An Adverse Pulmonary Reaction to Cryoprecipitate in a Hemophiliac E. P. REESE,JR., J. J. MCCULLOUGH, AND P. R. CRADDOCK From the Departments of Medicine and Laboratory Medicine. University of Minnesota Medical School. Minneapolis. Minnesota
An adult with classic Hemophilia A experienced a very severe reaction to transfusion with cryoprecipitate which was manifested as an adverse pulmonary reaction with marked hypoxemia in spite of oxygen therapy. The patient had neither leukoagglutinins nor lymphocytoxic, anti-platelet, or anti-Gm antibodies. His IgA level was normal. The possibility that debris in the cryoprecipitate from leukocytes and platelets contributed to the reaction is discussed.
SEVERE REACTIONS to cryoprecipitate have been rare during the decade of its availability. Poolzohas recommended t h e use of cryoprecipitate because the nonspecific allergic reactions seen with whole plasma are almost entirely absent with cryoprecipitate. Ahrons, et aL,I Rizza and matt hew^,^^ and Burman, et al.e have reported a few severe reactions to cryoprecipitate. Maycock, et aI.l5 and Rizza and BiggsZ3have noted severe reactions after infusions of A H G concentrate. Adverse pulmonary reactions, characterized primarily by pulmonary insufficiency with patchy infiltrates radiographically, have infrequently been cited as a complication to transfusion with whole blood, packed red blood cells, and fresh frozen 19.27*30*31 Similar reactions have been termed allergic pulmonary edema or pulmonary hypersensitivity reactions. This is a report of an adverse pulmonary reaction to cryoprecipitate.
Received for publication January 18, 1975; accepted April 7, 1975. This work was supported in part by Training Grant T R 159 Veterans Administration.
Transfusion Nov.-Dec. 1975
Case Report The patient is an IS-year-old with hemophilia A (Factor VIII activity less than 2 per cent) who has received more than 6,000 donor units of cryoprecipitate, fresh frozen plasma, plasma, blood, and human AHG concentrate transfusions since 1968, when he first came to the University of Minnesota Hospital. Since 1969, he has had several mild febrile and urticaria1 reactions to transfusion with cryoprecipitate and AHG concentrates. In addition, he has had an allergic skin rash due to erythromycin. On April 11, 1974, he received 20 donor units of ABO and Rh specific cryoprecipitate, which had a total volume of 200 ml. Shortly after administration of the cryoprecipitate, he complained of a severe headache and had a shaking chill. His temperature was 37.9 C (oral) and his blood pressure rose to 144/SO mm Hg. Fifteen minutes later his blood pressure was his usual 130/80 mm Hg, and his headache subsided. There were no other positive physical findings. He was treated with acetominophen, remained stable, and was sent home after 30 minutes. About three hours later, he returned with an exacerbation of the headache, now accompanied by dizziness. He was still febrile (37.8 C oral), had a tachycardia (120 per minute), and a blood pressure of 120/80 mm Hg. There was hyperpnea on physical examination which was otherwise not remarkable. The hemoglobin was 14.2 gm/100 ml. The hematocrit was 42.5 per cent. The leukocyte count was 6,000 per mm3 with 79 per cent neutrophils, 17 per cent lymphocytes, and 4 per cent monocytes. The platelets were described as adequate. The urinalysis was negative except for I + proteinuria and an occasional red blood cell. He was sent home after a period of observation. He returned at midnight with new complaints of a dry cough and difficulty breathing accompanied by the persistent headache and dizziness. He had had no more chills. His vital signs were unchanged. Although hyperpnea (44 per minute) was present,
583
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REESE, ET AL.
FIG. I. Chest x-ray with a diffuse patchy alveolar infiltrate throughout both lung fields, taken on admission to the hospital, April 12, 1974, approximately ten hours after the cryoprecipitate transfusion. his lungs were resonant and clear on examination. The chest x-ray showed the acute development of a diffuse patchy alveolar infiltrate present throughout both lung fields (Fig. I). The patient was admitted to the hospital at which time his temperature had risen to 38.9 C (oral). He was an obese male, tachypneic (32 to 40 per minute), with a nonproductive cough, and in moderate respiratory distress. There was no venous distention in the neck. Examination o f the lungs revealed bilateral decreased breath sounds and some diffuse expiratory rales. A tachycardia (120 per minute) was present, but neither gallop sounds nor murmurs were heard on examination of the heart. The nail beds were dusky. He was given 200 mg of methylprednisolone sodium succinate intravenously and started on oxygen (Table I). The blood
pressure dropped transiently to 96/60, but returned to the previous levels. Later in the morning he was listless and was having more difficulty inspiring deeply. On examination, he had markedly decreased breath sounds bilaterally, and he was admitted to the intensive care unit. The repeat chest x-ray demonstrated the persistence of the diffuse infiltrate. Because of the marked hypoxemia, he was placed on a rebreathing mask and improved. Throughout the remainder of the day, he received 250 mg of methylprednisolone sodium succinate intravenously at two-hour intervals. At 6:OO p.m. on April 12, he stated that he was beginning to feel better and asked for something to eat. His lungs at that time were clear to auscultation and his breath sounds were increased from earlier in the day. The morning of April 13, he was markedly improved symptomatically. He was able to be off of oxygen intermittently, although a repeat chest x-ray was unchanged. Repeat urinalysis was normal. He continued to improve and on April 15, he was able to ambulate normally. Throughout his hospitalization, he continued to receive Factor VIlI replacement with commercial A H F concentrate.* His Factor V l l l activity was kept above 37 per cent of normal because of the uncertainty of the pathological process in the lung and the possibility o f intraalveolar hemorrhage. He also received phenobarbital, 30 mg q.i.d. because of a seizure disorder dating to the evacuation of a subdural hematoma at age 13. He received no cardiac glycosides, diuretics, or antibiotics. By April 16, the ~
*Hemofil, Antihemophiliac Factor (Human), Hyland Division, Travenol Laboratories, Inc., Costa Mesa, California.
Table 1. Arterial Blood Gases Related to Oxygen Therapy Supplemental Oxygen (liters/minute) Nasal Rebreathing
Date
Time April 12 2:OO AM' 4:OO AM 11:00AM**
Cannulae
p C 0 2 mm Hg
8
7.47 7.45
36
57
10
7.44
43
Mask
4
"Admission to ICU.
0
50
13
7.42 7.42
12
7.44
38
86
7.49
34
60
9
Room air
34
~
30 37 37
The cryoprecipitate transfusion was administered a t 2:30 PM, April 1 1 , 1974. 'Admission.
mm 2 Hg
PH
2:OO PM 6:OO PM April 13 11 :00 AM April 14 1O:OO AM
Arterial Blood Gases
56 72
Volume 15 Number6
REACTION TO CRYOPRECIPITATE
585
chest x-ray had returned to normal (Fig. 2), and the patient was discharged. He has since been treated only with commercial AHG concentrates and has not had any further reactions.
Investigative Studies Serum complement levels, both CHSoand P I A were normal on admission and on April 13 and 15. On April 12, no leukoagglutination by the patient’s serum was seen when tested with seven random donors’ leukocytes which included HL-A antigens 1, 2, 10, W19, 12, 13, WIO, W14, and W15. Lymphocyte cytotoxic antibodies were negative to a panel of cells from 18 random donors. Aerobic and anaerobic cultures of the pooled cryoprecipitate from the donor bag were negative. Additional studies were performed on the patient’s serum three weeks after the reaction. No leukoagglutination was seen to leukocytes from nine random donors which included HL-A antigens 1, 2, 3 , 9 , 1 I , W19, W28,5, 7, 8, 13, W5, WIO, and W22. Antiplatelet antibodies were negative by agglutination and complement fixation techniques. Serum IgA was 220 mg/100 ml (normal 44 to 540 mg/100 ml), IgG 1240 mg/100 ml (normal 520 to 1800 mg/100 ml), IgM I15 mg/100 ml (normal 36 to 280 mg/ 100 ml), and IgE 37 IU/ml (normal 12 to 444 I U / ml). Anti-Gm antibody studies were negative. Two units of cryoprecipitate were centrifuged at 550 x g for ten minutes and the sediment examined. By light microscopic examination, each unit contained a button consisting of apparent fragmented leukocytes and platelets. We determined the number of identifiable leukocytes in five units of fresh whole blood and in the plasma removed to be processed into cryoprecipitate.2 An average of 3.7 x lo9 leukocytes were in each unit of blood, whereas only 6.8 x lo’ leukocytes, or less than 2 per cent of the original number, were identifiable in the separated plasma. Discussion Descriptions of reactions to cryoprecipitate are scarce in the literature. Ahrons, et al.’ reported three patients with hemophilia who had severe reactions to pooled lyophilized cryoprecipitate. These included in different patients: anaphylactic shock, a fever of 40 C, an extensive urticaria1 rash, tachycardia, and a choking sensation which disappeared upon discontinuing the infusion. None of the reactions persisted more than six hours and none was delayed in
FIG.2. Chest x-ray with clearing of both lung fields, taken April 16, 1974, five days after the cryoprecipitate transfusion.
onset. The etiologies of these reactions were not found, but deficient IgA and an anti-IgA reaction were not excluded.I0 Rizza and MatthewsZ4related that reactions to AHG concentrates, cryoprecipitate, and plasma included aches in the limbs, headache, chills, fever, and urticaria. They also noted bronchospasm and wheezing as an allergic response, but did not include any description of a reaction characteristic of an adverse pulmonary reaction. Rizza and Biggsz3noted similar reactions to AHG concentrate, but apparently did not include cryoprecipitate in their observation. Burman, et al.Oreported a case of acute anaphylaxis, pulmonary edema, hemoptysis, and intravascular hernolysis in response to cryoprecipitate. Their 5%-year-old patient was treated with hydrocortisone, antihistamines, and diuretics with clearing of the chest x-ray in 24 hours. The reaction was thought to be related to a high titer of anti-A in the cryoprecipitate, kinin formation, or a bee sting protein residual from one of the donors. A severe hemolytic reaction due to Rh antibody in AHG concentrate was reported by Schricker and Sch ren k. 26 Kernoff, et reported three patients with hemophilia who developed severe febrile reactions and allergic pulmonary edema after transfusion with fresh frozen plasma. Two of these responded to treatment with
586
REESE, ET AL.
Transfusion Nov.-Dec. 1975
d . I R and may have contributed to the paoxygen, antibiotics, diuretics, and hydrocortient’s reaction in spite of no demontisone. The third, a nine-year-old patient, strated leukoagglutinins. Twelve of the 20 after becoming febrile and complaining of cryoprecipitate donors were female and back pain following transfusion with fresh eight had been pregnant more than two frozen plasma, was found to be anemic. He times. However, it seems unlikely that a received one unit of whole blood and 350 ml significant amount of donor leukoagglutinins of Factor V I I I concentrate. He then dewere transfused in the cryoprecipitate to acveloped a clinical and x-ray picture of pulmonary edema and died within 24 hours. count for the reaction, but this possibility The etiologies of these reactions were felt to cannot be excluded. The reaction in our patient was charbe related to anti-Gm and anti-leukocyte anacterized by an abrupt onset of a severe tibodies, but the possibility of fluid overload headache, shaking chills, mild fever, and in the fatal case cannot be excluded. minimal transient hypertension. He subseWolf and Canale32 recently reported a quently developed dizziness, tachycardia, hyfatal pulmonary hypersensitivity reaction to perpnea, mild proteinuria and later a dry a partial unit of packed red blood cells in cough, marked dyspnea, hypoxemia, and a 13y$year-old patient with thalassemia patchy lung infiltrates. There was no sputum major. The patient failed to respond to production at any time. Wheezing was not steroids and other intensive therapy for the heard at any time although frequent obacidosis and the decreased oxygen saturation servations were made. There was a striking which developed. At autopsy, there was exdecrease in breath sounds at the time of his tensive nonspecific acute alveolar injury with pronounced hypoxia. He did not display any exudates of polymorphonuclear cells and numanifestations of circulatory overload other merous eosinophils, hyaline membranes, than tachycardia. Furthermore, the small and aspiration pneumonitis. No leukocyte volume of cryoprecipitate (200 ml) would be thrombi were seen. The recipient’s serum unusual to initiate a volume overload state in contained lymphocytotoxic antibodies to this otherwise healthy 18-year-old male. The HL-A I 1 and possibly W14 which were degree of hypoxia (arterial PO, 43 mm Hg), found on the donor cells and were felt to be in spite of concurrent nasal oxygen, was the cause of the fatal reaction. striking and accentuated the dramatic raAdverse pulmonary reactions not due to diographic changes. These symptoms and fluid overload have been an infrequent form physical findings are similar to those preof reaction to blood transfusions since viously described in the l i t e r a t ~ r e . ~ ’ ~ ~ . ’ ~ . ~ ~ initially noted by B a ~ n a r d .This ~ type of 27.30.3 I reaction has been associated with either The possibility of this reaction being more leukoagglutinins or multiparity or both in most of the reported c a ~ e ~ . ~ ’All ~ of ~ . ~ than ~ . an ~ allergic ~ . ~ ~one. and ~ ~including a response to debris from the cryoprecipitate lodging in the previous cases have been associated with the pulmonary microvasculature cannot be whole blood, packed red blood cells, or fresh excluded. Reul and co-workersZ2found that, frozen plasma transfusions, although the in the trauma patient transfused with more quantities of whole blood have been as small than ten units of whole blood within the first as 50 ml.5 Our patient had no demonstrable 24 hours after injury, the incidence of shock leukoagglutinins. We estimate that the 20 lung, radiographically similar to cases of units of cryoprecipitate transfused to our patient would contain approximately 1.4 x adverse pulmonary reactions, was decreased with the use of a 40-micron pore size blood lo9 leukocytes. This is more than the filter in place of the usual 170 micron pore threshold number associated with nonhemolytic febrile reactions by Perkins, et size blood filter. We found fragmented
Volume
IS
Numkr 6
587
REACTION TO CRYOPRECIPITATE
leukocytes and platelets in the cryoprecipitate which are presumedly damaged by the freezing process. The technique used in the production of cryoprecipitate includes draining the plasma through the cryoprecipitate, in that the bags are centrifuged inverted, and may well concentrate the residual fragmented leukocytes with the cryoprecipitate fraction. Over 50 per cent of the platelets have been shown to distribute with Factor VIII in the production of cryoprecipitate.2B Together, the leukocyte fragments and platelets may make a significant contribution to the observed reaction. Another mechanism that has been associated with severe reactions to compatible blood transfusions include anti-IgA antibodies. This usually occurs in patients who are IgA d e f i ~ i e n t ' ~ . ' although ~ . ~ ~ * ~ others ~ who were not deficient have been reported.2g Reactions to IgA have usually been acute and anaphylactic in nature. Since this patient has normal IgA levels, and anti-IgA antibodies have not been associated with an adverse pulmonary reaction, it is unlikely that anti-IgA antibodies were the basis of the reaction. Anti-Gm antibodies have been implicated in the febrile reactions of multitransfused patient^.^*^*^.''.*' The occurrence of anti-Gm antibodies did not correlate well with a history of severe transfusion reactions in one group of Factor VIII and IX deficient patients.'* Anti-Gm antibodies have been associated with an allergic pulmonary edema reactionI3 in a fatal case who was Gm(l) positive and received a fresh frozen plasma transfusion from a donor with antiGm(l) with a titer of 1:32. Anti-Gm antibodies were not demonstrated in our patient. Physicians who use cryoprecipitate to treat hemophilia or for other component therapy should be aware that an adverse pulmonary reaction may occur and may be accompanied by very severe hypoxia. It is probably more likely to occur in the patient with a history of multiple transfusions, such
as this case, than in a patient without a history of transfusion. The reactions may be due to a yet unidentified antigen-antibody reaction, caused by either the recipient or donor's leukoagglutinins, partially related to the cellular debris in the cryoprecipitate fraction or to some combination of the three. Transfusion in a hemophiliac who has had an adverse pulmonary reaction should be limited to AHG concentrates, which our patient has tolerated well. When red blood cell transfusions are necessary, the use of leukocyte poor preparations should be considered as should the microemboli filters which are now available. Acknowledgments HL-A typing, lymphocyte cytotoxicity and antiplatelet antibody studies were performed in the Clinical Immunology Laboratory of the University of Minnesota Hospital, directed by Dr. Edmund J. Yunis. AntiGm antibody studies were kindly performed by Dr. Herbert Polesky, Minneapolis War Memorial Blood Bank. The authors are grateful to Drs. J. Roger Edson and Peter R. Olson for suggestions and reviewing the manuscript, Ms. Jane Swanson for technical assistance, and Ms. Marilyn Mudge and Ms. Nancy Grunz for secretarial assistance.
References I.
2. 3.
4. 5.
6.
7.
8.
Ahrons, S., S. Glavind-Kristensen, 0. Drachmann, and F. Kissmeyer-Nielsen: Severe reactions after cryoprecipitated human Factor VIII. Vox Sang. 18:182, 1970. American National Red Cross, Blood Program Directive. 6.21-1, 1972. Barandum, S., P. Kistler, F. Jeunet, and H. Isliker: Intravenous administration of human gamma-globulin. Vox Sang. 7:157, 1962. Barnard, R. D.: Indiscriminate transfusion: a critique of case reports illustrating hypersensitivity reactions. N.Y. State J. Med. 51:2399, 1951. Brittingham, T. E.: Immunologic studies on leukocytes. Vox Sang. 2:242, 1957. Burman, D., A. K. Hodson, C. B. S. Wood, and N. F. W. Brueton: Acute anaphylaxis, pulmonary oedema and intravascular haemolysis due to cryoprecipitate. Arch. Dis. Child. 48:483, 1973. Byrne, J. P. Jr., and J. A. Dixon: Pulmonary edema following blood transfusion reaction. Arch. Surg. 102:91, 1971. Fischer, K.: ImmunhBmatologische und klinische Befunde bei einem Transfusionszwischenfall in-
REESE, ET AL.
9.
10.
I I.
12.
13.
14.
IS.
16.
17.
18.
19.
20. 21.
folge Gm(atAntikb;rperbildung, Bibl. Haematol. 23 (part 2):434, 1965. Fudenberg, H. H., E. R. Stiehm, E. C. Franklin, M. Meltzer, and B. Frangione: Antigenicity of hereditary human gamma globulin (Gm) factors-biological and biochemical aspects. Cold Spring Harbor Symp. Quant. Biol. 29:463, 1964. Holland, P. V., and M. A. Gralnick: Clinical reactions to cryoprecipitated Factor V111. Vox Sang. 21:94, 1971. Jensen, K. G., H. Giirtler, and A. Bruusgaard: Blood transfusion reaction caused by serum group incompatibility, Bibl. Haematol. 29 (part 1):327, 1968. Kernoff, P. B. A,, and P. J. Bowell: Gm types and antibodies in multitransfused haemophiliacs. Br. J. Haematol. 24:443, 1973. ~, 1. J. Durrant, C. R. Rizza, and F. W. Wright: Severe allergic pulmonary oedema after plasma transfusion. Br. J. Haematol. 23:777, 1972. Leikola, J., J. Koistinen, M. Lehtinen, and M. Virolainen: IgA-induced anaphylactic transfusion reactions: a report of four cases. Blood 42:l I I , 1973. Maycock, W. d’A., S. Evans, L. Vallet, B. Combridge, P. Wolf, N. McGibbon, E. E. French, L. H. Wallett, J. V. Dacie, R. Biggs, D. Handley, and R. G. Macfarlane: Further experience with a concentrate containing human antihaemophilic factor. Br. J . Haematol. 9:215, 1963. Miller, W. V., P. V. Holland, E. Sugarbaker, W. Strober, and T. A. Waldmann: Anaphylactic reactions to IgA: a difficult transfusion problem. Am. J. Clin. Pathol. 54:618, 1970. Pearlstein, A. T.: Pulmonary hypersensitivity reaction during blood transfusion. N.Y. State J. Med. 71:2683, 1971. Perkins, H. A., R. Payne, J. Ferguson, and M. Wood: Nonhemolytic febrile transfusion reactions. Quantitative effects of blood components with emphasis on isoantigenic incompatibility of leukocytes. Vox Sang. 11:578, 1966. Philipps, E., and F. G. Fleischner: Pulmonary edema in the course of a blood transfusion without overloading the circulation. Dis. Chest 50:619, 1966. Pool, J. G.: Cryoprecipitated Factor V I I I concentrate. Bibl. Haematol. 34:23, 1970. Prentice, C. R. M., M. M. Izatt, J. F. Adams, G. P. McNicol, and A. S. Douglas: Amyloidosis associated with the nephrotic syndrome and transfusion reactions in a haemophiliac. Br. J . Haematol. 21:305, 1971.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
Transfusion Nov.-Dec. 1975
Reul, G. J. Jr., S. D. Greenberg, E. A. Lefrak, W. B. McCollum, A. C. Beall, Jr., and G. L. Jordan, Jr.: Prevention of posttraumatic pulmonary insufficiency. Arch. Surg. 106:386, 1973. Rizza, C. R., and R. Biggs: The use of plasma fractions in the treatment of hemophilia and von Willebrand’s disease. Prog. Hematol. 6:181, 1969. -, and J . M. Matthews: Management of the haemophiliac child. Arch. Dis. Child. 47:451, 1972. Schmidt, A. P., H. F. Taswell, and G. J . Gleich: Anaphylactic transfusion reactions associated with anti-lgA antibody. N. Engl. J. Med. 280:188, 1969. Schricker, K. T., and K. H. Schrenk: Schwere serogene hzlmolytische Anamie verursacht durch ein Anti-D im Faktor-VIIIKonzentraten. Thromb. Diath. Haemorrh. 27523, 1972. Thompson, J. S., C. D. Severson, M. J. Parmely, B. L. Marmorstein, and A. Simmons: Pulmonary “hypersensitivity” reactions induced by transfusion of non-HL-A leukoagglutinins. N. Engl. J. Med. 284:1120, 1971. Uteg, K. H., and W. Sander: Untersuchungen an Kryoprazipitaten I . Mitteilung: Verteilung des antihamophilen Globulins A (Faktor VIII) und den Th rombozyten bei der K ryoprazipitation. Folia Haematol. ;Leipz)97:322, 1972. Vyas, G. N., H. A. Perkins, and H. H. Fudenberg: Anaphylactoid transfusion reactions associated with anti-IgA. Lancet 2:312, 1968. Ward, H. N.: Pulmonary infiltrates associated with leukoagglutinin transfusion reactions. Ann. Intern. Med. 73:689, 1970. Ward, H. N., T. S. Lipscomb, and L. P. Cawley: Pulmonary hypersensitivity reaction after blood transfusion. Arch. Intern. Med. 122:362, 1968. Wolf, C. F. W., and V. C. Canale: Fatal pulmonary hypersensitivity reaction to HL-A incompatible blood transfusion. Report of a case. Transfusion 14509, 1974 (abstract).
.
E. P. Reese, Jr., Department of Medicine, University of Minnesota Medical School; Hennepin County Medical Center, Fifth Street and Portland Avenue South, Minneapolis, Minnesota 55415 (reprint requests). J. J. McCullough, Department of Laboratory Medicine, University of Minnesota Medical School, Minneapolis, Minnesota. P. R. Craddock, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota.
An adult with classic Hemophilia A experienced a very severe reaction to transfusion with cryoprecipitate which was manifested as an adverse pulmonary reaction with marked hypoxemia in spite of oxygen therapy. The patient had neither leukoagglutinins nor lymphocytoxic, anti-platelet, or anti-Gm antibodies. His IgA level was normal. The possibility that debris in the cryoprecipitate from leukocytes and platelets contributed to the reaction is discussed.
SEVERE REACTIONS to cryoprecipitate have been rare during the decade of its availability. Poolzohas recommended t h e use of cryoprecipitate because the nonspecific allergic reactions seen with whole plasma are almost entirely absent with cryoprecipitate. Ahrons, et aL,I Rizza and matt hew^,^^ and Burman, et al.e have reported a few severe reactions to cryoprecipitate. Maycock, et aI.l5 and Rizza and BiggsZ3have noted severe reactions after infusions of A H G concentrate. Adverse pulmonary reactions, characterized primarily by pulmonary insufficiency with patchy infiltrates radiographically, have infrequently been cited as a complication to transfusion with whole blood, packed red blood cells, and fresh frozen 19.27*30*31 Similar reactions have been termed allergic pulmonary edema or pulmonary hypersensitivity reactions. This is a report of an adverse pulmonary reaction to cryoprecipitate.
Received for publication January 18, 1975; accepted April 7, 1975. This work was supported in part by Training Grant T R 159 Veterans Administration.
Transfusion Nov.-Dec. 1975
Case Report The patient is an IS-year-old with hemophilia A (Factor VIII activity less than 2 per cent) who has received more than 6,000 donor units of cryoprecipitate, fresh frozen plasma, plasma, blood, and human AHG concentrate transfusions since 1968, when he first came to the University of Minnesota Hospital. Since 1969, he has had several mild febrile and urticaria1 reactions to transfusion with cryoprecipitate and AHG concentrates. In addition, he has had an allergic skin rash due to erythromycin. On April 11, 1974, he received 20 donor units of ABO and Rh specific cryoprecipitate, which had a total volume of 200 ml. Shortly after administration of the cryoprecipitate, he complained of a severe headache and had a shaking chill. His temperature was 37.9 C (oral) and his blood pressure rose to 144/SO mm Hg. Fifteen minutes later his blood pressure was his usual 130/80 mm Hg, and his headache subsided. There were no other positive physical findings. He was treated with acetominophen, remained stable, and was sent home after 30 minutes. About three hours later, he returned with an exacerbation of the headache, now accompanied by dizziness. He was still febrile (37.8 C oral), had a tachycardia (120 per minute), and a blood pressure of 120/80 mm Hg. There was hyperpnea on physical examination which was otherwise not remarkable. The hemoglobin was 14.2 gm/100 ml. The hematocrit was 42.5 per cent. The leukocyte count was 6,000 per mm3 with 79 per cent neutrophils, 17 per cent lymphocytes, and 4 per cent monocytes. The platelets were described as adequate. The urinalysis was negative except for I + proteinuria and an occasional red blood cell. He was sent home after a period of observation. He returned at midnight with new complaints of a dry cough and difficulty breathing accompanied by the persistent headache and dizziness. He had had no more chills. His vital signs were unchanged. Although hyperpnea (44 per minute) was present,
583
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Transfusion Nov.-Dec. 1975
REESE, ET AL.
FIG. I. Chest x-ray with a diffuse patchy alveolar infiltrate throughout both lung fields, taken on admission to the hospital, April 12, 1974, approximately ten hours after the cryoprecipitate transfusion. his lungs were resonant and clear on examination. The chest x-ray showed the acute development of a diffuse patchy alveolar infiltrate present throughout both lung fields (Fig. I). The patient was admitted to the hospital at which time his temperature had risen to 38.9 C (oral). He was an obese male, tachypneic (32 to 40 per minute), with a nonproductive cough, and in moderate respiratory distress. There was no venous distention in the neck. Examination o f the lungs revealed bilateral decreased breath sounds and some diffuse expiratory rales. A tachycardia (120 per minute) was present, but neither gallop sounds nor murmurs were heard on examination of the heart. The nail beds were dusky. He was given 200 mg of methylprednisolone sodium succinate intravenously and started on oxygen (Table I). The blood
pressure dropped transiently to 96/60, but returned to the previous levels. Later in the morning he was listless and was having more difficulty inspiring deeply. On examination, he had markedly decreased breath sounds bilaterally, and he was admitted to the intensive care unit. The repeat chest x-ray demonstrated the persistence of the diffuse infiltrate. Because of the marked hypoxemia, he was placed on a rebreathing mask and improved. Throughout the remainder of the day, he received 250 mg of methylprednisolone sodium succinate intravenously at two-hour intervals. At 6:OO p.m. on April 12, he stated that he was beginning to feel better and asked for something to eat. His lungs at that time were clear to auscultation and his breath sounds were increased from earlier in the day. The morning of April 13, he was markedly improved symptomatically. He was able to be off of oxygen intermittently, although a repeat chest x-ray was unchanged. Repeat urinalysis was normal. He continued to improve and on April 15, he was able to ambulate normally. Throughout his hospitalization, he continued to receive Factor VIlI replacement with commercial A H F concentrate.* His Factor V l l l activity was kept above 37 per cent of normal because of the uncertainty of the pathological process in the lung and the possibility o f intraalveolar hemorrhage. He also received phenobarbital, 30 mg q.i.d. because of a seizure disorder dating to the evacuation of a subdural hematoma at age 13. He received no cardiac glycosides, diuretics, or antibiotics. By April 16, the ~
*Hemofil, Antihemophiliac Factor (Human), Hyland Division, Travenol Laboratories, Inc., Costa Mesa, California.
Table 1. Arterial Blood Gases Related to Oxygen Therapy Supplemental Oxygen (liters/minute) Nasal Rebreathing
Date
Time April 12 2:OO AM' 4:OO AM 11:00AM**
Cannulae
p C 0 2 mm Hg
8
7.47 7.45
36
57
10
7.44
43
Mask
4
"Admission to ICU.
0
50
13
7.42 7.42
12
7.44
38
86
7.49
34
60
9
Room air
34
~
30 37 37
The cryoprecipitate transfusion was administered a t 2:30 PM, April 1 1 , 1974. 'Admission.
mm 2 Hg
PH
2:OO PM 6:OO PM April 13 11 :00 AM April 14 1O:OO AM
Arterial Blood Gases
56 72
Volume 15 Number6
REACTION TO CRYOPRECIPITATE
585
chest x-ray had returned to normal (Fig. 2), and the patient was discharged. He has since been treated only with commercial AHG concentrates and has not had any further reactions.
Investigative Studies Serum complement levels, both CHSoand P I A were normal on admission and on April 13 and 15. On April 12, no leukoagglutination by the patient’s serum was seen when tested with seven random donors’ leukocytes which included HL-A antigens 1, 2, 10, W19, 12, 13, WIO, W14, and W15. Lymphocyte cytotoxic antibodies were negative to a panel of cells from 18 random donors. Aerobic and anaerobic cultures of the pooled cryoprecipitate from the donor bag were negative. Additional studies were performed on the patient’s serum three weeks after the reaction. No leukoagglutination was seen to leukocytes from nine random donors which included HL-A antigens 1, 2, 3 , 9 , 1 I , W19, W28,5, 7, 8, 13, W5, WIO, and W22. Antiplatelet antibodies were negative by agglutination and complement fixation techniques. Serum IgA was 220 mg/100 ml (normal 44 to 540 mg/100 ml), IgG 1240 mg/100 ml (normal 520 to 1800 mg/100 ml), IgM I15 mg/100 ml (normal 36 to 280 mg/ 100 ml), and IgE 37 IU/ml (normal 12 to 444 I U / ml). Anti-Gm antibody studies were negative. Two units of cryoprecipitate were centrifuged at 550 x g for ten minutes and the sediment examined. By light microscopic examination, each unit contained a button consisting of apparent fragmented leukocytes and platelets. We determined the number of identifiable leukocytes in five units of fresh whole blood and in the plasma removed to be processed into cryoprecipitate.2 An average of 3.7 x lo9 leukocytes were in each unit of blood, whereas only 6.8 x lo’ leukocytes, or less than 2 per cent of the original number, were identifiable in the separated plasma. Discussion Descriptions of reactions to cryoprecipitate are scarce in the literature. Ahrons, et al.’ reported three patients with hemophilia who had severe reactions to pooled lyophilized cryoprecipitate. These included in different patients: anaphylactic shock, a fever of 40 C, an extensive urticaria1 rash, tachycardia, and a choking sensation which disappeared upon discontinuing the infusion. None of the reactions persisted more than six hours and none was delayed in
FIG.2. Chest x-ray with clearing of both lung fields, taken April 16, 1974, five days after the cryoprecipitate transfusion.
onset. The etiologies of these reactions were not found, but deficient IgA and an anti-IgA reaction were not excluded.I0 Rizza and MatthewsZ4related that reactions to AHG concentrates, cryoprecipitate, and plasma included aches in the limbs, headache, chills, fever, and urticaria. They also noted bronchospasm and wheezing as an allergic response, but did not include any description of a reaction characteristic of an adverse pulmonary reaction. Rizza and Biggsz3noted similar reactions to AHG concentrate, but apparently did not include cryoprecipitate in their observation. Burman, et al.Oreported a case of acute anaphylaxis, pulmonary edema, hemoptysis, and intravascular hernolysis in response to cryoprecipitate. Their 5%-year-old patient was treated with hydrocortisone, antihistamines, and diuretics with clearing of the chest x-ray in 24 hours. The reaction was thought to be related to a high titer of anti-A in the cryoprecipitate, kinin formation, or a bee sting protein residual from one of the donors. A severe hemolytic reaction due to Rh antibody in AHG concentrate was reported by Schricker and Sch ren k. 26 Kernoff, et reported three patients with hemophilia who developed severe febrile reactions and allergic pulmonary edema after transfusion with fresh frozen plasma. Two of these responded to treatment with
586
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d . I R and may have contributed to the paoxygen, antibiotics, diuretics, and hydrocortient’s reaction in spite of no demontisone. The third, a nine-year-old patient, strated leukoagglutinins. Twelve of the 20 after becoming febrile and complaining of cryoprecipitate donors were female and back pain following transfusion with fresh eight had been pregnant more than two frozen plasma, was found to be anemic. He times. However, it seems unlikely that a received one unit of whole blood and 350 ml significant amount of donor leukoagglutinins of Factor V I I I concentrate. He then dewere transfused in the cryoprecipitate to acveloped a clinical and x-ray picture of pulmonary edema and died within 24 hours. count for the reaction, but this possibility The etiologies of these reactions were felt to cannot be excluded. The reaction in our patient was charbe related to anti-Gm and anti-leukocyte anacterized by an abrupt onset of a severe tibodies, but the possibility of fluid overload headache, shaking chills, mild fever, and in the fatal case cannot be excluded. minimal transient hypertension. He subseWolf and Canale32 recently reported a quently developed dizziness, tachycardia, hyfatal pulmonary hypersensitivity reaction to perpnea, mild proteinuria and later a dry a partial unit of packed red blood cells in cough, marked dyspnea, hypoxemia, and a 13y$year-old patient with thalassemia patchy lung infiltrates. There was no sputum major. The patient failed to respond to production at any time. Wheezing was not steroids and other intensive therapy for the heard at any time although frequent obacidosis and the decreased oxygen saturation servations were made. There was a striking which developed. At autopsy, there was exdecrease in breath sounds at the time of his tensive nonspecific acute alveolar injury with pronounced hypoxia. He did not display any exudates of polymorphonuclear cells and numanifestations of circulatory overload other merous eosinophils, hyaline membranes, than tachycardia. Furthermore, the small and aspiration pneumonitis. No leukocyte volume of cryoprecipitate (200 ml) would be thrombi were seen. The recipient’s serum unusual to initiate a volume overload state in contained lymphocytotoxic antibodies to this otherwise healthy 18-year-old male. The HL-A I 1 and possibly W14 which were degree of hypoxia (arterial PO, 43 mm Hg), found on the donor cells and were felt to be in spite of concurrent nasal oxygen, was the cause of the fatal reaction. striking and accentuated the dramatic raAdverse pulmonary reactions not due to diographic changes. These symptoms and fluid overload have been an infrequent form physical findings are similar to those preof reaction to blood transfusions since viously described in the l i t e r a t ~ r e . ~ ’ ~ ~ . ’ ~ . ~ ~ initially noted by B a ~ n a r d .This ~ type of 27.30.3 I reaction has been associated with either The possibility of this reaction being more leukoagglutinins or multiparity or both in most of the reported c a ~ e ~ . ~ ’All ~ of ~ . ~ than ~ . an ~ allergic ~ . ~ ~one. and ~ ~including a response to debris from the cryoprecipitate lodging in the previous cases have been associated with the pulmonary microvasculature cannot be whole blood, packed red blood cells, or fresh excluded. Reul and co-workersZ2found that, frozen plasma transfusions, although the in the trauma patient transfused with more quantities of whole blood have been as small than ten units of whole blood within the first as 50 ml.5 Our patient had no demonstrable 24 hours after injury, the incidence of shock leukoagglutinins. We estimate that the 20 lung, radiographically similar to cases of units of cryoprecipitate transfused to our patient would contain approximately 1.4 x adverse pulmonary reactions, was decreased with the use of a 40-micron pore size blood lo9 leukocytes. This is more than the filter in place of the usual 170 micron pore threshold number associated with nonhemolytic febrile reactions by Perkins, et size blood filter. We found fragmented
Volume
IS
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587
REACTION TO CRYOPRECIPITATE
leukocytes and platelets in the cryoprecipitate which are presumedly damaged by the freezing process. The technique used in the production of cryoprecipitate includes draining the plasma through the cryoprecipitate, in that the bags are centrifuged inverted, and may well concentrate the residual fragmented leukocytes with the cryoprecipitate fraction. Over 50 per cent of the platelets have been shown to distribute with Factor VIII in the production of cryoprecipitate.2B Together, the leukocyte fragments and platelets may make a significant contribution to the observed reaction. Another mechanism that has been associated with severe reactions to compatible blood transfusions include anti-IgA antibodies. This usually occurs in patients who are IgA d e f i ~ i e n t ' ~ . ' although ~ . ~ ~ * ~ others ~ who were not deficient have been reported.2g Reactions to IgA have usually been acute and anaphylactic in nature. Since this patient has normal IgA levels, and anti-IgA antibodies have not been associated with an adverse pulmonary reaction, it is unlikely that anti-IgA antibodies were the basis of the reaction. Anti-Gm antibodies have been implicated in the febrile reactions of multitransfused patient^.^*^*^.''.*' The occurrence of anti-Gm antibodies did not correlate well with a history of severe transfusion reactions in one group of Factor VIII and IX deficient patients.'* Anti-Gm antibodies have been associated with an allergic pulmonary edema reactionI3 in a fatal case who was Gm(l) positive and received a fresh frozen plasma transfusion from a donor with antiGm(l) with a titer of 1:32. Anti-Gm antibodies were not demonstrated in our patient. Physicians who use cryoprecipitate to treat hemophilia or for other component therapy should be aware that an adverse pulmonary reaction may occur and may be accompanied by very severe hypoxia. It is probably more likely to occur in the patient with a history of multiple transfusions, such
as this case, than in a patient without a history of transfusion. The reactions may be due to a yet unidentified antigen-antibody reaction, caused by either the recipient or donor's leukoagglutinins, partially related to the cellular debris in the cryoprecipitate fraction or to some combination of the three. Transfusion in a hemophiliac who has had an adverse pulmonary reaction should be limited to AHG concentrates, which our patient has tolerated well. When red blood cell transfusions are necessary, the use of leukocyte poor preparations should be considered as should the microemboli filters which are now available. Acknowledgments HL-A typing, lymphocyte cytotoxicity and antiplatelet antibody studies were performed in the Clinical Immunology Laboratory of the University of Minnesota Hospital, directed by Dr. Edmund J. Yunis. AntiGm antibody studies were kindly performed by Dr. Herbert Polesky, Minneapolis War Memorial Blood Bank. The authors are grateful to Drs. J. Roger Edson and Peter R. Olson for suggestions and reviewing the manuscript, Ms. Jane Swanson for technical assistance, and Ms. Marilyn Mudge and Ms. Nancy Grunz for secretarial assistance.
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Ahrons, S., S. Glavind-Kristensen, 0. Drachmann, and F. Kissmeyer-Nielsen: Severe reactions after cryoprecipitated human Factor VIII. Vox Sang. 18:182, 1970. American National Red Cross, Blood Program Directive. 6.21-1, 1972. Barandum, S., P. Kistler, F. Jeunet, and H. Isliker: Intravenous administration of human gamma-globulin. Vox Sang. 7:157, 1962. Barnard, R. D.: Indiscriminate transfusion: a critique of case reports illustrating hypersensitivity reactions. N.Y. State J. Med. 51:2399, 1951. Brittingham, T. E.: Immunologic studies on leukocytes. Vox Sang. 2:242, 1957. Burman, D., A. K. Hodson, C. B. S. Wood, and N. F. W. Brueton: Acute anaphylaxis, pulmonary oedema and intravascular haemolysis due to cryoprecipitate. Arch. Dis. Child. 48:483, 1973. Byrne, J. P. Jr., and J. A. Dixon: Pulmonary edema following blood transfusion reaction. Arch. Surg. 102:91, 1971. Fischer, K.: ImmunhBmatologische und klinische Befunde bei einem Transfusionszwischenfall in-
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Reul, G. J. Jr., S. D. Greenberg, E. A. Lefrak, W. B. McCollum, A. C. Beall, Jr., and G. L. Jordan, Jr.: Prevention of posttraumatic pulmonary insufficiency. Arch. Surg. 106:386, 1973. Rizza, C. R., and R. Biggs: The use of plasma fractions in the treatment of hemophilia and von Willebrand’s disease. Prog. Hematol. 6:181, 1969. -, and J . M. Matthews: Management of the haemophiliac child. Arch. Dis. Child. 47:451, 1972. Schmidt, A. P., H. F. Taswell, and G. J . Gleich: Anaphylactic transfusion reactions associated with anti-lgA antibody. N. Engl. J. Med. 280:188, 1969. Schricker, K. T., and K. H. Schrenk: Schwere serogene hzlmolytische Anamie verursacht durch ein Anti-D im Faktor-VIIIKonzentraten. Thromb. Diath. Haemorrh. 27523, 1972. Thompson, J. S., C. D. Severson, M. J. Parmely, B. L. Marmorstein, and A. Simmons: Pulmonary “hypersensitivity” reactions induced by transfusion of non-HL-A leukoagglutinins. N. Engl. J. Med. 284:1120, 1971. Uteg, K. H., and W. Sander: Untersuchungen an Kryoprazipitaten I . Mitteilung: Verteilung des antihamophilen Globulins A (Faktor VIII) und den Th rombozyten bei der K ryoprazipitation. Folia Haematol. ;Leipz)97:322, 1972. Vyas, G. N., H. A. Perkins, and H. H. Fudenberg: Anaphylactoid transfusion reactions associated with anti-IgA. Lancet 2:312, 1968. Ward, H. N.: Pulmonary infiltrates associated with leukoagglutinin transfusion reactions. Ann. Intern. Med. 73:689, 1970. Ward, H. N., T. S. Lipscomb, and L. P. Cawley: Pulmonary hypersensitivity reaction after blood transfusion. Arch. Intern. Med. 122:362, 1968. Wolf, C. F. W., and V. C. Canale: Fatal pulmonary hypersensitivity reaction to HL-A incompatible blood transfusion. Report of a case. Transfusion 14509, 1974 (abstract).
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E. P. Reese, Jr., Department of Medicine, University of Minnesota Medical School; Hennepin County Medical Center, Fifth Street and Portland Avenue South, Minneapolis, Minnesota 55415 (reprint requests). J. J. McCullough, Department of Laboratory Medicine, University of Minnesota Medical School, Minneapolis, Minnesota. P. R. Craddock, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota.
