acquired hemophilia a ( aha ) is a relatively rare and life - threatening bleeding disorder caused by spontaneous development of autoantibodies against factor viii ( fviii ) .
the reported annual incidence of aha is of the order of 1.5 individuals per million ( 1 ) .
the disease most commonly presents as spontaneous excessive hemorrhage in muscles , skin or soft tissues , or uncontrolled bleeding during surgery . to date
there is no apparent underlying cause in ~50% of the reported cases ; other cases are typically associated with autoimmune disorders , malignancy , adverse drug reactions and various skin diseases ( 2 ) . in 1993 , a 78-year old male patient developed generalized lymphadenopathy accompanied with a disproportionately elevated serum igg4 level .
in addition to the elevated igg4 levels , the disease is characterized by lymph node involvement due to lymphoplasmacytic infiltration with igg4-positive plasma cells , marked interstitial fibrosis , eosinophilic infiltration and obliterative phlebitis of the terminal venules ( 4 ) .
igg4-related disease is a fibroinflammatory systemic disease which affects multiple organs , including the biliary system , salivary glands , lymph nodes , pancreas , retroperitoneum , periorbital tissue , lungs , meninges , aorta , breast , prostate , thyroid gland , pericardium , skin and kidney ( 3,512 ) .
owing to multisystemic involvement , clinical manifestation of igg4-related disease varies widely , and depends on the severity of the affected organs .
an extensive literature search revealed only two documented cases of aha with co - existing igg4 related disease ( 13,14 ) . herein ,
a rare case of igg4 -related aha with multisystemic involvement is described that presented with a myriad of clinical characteristics .
the clinical relevance of aha has been discussed to provide a better understanding of this rare disorder .
a 55-year - old chinese male , who provided written informed consent , presented at shanxi dayi hospital of shanxi medical university ( shanxi , china ) in november 2014 with a history of chronic cough since half a year ago with no obvious cause .
there was progressive aggravation of cough , which could be induced by cooking fumes or pungent odor .
six days prior to admission , the patient caught a cold with further aggravation of cough , but without fever , hemoptysis , chest pain , palpitations and sweating .
the patient did not respond to antibiotic therapy prescribed at a local health clinic . on examination , the patient was not febrile ( 36.5c ) , and his vitals were stable with a systolic blood pressure of systolic 141 mmhg and diastolic 94 mmhg .
his systemic examination was unremarkable except for the presence of a small palpable submandibular lymph node and an enlarged left inguinal lymph node measuring 31 cm .
his abdomen was soft , non - tender with non - palpable liver and spleen .
the result of bronchial provocation test was positive and the patient was diagnosed as having bronchial asthma .
the patient had a significant past medical history , including hospitalization for autoimmune hepatitis with serum alanine aminotransferase ( alt ) 421 iu / ml and aspartate aminotransferase ( ast ) 600 iu / ml . anti - smooth muscle antibody was positive ( titre , 1:100 ) . abdominal computed tomography ( ct ) showed multiple enlarged lymph nodes in the ligament of liver and stomach , around the abdominal aorta and bilateral inguinal regions , with the left inguinal region being more affected .
the upper pancreatic bile duct was widened , indicating a possibility of cholecystitis or cholangitis . furthermore , there was thickening and consolidation in the wall of left ureter , indicating a possibility of a space occupying lesion ( sol ) of the ureter , accompanied with an inflammatory response in the renal pelvis and the upper ureter .
magnetic resonance cholangiopancreatography revealed multiple gallbladder and bile duct calculi , intra- and extrahepatic bile duct dilation , and abnormal signals in caput pancreatis accompanied with multiple enlarged small lymph nodes around the abdominal artery .
based on these findings , the patient was diagnosed with gallbladder and cystic duct calculi , acute cholecystitis and acute pancreatitis .
the symptoms of the patient improved with anti - inflammatory drugs and supportive treatment , with restoration of normal serum alt ( 25.2 iu / ml ) and ast ( 19.4 iu / ml ) levels . to rule out the possibility of sol in the left ureter
positron emission tomography ( pet)/ct performed three months prior to admission showed abnormal hypermetabolic signals in multiple organ systems ( including bone marrow , multiple lymph nodes , parotid gland , lung , gallbladder , bile duct , pancreas , prostate and testis ) , left hydronephrosis and dilatation of the upper left ureter .
assays for serum lupus anticoagulant combination , antinuclear antibody , antineutrophil cytoplasmic antibodies , immunoglobulin and complement levels were all negative .
three days after admission , the patient developed subcutaneous hemorrhages and pain in the right hip ( fig .
ultrasound examination revealed a subdermal hematoma over the right hip measuring 93x5 cm . on detailed enquiry , the patient revealed a past history of spontaneous bleeding in bilateral upper extremities 2 months prior to admission .
chest ct showed multiple diffuse nodular lesions with thickening of bronchovascular bundles , and multiple scattered high density spots in both lung lobes .
in addition , there was multiple lymph node enlargement in the mediastinum and pulmonary hila ( fig .
laboratory investigations at admission showed activated partial prothrombin time ( aptt ) of 120.0 sec ( normal range , 24.040.0 sec ) , but with normal prothrombin time , thrombin time and fibrinogen levels .
coagulation factor assay revealed a markedly decreased factor viii ( fviii ) activity at 0.5% ( normal range , 60150% ) , and a high - titer of fviii inhibitor at 27.2 bethesda units / ml ( bu / ml ) ( normal range , 00.6 bu / ml ) .
g / l ) . left inguinal lymph node biopsy revealed capsular thickening , marked lymphoplasmacytic infiltration with irregular fibrosis and obliterative phlebitis ( fig .
further positive immunostaining for human herpes virus type 8 , lambda and kappa light chains showed reactive lymphoid hyperplasia in the nodular lesion ( fig .
, immunohistochemical staining for igg4 revealed numerous igg4-positive plasma cells [ > 100 cells / human plasma fibronectin ( hpf ) ] in the nodular lesion , with an increased igg4/igg ratio of > 40% ( fig . 5 ) .
the patient was treated with oral prednisone ( initial dose , 40 mg / day ; maintenance dose , 15 mg / day ; cat .
after 2 weeks of treatment , the activated partial thromboplastin time was within the normal range .
furthermore , one month after treatment , chest ct scan showed clearing of the nodular lesions and lymph nodes .
there was no instance of relapse during follow - up ( table i ) after one and three months .
since the first reported case of igg4-related disease in 1993 ( 3 ) , there have been numerous reports of complicated diseases overlapping this clinical entity ( 14,15 ) .
although the understanding of igg4-related disease has rapidly increased , its etiology remains elusive . according to the clinicopathological characteristics of igg4-related disease , its proposed comprehensive diagnostic criteria consists of the following ( 14,16 ) :
i ) diffuse or localized swelling or masses in single or multiple organs on clinical examination ; ii ) elevated serum igg4 level ( 135 mg / dl ) ; and iii ) marked lymphocyte and plasmacyte infiltration , fibrosis and infiltration of igg4-positive plasma cells with a ratio of igg4/igg positive cells > 40% , and > 10 igg4-positive plasma cells / hpf on histopathological examination .
aha is a rare but life - threatening hemorrhagic disorder caused by the presence of spontaneous antibodies against fviii ( 17 ) .
although igg4-related disease can potentially affect any organ besides co - existence with other complicated diseases ; it is extremely rare for this condition to overlap aha disease .
only two documented cases of aha overlapping with igg4 related disease have been identified in the literature ( 13,14 ) . in the present case ,
the patient was diagnosed with aha based on the laboratory findings that included markedly increased aptt , markedly decreased factor viii ( fviii ) activity , and a high - titer of fviii inhibitor .
notably , the clinicopathological characteristics of the patient fulfilled all the diagnostic criteria of igg4-related disease described above .
a review of the patient 's past history revealed multiple organ diseases , including gallbladder and cystic duct calculi , acute cholecystitis , acute pancreatitis , urticaria , diabetes and low t3 syndrome . considering that igg-4-related disease could affect
any organ and can present with myriad manifestations , it is suggested that the multiple organ disease identified in this patient was caused by igg4-related aha .
the specific treatment of igg4-related aha resulted in the following response : i ) the manifestations of igg4-related aha , such as cough , nausea , abdominal pain and subcutaneous hemorrhage , were completely resolved ; ii ) blood glucose level and thyroid function were restored to normal range and remained stable , unlike that in igg4-related disease only , which frequently involves the pancreas and thyroid gland , causing diabetes and low t3 syndrome ; iii ) the specific serological markers of igg4-related aha , such as igg , aptt , fviii and fviii inhibitor were within normal range ; iv ) the abnormal hypermetabolic signals in multiple organ systems identified by pet / ct were alleviated .
igg4-related disease is a glucocorticoid - responsive disorder ( 18 ) , and this was well manifested in the present case .
the initial findings of multiple diffuse nodular lesions with thickening of bronchovascular bundles and scattered high - density spots were markedly diminished in both lung lobes , and there was a decrease in the lymph nodes .
the patient 's symptoms further improved and there was no relapse on follow - up .
the efficacy of glucocorticoid treatment in multiple organ diseases in this patient was consistent with the diagnosis of igg4-related aha . however , the serum igg4 level remained high even after glucocorticoid treatment , which was not consistent with most of the other documented cases .
although igg4-related disease typically demonstrates high serum igg4 levels , approximately 20% of patients with biopsy - proven igg4-related disease may have normal serum igg4 level ( 15,19,20 ) .
a review of the literature revealed a case report wherein a patient was diagnosed with igg4-related sclerosing disease , despite serum igg4 levels remaining normal .
the patient responded to corticosteroid treatment ( prednisolone ) with alleviation of pulmonary lesions and improved renal function ; however , the serum igg4 level increased ( 6 ) . a plausible explanation for the seronegativity of the patient may be that active synthesis blocked igg4 secretion , and then corticosteroid treatment suppressed the synthesis , which restored igg4 secretion from the plasma cells .
thus , igg4-related disease may have various pathological features , and is likely to be associated with a variable response to treatment .
the current patient is currently being followed - up with monitoring of serological markers , including igg4 . in conclusion
, the present study describes the first reported case of igg4-related aha in a 55-year - old male who presented with unusual clinical features and systemic manifestations .
awareness of such an entity is necessary as it is a curable disease , and timely treatment could be life - saving .
documentation of such rare cases will help in further characterizing the pathogenesis of this rare disorder .
 acquired hemophilia a ( aha ) is a relatively rare and life - threatening bleeding disorder whose pathogenesis is not completely understood . 
 the present study reports a rare case of immunogubulin ( igg)4-related aha with multisystemic involvement . a 55-year old male patient presented with symptoms of bronchial asthma and multiple subdermal hematomas . 
 chest computed tomography showed multiple diffuse nodular lesions with thickening of bronchovascular bundles , and scattered high - density spots in both lung lobes . 
 laboratory investigations showed increased activated partial prothrombin time ( 120.0 sec ) , a markedly decreased factor viii ( fviii ) activity ( 0.5% ) , a high - titer of fviii inhibitor ( 27.2 bethesda units / ml ) and a marked increase in serum igg4 ( > 4.03 
 g / l ) level . left inguinal lymph node biopsy revealed capsular thickening with marked lymphoplasmacytic infiltration , occlusive phlebitis and irregular fibrosis . 
 immunostaining revealed numerous igg4-positive plasma cells ( > 100 cells / human plasma fibronectin ) in the nodular lesions , with an igg4/igg ratio of > 40% . 
 the symptoms were markedly alleviated following corticosteroid therapy . 
 the current study presents the first reported case of a rare igg4-related aha that presented with unusual clinical features and multisystemic involvement . 
 the patient responded well to corticosteroid therapy . 
 documentation of such rare cases will help in characterizing the pathogenesis , and prompt recognition and timely treatment of this rare disorder . 
Introduction
Case report
Discussion