by Richard Atwood
By 1940, leading hematologists considered the presence of an inhibitor in circulating blood to be a theoretical possibility. But there were no known cases of hemophilia with an inhibitor, or a “circulating anticoagulant,” as it was commonly identified.
University of Rochester School of Medicine and Dentistry in Rochester, New York
Then in a 1942 medical journal article, Dr. John S. Lawrence and Dr. John B. Johnson at the University of Rochester School of Medicine and Dentistry in Rochester, New York reported a case of hemophilia with a circulating anticoagulant in his blood. W. Purcell, a 44-year-old unmarried patient with hemophilia was, identified as patient No. 27899.
There was a history of hemophilia in the extended Purcell family: in addition to Purcell, a maternal uncle had died from bleeding following an incision and Purcell’s brother had a typical picture of hemophilia.
Purcell was born in 1897. When he was 3, he had a bleeding episode lasting 22 days from a cut in the lip. At the age of 6, he had blood in his urine, and up to age 15, he oozed blood from his gums. Purcell also suffered from sporadic pain and swelling in the elbows and knees with subsequent stiffening or ankylosis of the joints. He had several tooth extractions with subsequent bleeding. His first hospital admission was on September 19, 1929 for bleeding following extraction of a tooth. He had 18 subsequent hospital admissions for bleeding from his teeth (twice), hematuria (9 times), gastro-intestinal bleeding (4 times), hemoptysis (once), and hemorrhages into his joints (7 times). Purcell received many transfusions as treatment.
Purcell’s coagulation time varied from 12 hours to 70 minutes. A standardized technic resulted in coagulation times of less than 2 hours. Strangely, repeated coagulation times in minutes taken from 1939 to 1941 were not markedly reduced after transfusions with normal blood or fresh plasma, and were reduced less than would be expected in patients with typical hemophilia. The circulating anticoagulant in the Purcell’s blood could not be identified. This led physicians to advise checking the coagulation time shortly after the administration of fresh normal blood to every patient with hemophilia to rule out the presence of a circulating anticoagulant.
Follow-up on Purcell was provided later in a 1947 medical journal article by Charles G. Craddock, Jr., MD and John S. Lawrence MD from the University of Rochester School of Medicine and Dentistry in Rochester, New York. Over the 5 year span since the previous report, the 50-year-old unmarried male had many recurrent episodes of bleeding in his joints, genito-urinary tract, and gastrointestinal tract. He was treated with transfusions of fresh blood or plasma, which had little effect. A test taken in 1945 for the presence of a circulating anticoagulant was negative.
Purcell was hospitalized from December 1945 until March 1946 because of a severe continuous rectal hemorrhage. During these 3 months, he received 30 transfusions of 500 cc. each of whole fresh blood. The patient did not improve and the coagulation time consistently varied from 60 to 120 minutes. No tests for a circulating anticoagulant were performed. The last transfusion was given on February 9, 1946 and the patient slowly improved once the bleeding ceased. A test on September 9, 1946 for the presence of a circulating anticoagulant was negative.
Purcell was readmitted on April 15, 1947 because of rectal bleeding of 3 to 4 hours duration. He was pale and suffered repeated attacks of precordial pain. He received 6 transfusions of fresh whole blood with no improvement by either clinical or laboratory findings. The transfusions with whole blood were stopped. Purcell then received 500 cc. of washed red cells and showed some signs of symptomatic improvement. Another transfusion of whole blood given inadvertently caused an immediate recurrence of symptoms. The patient then received another 500 cc. units of washed red cells and showed steady symptomatic improvement. Though the clotting time remained prolonged, and the circulating anticoagulant persisted, Purcell gradually improved.
His physicians believed that Purcell was deficient in or lacked antihemophilic globulin in his blood. With laboratory testing, his circulating anticoagulant was shown to be associated with the gamma globulin fraction of plasma. The physicians hypothesized that the action of the anticoagulant against antihemophilic globulin was essentially that of an antibody-antigen reaction, or “isoimmunization,” as a result of repeated transfusions or injections of antihemophilic globulin, either in the form of whole blood, plasma, or Fraction I of Cohn (commercially available from Cutter or Squib).
They concluded that certain hemophiliacs deficient in a globulin fraction may be capable of developing antibodies against the antihemophilic globulin when it is given repeatedly. Purcell is truly the first person with hemophilia known to have an inhibitor!
Craddock CG and JS Lawrence. 1947 Hemophilia: A report of the mechanism of the development and action of an anticoagulant in two cases. Blood 2:505-18.
Lawrence JS and JB Johnson. 1942 The presence of a circulating anti-coagulant in a male member of a hemophiliac family. Trans Am Clin Clim Assoc 57:223-31.