Haemophilia Complicated by an Acquired Circulating Anti-Coagulant :sx A Report of Three Cases .sx MICHAEL HALL .sx The Radcliffe Infirmary , Oxford .sx 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) .sx 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 :sx Biggs and Bidwell , 1959) .sx The presence of an anticoagulant may , therefore , account for the failure of some patients to respond to treatment with AHG-containing material .sx 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) .sx Since the management of these patients may be difficult three cases are described .sx 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) .sx The human AHG was prepared and supplied by the Lister Institute of Sterile Products .sx CASE REPORTS .sx CASE 1 .sx This patient ( R. I. No .sx 80047 ) , aged 23 years was admitted on May 23rd , 1958 .sx He had a family history of haemophilia , one younger brother being affected .sx He was first recognized as haemophilic at the age of 2 years when he bled profusely following circumcision .sx Since then he had been admitted to hospital on many occasions with various bleeding episodes , mainly haemarthroses and haematomata .sx 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 .sx 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 .sx Since the diagnosis of acute appendicitis was raised , he was transferred to the Radcliffe Infirmary .sx On examination he looked pale and ill , and his right knee and hip were flexed .sx There were guarding and tenderness in the right iliac fossa and right groin , with tenderness high on the right posterior rectal wall .sx There was anaesthesia in the distribution of the right femoral nerve .sx Blood pressure was 115/70 .sx The haemoglobin was 11.4 g. per 100 ml .sx A diagnosis of a right-sided retroperitoneal haematoma was made and he was treated with analgesics , transfusions of fresh plasma and blood .sx In spite of this , bleeding continued and the haemoglobin dropped to 7.7 g. per 100 ml .sx His general condition was weaker and he appeared jaundiced .sx The lack of response to the transfusion treatment was unusual and some routine laboratory tests , in which a sample of the patient's blood had been used as a control , suggested that an inhibitor of AHG was present .sx He was then treated with 2200 plasma equivalents of human AHG intravenously .sx 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 .sx The following day he complained of dysphagia and difficulty in breathing , and a chest X-ray showed evidence of mediastinal extension of this haematoma .sx Haematological investigation had by this time shown the presence of an inhibitor , the level being 33-50 units per ml .sx ( 1 unit of inhibitor is the amount which will destroy 75 per cent of added AHG in 1 hour ( Biggs and Bidwell , 1959)) .sx 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 .sx The only possible way of reducing the level of the inhibitor seemed to be by exchange transfusion .sx Therefore , an exchange transfusion equivalent to twice the blood volume was performed .sx The inhibitor level fell to 5.9 units per ml .sx and the clotting time to 23-30 minutes .sx To take advantage of the improved circumstances , two doses of animal AHG , equivalent to 3200 ml .sx and 3300 ml .sx of fresh plasma were given .sx The effect was to reduce the clotting time to 6 3/4 minutes and the inhibitor level to 5.0 units per ml .sx , and a trace of AHG was measurable .sx The following day two further doses of animal AHG , equivalent to 3000 ml .sx and 8000 ml .sx of fresh plasma , were given .sx The clotting time was reduced from 60 minutes to 15 minutes and the inhibitor level to 3.9 units .sx No plasma AHG level was , however , obtained .sx There was a marked improvement in general condition following the exchange transfusion , and the jaundice and haematomata disappeared .sx Dysphagia disappeared after about 24 hours .sx Pain in the abdomen and groin lessened and he gradually became able to straighten his leg .sx A mild pyrexia developed after the exchange transfusion and there were signs of pneumonia in the right side of the chest .sx He was treated with tetracycline , 500 mg .sx 6-hourly , and improved .sx Hydrocortisone at a daily dose of 200 mg .sx was given in the hope of preventing further formation of anticoagulant .sx He was able to get up and sit in a chair .sx The only troublesome complication was persistent bleeding from the 'cut down' site through which the cannula had been inserted .sx 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's viper venom .sx The cannula was left 6in situ for several days following the exchange in case of emergency , but was finally removed on June 12th , when nearly all bleeding had stopped .sx Further intermittent oozing continued for 10 days after this and another seven pints of blood were transfused .sx On the night of June 14th his temperature rose abruptly and in the next 72 hours reached 104@ 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 .sx Blood cultures remained sterile :sx 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 .sx The pyrexia was , therefore , ascribed to the blood transfusions and absorption of blood .sx However , the administration of hydrocortisone was discontinued , and penicillin was given at a dose of 125 mg .sx t.d.s. and sulphamethoxypyridazine at 0.5 g. daily .sx 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 .sx 00 ml .sx of bloodstained pus was aspirated and the abcess was therefore incised .sx Staph .sx aureus resistant to penicillin , aureomycin and tetracycline was cultured from the pus .sx Management was now directed to the treatment of the staphylococcal infection , and of the bleeding diathesis .sx 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 .sx 6-hourly , and intravenous Furadantin , 30 ml .sx per litre of normal saline b.d. , appeared to have controlled the infection .sx But relapse ensued on July 27th and a blood culture grew Staph .sx aureus resistant to penicillin , tetracycline and erythromycin , but still sensitive to Furadantin and chloramphenicol .sx A similar organism was also grown from the pus from the left elbow .sx The patient was now desperately ill .sx Intravenous penicillin was given at a dose of 12 million units per 100 ml .sx of normal saline 6-hourly with Benemid , 0.5 g. 6-hourly by mouth .sx Penicillin blood levels as high as 32 units per ml .sx were obtained ; there was no dramatic fall in temperature but the general condition and appetite improved .sx By August 18th he was so much better that the administration of all antibiotics was discontinued .sx 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 .sx These shrank considerably and eventually healed ( Fig 2) .sx During this period continual blood loss occurred from the incised abscess and from the anterior slough .sx Treatment was difficult because there were few veins into which needles or metal cannulae could be inserted .sx 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 .sx 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 6in situ .sx These procedures , though necessary , only aggravated the transfusion problem and a large volume of blood had to be transfused ( Fig. 1) .sx By this time the patient was debilitated , but felt much better , and was able to take a 3000 calorie diet .sx 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 .sx The haemoglobin fell and a further blood transfusion was given .sx In the middle of September melaena began and became more frequent and more fluid .sx Further deterioration ensued .sx A large haematoma appeared in the left groin and thigh and became grossly infected .sx By October 8th large fluid stools containing almost pure blood were passed .sx In spite of further blood transfusions he died in coma on October 9th .sx During admission he received 270 pints of blood .sx Necropsy report ( R.I.P.M. No .sx 771/58 .sx Dr. W. C. D. Richards ) .sx At 6post-mortem examination a large infected cystic haematoma was found in the retroperitoneal tissues on the right side of the abdomen .sx This involved the psoas , quadratus lumborum and iliacus muscles .sx A similar haematoma on the left side had ruptured into the colon .sx The haematomata contained turbid brown fluid and masses of brown altered blood .sx On the left side the iliac haematoma communicated with a large infected haematoma of the thigh .sx Both ureters were surrounded by the fibrous tissue forming the anterior wall of the abdominal haematomata , the pelves of the kidneys being slightly dilated .sx The liver ( 3020 g. ) and spleen ( 850 g. ) were both enlarged .sx Microscopically the liver , spleen and iliac lymph nodes showed siderosis and there was amyloidosis of the spleen and liver .sx The liver was fatty .sx Masses of Gram-positive cocci were present in the blood clot filling the haematomata .sx Inflammatory granulation tissue lined the inner surface of the haematomata .sx CASE 2 .sx This patient ( R. I. No .sx 42050 ) , aged 43 years , was admitted on May 5th , 1958 , for weight reduction prior to extensive dental extractions .sx His haemophilia had been recognized for many years and numerous haemorrhagic episodes of variable severity and duration had occurred , many necessitating hospital admission .sx 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 .sx There was a family history of obesity , but not of haemophilia .sx On examination he was obese , weighing 16 st. 9 1/2 lb .sx There was evidence of old haemarthroses involving both knees , both elbows , the right ankle and left shoulder .sx There was severe dental caries of both upper and lower teeth and it was decided that root remnants would have to be extracted .sx An 800 Calorie diet was begun and Dexedrine spansules mg .sx 15 mane , Saluric , 0.5 g. b.d. and potassium chloride , 1 g. twice daily were prescribed .sx His weight dropped to 15 st. 6 lb .sx At first , a few superficial bruises were the only haemorrhagic manifestations .sx Active physiotherapy to the knee was given with considerable improvement .sx After about 6 weeks several deep painful haematomata developed at various sites .sx On July 17th 10 roots and carious teeth were extracted from the upper jaw under general anaesthesia .sx His subsequent progress is summarized in Fig 3 .sx 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 .sx ( 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 .sx )