Clinical guidelines for testing for heritable thrombophilia

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 (1B). • A of may be to 2 when levels of protein C or are not (1B). • It is that who in with are tested for protein C and after treatment is • Case finding of asymptomatic relatives with low risk thrombophilia, such as factor or is not indicated (1B). • Case finding of asymptomatic relatives with risk thrombophilia, such as of protein C or protein should only be in selected thrombosis-prone families (1B). testing is the benefits and of testing should be in the of and It is not possible to give a validated recommendation as to how such patients and families should be selected. • Case finding for or heritable thrombophilia is not indicated as these are they are not by family and the risk of unprovoked thrombosis is low • a with venous thrombosis has not tested that women an or hormone therapy Testing for heritable thrombophilia an uncertain of risk and is not recommended (1C). • a with venous thrombosis has tested and the result is that a an or Testing for heritable thrombophilia an uncertain of risk and is not recommended (1C). • a with venous thrombosis has tested and the result is that women an or testing as a test result not an risk of venous thrombosis. Testing for heritable thrombophilia may of selected women if a risk thrombophilia has in the symptomatic (C). • should be for risk of pregnancy-associated venous thrombosis in relation to clinical risk (1B). • pregnant women with a unprovoked venous thrombosis or pregnancy or thrombosis for on clinical risk and testing for heritable thrombophilia is not • women with a to a or not require or testing • women with a to a should be tested and for if a thrombophilia is • the asymptomatic pregnant with a family history of venous thrombosis, testing is not if the clinical are to result in • It is that asymptomatic pregnant women with a family history of venous thrombosis be tested if an in a was or provoked by or a risk factor The result be if the has a known • therapy should not be to pregnant women with a history of pregnancy based on testing for heritable with a or in women with a history of pregnancy are in these a benefit in women with pregnancy and heritable thrombophilia, as with women without thrombophilia, only there be a for that therapy is to pregnant women with a history of pregnancy based on testing for heritable • Testing asymptomatic women conception and those with ovarian hyperstimulation syndrome is not indicated (1B). • of hospitalised patients to patients at risk of venous thrombosis is not indicated • hospitalised patients should be for risk of venous thrombosis regardless of heritable thrombophilia based on a clinical risk (1B). The of a known heritable thrombophilia may influence the of • Testing for heritable thrombophilia is not indicated in patients with arterial thrombosis (1B). • It is that testing for heritable thrombophilia is not indicated in children with stroke for laboratory are the of the the on laboratory methodology and testing thrombophilia an inherited for venous thrombosis vein thrombosis, with or without associated pulmonary of the anticoagulant was the first inherited risk factor for venous of the protein C et al, and protein et al, with venous thrombosis. other risk only the factor et al, and the et al, to be associated with an risk of venous thrombosis & of 2 or the and thrombophilia testing in unselected patients and relatives the that there was evidence that testing clinical It is apparent that testing for heritable thrombophilia not of recurrence in unselected patients with symptomatic venous thrombosis et al, et al, and testing for inherited thrombophilia did not reduce recurrence of venous thrombosis in a large study (Coppens et al, 2008). is a low risk of thrombosis in asymptomatic relatives & and the results of thrombophilia tests are et al, The of this guideline is to recommendations to in relation to testing for heritable thrombophilia in the of clinical management of venous thrombosis and pregnancy morbidity. guideline is to heritable thrombophilias to be associated with at a risk of venous thrombosis, of protein C and protein to in the and the two factor and to as the the of the Committee for Standards in Haematology) guideline and of in randomised of treatment in relation to heritable thrombophilia A of the clinical of thrombophilia testing was in & and of the of heritable thrombophilias with the clinical of testing has not in these where the clinical of testing is testing is not as the of a test to influence or clinical used thrombophilia test results to clinical example of this is the management of women at risk of pregnancy-associated venous thrombosis. The guideline pregnancy-associated venous thrombosis risk on the of thrombophilia test results and testing was in to the the recommendations on low quality It is that randomised the of risk of pregnancy-associated venous thrombosis and is in this guideline recognising that there is only low evidence and that of clinical risk is in Criteria for thrombosis-prone families not The family history of venous thrombosis and of inherited thrombophilia is et al, 2006). a family history of venous thrombosis is not a risk factor for recurrent venous thrombosis if patients with protein C or protein are et al, 2006). The influence of family history on recurrence risk in patients with of protein C or protein is evidence that heritable thrombophilia should influence the intensity of anticoagulation with or a of in with was and recurrence or of thrombosis on treatment was than in patients for venous thrombosis & is in patients with protein C or such that most with protein C or do not there is indication that of anticoagulant treatment patients are should be in patients known to protein C or The intensity of therapy with should not be by laboratory evidence of inherited is evidence that recurrence on treatment is likely in patients with heritable thrombophilia et al, • 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). that finding a heritable thrombophilia not recurrence et al, et al, of the study showed that testing for inherited thrombophilia did not reduce recurrence of venous thrombosis (Coppens et al, 2008). of the risk of recurrent venous in patients for the a risk of and for the et al, 2006; et al, The that the magnitude of the in risk was and by did not an duration of patients with of a anticoagulant protein protein the risk of recurrence is uncertain of recurrence to be in patients who are not selected from thrombosis-prone families et al, et al, et al, a of patients selected on the of age at of first venous thrombosis and a family history of venous thrombosis, of of a anticoagulant a risk of recurrence of to in patients with or a this a risk of recurrence of et al, is strategy in of patients with patients may be by clinical risk or in with tests of such as et al, 2008). the duration of anticoagulant therapy should be by a clinical of risk and benefit after an of anticoagulant therapy et al, the of patients this not or be testing for heritable • 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. than of of upper limb DVT are associated with central venous et al, with and the risk et al, 2008). syndrome is less thrombophilias are in of patients without these and there is an thrombophilias and et al, The risk of recurrence is either not or in patients with heritable thrombophilias the risk of recurrence in the of thrombophilia is and of patients are after anticoagulant therapy et al, et al, 2008). study an risk of thrombosis in patients with thrombophilia the study was and is uncertain how treatment be by of a in this • Testing is not recommended in unselected patients with upper limb venous thrombosis (1B). • Testing is not recommended in patients with venous thrombosis (1C). is an thrombophilia and cerebral vein thrombosis with an and et al, 2006; et al, 2008). the risk of recurrence of is lower than to of et al, recurrence may be to of anticoagulant therapy in those patients to be at A study in children the as an risk factor for recurrence It has to test patients for heritable thrombophilia after and experts anticoagulation if there is a patients should be or or • Testing for heritable thrombophilias after a first episode of has uncertain predictive value for recurrence (C). Decisions regarding duration of anticoagulant therapy in relation to the results of testing are not evidence-based. vein occlusion is associated with and did not a with heritable thrombophilia that and be risk et al, A an of for a weaker than with lower limb DVT et al, 2008). It is uncertain to is a factor in this and the risk of recurrence is there is evidence that anticoagulant therapy is is not recommended that decisions regarding treatment are made in relation to the results of testing for heritable • Testing is not indicated in patients with retinal vein occlusion (1B). and are strong risk for intra-abdominal venous thrombosis. The is a risk factor in the of an in of & 2008). A of of vein thrombosis an of for and for et al, 2008). how the finding of a heritable thrombophilia should influence • 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 syndrome by that in with protein C at or in the first of and in with in children and The may in children without inherited anticoagulant following with an of protein has in purpura fulminans following and is associated with a morbidity and without treatment. is for example in patients with or purpura fulminans to treatment with protein C should be patients with testing for protein C or should be as may be Neonates for protein C or may be with or may be with a of 1 and 2 and may be to as as to a in the of protein C not be by a on testing should be in for protein C or protein may when with this is and may be to of anticoagulation in the of • Neonates and children with purpura fulminans should be tested urgently for protein C and (1B). • A of may be to 2 when levels of protein C or are not (1B). • It is that who in with are tested for protein C and when treatment is It has that testing for heritable thrombophilia in patients presenting with venous thrombosis of asymptomatic family The is that this of as of by or an for at of risk as risk is by and factors, be the risk of venous thrombosis in asymptomatic family by testing unselected patients presenting with venous thrombosis et al, et al, et al, et al, in a in & The of the the risk of venous thrombosis in asymptomatic family relatives of patients was for those with for protein C for protein and for & risk to of in patients with and to reduce a of asymptomatic relatives with the the of venous thrombosis was in and in a that was not et al, a study of asymptomatic of of protein C or protein the of venous thrombosis was confidence with provoked with an of of risk et al, finding of asymptomatic relatives of patients with venous thrombosis has not to reduce the of venous thrombosis and the risk of unprovoked thrombosis in family is the on patients to for thrombophilia testing if they a or family history of venous thrombosis. The of venous thrombosis on study was in asymptomatic The risk of venous thrombosis was in with the risk in relatives of patients with of a anticoagulant or et al, a an of of asymptomatic a first episode of venous thrombosis, to in a of the unprovoked et al, The was in and in The was in with or a study of families with 1 the of venous thrombosis was in family was on et al, this study the of venous thrombosis in family in in they to or was in in there was the of unprovoked venous thrombosis was only is only than the in an unselected et al, of relatives with or thrombophilia, such as of protein C or protein has & there is evidence to the clinical of such an and the the experts that is to testing if is that clinical management be for example an or of a risk a family history a of be to test a symptomatic patient and with a to at of risk in example in in pregnancy when there is a family history of pregnancy-associated venous thrombosis, or or when there is a history of in the benefits and of testing should be in the of and risk 2008). The of this is by after testing et al, et al, et al, and an of risk et al, the of in thrombosis-prone families has not for a family history do not patients with and without thrombophilia and the decision to test for inherited thrombophilia be by the or of a family • Case finding of asymptomatic relatives with low risk thrombophilia, such as is not indicated (1B). • Case finding of asymptomatic relatives with risk thrombophilia, such as of protein C or protein should only be in selected thrombosis-prone families (1B). testing is the benefits and of testing should be in the of and It is not possible to give a validated recommendation as to how such patients and families should be selected. • Case finding for or heritable thrombophilia is not indicated as these are they are not by family and the risk of unprovoked thrombosis is low women heritable thrombophilia has in is that testing decision regarding of a or the risk of thrombosis is low and the that venous thrombosis has a with in relation to testing uncertain an is to the risk is as the is is there a indication for and in most there is only a is are associated with a lower risk of venous thrombosis et al, 2008). the in thrombophilia be in decision a for unselected women was as the most et al, A has for testing relatives of et al, 2008). the on such as women testing not a or and that of venous thrombosis are to these low risk has not in the A with a history of venous thrombosis is a to an oestrogen-containing The risk is on the of thrombosis in the a history of an who venous thrombosis as a of is not a a with unprovoked venous thrombosis, or specifically a venous thrombosis a should be a strong families with known heritable the risk of venous thrombosis can be in as as and a thrombophilia result not an risk of venous thrombosis. decisions regarding of oestrogen-containing preparations and whether thrombophilia testing is likely to be should be made with reference to clinical risk and the associated with venous thrombosis in the • a with venous thrombosis has not tested an or Testing for heritable thrombophilia an uncertain of risk and is not recommended (1C). • a with venous thrombosis has tested and the result is an or Testing for heritable thrombophilia an uncertain of risk and is not recommended (1C). • a with venous thrombosis has tested and the result is an or testing as a test result not an risk of venous thrombosis. Testing for heritable thrombophilia may of selected women if a risk thrombophilia has in the symptomatic (C). to from the of and is recommended of and Pregnancy is associated with a to risk of venous thrombosis to women of age with an risk of 1 to 2 et al, 2006). The risk of venous thrombosis, to the is in pregnancy in women with a thrombosis et al, an of of from 1 pregnancy in the the risk for pregnancy-associated venous thrombosis thrombophilia and a history of thrombosis et al, 2006). of and of not in a study of women with venous thrombosis for whom on the thrombophilia was the of recurrence was in women with and without thrombophilia, only women risk thrombophilias et al, this study women with a episode of venous thrombosis pregnant and did not in thrombosis in of did not in women was a finding to a study et al, a study of women with of protein C or protein from families from testing patients with venous thrombosis the risk of pregnancy-associated venous thrombosis was after of the et al, of women and of women venous thrombosis of of in women by venous thrombosis with of in a of thrombophilias there was an associated risk of venous thrombosis in those with thrombophilia et al, 2006). The risk was in and in women who for the or for the The risk of venous thrombosis in women with was and for protein C and protein as to not the risk of pregnancy-associated venous thrombosis in women with heritable thrombophilia with history is women with or those for the or the or who are should be as at The of women with these is women with a history of venous thrombosis the factor in whether should be is if venous thrombosis was provoked or the episode was should be and thrombophilia testing is not if is women with a first provoked the decision to test or not should be by the strength of the for example venous thrombosis associated with and not be an indication for or women with a with thrombosis the decision to test should be by whether or not the in the was unprovoked or provoked and the strength of the the in the was pregnancy or testing and finding thrombophilia should of if the symptomatic was known to the same of or protein testing in pregnancy is to the results with reference to the of pregnancy on the • should be for risk of pregnancy-associated venous thrombosis in relation to clinical risk (1B). • women with a unprovoked venous thrombosis or pregnancy or thrombosis for on clinical risk and testing for heritable thrombophilia is not • with a to a or not require or testing • with a to a should be tested and for if a thrombophilia is • the asymptomatic with a family history of venous thrombosis testing is not if the clinical are to result in • It is that asymptomatic women with a family history of venous thrombosis be tested if an in a was or provoked by or a risk factor The result be if the has a known is evidence of an heritable thrombophilia and pregnancy morbidity early and pregnancy and et al, & et al, 2006; & 2008). decisions should be based on clinical and not on the results of thrombophilia in the of the years) with a history a decision to with low should not be by the results of testing for heritable • therapy should not be to pregnant women based on tests for heritable with a treatment or in women with a history of pregnancy are in these a benefit in women with pregnancy and heritable thrombophilia, as with women without thrombophilia, only there be a for that therapy is to pregnant women with a history of pregnancy based on testing for heritable hyperstimulation is associated with an risk of venous and arterial thrombosis. the risk of venous thrombosis in these women is and to be treatment & a to that of pregnancy-associated venous thrombosis. who venous thrombosis in with ovarian hyperstimulation with upper limb or vein thrombosis for that are The of thrombophilia is not in women with hyperstimulation As the of the is low the predictive value of thrombophilia testing be low and testing should not be used to influence strategies in women ovarian • Testing asymptomatic women conception and those with ovarian hyperstimulation syndrome is not indicated (1B). for hospitalised patients should be in with a risk based on and risk for venous thrombosis. for heritable thrombophilia is not indicated a heritable thrombophilia may influence the of • of hospitalised patients to patients at risk of venous thrombosis is not indicated • hospitalised patients should be for risk of venous thrombosis regardless of heritable thrombophilia based on a clinical risk (1B). The of a known heritable thrombophilia may influence the of of an heritable thrombophilia and arterial thrombosis is to and & 2008). It is possible that heritable that result in the of & as there is an arterial and venous thrombosis risk et al, patients presenting with venous thrombosis the age of there is an risk of acute et al, 2008). the of heritable thrombophilia, as with risk factors, is not to therapy for and patients are tested after an arterial (Coppens et al, As there is and as treatment and should be in relation to risk factors, thrombophilia testing is not • Testing for heritable thrombophilia is not indicated in patients with arterial thrombosis (1B). Testing may a factor not management decisions. anticoagulant therapy is not and in children there may be a a is or the of stroke stroke in the • It is that testing for heritable thrombophilia is not indicated in children with stroke for laboratory Committee for Standards in Haematology should be used where and are a protein C not a protein C with to a in the a protein C be to this the of the result in for other as to a the of be by and the with as as the of and the example an a may not be associated with an risk of venous thrombosis. in families with a may to and et al, The of thrombophilia test results is and in are results in and et al, and may not be and are thrombosis to is diagnosis should be when there is a in the of of the heritable thrombophilias by this and levels of and and the of patients with is indicated by and the of results on the of • Testing at the of acute venous thrombosis is not indicated as the and of testing to be and the patient to be As treatment of acute venous thrombosis is not by test testing can be if • The should be to the of a in protein C and • should be used to and protein C • of protein C are less to than and are • of protein are to a protein is used in the low results should be with an of protein • an protein is to the the test of the test in factor as to the test should be the should be by a is if a test for is used • testing for of of protein C and protein is indicated and a low should be on or should not be on a • quality and in quality are • testing be by laboratory and the clinical of the results be by an who is of that may influence test results in The recommended (grade and (grade for testing or not testing can be used as to for thrombophilia It is that clinical management decisions in patients for whom thrombophilia testing was to that decisions regarding intensity and duration of anticoagulation are not made on the of the thrombophilia test anticoagulation after a first episode of venous thrombosis on the of testing and finding the in quality should be the and in these is to be and at the of to the the British Society for Haematology the for the of these of the British Committee for Standards in