Coronary bypass in a patient with hemophilia B, or Christmas disease

Coronary bypass In a patient with hemophilia B, or Christmas disease Case report A 40-year-old patient with moderate factor IX deficiency (Christmas disease) underwent quadruple saphenous vein coronary bypass grafts for angina and severe coronary atherosclerosis involving the left and right main, left anterior descending, and circumflex coronary arteries. Excessive bleeding was prevented by infusion offactor IX concentrates during and after the operation. The surgical procedure and total body perfusion were carried out in the same manner as in patients without a hemorrhagic disorder. The patient was discharged after 13 days of hospitalization. He is doing well at the time of this publication and has returned to work.

K. D. Tourbaf, M.D.,* R. E. Bettigole, M.D.,** J. A. Zizzi, M.D.,* S. Subramanian, M.D., *** and M. N. Andersen, M.D., *** Buffalo, N. Y.

HemoPhilia B, or Christmas disease, is a sex-linked, hemorrhagic disorder of coagulation caused by a deficiency of factor IX or plasma thromboplastin component. I Like hemophilia A (factor VIII deficiency), the disease is characterized by repeated epidoses of bleeding for little or no apparent reason or by persistent bleeding after surgery or minor trauma. The severity of the disease varies markedly from family to family but is about the same in affected members of the same family. There is a good correlation between severity and the level of plasma factor IX activity. The reported incidence of hemophilia B is about one in 40,000 of the male population. There is approximately one case of hemophilia B for every four cases of hemophilia A. The exact number of persons who have hemophilia B in

From the Departments of Internal Medicine and Surgery, Erie County Medical Center, State University of New York at Buffalo, and The Hemophilia Center of Western New York, Inc., Buffalo, N. Y. Received for publication March 3, 1978. Accepted for publication Dec. 29, 1978. Address reprints: Kamal D. Tourbaf, M.D., The Hemophilia Center of Western New York, Inc., 462 Grider St., Buffalo, N. Y. 14215. *Clinical Associate Professor of Medicine. **Associate Professor of Medicine. ***Professor of Surgery.

562

the United States is unknown. According to the estimates in the National Heart and Lung Institute's Blood Resource Studies Report," there are 20,297 cases of severe and moderate hemophilia A and 5,200 cases of severe and moderate hemophilia B in this country. However, other observations suggest that the actual prevalence rates for hemophilia A and B are lower than this." With the advent of potent factor IX concentrates, major surgery in such a patient has become less dangerous. However, operations on patients with hemophilia B should be performed in hospitals where personnel are experienced in the treatment of these patients and where factor IX concentrates for transfusion and proper laboratory facilities for monitoring the adequacy of the correction of the coagulation defect are available. The purpose of this article is to report the hematologic management of a patient with moderate hemophilia B who underwent quadruple coronary artery bypass grafts for coronary insufficiency with angina. He appears to be the first reported patient with hemophilia B who has had cardiac surgery for coronary artery disease. His case also demonstrates that life-long "anticoagulation" with low factor IX levels does not prevent occlusive coronary artery disease. Case report The patient, a 40-year-old man with moderate hemophilia B, was admitted to the E. J. MeyerMemorial Hospital for the

0022-5223/79/040562+08$00.80/0 © 1979 The C. V. Mosby Co.

Volume n Number 4 April,1979

Hemophilia B

563

Table I. Pertinent bleeding history and surgical procedure Date

Nature of bleeding and operation

May, 1936 May, 1942 July, 1942 December, 1943 April, 1944

Circumcision Bleeding from tooth socket Laceration of tongue Extraction of 2 deciduous molars Contusion of forehead (hit head with baseball bat) Traumatic bleeding of left hip Cut right palm with milk bottle

October, 1946 October, 1949

April, 1956 May, 1956

Hemorrhage of thigh muscle (bumped on a pipe) Bilateral epistaxis Acute suppurative appendicitis

May, 1962

Tonsillitis

1967

Dental extractions

1951

first time on Feb. 19, 1977, for an investigation of coronary heart disease. History. He was well until IO months prior to this admission when he experienced his first episodes of fairly typical angina pectoris. He had smoked one pack of cigarettes per day for 20 years. His father died at age 59 of myocardial infarction and his paternal grandfather had hypertension and died at age 65 to 70 of a heart attack. His mother also had "heart trouble" at age 36. He denied any history of hypertension or heart failure, and the review of systems otherwise revealed no abnormalities. The diagnosis of hemophilia was made during an episode of excessive bleeding from a tooth socket when he was 6 years old. The diagnosis of hemophilia B was made in the early 1950's. He gave no history 'of spontaneous musculoskeletal bleeding, but he had moderate bruising, usually after trauma. Table I illustrates his pertinent history relating to hemophilia. He had no history of hepatitis or transfusion reactions and no known allergies. Fig. I shows the pedigree of the patient. Unfortunately, most of his relatives live in other states and could not be tested. Physical examination. The patient was a healthy appearing, slightly obese white man (weight 80 kilograms) in no acute distress. Blood pressure was 120/80 mm. Hg while lying down and 120(90 mm. Hg while standing. No abnormalities were detected in the examination, except that the spleen tip was palpable. The patient stated that he had known this for at least 20 years and its cause was unknown. Laboratory data. Results of the following laboratory studies were within normal limits: urinalysis, complete blood count, platelet count, glucose, creatinine, cholesterol, triglyceride, and electrolyte levels, and prothrombin time. Activated partial thromboplastin time (APTI) was 51.9 seconds with a control of 33.7 seconds. Factor IX level was 2 percent with a control of 95 percent, and a screening test for inhibitors against factor IX was negative. Electrocardiogram revealed

Therapy

Duration ofdisability

Conservative Packing Suture, transfusion of 6 units of blood Packing and conservative Conservative

None Few days Several weeks None Several days

Conservative Transfusion with whole blood, suture

Several months Delayed healing I to 2 mo. 2 to 3 mo.

Bed rest (3 wk.) and conservative Packing and transfusion of 2 units of blood Appendectomy, transfusion of 5 units of whole blood Tonsillectomy and transfusion of 2 units of whole blood, complicated with post-tonsillectomy bleeding; treatment with AgN0 3 stick Whole blood

I wk. I mo.

4 wk.

2 wk.

normal sinus rhythm with a rate of 60 beats per minute. There was slight flattening of the T wave in Lead a VF and slight T-wave inversion in Lead III, but there were no Q waves and the voltage was normal. The chest x-ray film showed no abnormalities. Coagulation studies. Venous blood was drawn by means of a double syringe technique with plastic syringes and mixed with 1/. 0 volume 3.8 percent trisodium citrate. The blood was centrifuged at 3,000 X gat 4° C. for 20 minutes. The plasma was transferred with plastic pipettes into plastic tubes and either placed in an ice-water bath and tested immediately or frozen and stored at - 80° C. Platelet-rich plasma was obtained by centrifugation at 130 x g for 15 minutes at room temperature. Platelet-poor plasma was obtained by centrifugation at 1,500 X g for 25 minutes at room temperature. Platelet aggregation was studied with a PAP-Z platelet aggregometer (Bio-Data Corp., Horsham, Pa.). The APTT's4 were determined with the General Diagnostics Automated APTT; the prothrombin times" was performed with General Diagnostics Simplastin; factor IX level, 6-8 clot retraction," and platelet aggregation!": II were determined as previously described. The factor IX inhibitor screening was performed by a modification of the Bethesda method": 13 for factor VIII inhibitors, substituting factor IX-deficient plasma substrate for factor VIII-deficient plasma substrate. Hospital course. The day after admission, the patient received 5 units of fresh-frozen plasma and then underwent cardiac catheterization and coronary arteriography. The factor IX level was 16 percent I hour after the last unit of freshfrozen plasma and just before the procedure. The results of coronary angiography were as follows: I. The right coronary artery was totally occluded I cm. from its origin. The distal right coronary, including the posterior descending branch, filled via collaterals from the left system.

The Journal of Thoracic and Cardiovascular Surgery

564 Tourbaf et al.

one must take into consideration the extravascular distribution of this factor. It has been postulated, but not proved, that the disappearance of factor IX after infusion follows two curves. Although the initial half-life is only about 5 hours (suggesting spread to the extravascular space), the second part of the curve has a half-life of about 24 hours 14-16; over-all, less than 50 percent of the administered factor is usually recovered in the plasma.!? Therefore, the initial dosage would be calculated as follows: 0.80 - 0.027 = 0.773 units/ml. (the factor IX level aimed for) and

o

Normal males

o

Normal females

•

Affected males

•

Carrier females

~

Females nottested

~ Males nottested

~

Bruises early not tested

Fig. 1. Pedigree of the patient. 2. There was distinct narrowing of the left main orifice, i.e., 80 percent of the cross-sectional diameter. 3. The circumflex coronary artery gave rise to two large marginal branches, each of which had a 70 percent fusiform narrowing at the origin. 4. The anterior descending had irregularities throughout its course but appeared suitable for bypass. 5. The left ventricular angiogram, taken in the right oblique projection, showed that the left ventricle contracted well in all its segments; it was of normal size and had an ejection fraction of 56 percent. The left oblique projection showed good septal motion and good posterior wall motion. The patient was discharged on a regimen of propranolol (Inderal), 10 mg. four times a day. On April 10, 1977, he was readmitted for cardiac surgery. He had been having less pain, and results of the physical examination were essentially unchanged. Additional laboratory studies at that time included blood gas studies that were normal. Results of platelet aggregation studies with epinephrine, adenosine diphosphate, ristocetin, and collagen were normal. Clot retraction was 70 percent. Repeat factor IX level was 2.7 percent and screening test for circulating anticoagulants to factor IX was again negative. The fibrin degradation products (FDP) were less than 10 meg. per milliliter. The electrocardiogram and chest x-ray film were unchanged from the previous admission. Hospital course on the second admission. After careful planning, between 4:00 and 5:00 A.M. on the day of operation, the patient received a loading dose of 9 vials of factor IX concentrate (Konyne), each containing 500 units of factor IX, to raise the plasma factor IX levels to 80 to 90 percent of normal. The dosage was calculated as follows: Units to be administered = (desired factor IX cone. - initial factor IX conc.) x plasma volume x 2 Factor concentration is in units per milliliter, and the plasma volume was estimated to be 40 ml. per kilogram of body weight. To reach a desired plasma level of factor IX,

Units to be administered = (0.773 units/rnl.) (40 mI.!Kg.) (80 Kg.) (2) = 4,947.2 units Because our patient had a moderate factor IX deficiency, we thought that the extravascular distribution of factor IX would be somewhat less than in a patient with severe factor IX deficiency; therefore, we infused 4,500 units of factor IX. The factor IX level 15 minutes after infusion of the 4,500 units of factor IX was 84 percent; this represents in vivo recovery of the infused material. In an attempt to decrease the possible thrombotic effects of factor IX concentrate, we used 60 units of heparin sodium per vial of Konyne. At 7:00 A.M., the patient was transferred to the operating room; prebypass procedures including anesthesia and intubation were performed as in a normal patient. Operative procedure. The saphenous vein was removed from each thigh through multiple short incisions and at the same time a conventional sternal-splitting incision was made. The patient was given 3.0 mg. of heparin per kilogram, and the ascending aorta and the right atrium were cannulated in the usual fashion. The oxygenator was primed with 3 vials of factor IX concentrate* (1,500 units of factor IX), 4 units of fresh-frozen plasma, 3 units of packed red cells, 1,500 ml. of Ringer's lactate solution, 300 ml. of 10 percent Osmitrol, 20 mg. of Lasix , and 40 mEg. of potassium chloride. An additional 1,000 units of factor IX concentrate and 4 additional units of fresh-frozen plasma were added serially. During the entire perfusion, therefore, if one assumes that fresh-frozen plasma averages I unit per milliliter, 4,100 units of factor IX was used in priming the oxygenator and during the procedure. Perfusion was initiated with a bubble oxygenator and the patient was cooled to 28° C. The ascending aorta was crossclamped intermittently during the distal anastomoses. A sequential graft was placed from one circumflex marginal artery across another, was led through the transverse sinus, and anastomosed to the right aspect of the ascending aorta. A single graft was constructed between the midportion of the left distal branch of the right coronary artery and the aorta. All anastomoses were performed with running 6(0 Prolene sutures. The wound was closed in conventional fashion with mediastinal drainage tubes. Heparin was neutralized with protamine sulfate, 3.0 mg. per kilogram, and an additional vial (500 units) of Konyne was given. The duration of total bypass was 120 minutes. Postoperative course. The patient was extubated on the first postoperative day and chest tubes were removed on the third postoperative day. The total drainage from the chest *Konyne, factor IX human complex (factors II, VII, IX, and X), Cutter Laboratories, Inc., Berkeley, Calif.

Volume 77 Number 4 April. 1979

Hemophilia B

565

1----------:;;;:::::::::::::---------,30 I I

I I

-...

Factor IX:

I r-----'A_

c:

cu u cu

I I (> 120")

..9-

~

...

0

U

~

50

I

50

: I

-

60 ~ c: o u

I

(> 120")

cu ~

~'~~i •

Anesthesia Time 1,500U.

12

Time (hours)

18

28

Fig. 2. Factor IX activity and activated partial thromboplastin time (A.P.T.T.) during the first 28 hours. Interrupted line indicates that no post-transfusion sample was taken. The amount and time of factor IX and freshfrozen plasma (F.F.P.) infusion is indicated on the abscissa. The shaded area represents the time of operation. A single dose of 240 mg. of sodium heparin was given before bypass and 240 mg. of protamine sulfate was given after bypass (arrows). tubes was 275 c.c. (The amount of factor IX concentrates, duration of therapy, and the level of factor IX with corresponding APTT and the fibrinogen level in our patient are shown in Figs. 2 and 3.) Total duration of hospitalization was 13 days and the total duration of factor IX infusions was 21 days. On the second postoperative day the patient had mild jaundice with an elevation of the concentration of liver enzymes. Testing for hepatitis-associated antigen was negative, but we assumed that the jaundice was related to the plasma infusion which he had received for catheterization during his previous admission. On the second postoperative day, the man had pleuritic retrosternal pain, worsened by arm motion and necessitating analgesics; this subsided in a few days. On the fourth postoperative day, the hemoglobin level was 9 Gm. per 100 ml. and the hematocrit value 27 percent, a fall from a hemoglobin level of 11.9 Gm. and a hematocrit value of 34.17 percent on the second postoperative day. There was no obvious evidence of blood loss or hemolysis. He was given I unit of packed red blood cells. He received a 5 day course of sodium cephalothin as prophylaxis against infection. The patient was discharged receiving Lanoxin, 0.25 mg. daily. He has returned to his job as a field service supervisor and is doing well at the time of this publication.

Discussion

Although the availability of concentrated human coagulation factors has dramatically improved and simplified the management of patients with hemophilia during surgical procedures, a successful outcome de-

pends on careful planning and monitoring of the patient. It is imperative to have a team approach. Our practice is to have a conference including all members of the team prior to any operation. In this case, the cardiac surgeons, cardiologist, hematologist, coagulation laboratory technician, cardiac nurse, surgical and medical house staff, the staff of the Hemophilia Center of Western New York, pump technician, and anesthesiologist were involved. The coagulation laboratory must be able to determine the nature and severity of the clotting deficiency and to perform an inhibitor study in which the patient's plasma is tested for a circulating anticoagulant directed against the deficient clotting factor. The presence of an inhibitor obviously would vastly complicate or preclude surgical procedures. Although subjects with mild-to-moderate hemophilia may seldom have had spontaneous bleeding, they are liable to have severe and life-threatening hemorrhage during and after a surgical procedure. The hematologic management of these patients during an operation is essentially the same as for those with severe hemophilia. However, the total required dosage may be somewhat less than for more severely affected patients. It is also important to have base-line screening tests: complete blood count, platelet count, reticulocyte count, prothrombin time, APTT, fibrinogen level, FDP, clot re-

The Journal of Thoracic and Cardiovascular Surgery

566 Tourbaf et al.

600

~500 Cl

.§ 400~-+----~""----------c

~300

o c

.;: 2 0 0 1 - j L - - - - - - - - - - - - - - - - .J::l

iZ

100 :;(>120")

60 ::

.-: -u; ~-g

50::

0 0.:.U

~~

~ 100 ~

...

8.

...

.2 u ~

20 2

4

6

8

10

15

20

Time (days) Fig. 3. Lowest factor IX level for each day with correspond-

ing A.P.T.T. and fibrinogen levels. traction, platelet aggregation, factor assay, inhibitor screening, blood type, irregular antibody testing, serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, alkaline phosphatase, bilirubin, and hepatitis B surface antigen (HBs AG). These tests provide the physician with a rational approach for treating the patient and enable him to set up a diagnostic and therapeutic plan and to assess carefully the prognosis and complication of the component therapy. Thromboembolic problems, including disseminated intravascular coagulation, have been reported in patients treated with factor IX cornplex.P't" especially in patients with associated liver disease.P Unfortunately the available data are meager and anecdotal. Prospective studies with appropriate laboratory investigations would be of particular interest. 23 Although we did not perform in vitro tests to determine the presence of activated clotting factors or thrombin in factor IX concentrates, both have been reported to be present in factor IX concentrates in varying and unpredictable amounts. Therefore, in an attempt to decrease these possible thrombotic effects, we added 60 units of heparin so-

dium to each vial of factor IX concentrate.v' We were particularly concerned about the possibility of early occlusion of the saphenous graft, although there is evidence that the thrombogenic potential of the recent commercial products has been substantially reduced.P Paradoxical bleeding has been reported in intensively transfused hemophilia A patients; this may be related to abnormal platelet function;" increased levels of circulating fibrin monomers, FDP's, or increased fibrinogen itself interfering with the thrombin/fibrinogen interaction.": 28 Immune hemolytic anemia is also recognized as a complication of the use of commercial concentrates ." When hemolysis has been demonstrated, red blood cell destruction has been attributed to anti-A found in transfused materials in patients of blood group A30 or B. 3 1. 32 Group AB patients obviously also could have similar complications. Because our patient has group 0 blood, we did not seriously consider the possibility of hemolytic anemia, although he had a slight and transient decline in the hemoglobin level on the fourth postoperative day. However, results of the direct and indirect antiglobulin tests were negative, haptoglobin was 296 mg. per 100 ml., and total reticulocyte count was 71.0 K per cubic millimeter. It has been suggested that increased fibrinogen may predispose red blood cells to rouleaux formation and subsequent hemolysis." The highest fibrinogen level in our patient was 580 mg. per 100 ml. from the third to the sixth postoperative days. One does not anticipate hemolysis at this level of fibrinogen. We thought the combination of the blood drawn for a variety of tests and a decrease in effective erythropoesis may have had a role in the transient decline in hemoglobin. Allergic reactions such as urticaria, fever, chills, nausea, leukopenia, and thrombocytopenia or, very rarely, an anaphylactic reaction may be associated with the infusion of factor IX concentrates ." One must be aware of such complications and not confuse them with other complications of operation such as infections, atelectasis, and drug reactions. Allergic reactions usually occur in a patient who has a history of previous allergy. The management of allergic or anaphylactic reactions in the hemophiliac is similar to that used for a nonhemophilic patient. Generally, we avoid aspirin, aspirin-containing compounds, and other drugs that may interfere with platelet function.s": 35 We also avoid intramuscular injections, ifpossible. Hepatitis is a significant complication of the treatment of hemophiliacs. This is due to hepatitisinducing viruses that may be present, but undetectable, in blood products used for the management of the patient. 33, 36 The pre valance in hemophiliacs of hepatitis-B surface antigen (HBs Ag) and antibody to this

Volumen Number 4 April,1979

antigen (Anti HBs) is proof of increased exposure of these multitransfused patients to the hepatitis B viruses (HBV), whether or not there is a history of clinical hepatitis.:": 38 Liver function studies and determination of the HBs Ag are a part of our preoperative workup. Unfortunately, our patient had abnormal results from the liver function studies for which no tenable explanation (i.e., congestive failure) was available other than the possibility of clinically mild hepatitis, probably related to the plasma infusion that he had received during February, 1977, as preparation for cardiac catheterization and coronary arteriography. He had no known history of hepatitis, and results of the liver function tests during the time of catheterization were normal. The course of hepatitis was benign and the liver function tests returned to normal within a relatively short period. Although factor IX concentrates have greatly facilitated the treatment of selected patients with Christmas disease, as well as inherited factor II, VII, or X deficiency, specifically providing effective hemostasis during surgical therapy, one must use these preparations with extreme caution because of the very high incidence ofhepatitis. 39 - 4 1 The incidence of hepatitis is higher than with any other blood product now available. Factor IX concentrate is made in large pools, utilizing up to 1,000 donors. It has been shown that HBs Ag can occur in the Cohn fraction of plasma used in these preparations. 42 More recently, it has been demonstrated that commercial factor IX concentrate that was negative for HBs Ag by radioimmunoassay showed the presence of hepatitis B virus-associated particles.:" Factor IX concentrates were used for our patient because we felt that volume considerations precluded using only fresh-frozen plasma. This patient may well be the first man with hemophilia B who has had coronary artery bypass. The operation was considered justified because of severe coronary artery disease documented by coronary arteriography. Cardiac surgery in a patient with hemophilia A was reported by Brockman and associates." The patient was a 49-year-old man with a factor VIII level of 3 percent who had aortic valve replacement. The patient survived the procedure but died 4 months later from a spontaneous intracerebral hemorrhage. Lusher's group" described a 20-year-old patient with severe hemophilia A (factor VIII level less than 1 percent) who had cardiac surgery for congenital heart disease (ostium primum defect and cleft mitral valve). Aris and co-workers:" described a 61-year-old woman with von Willebrand's disease who also was a carrier of hemophilia A. She had cardiac surgery for replacement of the aortic valve.

Hemophilia B

567

Cardiac surgery, like other operations, can be performed on patients with congenital coagulation disorders if adequate replacement therapy is given, providing the patient does not have an inhibitor directed against the deficient factor. The availability of factor VIII and factor IX concentrates should allow patients with hemophilia A and B to undergo cardiac operations without major difficulties. In preparing such a patient for the operation, an initial loading dose is given just before the operation. Maintenance doses are infused to achieve the desired factor level from the day of operation until complete wound healing. Because of the nature of this patient's operation, our initial goal for the factor IX level before and during the first 18 to 24 hours after the operation was 80 to 90 percent. For less complicated operations, a level of 50 to 60 percent would be adequate; in many patients, only fresh-frozen plasma would be needed and thereby the very significant risk of hepatitis and thromboembolic events which is associated with the use of factor IX concentrates would be avoided. We planned to keep the factor IX level at 40 to 50 percent for the first few days and gradually reduce the dosage. We wanted to maintain the factor IX level at no less than 20 percent during the second week for proper wound healing. By administration of factor IX in the third week after the operation (level of 10 to 20 percent), we intended to minimize any chance of bleeding in the pericardial sac and surrounding tissue. The nature and severity of the deficiency, the type of procedure, and the in vivo disappearance rate of the deficient clotting factor are all crucial in establishing the desired factor level prior to operation and the level and frequency of administration of the deficient clotting factor during the maintenance period. We were infusing factor IX concentrates every 8 to 12 hours initially, with the frequency gradually reduced first to every 24 hours and, at the end of therapy, to every 2 or 3 days. One must reassess the desired level in case of bleeding, complicating infection, or any other problems that may arise. Moreover, the response of the individual patient must be kept in mind, because factor IX recovery or survival might be different in different patients. Finally, if fibrin deposition on the arterial wall plays a role in the pathogenesis of atherosclerosis;" one would expect a decreased incidence of coronary artery disease in hemophiliacs. Unfortunately the prevalence of atherosclerosis in hemophiliacs is unknown at the present time. The median age of hemophiliacs is about lllh years" and extensive autopsy information on these patients is not available.:" Further data will be required to learn if there is any relationship between hypocoagu-

The Journal of

568

Tourbaf et al.

lability of hemophiliacs and their incidence of coronary artery disease. Hemophiliacs, like others, should be aware of "risk factors" associated with atherosclerosis, mainly hypertension, smoking, diabetes, hyperlipidemia, obesity, heredity, and lack of physical activity. We wish to acknowledge the assistance particularly of Richard Derr, Constance Gorski, R.N., Joan Harris, R.N., Angela Toland, R.N., and Rose Mary Holmberg, R.N., who, along with many others, helped to make this patient's hospital course seemingly uneventful.

REFERENCES

2

3

4

5 6

7

8

9

10

II

12

Biggs R, Douglas AS, MacFarlane RG, Dacie JV, Pitney WR, Merskey C: Christmas Disease. A condition previously mistaken for hemophilia. Br Med J 2: 1378-1382, 1952 Summary Report: N.H.L.1. Blood Resource Studies, DHEW Publ. No. (NIH) 73-416, Bethesda, 1972, U. S. Department of Health, Education and Welfare, pp 101130 Shapiro SS, Eyster ME, Lewis J: Collected experience of the Pennsylvania Hemophilia Program (abstr). Thromb Haemostas 38:370, 1977 (Suppl) Langdell RD, Wagner RH, Brinkhous KM: Effect of antihemophilic factor on one-stage clotting tests. A presumptive test for hemophilia and a simple one-stage antihemophilic factor assay procedure. J Lab Clin Med 41:637-647, 1953 Quick AJ: Prothrombin time in hemophilia and in obstructive jaundice. J BioI Chern 109:73-74, 1935 Didisheim P, Pizzuto J, Bunting D: An improved assay for factor IX (PTC, Christmas Disease), The Hemophilias, KM Brinkhous, ed., Chapel HilI, N. C, 1964, University of North Carolina Press, pp 148-155 Palkuti HA, Longberry JF: A precision study of coagulation factor assay technics. Am J Clin Pathol 59: 231-235, 1973 Biggs R: Human blood coagulation, Progress in Hemostasis and Thrombosis, TH Spaet, ed., New York, 1972, Grune & Stratton, lnc., p 616 Widmer K, Moake JL: Clot retraction. Evaluation in dilute suspensions of platelet-rich plasma and gel-separated plasma. J Lab Clin Med 87:49-57, 1976 Weiss HJ, Rogers J, Brand H: Defective ristocetininduced platelet aggregation in von WilIebrand's disease and its correction by factor VIII. J Clin Invest 52:26972707, 1973 Born GV: Aggregation of platelets by adenosine diphosphate and its reversal. Nature 194:927-929, 1962 Kasper CK, Aledort LM, Counts RB, Edson JR, Fratantoni J, Green D, Hampton JW, Hilgartner MW, Lazerson J, Levine PH, McMillan CW, Pool JG, Shapiro SS, Shulman NR, van Eys J: A more uniform measurement of factor VIII inhibitors. Thromb Haemostas 34:869-872, 1975

Thoracic and Cardiovascular Surgery

13 Breckenridge RT, Ratnoff OD: Studies on the nature of the circulating anticoagulant directed against antihemophilic factor. With notes on an assay for antihemophilic factor. Blood 20:137-149, 1962 14 Biggs R: Christmas disease, Treatment of Haemophilia and Other Coagulation Disorders, R Biggs, RG MacFarlane, eds., Oxford, England, 1966, Blackwell Scientific Publications, pp 222-239 15 Hoag MS, Johnson FF, Robinson JA, Aggeler PM: Treatment of hemophilia B with a new clotting factor concentrate. N Engl J Med 280:581-586, 1969 16 Menache D: The turnover rate of coagulation factors II, VII, and IX under normal metabolic conditions. Thromb Haemostas (Suppl) 13:187-194,1963 17 Johnson AJ, Aronson DL: Clinical use of plasma and plasma fractions, Hematology, WJ Williams, ed., New York, 1972, McGraw-Hill Book Company, Inc., pp 1329-1353 18 Blatt PM, Lunbald RL, Kingdon HS, McLean G, Roberts HR: Thrombogenic materials in prothrombin complex concentrates. Ann Intern Med 81:766-770, 1974 19 Kasper CK: Postoperative thromboses in hemophilia B. N Engl J Med 289: 160, 1973 20 Gershwin ME, Gude JK: Deep vein thrombosis and pulmonary embolism in congenital factor VII deficiency. N Engl J Med 288: 141-142, 1973 21 Campbell EW, Neff S, Bowdler AJ: Therapy with factor IX concentrate resulting in D. I. C. and thromboembolic phenomena. Transfusion 18:94-97, 1978 22 Cederbaum AI, Roberts HR: Complications of the use of prothrombin complex concentrates in liver disease (abstr). Clin Res 21:92, 1973 23 Kasper CK: Thromboembolic complications (Task Force Report). Thromb Haemostas 33:640-644, 1975 24 Aronson DL: Inhibition of thrombotic effect of factor IX. N Engl J Med 290:861, 1974 25 Kingdon HS: Recent reduction in thrombogenic enzyme content of prothrombin complex concentrates. Thromb Haemostas 38:340, 1977 (Suppl) 26 Hathaway WE, Mahasandana C, Clarke S, Humbert JR: Paradoxical bleeding in intensively transfused hemophiliacs. Alteration of platelet function. Transfusion 13:6-12, 1973 27 Bark CJ, Orloff MJ: The partial thromboplastin time and factor VIII therapy. Am J Clin PathoI57:478-48I, 1972 28 McMillan CW, Diamond LK, Surgenor DM: Treatment of classic hemophilia. The use of fibrinogen rich in factor VIII for hemorrhage and for surgery (concluded). N Engl J Med 265:277-283, 1961 29 Orringer EP, Koury MJ, Blatt PM, Roberts HR: Hemolysis caused by factor VIII concentrates. Arch Intern Med 136:1018-1020, 1976 30 Rosati LA, Barnes B, Oberman HA, Penner JA: Hemolytic anemia due to anti-A in concentrated antihemophilic factor preparations. Transfusion 10: 139-141, 1970 31 Ashenhurst IB, Langehenning PL, Seeler RA, Telfer MC: Hemolytic anemia due to anti-B in antihemophiliac factor concentrates. 1 Pediatr 88:257-258, 1976

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Number 4 April,1979

32 Seeler RA, Telischi M, Langehenning PL, Ashenhurst 18: Comparison of anti-A and anti-B titers in factor VIII and IX concentrates. J Pediatr 89:87-89, 1976 33 Sturgeon P, Adashek EP, Self JL, Stiehm ER, Tishkoff GH: Recent developments in blood components therapy. Ann Intern Med 74:113-125, 1971 34 Weiss HJ, Aledort LM, Kochwa S: The effect of salicylates on the hemostatic properties of platelets in man. J Clin Invest 47:2169-2180, 1968 35 Mills DCB: Drugs that effect platelet behaviour. Clin Hematol 1:295-305, 1972 36 Seeff LB, Hoofnagle J: Acute and chronic Ii ver disease in hemophilia, Unsolved Therapeutic Problems in Hemophilia, DHEW Pub!. (NIH) 77-1089, JC Fratantoni, DL Aronson, eds., Bethesda, Md., 1976, U. S. Department of Health, Education and Welfare, pp 61-72 37 Peterson MR, Barker LF, Schade DS: Detection of antibody to hepatitis-associated antigen in hemophilia patients and in voluntary blood donors. Vox Sang 24:66-75, 1973 38 Mannucci PM, Capitanio A, del Ninno E, Colombo M, Pareti F, Ruggeri ZM: Asymptomatic liver disease in haemophiliacs. J Clin Pathol 28:620-624, 1975 39 Oken MM, Hootkin L, Dejager RL: Hepatitis after Konyne administration. Dig Dis 17:271-274, 1972 40 Faria R, Fiumara NJ: Hepatitis-B associated with Konyne. N Engl J Med 287:358-359, 1972

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