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Acquired coagulation inhibitors result from immune-mediated depletion or inhibition of a coagulation factor. Inhibitors are most commonly directed against factor VIII (FVIII) and von Willebrand factor (VWF) and inhibitors against other coagulation factors are only occasionally reported. Since the publication of previous guidelines (Laffan et al, 2004; Pasi et al, 2004; Hay et al, 2006) substantial new data has been published on acquired FVIII inhibitors, necessitating updated guidelines. The rarity of acquired inhibitors to other coagulation factors means that limited information is available to guide management and the treatment strategies suggested are necessarily by consensus and often extrapolated from data derived from FVIII inhibitors. Inhibitors to VWF will not be covered because a revised von willebrand disease (VWD) guideline is in preparation (Laffan et al, 2004; Pasi et al, 2004). The writing group reviewed publications known to them, supplemented with papers identified through Pubmed, using index terms H(a)emophilia, acquired h(a)emophilia, factors VIII, II, V, VII, IX, X, XI, XIII, fibrinogen, fibrin, inhibitors, autoantibodies, rFVIIa, Novoseven, FEIBA, aPCC, rituximab, management. The writing group produced the draft guideline, which was reviewed and revised by members of the United Kingdom Haemophilia Centre Doctors’ Organization (UKHCDO) Advisory Board. The guideline was also reviewed by a sounding board of approximately 50 UK haematologists, the British Committee for Standards in Haematology (BCSH) and the British Society for Haematology (BSH) Committees and comments incorporated where appropriate. The ‘GRADE’ system was used to quote levels and grades of evidence, details of which can be found at http://www.bcshguidelines.com/BCSH_PROCESS/EVIDENCE_LEVELS_AND_GRADES_OF _RECOMMENDATION/43_GRADE.html. The objective of this guideline is to provide healthcare professionals with pragmatic guidance on the management of patients with acquired coagulation factor inhibitors although individual patient circumstances may dictate an alternative approach. Patients should be registered, and treated jointly with a Comprehensive Care Haemophilia Centre (CCC) experienced in the management of inhibitors (National Service Specification available at www.ukhcdo.org). CCCs must provide 24-h access to senior clinicians with experience in inhibitor management and laboratory services for the measurement of factor levels and inhibitor titres. An underlying cause of the acquired inhibitor should be sought and patients should be investigated for autoimmune disease and malignancy. Patients should be offered inclusion in appropriate clinical trials and reported to registries. UK patients must be registered with the National Haemophilia Database. Acquired haemophilia A (AHA) has an incidence of about 1·5/million/year and presents most commonly in the elderly at a median age of 75–80 years (Collins et al, 2004, 2007; Knobl et al, 2012). Other inhibitors are much less common. AHA is associated with polymyalgia, rheumatoid arthritis, systemic lupus erythematosus (SLE) and other autoimmune diseases, malignancy, pregnancy and pemphigoid. No association is identified in about half of patients (Green & Lechner, 1981; Morrison & Ludlam, 1995; Collins et al, 2007). Inhibitors to other coagulation factors have been associated with auto-immune disease and malignancy (Hay, 2012). The mortality associated with AHA has been reported to be between 8% and 42% (Green & Lechner, 1981; Morrison et al, 1993; Hay et al, 1997; Delgado et al, 2003; Collins et al, 2007). In recent studies, 3–12% of deaths were attributed to the effects of immunosuppression and infection whilst 3–8% were attributed to bleeding (Collins et al, 2007; Knobl et al, 2012). An acquired inhibitor should be considered in patients with recent onset of abnormal bleeding. Patients usually present to clinicians with limited experience of the disorder and diagnosis and appropriate treatment is often delayed. Severe and life-threatening bleeding is common in AHA, although, in contrast no haemostatic treatment is required in 25–33% of cases (Lottenberg et al, 1987; Collins et al, 2007; Knobl et al, 2012). Some patients present without clinical bleeding. The severity of bleeding at presentation does not predict future bleeding and patients remain at risk of fatal bleeding until the inhibitor has been eradicated (Collins et al, 2007). The clinical features of AHA differ from those of congenital haemophilia because bruising, retroperitoneal, muscle, gastrointestinal and urogenital bleeding are common whereas haemarthroses are uncommon (Morrison et al, 1993; Hay et al, 1997; Delgado et al, 2003; Collins et al, 2007; Knobl et al, 2012). Fatality is associated with gastrointestinal, intracranial and retroperitoneal bleeds (Collins et al, 2007). Compartment syndromes and critical compression of nerves and blood vessels may be seen. There is limited information on the clinical features associated with inhibitors to other coagulation factors and this will be covered in specific sections of this guideline. Acquired haemophilia A has been reported in association with anticoagulation and anti-platelet agents and diagnosis may be delayed because the bleeding is assumed to be caused by these agents (Uggla et al, 2003; Dragani et al, 2004; Haj et al, 2004; Vadikolia et al, 2007). Excessive bruising or unexpected bleeding in patients on anticoagulants should be further investigated. Diagnosis of acquired coagulation factor inhibitors, and their differentiation from other coagulation abnormalities, requires specialized investigation, often necessitating referral to a reference laboratory. When investigating abnormal clotting times in patients presenting with bleeding, is to treatment with for further laboratory are of abnormal coagulation that not with with an or The of of on the of the inhibitor The diagnosis is by of specific factors and of an inhibitor in the for FVIII for other a of the In the should be to In the of a is to a without the A lupus should be a cause of coagulation factor levels et al, in the of bleeding. Acquired coagulation factor inhibitors may with a to In cases an inhibitor to factor may with the of other is with FVIII inhibitors, where factors may be to inhibition of FVIII in the this to In these cases will result in of the factors whilst the factor will remain is that factor of and an of against the In for for of may be Some specialized may to this is not FVIII inhibitors are and and with may inhibition on that is not present Inhibitors to other coagulation factors have not been reported to be have been reported for FVIII inhibitor which may by FVIII may be because not with this is often to the of an acquired FVIII inhibitor to the the of is and may to the inhibitor is to the that most half the FVIII FVIII inhibitor to this should be The laboratory of other acquired inhibitors will be covered in appropriate in diagnosis and treatment is patients at risk of bleeding, are In AHA, were in and in of cases and between the onset of bleeding and and the of a and diagnosis et al, 2012). should have in that appropriate of abnormal coagulation of an the does not with and the is factor levels should be A is suggested which can be to should be in to clinicians of the of abnormal and to further are to or the should for the bleeding of the disease a diagnosis is and consensus treatment guidelines on the treatment of AHA have been published et al, et al, Patients should not be to are because bleeding may result from The of available haemostatic agents is and are for that be considered for the and of in the of an inhibitor should be against the of management until FVIII levels have and the of a may also to bleeding and should be to a Some not to in which are by haemophilia should be about the risk of bleeds and blood and blood are only Patients should be against the risk of are of bleeding should be by a experienced in the treatment of patients with inhibitors because bleeds may be and haemostatic is required to and In patients not haemostatic (Collins et al, 2007; et al, because of the risk of associated with for may be haemostatic treatment is required should be with a et al, 2012). The available agents are factor and the on the haemostatic and effects of agents in patients with AHA to these and can not necessarily be extrapolated to other or with FVIII is less agents with et al, 2012). may FVIII levels in although this treatment may be in patients to & 1993; & FVIII was to be in bleeding in AHA (Morrison et al, data on the treatment of bleeds for patients with FVIII inhibitors to congenital haemophilia and on haemarthroses (Collins et al, The that cause AHA have to the associated with congenital haemophilia and the bleeding In haemarthroses are means that data derived from patients with congenital inhibitors necessarily be extrapolated to A of AHA patients treated with data from that inclusion a et al, the and Society and the published reported on patients and bleeds et al, 2007). In the where was used treatment was or in of cases et al, 2007). were reported to the Acquired Haemophilia where bleeds treated with in of cases et al, 2012). In bleeds were treated with with et al, 2012). In a of in bleeds and bleeds haemostatic at a median of 2004). When used in was reported or in of cases et al, 2007). The haemostatic of and has not been in an of data in the which for and patient by found that the agents were et al, 2012). In congenital haemophilia that and for treatment of haemarthroses also et al, 2007; et al, can be used treatment for bleeding in The of will on of the previous of of and to is the alternative may be and should be at an The of should be and for with a of A of treatment at and is often to and must be on a In for and patient the of haemostatic was with agents to FVIII or et al, 2012). patients with AHA are to FVIII the inhibitor is the is and the is not of FVIII FVIII is usually with an to a which is by a in a of FVIII that may for & The FVIII is not a guide to clinical The of FVIII must be to the inhibitor and provide an haemostatic have been suggested for the the in the laboratory measurement of inhibitor in AHA at FVIII is a is to be required with or and of FVIII and clinical is a is an to an alternative is The of FVIII in with may result in haemostatic FVIII levels and of bleeding, inhibitor et al, treatment may be or agents have although is available in only a limited of et al, et al, Some patients with a inhibitor and FVIII may to clinical is and haemostatic is not that with agents & 1993; & et al, 2012). may be to bleeds laboratory and clinical of is In AHA, the inhibitor to FVIII is usually that of the (Morrison et al, and FVIII may in where FVIII is FVIII has in AHA (Morrison et al, is no The of a FVIII is in is a for should be considered for bleeds from bleeding. about of with of are and clinicians in with et al, 2012). may be for or bleeding. The of an to other haemostatic is in the UK clinical guidelines for patients with acquired inhibitors of coagulation factors and or that has to to other although is only limited data data on the for this will be available in the future of the management of in the should only be at the of agents or with FVIII be and life-threatening bleeding may with or is associated with and and the incidence of to be these agents are used in congenital haemophilia is to risk factors associated with the age and the often clinical of these A of patients with AHA treated with reported in patients et al, 2007). reported and in patients treated with a haemostatic and in patients not treated with a haemostatic There were associated with rFVIIa, with FEIBA, with FVIII or and in cases the haemostatic was not reported et al, 2012). a between agents and the reported be is required and the to a is not of bleeding should not be because the of of bleeding the risk of should be to which often The of at has been to be and for the treatment of haemarthroses in congenital haemophilia et al, et al, should be considered only in circumstances in patients with AHA because has not been to be in this patient group or for the of bleeds associated with AHA et al, in the management of bleeds to may be on a The of and should be & in or to et al, 2007). is often associated with FVIII levels because patients are to have other risk factors for should be and treated with appropriate No laboratory have been for haemostatic of agents in FVIII levels can be and haemostatic used not necessarily with haemostatic et al, and should only be used of a clinical of is by measurement of and appropriate to an inhibitor should be the diagnosis has been to the a patient is at risk of bleeding (Collins et al, although haemostatic should be the in the The of to the of the Patients should be for of on the of immunosuppression are to because of the of and in are to patients and publication of (Collins & reported a in of patients a median although was associated and patients of bleeding (Lottenberg et al, this has not been have identified age and underlying malignancy risk factors for mortality et al, 2003; et al, Patients presenting with FVIII levels and inhibitor are to to immunosuppression the is to be the for treatment (Collins et al, 2007). The median to the of immunosuppression is about (Collins et al, 2012). treatment in is with or with a et al, The most of immunosuppression from the of Patients treated with were to those treated with and The were by and a for inhibitor FVIII and underlying The reported an of of a using to the a of (Collins et al, 2012). A patients treated with and The of this although the were not for presenting The patients treated with at a median of to at for the and group (Collins et al, 2007). A of reported that the of and in patients to et al, A recent of the previous found that patients immunosuppression a of for acquired haemophilia to those no and an of for et al, The only patients (Green et al, is often to the of to a has not been by The not provide that this is to that patients treated with a of and were to a the in terms of and is the in et al, 2003; Collins et al, 2012). immunosuppression have been reported to have without the must be treated with because are et al, is a common treatment for AHA are no data to the that or with other in patients or a to A of patients treated with and a of other agents reported a of is and no were & A recent reported that patients treated with to patients treated with and et al, 2007). reported that of patients treated with and a to treated with and (Collins et al, 2012). the patients treated with a (Collins et al, 2012). on is not associated with The patients in the a median to a inhibitor of which is a to other to (Collins et al, 2012). In a of patients treated with with a median to of et al, Some patients are to to (Collins et al, 2012). There is no to the of in patients with inhibitors, has been suggested by et al, The of or and has been reported treatment with in patients at a median of no were reported in this et al, 2012). A of cases have been reported in which has et al, et al, et al, 2004; Haj et al, 2004). The available does not the of a or in with and an The and no for to other immunosuppression (Collins et al, and a the et al, FVIII in with agents has been reported. The of in these means that the of FVIII is to A of of FVIII for for a and for a with and reported in of patients a median to at a median of in treated with & A of patients treated with of FVIII with and in a in patients et al, The group reported patients were treated with and without FVIII and found et al, The of FVIII is because the of immunosuppression was for other et al, these are to that with FVIII is in AHA and the of FVIII in these must be A of patients with bleeding was treated with a of on and FVIII of bleeding was reported with an inhibitor at a median of and in of patients at a median of et al, The group has published updated data on patients with et al, no patients are reported and the of the FVIII is this treatment to be for bleeding and in with a of In the was reported in of patients at a median of to (Collins et al, 2007). was by which reported in of those treated with for and and in those treated with rituximab, a median of (Collins et al, 2012). patients a although required immunosuppression (Collins et al, 2012). Patients should be about and of and to of bleeding or bruising The risk of of AHA is are with of and In recent 3–12% of deaths have been attributed to the effects of through infection (Collins et al, 2012). of should be considered the FVIII is not and the inhibitor not In patients not to a a inhibitor or can be a patient treatment with rituximab, agents or inhibitors may be may be a alternative although are no in the of using this in cases may to immunosuppression and or In of patients a with with of a of agents (Collins et al, 2012). There is consensus that immunosuppression at the inhibitor should be the diagnosis of AHA has been The of and in a in terms of and is not by the of in further data available is not to and is at the of the on the clinical circumstances and the effects of AHA is a of reported in in the UK (Collins et al, and in cases years in of Haemophilia Patients present at a median of about can present to a et al, 1995; of Haemophilia et al, 1997; et al, patients of cases in the of an inhibitor et al, have reported a to to AHA caused by other although this was not in the patients reported to et al, can et al, 1995; of Haemophilia with agents should the age of the patients and the effects of in of age et al, has been used are no data to that is to other treatment et al, et al, in to be uncommon should be that this is a A of a risk of from in in of to no reported in et al, and in patients reported by an of Haemophilia The may the FVIII of the and this must be at the of et al, 1995; et al, of bleeds should the for AHA in et al, 1995; of Haemophilia about the risk of associated with agents in the should be in on the clinical treatment of bleeds and of coagulation factor inhibitors other FVIII is and patient should be Some inhibitors are on laboratory Patients presenting with bleeding should be treated with immunosuppression a of may be considered in cases because inhibitors are or In patients immunosuppression the used for FVIII may be a with (Hay, 2012). treatment on the of the inhibitor levels can be to laboratory to the inhibitors are limited data haemostatic of or FEIBA, to an may to the of other coagulation the risk of et al, a factor to an inhibitor will be by the of the is to be in most cases because will not be to to the inhibitor and factor levels without or coagulation factor may be considered in association with or Acquired autoimmune may with and with factor in a of may with or and may the of or (Hay, 2012). Inhibitors have been reported with and and are associated with against or should be the and are and the is using the with no the of or may for a should be features are may be and bleeding associated with a and bleeding often in with and has also has been et al, inhibitors that or the of in with and may be considered is not available are to be is to be In patients with abnormal bleeding, immunosuppression should be the diagnosis has been used to acquired FVIII inhibitors can be used and data to agents and have been reported et al, 1995; et al, & against in patients to of or and these with coagulation have found of to factor in of patients et al, to associated with may cause the patient is to the risk of Other acquired inhibitors directed against are usually associated with autoimmune or a in et al, et al, et al, Some cause acquired and may cause bleeding et al, et al, is most common infection in and should be considered in a with a and and recent onset of bruising or bleeding. The is often the may to An against be to cause a and that not with and to have a An against be to cause a with a The is often in patients to a of and of in the The will be and the inhibitor can be in a are most commonly associated with and this should be investigated et al, 2012). for may be Inhibitors to or may be associated with bleeding et al, et al, et al, et al, or are laboratory et al, using to the inhibitor and also to provide the inhibitor of to and the of may be used to the inhibitor whilst and factor VII, and associated with a is often to of and in these cases a can be used with of factor with may be considered for is less to be because of is through of the patient is abnormal bleeding, used for AHA can be to usually in and have been reported in association with or or malignancy. or usually to The is and patients to to have a inhibitors. inhibitors may a Knobl et al, An inhibitor to should be a and not with will be The of the can be with a The is to be no with of will be diagnosis from of a blood with will a inhibitor a or measurement of in the can an et al, are to those of congenital and from or bleeding, to life-threatening retroperitoneal et al, Other and gastrointestinal bleeding. The severity of bleeding and may with the Some patients have no bleeding with abnormal laboratory The bleeding may be to the of in the to be et al, et al, Severe bleeding have been with an that was present in the and et al, A was in a with an that the et al, Patients can often be with and because can inhibitors et al, for bleeds of and with et al, or be to be in this has also been used et al, autoimmune inhibitors may to is the used to FVIII inhibitors may be Acquired inhibitors may or and have been in association with the of in the of and and malignancy, A specific autoimmune has been from the of a patient with acquired a these are or is (Hay, 2012). will be of an that does not with In these cases is to a The will be and the inhibitor can be with a The of bleeding may be and intracranial is reported. are uncommon in congenital and autoimmune for (Hay, 2012). treatment with because coagulation without the for Other rFVIIa, and although these are less to a to the inhibitor can be is to be these strategies are with or without may be that of the associated underlying disease is and may be et al, can be inhibitors are associated with to those underlying acquired FVIII inhibitors and have bleeding et al, et al, Collins & are of an that does with to are The of the inhibitor can be with a and the of inhibition can be using a treatment with or using for acquired FVIII bleeding is not the alternative should be with of or a is less to be inhibitors in congenital haemophilia has not been although patients have been treated and of patients is inhibitors a and is not the is by The of with or without has been reported to be et al, these are for the treatment of AHA can be acquired is usually associated with are of acquired caused by an inhibitor to with cases in a recent et al, 2012). cases with onset of bleeding and underlying were The is not of infection and a malignancy, patients with et al, 2012). are to a and that not with The and will be The may also be and does not with or will be and the inhibitor can be with a The diagnosis is associated with to systemic In this the and with and will be no of an In systemic other coagulation factors VII, and and VWF may be et al, The reported bleeding in cases was gastrointestinal by Other bleeding bleeds and in cases There was no bleeding in at presentation The bleeding severity or not with the patients with a bleeding et al, et al, et al, & et al, & et al, 2012). haemostatic to and (Hay, 2012). are where and have not been is to be because of is through of and although in of & patients with the of rFVIIa, a of and the other a of et al, haemostatic has been reported in patient treated with et al, can with et al, that bleeds are treated with FEIBA, to the inhibitor and provide and also to an a is used to the inhibitor and the may to be used with laboratory of the and levels is required to levels whilst and of underlying disease to be for the of acquired inhibitors. using used to AHA can be used is these the of the to are associated with an underlying have less been reported in association with malignancy, autoimmune gastrointestinal or treatment with The bleeding is and is often et al, et al, et al, & et al, & et al, et al, et al, Patients with inhibitors have an that does not with is and the inhibitor can be with a acquired inhibitors are and are coagulation is for other that bleeding should be treated with et al, or with to those used for this is with be Acquired is often not associated with bleeding and immunosuppression may not be for In those with bleeding, used to AHA can be has been in patients with & and for et al, Acquired inhibitors to have been reported to by or on et al, 2012). coagulation the and are usually although the may be abnormal & may be although is on or usually levels can be using studies, although may be required to may be with which may levels et al, The of and inhibitors of can usually be in with using patient or to the of of in The bleeding of acquired may be congenital and bleeding, and bleeds to be common et al, et al, et al, of bleeding et of are to be the and most treatment et al, in with and has also been used & have been reported et al, In patients with abnormal bleeding, immunosuppression should be the diagnosis has been used to acquired FVIII inhibitors can be used and data to agents and have been reported et al, 1995; et al, & A immunosuppression has been et al, the and information in these guidelines is to be and at the of to the the the the for the of these guidelines.