Best Practices in Thrombophilia Testing.

Venous Thromboembolism in Pediatric Cystic Fibrosis

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

Thrombophilia Testing in Hospitalized Patients with Acute Ischemic Stroke: An Opportunity for Hematology Input

Trevor Baglin, Elaine Gray, Mike Greaves, Beverley J. Hunt, David Keeling, Sam Machin, Ian Mackie, Mike Makris, Tim Nokes, David Perry, R. C. Tait, Isobel Walker and Henry Watson Addenbrooke’s Hospital, Cambridge, NIBSC, South Mimms, University of Aberdeen, Aberdeen, Guy’s and St Thomas’, London, Churchill Hospital, Oxford, University College Hospital, London, Royal Hallamshire Hospital, Sheffield, Derriford Hospital, Plymouth, Glasgow Royal Infirmary, Glasgow and Aberdeen Royal Infirmary, UK

Background Diagnosing agents causing respiratory infections remains a global challenge due to the numerous coexisting agents and similar symptoms. This study evaluates the epidemiology of viral and bacterial agents responsible for major respiratory infections through molecular detection in patients across various Brazilian hospital units served by a clinical diagnostic and health laboratory. Understanding the distribution and prevalence of these pathogens is crucial for effective diagnosis, treatment, and prevention strategies in the face of evolving epidemiological landscapes. Methods Utilizing an internal database, we conducted a comprehensive analysis of tests performed on the FilmArray® system. This system employs multiplex PCR technology, capable of simultaneously identifying 21 respiratory agents in a single sample obtained from nasopharyngeal and bronchial lavage specimens collected from diverse geographical regions across Brazil. The data for the examination of patient samples with respect to gender, age group, geographical regions, and the prevalence of various agents between January 2021 and April 2023 were retrieved from the database and analyzed. To ensure privacy, sensitive and individual data from all patients were meticulously preserved throughout the study. Results The analysis encompassed a diverse sample of 477 patients, originating from 26 cities across 11 Brazilian states, including Goiás, Minas Gerais, Mato Grosso, Pará, Paraná, Rio de Janeiro, São Paulo, Tocantins, Amazonas, Bahia, and Distrito Federal. The distribution of patients was nearly split between hospital settings (39.8%) and outpatient units, with hospital patients predominantly from departments such as internal medicine, cardiology, and nephrology. In contrast, outpatient samples were primarily requested by specialists in pulmonology and infectious diseases. The demographic profile revealed an average age of 36 years, with a majority male representation (54%). However, a notable shift occurred in the first four months of 2023, where females constituted 60.8% of the sample. The overall test positivity rate stood at 42.3%, with a significant detection of 71% (15 out of 21) of the surveyed respiratory agents at some point during the study period. The most frequently identified pathogens were Rhinovirus, Enterovirus, and SARS-CoV-2, collectively accounting for 55.1% of the positive findings. Additionally, mixed infections were observed in 29 (6%) of the patients, with combinations such as SARS-CoV-2 and Rhinovirus, SARS-CoV-2 and H3N2, and SARS-CoV-2 and RSV, among others, highlighting the complexity of respiratory infections. Conclusions The findings from this study underscore the critical role of advanced molecular diagnostics in the Brazilian clinical-laboratory landscape. The utilization of multiplex PCR technology has proven to be a pivotal tool in accurately identifying a wide array of respiratory pathogens, thereby enhancing the precision of diagnosis and treatment strategies. The detection of a high prevalence of agents such as Rhinovirus, Enterovirus, and SARS-CoV-2, along with the identification of mixed infections, highlights the complexity of respiratory infections and the necessity for robust diagnostic tools. This study not only contributes to the understanding of the epidemiology of respiratory infections in Brazil but also emphasizes the importance of continuous advancements in molecular diagnostics for better patient care and public health management.

Thrombophilia Testing Practices: The Mayo Clinic Experience

This guideline was compiled according to the BSH process at [https://b-s-h.org.uk/media/16732/bsh-guidance-development-process-dec-5-18.pdf]. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org. A literature search was carried out using the terms given in Appendix S1 until April 2021. Review of the manuscript was performed by the BSH Haemostasis and Thrombosis Task Force, the BSH Guidelines Committee and the sounding board of BSH. It was also placed on the members section of the BSH website for comment. It has also been reviewed by Royal College of Obstetricians and Gynaecologists, Royal College of Paediatrics and Child Health, Royal College of Physicians and Thrombosis UK, a patient-centred charity dedicated to promoting awareness, research and care of thrombosis; these organisations do not necessarily approve or endorse the contents. This guideline updates and widens the scope of the previous British Society for Haematology (BSH) Clinical guidelines for testing for heritable thrombophilia1 to include both heritable and acquired thrombophilia. The term thrombophilia is generally used to describe hereditary and/or acquired conditions associated with an increased predisposition to thrombosis. Heritable thrombophilia refers to genetic disorders of specific haemostatic proteins. These guidelines focus only on the factors that are identified from laboratory testing and therefore exclude disorders such as cancer, inflammatory conditions and obesity that are associated with thrombosis through multiple mechanisms. The most clearly defined heritable thrombophilias are the factor V Leiden (FVL) variant (F5 G1691A), the prothrombin gene variant (F2 G20210A), protein C (PC) deficiency, protein S (PS) deficiency, and antithrombin (AT) deficiency.2 Important acquired thrombophilias include the antiphospholipid syndrome (APS), paroxysmal nocturnal haemoglobinuria (PNH), myeloproliferative neoplasms (MPN) and the presence of a JAK2 mutation in the absence of an MPN phenotype. Pregnancy is a hypercoagulable state due partly to physiological changes in both the coagulation and fibrinolytic systems. Heritable and acquired thrombophilias can interact to further increase the risk of thrombosis, for example during pregnancy and the puerperium. As there is evidence that some thrombophilias may be associated with pregnancy failure and complications, testing for this purpose is included. Elevated levels of procoagulant factors may increase the risk of thrombosis but the relationship is not straightforward. First, part of the variance is genetic, and therefore lifelong, but some is acquired so that comorbidities such as obesity or inflammation confound the estimate of effect. Second, some factors, most notably factor V (FV), have anticoagulant effects that counterbalance a procoagulant effect from their elevation. A meta-analysis of 12 genome-wide association studies (GWAS) for venous thromboembolism (VTE) identified variants in F2, F5, F11, and FGG (encoding fibrinogen gamma chain) linked to thrombosis as well as non-O alleles of ABO which mediate their effect via elevation of von Willebrand factor (VWF) and secondarily factor VIII (FVIII).3 This approach does not detect rare variants with functional effects increasing thrombotic risk as reported in factor IX (F9), factor II (F2) and fibrinogen-alpha (FGA), fibrinogen-beta (FGB), and FGG.4-6 However, the relevance of these genetic variants to routine clinical practice is not clear at present. A phenotypic analysis was carried out as part of the Multiple Environmental and Genetic Assessment (MEGA) case–control study of VTE. After adjustment for age and sex, levels of factors II, X, IX, XI, VIII and fibrinogen all showed a positive association with risk of thrombosis. After additional correction for FVIII levels, only FIX and FXI retained significance with odds ratios (ORs) for levels >95th centile of 1.8 (95% confidence interval [CI]: 1.1–2.9) and 1.8 (1.1–3.0), respectively. In contrast, the OR for FVIII>95th centile was 16.0 (9.7–26.3) after correction for age, sex, and all the other coagulation factors.7 However, because of interacting heritable and acquired influences on FVIII activity, variability in levels over time, and as yet, lack of evidence of a role in the management of individuals with thrombosis or asymptomatic family members, routine testing for FVIII is not currently recommended. Despite results from animal studies, there remains no genetic or phenotypic8-10 evidence that variation in FXII is associated with thrombosis in humans.11 FXIII has a complex relationship with thrombosis due to interactions with other factors and the effects of genetic variants on FXIII activity assays. Genetic studies showed that the Val24Leu variant was associated with a reduced risk of venous thrombosis (OR: 0.85; 95% CI: 0.77–0.95).12, 13 The associations of PC, PS and AT deficiencies with increased risks of VTE are well-established.14 The degree of deficiency is variable and sensitive to assay type but in general thrombosis risk rises as soon the levels of protein C, S or AT fall below the normal range. In contrast, although tissue factor pathway inhibitor (TFPI), heparin cofactor II, and protein Z-dependent protease inhibitor (ZPI) and its cofactor, protein Z, are also natural anticoagulants, the clinical significance of genotypic or phenotypic variation in these is uncertain and testing for clinical purposes is not recommended. Guidelines on laboratory aspects of testing for deficiencies of natural anticoagulants have recently been published by the British Society for Haematology15 and the International Society on Thrombosis and Haemostasis.16-18 The risk of a first episode of VTE is increased around 15-fold in heterozygous AT deficiency.19 Overall, the risks are similar in those with type I and type II defects with the exception of most type II heparin binding defects, which appear to have a 4-fold lower risk.19 In contrast, homozygous heparin binding site defects appear to be associated with a high thrombotic risk.20 Further differences within antithrombin subtypes have also been observed.21 However, data on differences in risk between and within different subtypes are limited, and findings vary according to study design, the population being studied (family or non-family members), and whether all or only unprovoked venous thrombotic events were included in the analysis. In those with heterozygous PC or PS deficiency, the risk of a first episode of VTE is increased around 5–7-fold.19, 22, 23 There are no clinically useful differences in thrombotic risk between type I and type II PC deficiency15 and no clear evidence of a difference in risk between different subtypes of PS deficiency. These risks for heterozygous PC and PS deficiency are similar to or greater than those associated with FVL variant or F2 G20210A variant, but deficiencies of the natural anticoagulants are much less common (population prevalence of <0.5% for each deficiency), at least in those of European origin, and contribute relatively little to the population burden of VTE. Deficiencies of physiological anticoagulants interact with acquired risks and a transient provoking factor is present in approximately 50% of episodes of VTE in genetically predisposed individuals.24, 25 Since deficiencies of these natural anticoagulants are caused by multiple different genetic variants, clinical laboratory assessment is generally based on measurement of plasma activities or concentrations rather than molecular analysis.15 Acquired causes of deficiencies (Table 1) should always be considered before testing and when interpreting results as, if present, it may not be possible to reliably diagnose a heritable deficiency. Acquired problems include warfarin and the potential assay-dependent impact of direct oral anticoagulants (DOACs).15 When the decision has been made to test for deficiencies of physiological anticoagulants, this should be performed only after 3 months of anticoagulation for acute thrombosis, as there is uncertainty over the validity of the results obtained earlier, leading to repeat testing and increased costs, and with there being no evidence that it influences acute management. Protein C activity Chromogenic assay Protein S Free protein S antigen Antithrombin activity Chromogenic assay Physiological reduction Neonates and children (different normal range from adults) Other causes of reduction Vitamin K antagonists (e.g., warfarin) Vitamin K deficiency Liver disease Disseminated intravascular coagulation Severe sepsis Artefactual increase DOACs or heparin if using clotting-based assay Artefactual decrease Factor V Leiden if using clotting-based assay Physiological reduction Neonates (Different normal range from adults) Pregnancy and puerperium Other causes of reduction Vitamin K antagonists (e.g., warfarin) Vitamin K deficiency Liver disease Nephrotic syndrome Disseminated intravascular coagulation Severe sepsis Recent thrombosis Oral oestrogen therapy (e.g., combined oral contraceptive pill or hormone therapy) Acute phase response Sickle cell disease Artefactual increase DOACs or heparin if using clotting-based assay. Artefactual decrease Factor V Leiden if using clotting-based assay Physiological reduction Neonates (Different normal range from adults) Late pregnancy, early postpartuma a James et al. 2014.176 Other causes of reduction Liver disease Disseminated intravascular coagulation Nephrotic syndrome Severe sepsis Recent thrombosis Heparin therapy L-asparaginase therapy Artefactual increase DOACs: Xa inhibitors – if using Xa-based assay Thrombin inhibitors – if using thrombin-based assay The FVL and F2 G20210A variants are the most commonly tested genetic variants predisposing to VTE.29 These are detected using polymerase chain reaction (PCR)-based methods. Their prevalence varies in populations of different ethnicity. For example, heterozygosity for FVL is present in about 5% of individuals of European descent but is rare or absent in peoples from sub-Saharan Africa, East Asia and indigenous populations of the Americas and Australia. Similarly, heterozygosity for the prothrombin gene variant is present in 1%–2% of Europeans and is rare or absent in other ethnic populations.30 The FVL variant abolishes a cleavage site for activated PC in factor V increasing procoagulant activity. The prothrombin gene variant is a point mutation (G20210A) in the 3′ untranslated region of the gene31 causing increased levels of prothrombin.32 These variants result in increased relative risks for first venous thrombosis of 5- and 3-fold, respectively.33 A large number of variants in other genes with a wide range of prevalences have been reported to confer an increased risk of thrombosis. These include variants of methylenetetrahydrofolate reductase (MTHFR), SERPINE1 (encoding plasminogen activator inhibitor type 1) (PAI-1) and factor XIII as well as variants linked to the quantitative changes in procoagulant factors discussed above.28 However, either their association with thrombosis is not convincingly consistent or their effect is too small to alter management and they should not be included in thrombophilia panels at present. Although it has been shown that multiple variants present in an individual can combine to identify a significant risk of recurrence,34 this requires validation and we do not yet know how and when to introduce this oligogenic model into practice. Paroxysmal nocturnal haemoglobinuria (PNH) and myeloproliferative neoplasms (MPN) are acquired genetic traits that increase the risk of thrombosis. PNH is an acquired clonal stem cell disorder characterised by the expansion of a population of blood cells deficient in glycosylphosphatidylinositol anchored proteins (GPI-AP) due to PIGA gene mutation resulting in a deficiency or absence of all GPI-anchored proteins including CD55 and CD59 on the cell surface. Absence of CD59 leads to chronic complement activation resulting in the classical clinical features of intravascular haemolysis and thrombosis.35 Up to 10% of patients with PNH will present with thrombosis. The neutrophil clone size correlates best with thrombosis risk and patients with a clone of over 50% have a cumulative 10-year incidence of thrombosis of 34.5% compared to 5.3% in those with a clone of <50%. MPNs are characterised by clonal expansion of an abnormal haematopoietic stem/progenitor cell and include polycythaemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). MPN or presence of a clone characterised by a JAK2 mutation in the absence of an MPN phenotype are associated with arterial and venous thromboses.36 The thromboses associated with PNH and MPN can occur anywhere in the venous or arterial systems but particularly in unusual sites for example, splanchnic vein thrombosis (SVT) (which includes portal vein (PVT), mesenteric vein (MVT) and splenic vein thrombosis, and the Budd–Chiari syndrome (BCS)) and cerebral venous sinus thrombosis (CVST).37, 38 In MPN, thrombosis often precedes disease recognition. Molecular abnormalities, primarily the V617F mutation in JAK2 exon 14, are found in 95% of PV (and an exon 12 mutation in most remaining patients) and in 60%–70% of ET and PMF patients.39 Isolated JAK2 mutations occur in approximately 0.1%–0.2% of the general population without an MPN phenotype and in 2.9%–5.6% of patients with CVST with no MPN phenotype40 (Table 2). A proportion of patients positive for JAK2 mutation with normal full blood count at presentation progressed into MPN during follow-up.41 Mutations of MPL exon 10 are present in about 5% of those with ET or PMF.42-44 In patients without JAK2 or MPL mutations, 67%–71% of those with ET and 56%–88% of those with PMF are positive for a calreticulin gene (CALR) mutation.45 In a study by Rumi et al. of 1235 consecutive patients diagnosed with ET or PV, the incidence of thrombosis associated with JAK2-mutated patients with ET and PV was similar; 7.1 and 10.5% respectively and was four times that of patients with ET and the CALR mutation (2.8%). The incidences of thrombosis associated with the JAK2 exon 12 and MPL mutations are not well documented due to the small number of patients with these mutations. Testing for JAK2, CALR, MPL variants in peripheral blood is sensitive and bone marrow samples are not required.39 Detailed guidance on assays used for detection of JAK2 mutations is available in separate guidelines.46 Diagnosis of PNH is based on flow cytometric analysis using antibodies directed against GPI-AP.47 The diagnosis of APS is dependent on the presence of at least one clinical feature (thrombosis or pregnancy morbidity) and at least one laboratory feature of antiphospholipid antibodies (aPL) which include lupus anticoagulant (LA), immunoglobulin (Ig) G or IgM anticardiolipin antibodies (aCL) or anti-β2-glycoprotein-I (anti-β2GPI) antibodies).48 The aPL need to be persistent, that is, present on two or more occasions at least 12 weeks apart.49 Of the three tests, a positive LA appears to be the most strongly associated with recurrent thrombosis, but individuals who are positive for all three assays ("triple positives") have the highest thrombotic risk.50-52 Although the BSH guidelines (2012) on the investigation and management of antiphospholipid syndrome stated that in patients with thrombosis, measuring IgM antibodies does not add useful information,53 both IgG and IgM aCL and anti-β2GPI are part of the international consensus on laboratory diagnostic criteria for APS.49 There is increasing evidence that IgM anticardiolipin and anti-β2GPI antibodies have a pathogenic role in patients with APS.54-57 In patients with thrombotic APS, uncertainties remain as to the recurrence risk in patients with an initial unprovoked, compared to provoked, VTE and in those with venous compared to an initial arterial thrombosis.58 There is increasing evidence that the recurrence risk of VTE provoked by minor risk factors is similar to that with unprovoked VTE.59, 60 Therefore, such patients may also benefit from extended anticoagulation therapy as in those with unprovoked VTE. As the presence of antiphospholipid antibodies may alter management including choice of antithrombotic therapy in these patients, it may be reasonable to test for antiphospholipid antibodies. Catastrophic APS (CAPS) is a rare, but potentially fatal, variant of APS characterised by sudden onset of extensive microvascular thrombosis at multiple sites leading to multiorgan failure.61 CAPS tends to occur usually in patients with triple positive APS. Recommendations on the timing of, and indications for, antiphospholipid antibody testing following venous or arterial thrombosis are provided in the Addendum to British Society for Haematology Guidelines on Investigation and Management of Antiphospholipid Syndrome (2020).62 In asymptomatic individuals with triple positive antiphospholipid antibodies (mostly identified because of a prolonged activated partial thromboplastin time or presence of an autoimmune disorder), the incidence of first thrombotic events (which were equally distributed between venous and arterial thrombosis) was estimated to be 5% per year.52 Lower incidences of thrombosis of 1% and 0.5% annually respectively have been described in asymptomatic single antibody positive individuals and in women with the obstetric antiphospholipid syndrome.63, 64 In situations where the clinical utility of testing is not clear, testing is clearly not mandatory (clinical utility is defined as the ability of a test to improve clinical outcome). It is important that patients are counselled in advance of any decision on whether or not to undertake testing. This should include discussion of the aims of testing and how it might alter management decisions. What is the utility of identifying a heritable thrombophilic trait in a patient who has had a venous thrombotic event in modifying their future management or the management of asymptomatic family members? The relative risk of thrombophilic traits for recurrent VTE is less than that for a first episode of thrombosis because the comparator group is different. Moreover, the risk is managed differently, and no clinical trials have been undertaken. There are conflicting data on the association of FVL and F2 G20210A variants with risk of recurrence in the overall population of patients with VTE.33, 65 Observational data suggest that FVL Leiden but not F2 G20210A is associated with an increased risk of recurrence.33, 65 However, in a study with of 354 consecutive patients aged ≥65 years with a first unprovoked VTE, 9.0% of patients had FVL and 3.7% had a F2 G20210A variant.66 After adjustment for age, sex, and periods of anticoagulation as a time-varying covariate, at 3-year follow up neither the FVL (HR 0.98; 95% CI: 0.35–2.77) nor the F2 G20210A mutation (HR 1.15; 95% CI: 0.25–5.19) was associated with recurrent venous thromboembolism compared to controls.66 Patients with natural anticoagulant deficiencies were from studies from which for recurrent VTE after of for a first event were A meta-analysis of individuals with AT deficiency the odds of recurrence were increased with an recurrence risk without anticoagulant therapy of (95% CI: for and (95% CI: for VTE A further study in which AT was in on only one found the odds of recurrent VTE were increased (95% CI: in those with AT activity centile and (95% CI: in those with AT activities of In a study of the risk of recurrent VTE in patients who not anticoagulant was (95% CI: in those with PC deficiency and (95% CI: in those with PS In a the odds of recurrent VTE were increased (95% CI: in PC deficient patients and (95% CI: in those with PS deficiency 10 the of recurrence were and patients with FXI activity between the and or Patients with the highest factor VIII had a for recurrence of (95% CI: compared to those with FVIII In terms this to a recurrence of 5% per compared to per Although these effects are their utility is Clinical in with such as in patients, can identify those risk of recurrence is high to anticoagulation and which is not by the absence of a thrombophilic These factors also identify patients with risk of recurrence not in the presence of heritable thrombophilic There is no evidence that the presence of heritable thrombophilia influences the choice or the of anticoagulant therapy when thrombosis potentially in those with AT In AT deficiency, diagnosis specific which can be and can also of laboratory of this is a rare disorder and so routine testing is not in the absence of a family as two or more with For patients with a and/or family of thrombosis in the absence of a clear risk genetic analysis via is available as and should be combined with phenotypic testing where The of a genetic trait with the strength of the family The heritable thrombophilic traits follow with variable of FVIII and FXI have clear genetic but also significant acquired so the of being is less of a heritable trait in a family does not a risk of thrombosis high to anticoagulation and does not alter most However, some guidelines include of heritable thrombophilic traits in their risk assessment with a impact on Absence of that trait in a family their risk of thrombosis but does not it to normal and the utility of testing will on their and the of the VTE Overall, the recurrence risk for VTE is by the clinical (e.g., provoked with risk factors (e.g., and rather than the thrombophilia Therefore, when a patient is to have a heritable thrombophilic it may be reasonable to testing of when this will alter their management for example, deficiencies of PC, PS or AT deficiency in a of for FVL is not in women with a first degree relative with FVL but no of thrombosis or to combined oral contraceptive or oestrogen However, the of family of thrombosis, thrombophilia testing and risk of thrombosis of should be discussed with all women to whether they will alter their therapy and should be documented Investigation and management of thrombosis at unusual sites are discussed in BSH For thrombosis at unusual which often or conditions the testing for thrombophilia should be for patients with The association of MPN and PNH with thrombosis at unusual which includes splenic vein thrombosis and the has been in and these disorders should be tested for in the absence of a clear for the such as or of data from found that in of patients, splanchnic vein thrombosis the diagnosis of For the remaining patients, thrombosis at a of years after Diagnosis of PNH and MPN is important because these have specific in to anticoagulation to recurrent thrombosis. In a and meta-analysis of small studies to assess the prevalence of heritable thrombophilia in patients with and the prevalence of PC, and PS deficiencies were and in and and in respectively. three studies compared the prevalence of heritable thrombophilia between patients and The odds ratios of heritable PC and PS deficiencies for were (95% CI: (95% CI: and (95% CI: These studies are only for the first thrombotic event and the risk of recurrent events associated with heritable thrombophilia and thrombosis at unusual sites is not well but to be Therefore, the of testing for heritable thrombophilia is and testing should be considered only if the thrombotic event in the absence of a clear risk factor for the event at a age CVST is a rare for of all The of CVST patients will have an risk the most common of which are oral contraceptive and Other rare causes that can contribute to CVST include APS, MPN, chronic inflammatory and factors such as or CVST is reported in of patients with and around of patients with of patients diagnosed with CVST are found to have a JAK2 mutation with normal full blood count at (Table 2). CVST are reported in to of patients with However, it is not clear how of these patients had a normal full blood count at presentation with studies have shown the presence of aPL the risk of thrombosis at unusual sites such as and As the type and of anticoagulation are by the presence of antiphospholipid testing for these antibodies is in an BSH In the absence of a clear risk patients with CVST may need anticoagulation and routine testing for heritable thrombophilia is not There is no evidence to suggest an association of heritable thrombophilia with vein The pathogenic role of antiphospholipid antibodies in is A meta-analysis of studies showed that presence of antiphospholipid antibodies was associated with incidence of 95% CI: A more study that included consecutive patients with and also showed that antiphospholipid antibodies were more in than in 10% OR 95% CI: with patients more lupus anticoagulant or triple positive antiphospholipid antibody than Testing for aPL may be considered in patients without risk factors and no other for such as and as those with positive aPL be considered for There is conflicting evidence with to the presence and the strength of associations between FVL and F2 G20210A variant and arterial thrombosis. Although some studies a increased risk of in patients with FVL or F2 G20210A variants, this has not been in S1 on the association of the FVL or with These variants are common in the European population and will be found in patients with their presence a role for events is not and is to from these When significant associations have been these have been too to be of clinical significance and there are no clinical trials to suggest that management should be as a result of the presence of these heritable deficiencies of PC and PS are rare, studies with to assess potential associations with risk of arterial thrombosis are Overall, there is no evidence to an association between heritable thrombophilia and arterial thrombosis in a

(1) Background and Aims: Patients with inflammatory bowel disease (IBD) and primary sclerosing cholangitis (PSC) face a significantly increased risk of malignancies, including a 10-fold higher risk for colorectal cancer (CRC) and a lifetime risk for cholangiocarcinoma (CCA) exceeding 20%. The mechanisms underlying this elevated risk remain elusive. This review consolidates recent findings on cancer risk in PSC-IBD patients, focusing on molecular pathways, diagnostic innovations, and prevention strategies. (2) Methods: A comprehensive PubMed search was performed to identify studies published through to March 2025 on oncogenic processes, molecular mechanisms, and advancements in diagnostic and preventive strategies for CRC and CCA in PSC-IBD patients. (3) Results: Surveillance guidelines recommend an annual colonoscopy for CRC and imaging combined with CA 19-9 monitoring for CCA. Recent studies highlight the role of molecular alterations, including epigenetic modifications, in tumorigenesis. Advances in molecular diagnostics, imaging, and endoscopic technologies are improving the accuracy and timeliness of cancer detection. (4) Conclusions: PSC-IBD patients remain at high risk for CRC and CCA, emphasizing the need for vigilant surveillance and advanced prevention strategies. Advances in early detection and precision diagnostics offer new opportunities to reduce the cancer burden in this high-risk population.

Ordering Patterns of Thrombophilia Testing and Its Appropriateness

Ideally, thrombophilia testing should be tailored to the type of thrombotic event without the influence of anticoagulation therapy or acute phase effects which can give false positive results that may result in long term anticoagulation. However, thrombophilia testing is often performed routinely in unselected patients. We analyzed all consecutive thrombophilia testing orders during the months of October and November 2009 at an academic teaching institution. Information was extracted from electronic medical records for the following: indication, timing, comprehensiveness of tests, anticoagulation therapy at the time of testing, and confirmatory repeat testing, if any. Based on the findings of this analysis, we established local guidelines in May 2013 for appropriate thrombophilia testing, primarily to prevent testing during the acute thrombotic event or while the patient is on anticoagulation. We then evaluated ordering practices 22 months after guideline implementation. One hundred seventy-three patients were included in the study. Only 34% (58/173) had appropriate indications (unprovoked venous or arterial thrombosis or pregnancy losses). 51% (61/119) with an index clinical event were tested within one week of the event. Although 46% (79/173) were found to have abnormal results, only 46% of these had the abnormal tests repeated for confirmation with 54% potentially carrying a wrong diagnosis with long term anticoagulation. Twenty-two months after guideline implementation, there was an 84% reduction in ordered tests. Thus, this study revealed that a significant proportion of thrombophilia testing was inappropriately performed. We implemented local guidelines for thrombophilia testing for clinicians, resulting in a reduction in healthcare costs and improved patient care.

An Audit of Thrombophilia Testing in Patients with Ischemic Stroke or Transient Ischemic Attack: The Futility of Testing

Inpatient Hypercoagulable Work-up in a Community Teaching Hospital: A Preventable Cost with No Added Benefit

Using Electronic Best Practice Alerts to Improve Thrombophilia Testing Based on ASH Choosing Wisely Guidelines

Thrombophilia testing patterns amongst patients with acute venous thromboembolism

Thrombophilia workup is typically inappropriate in the inpatient setting as testing may be skewed by anticoagulation, acute thrombosis, or acute illness. To determine adherence of inpatient thrombophilia testing with institutional guidelines. A retrospective study to evaluate thrombophilia testing practices of adult patients who were admitted to Lehigh Valley Hospital at Cedar Crest with either venous thromboembolism or ischemic stroke in 2019. Testing included inherited and acquired thrombophilia. Patient charts were individually reviewed for three measured outcomes: 1) the number of appropriate thrombophilia testing in the inpatient setting; 2) the indications used for thrombophilia testing; 3) the proportion of positive thrombophilia tests with change in clinical management. 201 patients were included in our study. 26 patients (13%) were tested appropriately in accordance with institution guidelines and 175 (87%) patients were tested inappropriately. The most common reason for the inappropriate testing was testing during acute thrombosis. 28 of the 201 patients had positive thrombophilia tests, but the reviewers only noted 7 patients with change in clinical management-involving anticoagulation change. Our study revealed that a majority of inpatient thrombophilia testing did not follow institutional guidelines for appropriate testing and did not change patient management. These thrombophilia tests are often overutilized and have minimal clinical utility in the inpatient setting.