orchestrator of iron metabolism and homeostasis, able to counteract iron disorders associated to different pathologies, including iron deficiency and anemia of inflammation in blood, Parkinson and Alzheimer diseases in the brain and cystic fibrosis in the lung.
... In our subsequent clinical trials, we have treated pregnant and non-pregnant women suffering from hereditary thrombophilia (HT) and affected by AI [23,82]. HT is an inherited genetic condition, involving aberrant coagulation processes, predisposing the subjects to venous thrombus formation [84,85]. In pregnancy, this status is exacerbated by the increased activity of several coagulation factors, such as VII, VIII, X and the von Willebrand factor, as well as higher levels of fibrinogen [86] and thrombin generation markers, such as prothrombin F1 and F2 [87]. ...
Lactoferrin (Lf), a cationic glycoprotein able to chelate two ferric irons per molecule, is synthesized by exocrine glands and neutrophils. Since the first anti-microbial function attributed to Lf, several activities have been discovered, including the relevant anti-inflammatory one, especially associated to the down-regulation of pro-inflammatory cytokines, as IL-6. As high levels of IL-6 are involved in iron homeostasis disorders, Lf is emerging as a potent regulator of iron and inflammatory homeostasis. Here, the role of Lf against aseptic and septic inflammation has been reviewed. In particular, in the context of aseptic inflammation, as anemia of inflammation, preterm delivery, Alzheimer’s disease and type 2 diabetes, Lf administration reduces local and/or systemic inflammation. Moreover, Lf oral administration, by decreasing serum IL-6, reverts iron homeostasis disorders. Regarding septic inflammation occurring in Chlamydia trachomatis infection, cystic fibrosis and inflammatory bowel disease, Lf, besides the anti-inflammatory activity, exerts a significant activity against bacterial adhesion, invasion and colonization. Lastly, a critical analysis of literature in vitro data reporting contradictory results on the Lf role in inflammatory processes, ranging from pro- to anti-inflammatory activity, highlighted that they depend on cell models, cell metabolic status, stimulatory or infecting agents as well as on Lf iron saturation degree, integrity and purity.
... Previous research suggests that VTE risk is greatest when genetic predisposition is combined with an environmental risk factor. 48,58,[122][123][124] Understanding how genes and environmental risk factors interact may provide key insight into the pathophysiology of VTE and may identify opportunities for targeted prevention and treatment. [125][126][127] However, few interactions have been explored in prospective cohort studies, with work focusing mostly on short-term environmental risk factors such as trauma or surgery. ...
Venous thromboembolism (VTE) includes deep vein thrombosis and pulmonary embolism, and a combination of environmental and genetic risk factors contributes to VTE risk. Within environmental risk factors, some are provoking (e.g., cancer, surgery, trauma or fracture, immobilization, pregnancy and the postpartum period, long-distance travel, hospitalization, catheterization, and acute infection) and others are nonprovoking (e.g., age, sex, race/ethnicity, body mass index and obesity, oral contraceptive or hormone therapy use, corticosteroid use, statin use, diet, physical activity, sedentary time, and air pollution). Additionally, VTE has a strong genetic basis, with approximately 50 to 60% of the variance in VTE incidence attributed to genetic effects. Some genetic susceptibility variants that contribute to risk have been identified in candidate genes, mostly related to the clotting system and responsible for inherited hypercoagulable states (e.g., factor V Leiden, prothrombin, fibrinogen gamma, or blood group non-O). Other susceptibility single-nucleotide polymorphisms have been identified from genome-wide association studies, such as the two new loci in TSPAN15 (rs78707713) and SCL44A2 (rs2288904) genes. Risk factors are not always associated with VTE in isolation; however, and an understanding of how environmental and genetic factors interact may provide insight into the pathophysiology of VTE, possibly identifying opportunities for targeted prevention and treatment.
... Venous thrombosis (VT) is a common and potentially lethal disorder with an estimated incidence of one to three per 1,000 individuals per year123. The occurrence of venous thrombotic events is influenced by acquired and inherited risk factors (e.g., oral contraception and Factor V Leiden) [4,5]. Combinations of these risk factors further increase the risk to potentially high levels [6]. ...
In case-control studies, elevated levels of interleukins 6 and 8 have been found to be associated with an increased risk of venous thrombosis (VT). Because of the design of these studies, it remained uncertain whether these alterations were a cause or a result of the VT. In order to distinguish between the two, we set out to measure the levels of six inflammatory markers prior to thrombosis in a population-based cohort using a nested case-cohort design.
Between August 1995 and June 1997, blood was collected from 66,140 people in the second Norwegian Health Study of Nord-Trøndelag (HUNT2). We identified venous thrombotic events occurring between entry and 1 January 2002. By this date we had registered 506 cases with a first VT; an age- and sex-stratified random sample of 1,464 controls without previous VT was drawn from the original cohort. Levels of interleukins 1beta, 6, 8, 10, 12p70, and tumour necrosis factor-alpha were measured in the baseline sample that was taken 2 d to 75 mo before the event (median 33 mo). Cut-off points for levels were the 80th, 90th, and 95th percentile in the control group. With odds ratios ranging from 0.9 (95% CI: 0.6-1.5) to 1.1 (95% CI: 0.7-1.8), we did not find evidence for a relationship between VT and an altered inflammatory profile.
The results from this population sample show that an altered inflammatory profile is more likely to be a result rather than a cause of VT, although short-term effects of transiently elevated levels cannot be ruled out.
Venous thromboembolism (VTE) is a massive clinical challenge, annually affecting millions of patients globally. VTE is a particularly consequential pathology, as incidence is correlated with extremely common risk factors, and a large cohort of patients experience recurrent VTE after initial intervention. Altered hemodynamics, hypercoagulability, and damaged vascular tissue cause deep-vein thrombosis and pulmonary embolism, the two permutations of VTE. Venous valves have been identified as likely locations for initial blood clot formation, but the exact pathway by which thrombosis occurs in this environment is not entirely clear. Several risk factors are known to increase the likelihood of VTE, particularly those that increase inflammation and coagulability, increase venous resistance, and damage the endothelial lining. While these risk factors are useful as predictive tools, VTE diagnosis prior to presentation of outward symptoms is difficult, chiefly due to challenges in successfully imaging deep-vein thrombi. Clinically, VTE can be managed by anticoagulants or mechanical intervention. Recently, direct oral anticoagulants and catheter-directed thrombolysis have emerged as leading tools in resolution of venous thrombosis. While a satisfactory VTE model has yet to be developed, recent strides have been made in advancing in silico models of venous hemodynamics, hemorheology, fluid–structure interaction, and clot growth. These models are often guided by imaging-informed boundary conditions or inspired by benchtop animal models. These gaps in knowledge are critical targets to address necessary improvements in prediction and diagnosis, clinical management, and VTE experimental and computational models.
Antithrombotic agents are commonly encountered among the elderly spine surgery patient population. Therefore, management of these medications is a key consideration for spine surgeons when preparing for surgery. Continuing antithrombotic therapy through the perioperative period increases the risk of perioperative bleeding. At the same time, stopping antithrombotic therapy prior to surgery increases the risk of perioperative thrombotic risk. This chapter reviews suggested guidelines for perioperative antithrombotic management for elective spine procedures, antithrombotic management for emergent procedures, and special considerations for antithrombotic management in the elderly.
Introduction
Of the inherited thrombophilias, the Factor V Leiden (FVL) and the prothrombin mutant (FII G20210A) are associated with increased risk of venous thromboembolism (VTE). The C677T mutation of the methylenetetrahydrofolate reductase gene, which may lead to hyperhomocysteinemia, is also considered a risk factor for VTE in some studies. However, the frequency of these genetic risk factors may vary significantly among different populations.
Material and methods
The FVL, FII G20210A and C677T mutations were investigated by PCR-RFLP in 275 young VTE Brazilian patients as well as in 324 biologically unrelated individuals selected to compose the control group.
Results
The C677T mutation in the MTHFR gene was detected in 135 (49.1%) patients, of which 117 (42.5%) were identified as heterozygous and 18 (6.5%) as homozygous. The G20210A mutation was detected in 14 (5.1%) patients in heterozygosis. In both cases, no significant difference was observed when these results were compared to the frequencies observed in the control group. FVL was detected in heterozygosis in 19 (6.9%) patients, corresponding to a significantly increased frequency when compared to that observed for the control group (1.2%) (OR 5.9; 95% CI 2.08–16.79; p < 0.001).
Conclusions
The data indicated that FVL is significantly associated with VTE among young Brazilian patients, but also supported previous evidence that VTE is a multi-factorial disease, resulting from the interaction of genetic and acquired risk factors.
Introduction:
Venous thromboembolism (VTE) is highly heritable. Physical activity, physical inactivity and body mass index (BMI) are also risk factors, but evidence of interaction between genetic and environmental risk factors is limited.
Methods:
Data on 2,134 VTE cases and 3,890 matched controls were obtained from the Nurses' Health Study (NHS), Nurses' Health Study II (NHS II), and Health Professionals Follow-up Study (HPFS). We calculated a weighted genetic risk score (wGRS) using 16 single nucleotide polymorphisms associated with VTE risk in published genome-wide association studies (GWAS). Data on three risk factors, physical activity (metabolic equivalent [MET] hours per week), physical inactivity (sitting hours per week) and BMI, were obtained from biennial questionnaires. VTE cases were incident since cohort inception; controls were matched to cases on age, cohort, and genotype array. Using conditional logistic regression, we assessed joint effects and interaction effects on both additive and multiplicative scales. We also ran models using continuous wGRS stratified by risk-factor categories.
Results:
We observed a supra-additive interaction between wGRS and BMI. Having both high wGRS and high BMI was associated with a 3.4-fold greater risk of VTE (relative excess risk due to interaction = 0.69, p = 0.046). However, we did not find evidence for a multiplicative interaction with BMI. No interactions were observed for physical activity or inactivity.
Conclusion:
We found a synergetic effect between a genetic risk score and high BMI on the risk of VTE. Intervention efforts lowering BMI to decrease VTE risk may have particularly large beneficial effects among individuals with high genetic risk.
A 26-year-old female who had an 8-year history of BD was hospitalized due to manic episode. Because of the ischemic lesions on the cranial resonance imaging and pyramidal tractus signs in the neurological examination, a comprehensive etiologic diagnostic work-up including consultation of the patient by the Rheumatology Department for the differential diagnosis of vasculitis was suggested by the consultant neurologist. Abnormal findings were heterozygotic fVL and MTHFR mutations and decreased Protein S level. Because of positive test results for thrombophilia factors, the Hematology Department consulted the patient and put her on acetylsalicylic acid 100 mg/day treatment. To our knowledge, this is a singular report of a case which suggests an association between thrombophilia, stroke, and BD. But answers to questions "Is BD caused by silent stroke?" and "Does silent stroke complicate the clinical picture of this patient?" in this case are not straightforward and confusing. It should be kept in mind that human being is a biopsychosocial entity. The patients should be evaluated globally not to stick on their signs only. This will result in the exact diagnosis of the patients providing them with accurate treatment that improves their quality of life.
Zusammenfassung
Ziel: Überblick über Pathogenese, Prophylaxe und Therapie thromboembolischer Komplikationen.
Methode: Literaturrecherche in Pubmed.
Ergebnisse und Diskussion: In der Schwangerschaft verändert sich die plasmatische Gerinnung zugunsten der prokoagulatorischen Eigenschaften des Blutes, um dem Blutverlust bei der Geburt entgegenzuwirken. Venöse Thromboembolien (VTE) gehören in der westlichen Welt weiterhin zu den führenden Ursachen für schwerwiegende mütterliche Morbidität und Sterblichkeit. Das Risiko, eine venöse Thromboembolie zu erleiden, steigt in der Schwangerschaft um das 4-5-fache und in der Postpartum-Periode sogar um das 20-fache. Insbesondere bei Patientinnen mit einer erworbenen oder hereditären Thrombophilie kann es zu vaskulär bedingten Schwangerschaftskomplikationen kommen. Hierzu zählen die tiefe Beinvenenthrombose, die Lungenembolie, aber auch rezidivierende Aborte bei AntiphospholipidSyndrom. Empfehlungen im Hinblick auf die Notwendigkeit einer prophylaktischen Gabe von niedermolekularem Heparin werden bei den verschiedenen Thrombophilien individuell getroffen. Sie sind abhängig von der Art der Thrombophilie, der Eigen- und Familienanamnese hinsichtlich tiefer Beinvenenthrombosen, Lungenembolien oder rezidivierender Aborte sowie dem Verlauf der Schwangerschaft. Eine generelle Empfehlung für eine prophylaktische Heparinisierung bei laborchemisch nachgewiesener Thrombophilie gibt es nicht.
Als antikoagulatorische Therapie der Wahl bei thromboembolischen Komplikationen in der Schwangerschaft gelten die niedermolekularen Heparine, da sie nebenwirkungsarm und nicht teratogen sind. Die Therapie der akuten VTE sollte in der Regel bis 6 Wochen post part-um bei einer Gesamtdauer von mindestens 3 Monaten durchgeführt werden. Liegt ein Anti-phospholipid-Syndrom vor, wird zusätzlich Acetylsalicylsäure (75–100 mg/Tag) empfohlen. Da ein Großteil der tiefen Beinvenenthrombosen in der Schwangerschaft proximal auftreten, ist das Risiko eines postthrombotischen Syndroms hoch. Zur Minimierung von Früh- und Spätkomplikationen bei Thromboembolien in der Schwangerschaft ist eine frühzeitige Diagnostik sowie eine risikoadaptierte Prophylaxe entscheidend.
