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W2112879444 abstract "• Introduction & methodology • Summary of recommendations • The scope of the guideline and concept of heritable thrombophilia as a risk factor for thrombosis • Treatment of lower limb deep vein thrombosis (DVT) and pulmonary embolus (PE) • Treatment of upper limb DVT • Treatment of cerebral vein (sinus) thrombosis (CVT) • Treatment of retinal vein thrombosis • Treatment of intra-abdominal vein thrombosis • Purpura fulminans • Case finding as a means to prevent venous thrombosis in asymptomatic relatives of patients with a history of venous thrombosis • Prevention of thrombosis associated with oestrogen-containing hormone preparations • Prevention of pregnancy-associated venous thrombosis • Pregnancy morbidity • Assisted conception and ovarian hyperstimulation syndrome • Prevention of thrombosis in hospitalised patients • Coronary, cerebral and peripheral arterial thrombosis • Perinatal stroke • Laboratory methodology and testing strategy • Audit The guideline group was selected to be representative of UK-based medical experts. The writing group met and communicated by email. The guideline was reviewed by a multidisciplinary sounding board, selected non-UK experts in thrombosis and thrombophilia, the British Committee for Standards in Haematology (BCSH) and the British Society for Haematology) (BSH and comments incorporated where appropriate. Criteria used to quote levels and grades of evidence are according to the GRADE system (Guyatt et al, 2006). As this guideline relates specifically to laboratory tests, reference is made to grading quality of evidence and strength of recommendations for diagnostic tests and strategies recognising that tests are only of value if they result in improved outcomes for patients (Schunemann et al, 2008). Strong recommendations (grade 1, ‘recommended’) are made when there is confidence that the benefits either do or do not outweigh the harm and burden and costs of treatment. Where the magnitude of benefit or not is less certain, a weaker grade 2 recommendation (‘suggested’) is made. Grade 1 recommendations can be applied uniformly to most patients whereas grade 2 recommendations require judicious application. The quality of evidence is graded as A (high quality randomised clinical trials), moderate (B) or low (C) (Guyatt et al, 2006; http://www.bcshguidelines.com). The target audience for this guideline is healthcare professionals involved in the management of patients and families with venous thrombosis or pregnancy morbidity. The summary recommendation of this guideline is that testing for heritable thrombophilias is not indicated in unselected patients presenting with venous thrombosis. Testing selected patients may give an indication of risk of recurrence following completion of anticoagulant therapy, for example those presenting with venous thrombosis at an early age (<40 years) and who are from apparent thrombosis-prone families (more than two other symptomatic family members). Analysis of the large Multiple Environmental and Genetic Assessment (MEGA) study showed that testing for inherited thrombophilia did not reduce recurrence of venous thrombosis (Coppens et al, 2008). Other selected patient groups in whom the results of testing may influence treatment are children with purpura fulminans and pregnant women at risk of venous thrombosis. The decision to test these selected patients should be based on whether or not test results are likely to influence treatment decisions. • Initiation and intensity of anticoagulant therapy following a diagnosis of acute venous thrombosis should be the same in patients with and without heritable thrombophilia (1B). • Indiscriminate testing for heritable thrombophilias in unselected patients presenting with a first episode of venous thrombosis is not indicated (1B). • Decisions regarding duration of anticoagulation (lifelong or not) in unselected patients should be made with reference to whether or not a first episode of venous thrombosis was provoked or not, other risk factors, and risk of anticoagulant therapy-related bleeding, regardless of whether a heritable thrombophilia is known (1B). • Testing for heritable thrombophilias in selected patients, such as those with a strong family history of unprovoked recurrent thrombosis, may influence decisions regarding duration of anticoagulation (C). It is not possible to give a validated recommendation as to how such patients should be selected. • Testing is not recommended in unselected patients with upper limb venous thrombosis (1B). • Testing is not recommended in patients with central venous catheter (CVC)-related thrombosis (1C). • Testing for heritable thrombophilia after a first episode of cerebral vein thrombosis (CVT) has uncertain predictive value for recurrence (C). Decisions regarding duration of anticoagulant therapy in relation to the results of testing are not evidence-based. • Testing is not indicated in patients with retinal vein occlusion (1B). • Testing for heritable thrombophilia after a first episode of intra-abdominal vein thrombosis has uncertain predictive value for recurrence (C). Decisions regarding duration of anticoagulant therapy in relation to the results of testing are not evidence-based. • Neonates and children with purpura fulminans should be tested urgently for protein C and S deficiency (1B). • A variety of functional methods may be required to identify specific severe type 2 functional defects when levels of protein C or S are not <5% (1B). • It is suggested that adults who develop skin necrosis in association with oral vitamin K antagonists (VKAs) are tested for protein C and S deficiency after VKA treatment is withdrawn (2B). • Case finding of asymptomatic relatives with low risk thrombophilia, such as F5G1691A (FVR506Q, factor V Leiden) or F2G20210A, is not indicated (1B). • Case finding of asymptomatic relatives with high risk thrombophilia, such as deficiency of antithrombin, protein C or protein S, should only be considered in selected thrombosis-prone families (1B). If testing is performed, the risks, benefits and limitations of testing should be discussed in the context of explained inheritance and disease risk. It is not possible to give a validated recommendation as to how such patients and families should be selected. • Case finding for very rare homozygosity or compound heterozygous heritable thrombophilia is not indicated as these defects are so rare, they are not predicted by family history, and the risk of unprovoked thrombosis is low (2C). • If a first-degree relative with venous thrombosis has not been tested then suggest that women consider an alternative contraceptive or transdermal hormone replacement therapy (HRT). Testing for heritable thrombophilia will provide an uncertain estimate of risk and is not recommended (1C). • If a first-degree relative with venous thrombosis has been tested and the result is negative then suggest that a woman considers an alternative contraceptive or transdermal HRT. Testing for heritable thrombophilia will provide an uncertain estimate of risk and is not recommended (1C). • If a first-degree relative with venous thrombosis has been tested and the result is positive then suggest that women consider an alternative contraceptive or transdermal HRT before offering testing as a negative test result does not exclude an increased risk of venous thrombosis. Testing for heritable thrombophilia may assist counselling of selected women particularly if a high risk thrombophilia has been identified in the symptomatic relative (C). • Women should be assessed for risk of pregnancy-associated venous thrombosis primarily in relation to clinical risk factors (1B). • Most pregnant women with a previous unprovoked venous thrombosis (1B) or pregnancy or combined oral contraceptive (COC)-related thrombosis (2C) will qualify for thrombophylaxis on clinical risk alone and so testing for heritable thrombophilia is not required. • Pregnant women with a previous event due to a major provoking factor, e.g. surgery or major trauma, would not usually require prophylaxis or testing (2B). • Pregnant women with a previous event due to a minor provoking factor, e.g. travel, should be tested and considered for prophylaxis if a thrombophilia is found (2C). • In the asymptomatic pregnant woman with a family history of venous thrombosis, testing is not required if the clinical risks alone are sufficient to result in thromboprophylaxis (2C). • It is suggested that asymptomatic pregnant women with a family history of venous thrombosis be tested if an event in a first-degree relative was unprovoked, or provoked by pregnancy, COC exposure or a minor risk factor (2C). The result will be more informative if the first-degree relative has a known thrombophilia. • Antithrombotic therapy should not be given to pregnant women with a history of pregnancy complications based on testing for heritable thrombophilia. Randomised controlled trials with a no-treatment or placebo arm in women with a history of pregnancy complications are in progress. If these studies indicate a benefit in women with pregnancy complications and heritable thrombophilia, as compared with women without thrombophilia, only then would there be a rational basis for recommending that antithrombotic therapy is given to pregnant women with a history of pregnancy complications based on testing for heritable thrombophilia. • Testing asymptomatic women before assisted conception and those with ovarian hyperstimulation syndrome is not indicated (1B). • Thrombophilia screening of hospitalised patients to identify patients at risk of hospital-acquired venous thrombosis is not indicated (1A). • All hospitalised patients should be assessed for risk of venous thrombosis regardless of heritable thrombophilia based on a clinical risk assessment (1B). The presence of a previously known heritable thrombophilia may influence the assessment of risk. • Testing for heritable thrombophilia is not indicated in patients with arterial thrombosis (1B). • It is suggested that testing for heritable thrombophilia is not indicated in children with stroke (2C). (Recommendations for laboratory practice are given toward the end of the document under the section on laboratory methodology and testing strategy). Heritable thrombophilia describes an inherited tendency for venous thrombosis (deep vein thrombosis, DVT, with or without associated pulmonary embolus, PE). Deficiency of the natural anticoagulant antithrombin was the first reported inherited risk factor for venous thromboembolism (Egeberg, 1965). Since then, deficiencies of the naturally occurring anticoagulants protein C (Griffin et al, 1981) and protein S (Comp et al, 1984) have been linked with familial venous thrombosis. In recent years, several other potential thrombophilic risk factors have been investigated but only the F5G1691A (FVR506Q, factor V Leiden) (Bertina et al, 1994) and the F2G20210A (Poort et al, 1996) gene mutations have been shown to be unequivocally associated with an increased risk of venous thrombosis (Reitsma & Rosendaal, 2007), i.e. odds ratio of 2 or greater. In the 1980s and 1990s thrombophilia testing became common in unselected patients and their relatives despite the fact that there was no evidence that testing had clinical utility. It is now apparent that testing for heritable thrombophilia typically does not predict likelihood of recurrence in unselected patients with symptomatic venous thrombosis (Baglin et al, 2003; Christiansen et al, 2005) and testing for inherited thrombophilia did not reduce recurrence of venous thrombosis in a large cohort study (Coppens et al, 2008). There is a low risk of thrombosis in affected asymptomatic relatives followed prospectively (Langlois & Wells, 2003) and the results of thrombophilia tests are frequently misinterpreted (Jennings et al, 2005). The aim of this guideline is to provide recommendations to clinicians in relation to testing for heritable thrombophilia in the context of clinical management of venous thrombosis and pregnancy morbidity. This guideline is restricted to heritable thrombophilias shown to be associated with at least a two-fold increased risk of venous thrombosis, namely deficiencies of antithrombin, protein C and protein S due to mutations in the corresponding genes SERPINC1, PROC, PROS1 and the two common mutations F5G1691A (FV R506Q, factor V Leiden) and F2G20210A (commonly referred to as the prothrombin gene mutation). Since the publication of the previous BCSH (British Committee for Standards in Haematology) guideline ‘Investigation and Management of Heritable Thrombophilia’ in 2001 no randomised studies of treatment in relation to heritable thrombophilia have been published. A review of the clinical utility of thrombophilia testing was published in 2008 (Middeldorp & van Hylckama Vlieg, 2008) and several systematic reviews of the association of heritable thrombophilias with specific conditions have been published but the clinical utility of testing has not been assessed in these reviews. In situations where the clinical utility of testing is unproven, testing is clearly not mandatory (clinical utility defined as the ability of a test to influence or alter clinical outcome). However, many clinicians have used thrombophilia test results to determine clinical management. An example of this is the management of women at risk of pregnancy-associated venous thrombosis. The 2001 BCSH guideline classified pregnancy-associated venous thrombosis risk on the basis of thrombophilia test results and so testing was necessary in order to follow the guidance. However, all the recommendations were opinion-based on low quality evidence. It is unlikely that randomised studies would address the issue of risk of pregnancy-associated venous thrombosis and so guidance is given in this guideline recognising that there is only low level evidence and that careful assessment of clinical risk factors is required in all cases. Criteria for defining thrombosis-prone families have not been validated. The association between family history of venous thrombosis and detection of inherited thrombophilia is weak (van Sluis et al, 2006). In addition, a family history of venous thrombosis is not a risk factor for recurrent venous thrombosis if patients with antithrombin, protein C or protein S deficiency are excluded (Hron et al, 2006). The influence of family history on recurrence risk in patients with deficiency of antithrombin, protein C or protein S requires study. There is no evidence that heritable thrombophilia should influence the intensity of anticoagulation with heparin or VKAs. In a review of 70 thrombotic events in 57 individuals with antithrombin deficiency, heparin resistance was infrequent and recurrence or extension of thrombosis while on treatment was no greater than ordinarily expected in patients treated for venous thrombosis (Schulman & Tengborn, 1992). Coumarin-induced skin necrosis is extremely rare, even in patients with protein C or S deficiency, such that most individuals with protein C or S deficiency do not develop skin necrosis; there is no indication that initiation of oral anticoagulant treatment whilst patients are receiving heparin should be different in patients known to have protein C or S deficiency. The intensity of maintenance therapy with warfarin should not be influenced by laboratory evidence of inherited thrombophilia. There is no evidence that recurrence on oral VKA treatment is more likely in patients with heritable thrombophilia (Kearon et al, 2008a). • Initiation and intensity of anticoagulant therapy following a diagnosis of acute venous thrombosis should be the same in patients with and without heritable thrombophilia (1B). Long-term prospective cohort outcome studies have shown that finding a heritable thrombophilia does not typically predict recurrence (Baglin et al, 2003; Christiansen et al, 2005). An analysis of the MEGA study showed that testing for inherited thrombophilia did not reduce recurrence of venous thrombosis (Coppens et al, 2008). Systematic reviews of the risk of recurrent venous thromboembolism in patients heterozygous for the F5G1691A mutation indicate a risk of 1·4 and for the F2G20210A 1·2–1·7 (Ho et al, 2006; Marchiori et al, 2007). The authors concluded that the magnitude of the increase in risk was modest and by itself did not justify an extended duration of anticoagulation. In patients with deficiency of a natural anticoagulant (antithrombin, protein C, protein S deficiency) the risk of recurrence is uncertain but relative risks of recurrence appear to be <2·0 in patients who are not selected from thrombosis-prone families (Baglin et al, 2003; Christiansen et al, 2005; De Stefano et al, 2006a). In a retrospective analysis of patients selected on the basis of young age at time of first venous thrombosis and a family history of venous thrombosis, detection of deficiency of a natural anticoagulant predicted a risk of recurrence of 6·23%, compared to 2·25% in patients with F5G1691A or F2G20210A. Over a 10-year period this translated into a cumulative risk of recurrence of 55% (Lijfering et al, 2009). However, it is unclear what selection strategy would, in practice, enable identification of high-risk patients with thrombophilia. Furthermore, high-risk patients may be identified by clinical risk assessment alone, or possibly in association with tests of coagulability, such as D-dimer (Verhovsek et al, 2008). In principle, the duration of anticoagulant therapy should be determined by a clinical assessment of risk and benefit after an initial period of anticoagulant therapy (Kearon et al, 2008b). In the majority of patients this assessment will not require, or be informed by, testing for heritable thrombophilia. • Indiscriminate testing for heritable thrombophilia in unselected patients presenting with a first episode of venous thrombosis is not indicated (1B). • Decisions regarding duration of anticoagulation (lifelong or not) in unselected patients should be made with reference to whether or not a first episode of venous thrombosis was provoked or not, other risk factors, and risk of anticoagulant therapy-related bleeding, regardless of whether a heritable thrombophilia is known (1B). • Testing for heritable thrombophilia in selected patients, such as those with a strong family history of unprovoked recurrent thrombosis, may influence decisions regarding duration of anticoagulation (C). It is not possible to give a validated recommendation as to how such patients should be selected. More than 60% of episodes of upper limb DVT are associated with central venous catheters (CVC) (Spencer et al, 2007), with CVCs and cancer being the predominant risk factors (Munoz et al, 2008). Thoracic outlet syndrome is less common. Heritable thrombophilias are found in one-third of patients without these factors and there is an interaction between common thrombophilias and oral contraceptive exposure (Martinelli et al, 2004). The risk of recurrence is either not higher or marginally higher in patients with heritable thrombophilias but the absolute risk of recurrence in the presence of thrombophilia is <5% per year and 80% of patients are recurrence-free 5 years after stopping anticoagulant therapy (Martinelli et al, 2004; Flinterman et al, 2008). One study demonstrated an increased risk of CVC-related thrombosis in patients with thrombophilia but the study was small and it is uncertain how treatment would be altered by knowledge of a defect in this situation. • Testing is not recommended in unselected patients with upper limb venous thrombosis (1B). • Testing is not recommended in patients with CVC-related venous thrombosis (1C). There is an association between thrombophilia and cerebral vein thrombosis with an interaction between common thrombophilias, particularly F2G20210A, and oral contraceptive use (Dentali et al, 2006; Wasay et al, 2008). Overall the risk of recurrence of CVT is lower than previously thought, affecting 2% to 3% of adults (Ferro et al, 2004). However, recurrence may be underestimated due to continuation of anticoagulant therapy in those patients thought to be at high risk. A study in children identified the F2G20210A mutation as an independent risk factor for recurrence (hazard ratio 4·1). It has become common practice to test patients for heritable thrombophilia after CVT and some experts continue anticoagulation lifelong if there is a thrombophilic defect. In all patients acquired risks should be removed or minimised, e.g. COC or HRT use, obesity. • Testing for heritable thrombophilias after a first episode of CVT has uncertain predictive value for recurrence (C). Decisions regarding duration of anticoagulant therapy in relation to the results of testing are not evidence-based. Retinal vein occlusion is associated with hypertension, hypercholesterolaemia and diabetes. An initial meta-analysis did not identify a statistically significant relationship with heritable thrombophilia but suggested that F5G1691A (OR 1·5) and F2G20210A (OR 1·6) mutations might be weak risk factors (Janssen et al, 2005). A more recent analysis confirmed an odds ratio of 1·5 for F5G1691A indicating a much weaker association than with lower limb DVT (Rehak et al, 2008). It is uncertain to what degree hypercoagulability is a material contributory factor in this condition and the risk of recurrence is low. Furthermore, there is no evidence that anticoagulant therapy is beneficial. Therefore, it is not recommended that decisions regarding treatment are made in relation to the results of testing for heritable thrombophilia. • Testing is not indicated in patients with retinal vein occlusion (1B). Myeloproliferative disorders, cirrhosis and surgery are strong risk factors for intra-abdominal venous thrombosis. The acquired JAK2 V617F mutation is a risk factor even in the absence of an overt myeloproliferative disorder, being found in 17% of cases (Austin & Lambert, 2008). A meta-analysis of 12 studies of portal vein thrombosis found an odds ratio of 1·9 (1·2–2·9) for F5G1691A and 4·5 (3·1–6·5) for F2G20210A (Dentali et al, 2008). No studies have investigated how the finding of a heritable thrombophilia should influence management. • Testing for heritable thrombophilias after a first episode of intra-abdominal vein thrombosis has uncertain predictive value for recurrence (C). Decisions regarding duration of anticoagulant therapy in relation to the results of testing are not evidence-based. Purpura fulminans is a rare syndrome characterised by progressive haemorrhagic skin necrosis that occurs in neonates with congenital severe protein C deficiency at birth or in the first few days of life, and rarely in association with infection in children and adults. The condition may occur in children without inherited anticoagulant deficiency following viral infection with an onset within 10 d of infection. Acquired severe protein S deficiency has been reported in purpura fulminans following chicken pox infection and is associated with a high morbidity and mortality without urgent treatment. With bacterial infections disseminated intravascular coagulation (DIC) is often present, for example in meningococcal infection. In patients with DIC or purpura fulminans due to sepsis, treatment with activated protein C should be considered. In patients with very severe skin necrosis testing for acquired protein C or S should be considered, as plasma exchange may be beneficial. Neonates homozygous for protein C or S deficiency may be born with skin necrosis or DIC. Patients may be compound heterozygotes with a mixture of type 1 and 2 defects and so it may be necessary to perform different functional assays as well as antigen measurement to confirm almost complete deficiency. For example, a defect in the Gla-domain of protein C will not be detected by a chromogenic assay. Expert advice on testing should be obtained in all suspected cases. Patients heterozygous for protein C or protein S deficiency may develop skin necrosis when treated with oral VKAs but this is very rare and may be due to rapid initiation of anticoagulation in the absence of heparin. • Neonates and children with purpura fulminans should be tested urgently for protein C and S deficiency (1B). • A variety of functional methods may be required to identify specific severe type 2 functional defects when levels of protein C or S are not <5% (1B). • It is suggested that adults who develop skin necrosis in association with oral VKAs are tested for protein C and S deficiency when VKA treatment is withdrawn (2B). It has been suggested that testing for heritable thrombophilia in patients presenting with venous thrombosis allows case-finding of affected asymptomatic family members. The rationale is that this permits avoidance of environmental risks (such as use of combined oral contraceptive pills by females) or provides an opportunity for targeted thrombophylaxis at times of unavoidable high risk (such as surgery). However, individual risk is affected by multiple genetic and environmental factors, which will be different even amongst first-degree relatives. Four prospective cohort studies determined the annual risk of venous thrombosis in asymptomatic family members identified by testing unselected patients presenting with venous thrombosis (Pabinger et al, 1994; Sanson et al, 1999; Middeldorp et al, 2001; Simioni et al, 2002). These studies were included in a meta-analysis published in 2003 (Langlois & Wells, 2003). The studies included 3641 patient-years of observation. In the prospective studies the annual risk of venous thrombosis in asymptomatic family relatives of index patients was 0·6% for those with F5G1691A, 1·0–2·5% for protein C deficiency, 0·7–2·2% for protein S deficiency and 4% for antithrombin deficiency (Langlois & Wells, 2003). High risk periods contributed to approximately half of all events (provoked occurence) in patients with F5G1691A and thromboprophylaxis appeared to reduce risk. In a further prospective follow up of asymptomatic relatives with the F2G20210A mutation the annual incidence of venous thrombosis was 0·11% in carriers and 0·07% in non-carriers, a difference that was not significant (Tormene et al, 2004). In a prospective cohort study of asymptomatic carriers of deficiency of antithrombin, protein C or protein S the annual incidence of venous thrombosis was 1·5% [95% confidence interval (CI) 0·7–2·8] with approximately half being provoked with an incidence of 10% per period of acquired risk (Sanson et al, 1999). In summary, case finding of asymptomatic relatives of patients with venous thrombosis has not been shown to reduce the incidence of venous thrombosis and the annual risk of unprovoked thrombosis in affected family members is low. In the European Prospective Cohort on Thrombophilia (EPCOT) registry patients were referred to specialist centres for thrombophilia testing if they had a personal or family history of venous thrombosis. The incidence of venous thrombosis on study entry was determined retrospectively in asymptomatic relatives. The risk of venous thrombosis was 16-times higher in affected relatives, with the greatest risk in relatives of patients with deficiency of a natural anticoagulant or multiple defects (Vossen et al, 2004). In a subsequent prospective follow-up over an average of nearly 6 years, 4·5% of 575 asymptomatic carriers suffered a first episode of venous thrombosis, compared to 0·6% in a control population. Nearly 60% of the episodes were unprovoked (Vossen et al, 2005). The incidence was 0·8% per year in carriers and 0·1% per year in controls. The highest incidence was in individuals with antithrombin deficiency (1·7% per year) or combined defects (1·6% per year). In a separate study of families with type 1 antithrombin deficiency the incidence of venous thrombosis was 20-times greater in affected family members but was strongly dependent on acquired risks (van Boven et al, 1999). In this study the annual incidence of venous thrombosis in affected family members in any year in which they were exposed to surgery, trauma, plaster cast, hospitalisation or immobilisation was 20·3% but in any year in which there was no exposure the incidence of unprovoked venous thrombosis was only 0.3%, which is only slightly higher than the background 0·15% in an unselected general population (Naess et al, 2007). Targeted case-finding of relatives with ‘severe’ or ‘high risk’ thrombophilia, such as deficiency of antithrombin, protein C or protein S, has been suggested (De Stefano, 2004; Spencer & Goldberg, 2005) although there is still no evidence to support the clinical utility of such an approach and the issue remains contentious. Given the uncertainty, some experts argue that it is reasonable to perform testing if it is anticipated that clinical management will be influenced, for example an intensified or extended period of prophylaxis during a high risk period. If a family history suggests a high degree of genetic penetrance then it might be reasonable to test a symptomatic patient and then their relatives, with a view to enhanced prophylaxis at times of high risk in affected members. For example in thromboprophylaxis in pregnancy when there is a family history of pregnancy-associated venous thrombosis, or intensified or extended surgical thromboprophylaxis when there is a history of thromboprophylaxis failure in affected members. In all cases the risks, benefits and limitations of testing should be discussed in the context of explained inheritance and disease risk (Varga, 2008). The importance of this is demonstrated by reported anxiety after testing positive (Hellmann et al, 2003; Bank et al, 2004; Cohn et al, 2008) and an overestimated perception of risk (Hellmann et al, 2003). At present the cost effectiveness of case-finding in thrombosis-prone families has not been demonstrated. Simple me" @default.
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W2112879444 title "Clinical guidelines for testing for heritable thrombophilia" @default.
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