we observed a successful re - challenge of warfarin therapy in a patient with atrial fibrillation and factor  vii ( fvii ) deficiency.challenges with using warfarin therapy in fvii deficiency include lack of a defined optimal target international normalized ratio range and a poor correlation between the degree of fvii deficiency and bleeding risk.we hypothesize anticoagulants which do not directly affect fvii , such as the direct oral anticoagulants , may carry less risk of bleeding complications than warfarin to reduce the risk of thromboembolic stroke in patients with atrial fibrillation and fvii deficiency . it involves a number of enzymatic steps , which activate circulating clotting factors , ultimately leading to clot formation ( see fig .  1 ) . circulating factor  vii ( fvii ) binds to tissue factor , and the resulting complex becomes activated fvii ( fviia ) . fviia then directly catalyses the conversion of factor  x to factor  xa ( fxa ) in the common pathway and indirectly via the activation of factor  ix to factor  ixa . while the extrinsic pathway initiates haemostasis , sustained haemostasis is dependent upon the continued and amplified procoagulant action of the intrinsic pathway , which involves factors viii , ix , xi and  xii [ 2 , 3].fig . 1effects of multiple anticoagulant medications on the coagulation cascade 
  effects of multiple anticoagulant medications on the coagulation cascade given the complex nature of the coagulation pathway , one can appreciate the complexity of coagulation disorders . classical bleeding disorders include haemophilia a and  b ; however , a number of rare bleeding disorders ( rbds ) exist . rbds represent only about 35  % of inherited coagulation deficiencies and include deficiencies in fibrinogen ; factors ii , v , v  +  viii , vii , x and  xiii ; and a combination of the vitamin  k - dependent factors . the most prevalent rbd is fvii deficiency , which affects approximately 1  out of every 500,000 people in the usa , and the prevalence varies in other countries . the hallmark of fvii deficiency is a prolonged prothrombin time ( pt ) and an elevated international normalized ratio ( inr ) in the setting of normal liver function and a normal activated partial thromboplastin time ( aptt ) . first , fvii can potentially exist in several different forms , and measuring fvii is further complicated by the many different assays available [ 810 ] . for the purposes of this article , fvii is reported as fvii coagulation activity ( fviic ) , expressed as a percentage , with normal activity being 50150  % . our institution utilized a one - step clotting assay , with the result being normalized to determine the percentage activity . second , determining disease severity on the basis of fviic is also difficult , as there is a poor correlation between fviic  and bleeding risk , as some patients with moderate to severe deficiency may remain asymptomatic , while others with mild deficiency may experience major bleeding events . disease severity may be better classified on the basis of the location and frequency of bleeding events [ 7 , 12 ] . a recent retrospective analysis of 83 patients with fvii deficiency undergoing surgical procedures recommended using fvii levels , the bleeding history and the type of surgery to help estimate bleeding risk and guide perioperative management . lastly , gene analysis is also difficult to interpret , as there are over 130 known mutations , with many still lacking defined phenotypic characteristics . progress is being made as national and international registries for rbds continue to provide information about fvii deficiency . although rbds inherently limit coagulation and may predispose patients to bleeding , patients with fvii deficiency may still require anticoagulation therapy if indicated . a case series analysed thromboembolic events in patients with fvii deficiency and concluded that those with mild fvii deficiency should not be precluded from receiving antithrombotic prophylaxis . historically , warfarin has been the initial treatment of choice in this limited patient population . warfarin works by blocking the regeneration of vitamin  k epoxide , thus inhibiting the synthesis of vitamin  k - dependent clotting factors ii , vii , ix and  x , as well as the anticoagulant proteins c and  s. there is evidence to suggest that not all of the vitamin  k - dependent clotting factors are affected equally by warfarin , with fvii and factor  ix being suppressed to a greater degree than factors ii and  x . the pt is used to monitor warfarin therapy and is converted to an inr for standardization . the pt reflects the functionality of several different clotting factors , including the vitamin  k - dependent clotting factors ; however , a prolonged pt is not seen until one of the clotting factors has decreased to < 3040  % . for conventional patients who are stable on warfarin therapy , however , in the presence of fvii deficiency , the inr may not as accurately represent the degree of coagulation ability , given the inherent decrease of fvii in this rbd . monitoring treatment through fvii activity may also prove to be difficult , as the minimal levels needed to sustain haemostasis are not well established . there is limited published literature to guide anticoagulation therapy and monitoring in this population  due to the rare nature of the disorder . three case reports involving the use of vitamin  k antagonists for atrial fibrillation in patients with fvii deficiency have been published : the first case was a 50-year - old male with a prolonged pt and an inr of 1.5 at baseline . he developed an inr of 19.6 after four doses of warfarin 5  mg , which prompted discontinuation . two weeks later , laboratory analysis revealed an fviic of 43  % , which led to the diagnosis of mild fvii deficiency . warfarin was re - started at a higher inr goal of 2.53.5 to ensure adequate anticoagulation in the presence of an elevated baseline inr . after 18 months , no bleeding or thrombotic events were reported , despite the inr being in the therapeutic range only 32  % of the time.the second case was a 77-year - old female . she developed an inr of 6.0 after two doses of warfarin 10  mg , which prompted discontinuation . warfarin was re - started , and over the next few months , the patient s inr ranged from 2.2 to 3.8 with doses ranging from 0.5 to 4  mg weekly . when warfarin was withheld for 2 weeks and the patient s inr remained elevated at  3.5 , she was evaluated for an rbd . it was concluded that the risks with warfarin outweighed the benefits , and the patient was switched to aspirin.the third case was an 80-year - old male with a baseline inr of 2.1 and an fviic of 10  % . his inr goal was set at 2.53.0 . while his inr was within the goal range , his fviic decreased to 5  % ( equal to a 50  % decrease from baseline ) , whereas none of the other vitamin  k - dependent clotting factors decreased more than 30  % in comparison with baseline . given the risk of bleeding and perceived inadequate anticoagulant effect , warfarin was discontinued , and enoxaparin ( a low molecular weight heparin [ lmwh ] ) was initiated , which was monitored using anti - fxa activity . the patient received enoxaparin for 3 months without any bleeding symptoms before undergoing successful cardioversion . the first case was a 50-year - old male with a prolonged pt and an inr of 1.5 at baseline . he developed an inr of 19.6 after four doses of warfarin 5  mg , which prompted discontinuation . two weeks later , laboratory analysis revealed an fviic of 43  % , which led to the diagnosis of mild fvii deficiency . warfarin was re - started at a higher inr goal of 2.53.5 to ensure adequate anticoagulation in the presence of an elevated baseline inr . after 18 months , no bleeding or thrombotic events were reported , despite the inr being in the therapeutic range only 32  % of the time . she developed an inr of 6.0 after two doses of warfarin 10  mg , which prompted discontinuation . warfarin was re - started , and over the next few months , the patient s inr ranged from 2.2 to 3.8 with doses ranging from 0.5 to 4  mg weekly . when warfarin was withheld for 2 weeks and the patient s inr remained elevated at  3.5 , she was evaluated for an rbd . it was concluded that the risks with warfarin outweighed the benefits , and the patient was switched to aspirin . the third case was an 80-year - old male with a baseline inr of 2.1 and an fviic of 10  % . his inr goal was set at 2.53.0 . while his inr was within the goal range , his fviic decreased to 5  % ( equal to a 50  % decrease from baseline ) , whereas none of the other vitamin  k - dependent clotting factors decreased more than 30  % in comparison with baseline . given the risk of bleeding and perceived inadequate anticoagulant effect , warfarin was discontinued , and enoxaparin ( a low molecular weight heparin [ lmwh ] ) was initiated , which was monitored using anti - fxa activity . the patient received enoxaparin for 3 months without any bleeding symptoms before undergoing successful cardioversion . in summary , although none of these patients developed major bleeding symptoms with vitamin  k antagonist therapy , all encountered challenges with monitoring and accurate assessment of the anticoagulant effect . such challenges lead to uncertainties in how to implement anticoagulation therapy in patients with this rbd , as further highlighted by the case summary below . a 70-year - old african american female with atrial fibrillation was referred to haematology in 2010 for evaluation of a mildly prolonged pt with persistent vaginal bleeding . laboratory test results revealed a decreased fviic of 33  % ( reference 50150  % ) , and fvii deficiency was diagnosed . the patient underwent endometrial cryotherapy , and after 4 months without recurrent vaginal bleeding , haematology cleared the patient to start warfarin therapy , with an inr goal of 2.03.0 . the patient s baseline inr was 1.4 , and warfarin was conservatively started at 2  mg daily . the inr remained at 1.4 for the first 4 weeks of therapy , despite gradual dose increases . nearly 6 weeks into therapy , the patient made a dosing error , which caused her inr to increase to  2.5 . she developed recurrent vaginal bleeding , and her fviic was found to be 10  % , which prompted warfarin discontinuation . it was decided to re - attempt warfarin therapy with a lower inr goal of 1.52.0 , as the risks of stroke without anticoagulation seemed to outweigh the risks of bleeding with anticoagulation . the patient s risk factors for stroke had not changed since her initial warfarin course . haematology recommended discontinuing warfarin if fviic decreased to < 15% or if the patient developed any clinical signs of bleeding . a total weekly dose of 40  mg was found to maintain her inr in the range of 1.61.8 . the fviic varied between 24 and 28  % during the first 6 months of warfarin therapy . during the seventh month , the patient s fviic decreased to 15  % , with a corresponding increase in her inr to 2.4 , despite no change in her weekly dose . her weekly doses , inr results and fviic results are shown in table  1.table  1case patient dose , international normalized ratio ( inr ) and factor  vii coagulation activity ( fviic ) resultsdatedose ( mg / week)inrfviic ( % ) commentsseptember 27 , 2010none1.333first haematology consultationapril 11 , 2011none1.4warfarin 2  mg daily started1st attemptmay 5 , 2011241.437may 23 , 2011562.510dose error , recurrent vaginal bleeding , warfarin discontinuedmarch 26 , 2014none1.244second haematology consultationjune 19 , 2014none1.2warfarin 2  mg daily started2nd attemptaugust 11 , 2014321.424october 7 , 2014401.728december 11 , 2014401.732january 27 , 2015402.415no signs / symptoms of bleeding , warfarin dose decreased to 38  mg / weekmarch 3 , 2015381.630 
  case patient dose , international normalized ratio ( inr ) and factor  vii coagulation activity ( fviic ) results our case report describes a successful re - challenge of warfarin therapy in a patient with fvii deficiency . however , we must recognize the varying degrees of fviic and the corresponding bleeding risk among patients with fvii deficiency . when our case is compared with the two patient cases that required vitamin k  antagonist discontinuation , our patient had a more mild fvii deficiency and maintained higher fviic activity during anticoagulation therapy . for patients with lower fviic at baseline or who experience bleeding events or significant decreases in fviic with warfarin therapy , alternative therapies could be considered . our patient was initially treated with warfarin in 2011 . at that time , evidence - based practice guidelines recommended long - term antithrombotic therapy with either warfarin or aspirin , since the patient had only one major risk factor  hypertension [ 21 , 22 ] . in 2014 , however , updated guidelines now favoured anticoagulation therapy for our patient , despite no change in her risk factors [ 23 , 24 ] . the american heart association / american college of cardiology / heart rhythm society ( aha / acc / hrs ) 2014 guidelines recommend using the cha2ds2-vasc scoring system to assess stroke risk . the cha2ds2-vasc score for our patient was  3 , due to hypertension , female sex , and age 65  years . for scores 2 , anticoagulation therapy is recommended ( warfarin : level of evidence  a ; dabigatran , rivaroxaban , apixaban : level of evidence  b ) . these changes in treatment guidelines are significant for our patient , as aspirin is no longer considered an acceptable treatment option on the basis of her risk factors . the new agents mentioned above represent a new group of anticoagulants known as direct oral anticoagulants ( doacs ) . this group currently includes direct thrombin ( factor  ii [ fii ] ) inhibitors ( dabigatran ) and direct fxa inhibitors ( rivaroxaban , apixaban and edoxaban ) . the mechanisms by which both classes of agents act target a clotting factor only in the common pathway of the coagulation cascade , independent from fvii . laboratory analysis has shown that these agents do not inhibit fvii [ 25 , 26 ] . clinical studies have shown dabigatran , rivaroxaban , apixaban and edoxaban to be comparably safe and effective in comparison with warfarin therapy for the treatment of atrial fibrillation , although patients with fvii deficiency and other rbds were excluded from the trials [ 2730 ] . however , because these agents provide therapeutic anticoagulation by targeting clotting factors below fvii in the clotting cascade ( fig .  1 ) and do not directly affect fvii activity , they may theoretically carry less bleeding risk than warfarin in patients with fvii deficiency . this suggestion to choose an anticoagulant that does not affect fvii activity is supported by the case report   in 2009 , which emphasized heparin use in patients with fvii deficiency . in that case , however , at that time , the doacs were not approved or available for use . interestingly , the doacs have mechanisms of action similar to those of heparin , targeting fxa and/or fii . while heparin remains a viable option , it must be administered parenterally , which is a disadvantage in comparison with orally administered medications . one important difference between lmwh and the doacs is the ability to monitor the anticoagulant effect beyond the fviic activity assay , as lmwh can be monitored using anti - xa levels , which correlate with the actual bleeding risk . this ability ( not requirement ) to monitor the anticoagulant effect may serve as an advantage in this population at higher risk of bleeding , as it gives the clinician a method to objectively assess the degree of anticoagulation being provided . the doacs rivaroxaban , apixaban and edoxaban are fxa inhibitors and , although anti - xa level monitoring is not performed clinically , it would seem reasonable that it could be utilized with these agents as well . lastly , the initial lack of antidotes or reversal agents for the doac class was considered to be a disadvantage but , recently , highly specific reversal agents have been developed and studied with positive results in clinical trials [ 32 , 33 ] . before reversal agents were available , a subgroup analysis from the rocket - af trial of 779 patients who experienced major bleeding revealed no differences in outcomes in patients treated with rivaroxaban versus warfarin , including death ( 20.4 vs 26.1  % ; hazard ratio 0.69 , 95  % confidence interval 0.461.04 ) . there was also less use of prothrombin complex concentrate ( pcc ) and significantly less use of fresh frozen plasma ( ffp ) with rivaroxaban compared with warfarin . this information supports the consideration of doacs as a potential alternative to vitamin  k antagonists , even in unique and high - risk patient situations . warfarin has been the treatment of choice for thromboembolic conditions for multiple decades , but the data are limited in patients with rbds . we have described a successful re - challenge of warfarin therapy in a patient with fvii deficiency . however , compared with our patient case , patients with more severe fvii deficiency at baseline or those who experience lower levels of fvii activity during warfarin therapy may not observe the same positive response . the emergence of the doac group of anticoagulants has provided more options for clinicians when treating patients with rbds in the outpatient setting . based on their mechanisms of action in relation to the coagulation cascade , it would seem doacs could potentially be safer alternatives to warfarin for patients with fvii deficiency by providing similarly therapeutic anticoagulation with less bleeding risk . future studies would be helpful to evaluate the safety and effectiveness of doac therapy in patients with fvii deficiency . however , because of the rare nature of the disorder , it is not feasible to conduct prospective , randomized studies . large clinical trials of anticoagulants typically exclude patients with fvii deficiency and other rbds , although this would be an excellent way to obtain more data . it is imperative for clinicians to publish case reports and other retrospective data to guide future therapy in this population .
factor vii ( fvii ) deficiency is the most prevalent rare bleeding disorder in the usa and affects approximately 1  out of every 500,000 people . 
 warfarin inhibits the synthesis of fvii , in addition to other clotting factors . 
 warfarin is contraindicated in patients with bleeding tendencies or blood dyscrasias ; therefore , the literature regarding the use of warfarin in fvii deficiency is very limited . 
 we report a successful re - challenge of warfarin therapy in a patient with fvii deficiency . a 70-year - old woman with fvii deficiency experienced a significant decrease in fvii activity and subsequent vaginal bleeding roughly 5 weeks after starting warfarin for atrial fibrillation . 
 the patient was switched to aspirin therapy . 
 nearly 4 years later , warfarin therapy was re - attempted by a different haematologist . after 9 months , 
 fvii activity remained in an acceptable range and no bleeding events had occurred . in addition , once the maintenance dose was established , the international normalized ratio remained within the goal range ( 1.52.0 ) for the majority of assessments . regarding future considerations , we hypothesize that anticoagulants that do not directly affect fvii , such as the direct oral anticoagulants , would carry less risk of bleeding complications and therefore may be safer alternatives to warfarin to reduce the risk of thromboembolic stroke in patients with atrial fibrillation and fvii deficiency .