haemophilia complicated by an acquired circulating anti-coagulant : a report of three cases . Michael Hall . the Radcliffe Infirmary , Oxford . a circulating anticoagulant may arise in patients with haemophilia and Christmas disease or may appear sporadically in normal people ( Lewis , Ferguson and Arends , 1956 ; Verstraete and Vandenbroucke , 1956 ; Hougie , 1955 ; Nilsson , Skanse and Eydell , 1958 ) . the anticoagulant has been studied by various workers , who suggest that it prevents the reaction between antihaemophilic globulin ( AHG ) and Christmas factor by destroying AHG ( Hougie and Fearnley , 1954 ; Bersagel and Hougie 1956 : Biggs and Bidwell , 1959 ) . the presence of an anticoagulant may , therefore , account for the failure of some patients to respond to treatment with AHG-containing material . recognition of the presence of an anticoagulant , even in very small amounts , is therefore important and a method for its detection and assay has recently been described ( Biggs and Bidwell , 1959 ) . since the management of these patients may be difficult three cases are described . the laboratory methods used for the haematological investigations were those of Biggs and Macfarlane ( 1957 ) , with the exception of the inhibitor assay which was by the method of Biggs and Bidwell ( 1959 ) . the human AHG was prepared and supplied by the Lister Institute of sterile products . case reports . case 1 . this patient ( R I no 80047 ) , aged 23 years was admitted on May 23rd , 1958 . he had a family history of haemophilia , one younger brother being affected . he was first recognized as haemophilic at the age of 2 years when he bled profusely following circumcision . since then he had been admitted to hospital on many occasions with various bleeding episodes , mainly haemarthroses and haematomata . as a result of the former , he had been admitted to the Nuffield orthopaedic centre in September 1956 , with a flexion contracture of the right hip , but this had responded well to treatment . on the present occasion he was admitted to the Nuffield orthopaedic centre for a similar reason , but within a day or two of admission developed severe right-sided abdominal pain which was associated with tenderness , pyrexia and vomiting . since the diagnosis of acute appendicitis was raised , he was transferred to the Radcliffe Infirmary . on examination he looked pale and ill , and his right knee and hip were flexed . there were guarding and tenderness in the right iliac fossa and right groin , with tenderness high on the right posterior rectal wall . there was anaesthesia in the distribution of the right femoral nerve . blood pressure was 115/70 . the haemoglobin was 11.4 g per 100 ml . a diagnosis of a right-sided retroperitoneal haematoma was made and he was treated with analgesics , transfusions of fresh plasma and blood . in spite of this , bleeding continued and the haemoglobin dropped to 7.7 g per 100 ml . his general condition was weaker and he appeared jaundiced . the lack of response to the transfusion treatment was unusual and some routine laboratory tests , in which a sample of the patient &apos;s blood had been used as a control , suggested that an inhibitor of AHG was present . he was then treated with 2200 plasma equivalents of human AHG intravenously . this produced a characteristic and severe reaction , but failed to halt the bleeding process and he developed a haematoma of the upper chest wall and right side of the neck . the following day he complained of dysphagia and difficulty in breathing , and a chest x-ray showed evidence of mediastinal extension of this haematoma . haematological investigation had by this time shown the presence of an inhibitor , the level being 33-50 units per ml ( 1 unit of inhibitor is the amount which will destroy 75 per cent of added AHG in 1 hour ( Biggs and Bidwell , 1959 ) ) . with this level of inhibitor no amount of AHG-containing material , either animal or human , was likely to be effective in halting the bleeding process . the only possible way of reducing the level of the inhibitor seemed to be by exchange transfusion . therefore , an exchange transfusion equivalent to twice the blood volume was performed . the inhibitor level fell to 5.9 units per ml and the clotting time to 23-30 minutes . to take advantage of the improved circumstances , two doses of animal AHG , equivalent to 3200 ml and 3300 ml of fresh plasma were given . the effect was to reduce the clotting time to 6 3/4 minutes and the inhibitor level to 5.0 units per ml , and a trace of AHG was measurable . the following day two further doses of animal AHG , equivalent to 3000 ml and 8000 ml of fresh plasma , were given . the clotting time was reduced from 60 minutes to 15 minutes and the inhibitor level to 3.9 units . no plasma AHG level was , however , obtained . there was a marked improvement in general condition following the exchange transfusion , and the jaundice and haematomata disappeared . dysphagia disappeared after about 24 hours . pain in the abdomen and groin lessened and he gradually became able to straighten his leg . a mild pyrexia developed after the exchange transfusion and there were signs of pneumonia in the right side of the chest . he was treated with tetracycline , 500 mg 6-hourly , and improved . hydrocortisone at a daily dose of 200 mg was given in the hope of preventing further formation of anticoagulant . he was able to get up and sit in a chair . the only troublesome complication was persistent bleeding from the cut down site through which the cannula had been inserted . this necessitated the transfusion of 20 pints of blood , but was eventually stopped by repeated packing of the wound with Calgitex ribbon gauze soaked in Russell &apos;s viper venom . the cannula was left in situ for several days following the exchange in case of emergency , but was finally removed on June 12th , when nearly all bleeding had stopped . further intermittent oozing continued for 10 days after this and another seven pints of blood were transfused . on the night of June 14th his temperature rose abruptly and in the next 72 hours reached 104 &amp;deg; F . no obvious cause was discernible for this , though he had a tender haematoma on the upper outer aspect of the left forearm which had resulted from a venepuncture . blood cultures remained sterile : a swab taken from the cut down site in the right arm grew a penicillin-resistant Staphylococcus aureus but this wound did not appear infected . the pyrexia was , therefore , ascribed to the blood transfusions and absorption of blood . however , the administration of hydrocortisone was discontinued , and penicillin was given at a dose of 125 mg t.d.s and sulphamethoxypyridazine at 0.5 g daily . the swinging pyrexia continued , the haematoma increased , brawny oedema developed , and there was oedema of the hand ; by June 28th the haematoma was obviously infected and was pointing over the lateral condyle of the humerus . 100 ml of bloodstained pus was aspirated and the abcess was therefore incised . Staph aureus resistant to penicillin , aureomycin and tetracycline was cultured from the pus . management was now directed to the treatment of the staphylococcal infection , and of the bleeding diathesis . as can be seen from fig 1 , various antibiotics were given in full dosage and between July 13th and 26th the administration of chloramphenicol , 500 mg 6-hourly , and intravenous Furadantin , 30 ml per litre of normal saline b.d , appeared to have controlled the infection . but relapse ensued on July 27th and a blood culture grew Staph aureus resistant to penicillin , tetracycline and erythromycin , but still sensitive to Furadantin and chloramphenicol . a similar organism was also grown from the pus from the left elbow . the patient was now desperately ill . intravenous penicillin was given at a dose of 12 million units per 100 ml of normal saline 6-hourly with Benemid , 0.5 g 6-hourly by mouth . penicillin blood levels as high as 32 units per ml were obtained ; there was no dramatic fall in temperature but the general condition and appetite improved . by August 18th he was so much better that the administration of all antibiotics was discontinued . the haematoma of the left forearm produced two sloughing discharging areas , one posteriorly and one anteriorly , both of which had superabundant granulations protruding from them . these shrank considerably and eventually healed ( fig 2 ) . during this period continual blood loss occurred from the incised abscess and from the anterior slough . treatment was difficult because there were few veins into which needles or metal cannulae could be inserted . to allow time for veins to recanalize , polyethylene cannulae had to be inserted through larger veins into the femoral , subclavian and the superior caval veins . the patient bled profusely from these cut down sites and it was not possible to control bleeding by pressure , Stypven or Calgitex gauze while the cannulae were still in situ . these procedures , though necessary , only aggravated the transfusion problem and a large volume of blood had to be transfused ( fig 1 ) . by this time the patient was debilitated , but felt much better , and was able to take a 3000 calorie diet . his pyrexia settled after 4 weeks , when a haematoma of the anterior abdominal wall developed and he complained of vomiting and of pain in the left groin . the haemoglobin fell and a further blood transfusion was given . in the middle of September melaena began and became more frequent and more fluid . further deterioration ensued . a large haematoma appeared in the left groin and thigh and became grossly infected . by October 8th large fluid stools containing almost pure blood were passed . in spite of further blood transfusions he died in coma on October 9th . during admission he received 270 pints of blood . necropsy report ( R.I.P.M no 771/58 . Dr W C D Richards ) . at post-mortem examination a large infected cystic haematoma was found in the retroperitoneal tissues on the right side of the abdomen . this involved the psoas , quadratus lumborum and iliacus muscles . a similar haematoma on the left side had ruptured into the colon . the haematomata contained turbid brown fluid and masses of brown altered blood . on the left side the iliac haematoma communicated with a large infected haematoma of the thigh . both ureters were surrounded by the fibrous tissue forming the anterior wall of the abdominal haematomata , the pelves of the kidneys being slightly dilated . the liver ( 3020 g ) and spleen ( 850 g ) were both enlarged . microscopically the liver , spleen and iliac lymph nodes showed siderosis and there was amyloidosis of the spleen and liver . the liver was fatty . masses of Gram-positive cocci were present in the blood clot filling the haematomata . inflammatory granulation tissue lined the inner surface of the haematomata . case 2 . this patient ( R I no 42050 ) , aged 43 years , was admitted on May 5th , 1958 , for weight reduction prior to extensive dental extractions . his haemophilia had been recognized for many years and numerous haemorrhagic episodes of variable severity and duration had occurred , many necessitating hospital admission . a bruising tendency had been noticed 14 days after birth and he had suffered prolonged haemorrhage after biting his tongue at the age of 2 years . there was a family history of obesity , but not of haemophilia . on examination he was obese , weighing 16 st 9 1/2 lb . there was evidence of old haemarthroses involving both knees , both elbows , the right ankle and left shoulder . there was severe dental caries of both upper and lower teeth and it was decided that root remnants would have to be extracted . an 800 calorie diet was begun and Dexedrine spansules mg 15 mane , Saluric , 0.5 g b.d and potassium chloride , 1 g twice daily were prescribed . his weight dropped to 15 st 6 lb . at first , a few superficial bruises were the only haemorrhagic manifestations . active physiotherapy to the knee was given with considerable improvement . after about 6 weeks several deep painful haematomata developed at various sites . on July 17th 10 roots and carious teeth were extracted from the upper jaw under general anaesthesia . his subsequent progress is summarized in fig 3 . before operation a polyethylene cannula was inserted into a forearm vein to a distance of 33 inches so that the tip should lie in a major vessel . ( venography later showed that the tip of the catheter was in the right ventricle ; the catheter was , therefore , withdrawn until the tip lay in the superior vena cava . ) 