Hereditary angiwdema: The use of fresh frozen plasma for prophylaxis in patients undergoing oral surgery Charles Gelfand,
J. JI m M.O
M.D., Ph.D., John P. Atkinson, M.D., d Michael M. Frank, M.D. Bethtisda, Md.
Je*ey
A.
Six patients with llereditary angioedema (HAh) undergoing Y episodes of dental surgery reoekned transfusions with fresh frozen plasma one day before surgery. Althozlgh the mrbidity observed in these patients following similar procedures had been high, no significant aomplications of surgery were noted with th.is therapy. Thus, fresh frozen plasma infusion appears to provide a safe and cffectiue method of prophylaxis in patients with HAE. Following infwion of fresh frozen plasma, serum levels of C4 and Cl &erase inhibitor (C/El) rose transiently, and then fell to preinfwtin levels within 1 to 12 days. In all but one patient the rise in 124 was greater than could be accowGed for by the amount of C4 ,&fused. In no patient did the level of ClEI or C4 rise to within the normal range. The data raise the question of the role of Clh;I in the pathogenesis of angioedema in these patients.
Hereditary angioedema (HAE) is a genetically transmitted disorder associated with spontaneous attacks of swelling of the extremities, gastrointestinal tract, and pharynx .’ The more common form of the disorder has been linked to a relative deficiency of the inhibitor of the first component of complement, Cl esterase inhibitor (CIEI).z Less commonly the disease is due to the presence of an inhibitor protein with no functional activity.3 Although the pathogenesis of the edema is poorly understood, it has been attributed to the release of a kinin-like molecule during uncontrolled activation of the classical complement pathway.4 This pathway proceeds through the activation of Cl, C4, and C2 to C3, and the later components of the complement sequence. Patients with HAE have circulating activated Cl during attacks and are depleted of C4 and C2. C3 levels are normal, although there is increased turnover of this component. 4-6 The kinin-like fragment is reported to be a result of C2 c1eavage.7 Although many attacks of swelling are not clearly related to a precipitating event, edema is produced in about half of the patients following direct blunt trauma.# Because these patients can undergo major surgical procedures (i.e., sharp dissection) without apparent complications, the role of local tissue reaction has been emphasized. This is particularly evident follawing oral
From the Laboratory of Clinical Diseases, Rational Institutes of Received for publication Feb. 28, Ke rint requests to: Charks J. K IH, Bethesda, Md. 20014. Vol. 55, No. 6, pp. 986-893
Investigation, Health. 1975. Jaffe, M.D.,
National
Laboratory
In&itute
of Allergy
of Clinical
and Infectious
Investigation,
NIAXD,
VOLUME 55 NUMBER 6
Hereditary
angioedema
387
manipulation required in dental extractions. The seriousness of secondary edema following extraction is primarily related to compromise of the airway. In fact, the rate of major complications in our patient population following dental extractions exceeds that of all other surgical procedures.8 One approach to this problem is the use of medications that interfere with the development of angioedema. Presently, there are no drugs that can be successfully used when edema formation has begun. However, epsilon aminocaproic acid (EACA) , which interferes with fibrinolysis and which is reported to block Cl function, has been effectively used in the long-term prophylaxis of this disease.“, lo EACA blocks the activation and enzymatic function of plasmin.ll Plasmin can activate Cl and it is believed that the antiplasmin activity of EACA may explain its therapeutic effectiveness9 One instance of its shortterm use prior to dental surgery has also been reported.12 In fact, we have used it in 2 instances as prophylaxis in anticipation of oral surgery. Nonetheless, we have had several reasons for exploring the use of fresh frozen plasma in patients undergoing dental surgery. First, although the frequency of attacks is reduced, patients can develop angioedema while on EACA therapy. Second, in patients prone to thromboembolic disorders, EACA is contraindicated. Lastly, fresh frozen plasma used to replace the inhibitor protein deficiency would appear to be a more physiologic method of preventing attacks. Previously reported trials of fresh frozen plasma transfusions were limited to patients suffering acute attacks of edema. 13pl4 In these studies, the authors reported that treatment was of some benefit; however, the rationale for treatment has been questioned by opponents of this mode of therapy.151 I6 They argue that patients suffering an acute attack are markedly depleted in a number of the early components of complement. Since fresh frozen plasma supplies these complement components in addition to ClEI, they might serve as additional substrate for activated Cl, and attacks might be made transiently worse before they improved. This contraindication for fresh frozen plasma does not apply to asymptomatic patients anticipating elective dental procedures, and these patients seemed ideal candidates for a trial of plasma therapy. On the other hand, because of the high incidence of life-threatening complications in our patient group, a double-blind study could not be ethically justified. MATERIALS AND METHODS Patients From January, 1973, to June, 1974, 6 patients were admitted to the Clinical Center of the NIH for elective dental surgery. Prior to admission, all of the patients had been followed by the Laboratory of Clinical Investigation of the NIAID. In each case, the diagnosis had been made previously on the basis of family and clinical history as well as serologic findings. Of the 6 patients, 5 were women, and their ages ranged from 15 to 64 (mean, 37). All of the patients had previously undergone complicated dental procedures, and 4 of them had experienced 1 or more life-threatening attacks of airway edema (see Table II). Five of 6 patients had attacks of HAE at a frequency of greater than 1 per month and had been treated with EACA in the past. Two patients were receiving EACA at the time of the plasma infusion, and 2 mere taking medroxyprogesterone (Provera) (see Table I). This drug does not significantly reduce the frequency of angioedema attacks.8 The remaining 2 patients were on no therapy, and all patients were asymptomatic at the time of the infusion. One patient
388
Jaffe
J. ALLERGY CLIN.
et al.
IMMUNOL. JUNE 1975
- ----I’ S. H 16
-( --. 0 WH 1 -7
-10
12
3 4 5 6 7 8 91011120
12
3 4
5
‘6 ‘5
i” ji t PO,
i2
i
101 & “r
l
_..
+
,...
+
+
c Jo M.c i7 16
4
---
3i , /
:5
500 c
-4
2-
ij I ‘2
’ I : 1 --.J i /IL
'-L---
------~------~
i’ \
y-y--
^ i
2
3
4
-..-.
5
6
7
LO
L-A-.
8
4
L..
5
6
_-.... 7
DAYS
FIG. 1. Effect of fresh frozen plasma transfusion on the levels of serum Cl& and C4. ClEl and C4 expressed in rng% and as reciprocal titer, respectively. Number above arrow indicates approximate volume of fresh frozen plasma infused.
had previously under lidocaine
received a transfusion during and nitrous oxide anesthesia.
general
surgery.
All
extractions
were performed
Cl El levels Determination of ClEI levels was made by radial immunodiffusion assay as report& previously.l(j Briefly, Ouchterlony plates impregnated with purified goat a&human CIET. (kindly supplied by Dr. John Robbins) were incubated overnight at room temperature with the patient’s fresh serum. The diameters of the preoipitin rings were compared against a known standard. Normal values in our laboratory are 15.8 5 1.4 mgs. C4
levels
of C4 levels was pig serum, and has been reported &timdtion
made by a functional assay utilizing in detail elsewhere. 17 The end point
~~--deficient
guinea
of tbc assay is sheep
VOLUME 55 NUMBER 6
Hereditary
TABLE I. Relationship produced
by fresh frozen
between clinical plasma therapy
status
and
alterations
in serum
Pretransfusion HAE therapy’
bVdS$
-
angioedema
ClEl
389
and
C4
Duration of elevation (daym)§
Patient
Age
sex
Previous
Current
Disease activityt
w. L.
52
M
EACA
3+
1.8-2.0
6,ooO-20,000
S. B.
31
F
Pro
4f
3.5-4.0
5,000-15,000
K. T.
21
F
-
4+
2.0-3.0
I0
Gvtyl two atltlit.ional units of plasma ‘LA hours after thcl II.0 folattack suhsittctl, antI un(lt~rwt~nt surgcy,- without scyu~~lat~.Sllhsef~ueJJtly, lowctl OJICpatient who was givthn plasma after thr onset of peripheral swelling. This milt1 ;lttac+ c*ontinucltl to CWIV~~.illl(l rrsot vc>cIover the (+oursc of 48 hours.
VOLUME 55 NUMBER 6
Hereditary
angioedema
393
derived from the 7 Klemperer, M. R., Rosen, F. S., and Donaldson, V. H.: A polypeptide second component of human complement (C’2) which increases vascular permeability, J. Clin. Invest. 48: 44a, 1969. (Abst.) 8 Atkinson, J. P., Gelfand, J. A., and Frank, M. M.: In preparation. 9 Lundh, B., Laurell, A., Wetterqvist, H., White, T., and Graverus, G.: A case of hereditary angioneurotic oedema, successfully treated by e-amino caproic acid: Studies on C’l esterase inhibitor, C’l activation, plasminogen, and histamine metabolism, Clin. Exp. Immunol. 3: 733, 1968. 10 Frank M. M., Sergent, J. S., Kane, M. A., and Alling, D. W.: Epsilon aminocaproio acid therapy of hereditary angioneurotic edema: A double blind study, N. Engl. J. Med. 286:
808,1972. 11 Alkjaersig, N., Fletcher, A. P., and Sherry, S.: e aminocaproic acid: An inhibitor of plasminogen activation, J. Biol. Chem. 234: 832, 1959. 12 Pence, H. L., Evans, R., Guernsey, L. H., and Gerhard, R. C.: Prophylactic use of epsilon aminocaproic acid for oral surgery in a patient with hereditary angioneurotic edema, J. ALLERGYCLIN. IMMUNOL. 53: 298, 1974. 13 Pickering, R. J., Kelly, J. R., Good, R. A., and Gemurz, H.: Replacement therapy in hereditary angioedema: Successful treatment of two patients with fresh frozen plasma, Lancet 1: 326, 1969. 14 Cohen, G., and Peterson, A.: Treatment of hereditary angioedema with frozen plasma, Ann. Allergy 30: 690, 1972. 16 Rosen, F. A., and Austen, K. F.: The “neurotic edema, ” N. Engl. J. Med. 280: 1356, 1969. 16 Donaldson, V. H.: Therapy of the “neurotic edema, ” N. Engl. J. Med. 286: 835, 1972. 17 Gaither, T. A., Alling, D. W., and Frank, M. M.: A new one-step method for the functional assay of the fourth component (C4) of human and guinea pig complement, J. Immunol. 113: 574, 1974. 18 Hutchinson, J. L., Freeman, S. O., Richards, B. A., and Burgen, A. S. V.: Plasma volume expansion and reactions after infusion of autologous and nonautologous plasma in man, J. Lab. Clin. Med. 56: 734, 1960. 19 Gruber, V. F., and Bergentz, J.: Autologous and homologous fresh human plasma as a volume expander in hypovolemio subjects, Ann. Surg. 165: 41, 1967. 20 Rosen, F. S., Alper, C. A., Pensky, J., Klemperer, M. R., and Donaldson, V. H.: Genetically determined heterogeneity of the Cl esterase inhibitor in patients with hereditary angioneurotic edema, J. Clin. Invest. 50: 2143, 1971.
J. JI m M.O
M.D., Ph.D., John P. Atkinson, M.D., d Michael M. Frank, M.D. Bethtisda, Md.
Je*ey
A.
Six patients with llereditary angioedema (HAh) undergoing Y episodes of dental surgery reoekned transfusions with fresh frozen plasma one day before surgery. Althozlgh the mrbidity observed in these patients following similar procedures had been high, no significant aomplications of surgery were noted with th.is therapy. Thus, fresh frozen plasma infusion appears to provide a safe and cffectiue method of prophylaxis in patients with HAE. Following infwion of fresh frozen plasma, serum levels of C4 and Cl &erase inhibitor (C/El) rose transiently, and then fell to preinfwtin levels within 1 to 12 days. In all but one patient the rise in 124 was greater than could be accowGed for by the amount of C4 ,&fused. In no patient did the level of ClEI or C4 rise to within the normal range. The data raise the question of the role of Clh;I in the pathogenesis of angioedema in these patients.
Hereditary angioedema (HAE) is a genetically transmitted disorder associated with spontaneous attacks of swelling of the extremities, gastrointestinal tract, and pharynx .’ The more common form of the disorder has been linked to a relative deficiency of the inhibitor of the first component of complement, Cl esterase inhibitor (CIEI).z Less commonly the disease is due to the presence of an inhibitor protein with no functional activity.3 Although the pathogenesis of the edema is poorly understood, it has been attributed to the release of a kinin-like molecule during uncontrolled activation of the classical complement pathway.4 This pathway proceeds through the activation of Cl, C4, and C2 to C3, and the later components of the complement sequence. Patients with HAE have circulating activated Cl during attacks and are depleted of C4 and C2. C3 levels are normal, although there is increased turnover of this component. 4-6 The kinin-like fragment is reported to be a result of C2 c1eavage.7 Although many attacks of swelling are not clearly related to a precipitating event, edema is produced in about half of the patients following direct blunt trauma.# Because these patients can undergo major surgical procedures (i.e., sharp dissection) without apparent complications, the role of local tissue reaction has been emphasized. This is particularly evident follawing oral
From the Laboratory of Clinical Diseases, Rational Institutes of Received for publication Feb. 28, Ke rint requests to: Charks J. K IH, Bethesda, Md. 20014. Vol. 55, No. 6, pp. 986-893
Investigation, Health. 1975. Jaffe, M.D.,
National
Laboratory
In&itute
of Allergy
of Clinical
and Infectious
Investigation,
NIAXD,
VOLUME 55 NUMBER 6
Hereditary
angioedema
387
manipulation required in dental extractions. The seriousness of secondary edema following extraction is primarily related to compromise of the airway. In fact, the rate of major complications in our patient population following dental extractions exceeds that of all other surgical procedures.8 One approach to this problem is the use of medications that interfere with the development of angioedema. Presently, there are no drugs that can be successfully used when edema formation has begun. However, epsilon aminocaproic acid (EACA) , which interferes with fibrinolysis and which is reported to block Cl function, has been effectively used in the long-term prophylaxis of this disease.“, lo EACA blocks the activation and enzymatic function of plasmin.ll Plasmin can activate Cl and it is believed that the antiplasmin activity of EACA may explain its therapeutic effectiveness9 One instance of its shortterm use prior to dental surgery has also been reported.12 In fact, we have used it in 2 instances as prophylaxis in anticipation of oral surgery. Nonetheless, we have had several reasons for exploring the use of fresh frozen plasma in patients undergoing dental surgery. First, although the frequency of attacks is reduced, patients can develop angioedema while on EACA therapy. Second, in patients prone to thromboembolic disorders, EACA is contraindicated. Lastly, fresh frozen plasma used to replace the inhibitor protein deficiency would appear to be a more physiologic method of preventing attacks. Previously reported trials of fresh frozen plasma transfusions were limited to patients suffering acute attacks of edema. 13pl4 In these studies, the authors reported that treatment was of some benefit; however, the rationale for treatment has been questioned by opponents of this mode of therapy.151 I6 They argue that patients suffering an acute attack are markedly depleted in a number of the early components of complement. Since fresh frozen plasma supplies these complement components in addition to ClEI, they might serve as additional substrate for activated Cl, and attacks might be made transiently worse before they improved. This contraindication for fresh frozen plasma does not apply to asymptomatic patients anticipating elective dental procedures, and these patients seemed ideal candidates for a trial of plasma therapy. On the other hand, because of the high incidence of life-threatening complications in our patient group, a double-blind study could not be ethically justified. MATERIALS AND METHODS Patients From January, 1973, to June, 1974, 6 patients were admitted to the Clinical Center of the NIH for elective dental surgery. Prior to admission, all of the patients had been followed by the Laboratory of Clinical Investigation of the NIAID. In each case, the diagnosis had been made previously on the basis of family and clinical history as well as serologic findings. Of the 6 patients, 5 were women, and their ages ranged from 15 to 64 (mean, 37). All of the patients had previously undergone complicated dental procedures, and 4 of them had experienced 1 or more life-threatening attacks of airway edema (see Table II). Five of 6 patients had attacks of HAE at a frequency of greater than 1 per month and had been treated with EACA in the past. Two patients were receiving EACA at the time of the plasma infusion, and 2 mere taking medroxyprogesterone (Provera) (see Table I). This drug does not significantly reduce the frequency of angioedema attacks.8 The remaining 2 patients were on no therapy, and all patients were asymptomatic at the time of the infusion. One patient
388
Jaffe
J. ALLERGY CLIN.
et al.
IMMUNOL. JUNE 1975
- ----I’ S. H 16
-( --. 0 WH 1 -7
-10
12
3 4 5 6 7 8 91011120
12
3 4
5
‘6 ‘5
i” ji t PO,
i2
i
101 & “r
l
_..
+
,...
+
+
c Jo M.c i7 16
4
---
3i , /
:5
500 c
-4
2-
ij I ‘2
’ I : 1 --.J i /IL
'-L---
------~------~
i’ \
y-y--
^ i
2
3
4
-..-.
5
6
7
LO
L-A-.
8
4
L..
5
6
_-.... 7
DAYS
FIG. 1. Effect of fresh frozen plasma transfusion on the levels of serum Cl& and C4. ClEl and C4 expressed in rng% and as reciprocal titer, respectively. Number above arrow indicates approximate volume of fresh frozen plasma infused.
had previously under lidocaine
received a transfusion during and nitrous oxide anesthesia.
general
surgery.
All
extractions
were performed
Cl El levels Determination of ClEI levels was made by radial immunodiffusion assay as report& previously.l(j Briefly, Ouchterlony plates impregnated with purified goat a&human CIET. (kindly supplied by Dr. John Robbins) were incubated overnight at room temperature with the patient’s fresh serum. The diameters of the preoipitin rings were compared against a known standard. Normal values in our laboratory are 15.8 5 1.4 mgs. C4
levels
of C4 levels was pig serum, and has been reported &timdtion
made by a functional assay utilizing in detail elsewhere. 17 The end point
~~--deficient
guinea
of tbc assay is sheep
VOLUME 55 NUMBER 6
Hereditary
TABLE I. Relationship produced
by fresh frozen
between clinical plasma therapy
status
and
alterations
in serum
Pretransfusion HAE therapy’
bVdS$
-
angioedema
ClEl
389
and
C4
Duration of elevation (daym)§
Patient
Age
sex
Previous
Current
Disease activityt
w. L.
52
M
EACA
3+
1.8-2.0
6,ooO-20,000
S. B.
31
F
Pro
4f
3.5-4.0
5,000-15,000
K. T.
21
F
-
4+
2.0-3.0
I0
Gvtyl two atltlit.ional units of plasma ‘LA hours after thcl II.0 folattack suhsittctl, antI un(lt~rwt~nt surgcy,- without scyu~~lat~.Sllhsef~ueJJtly, lowctl OJICpatient who was givthn plasma after thr onset of peripheral swelling. This milt1 ;lttac+ c*ontinucltl to CWIV~~.illl(l rrsot vc>cIover the (+oursc of 48 hours.
VOLUME 55 NUMBER 6
Hereditary
angioedema
393
derived from the 7 Klemperer, M. R., Rosen, F. S., and Donaldson, V. H.: A polypeptide second component of human complement (C’2) which increases vascular permeability, J. Clin. Invest. 48: 44a, 1969. (Abst.) 8 Atkinson, J. P., Gelfand, J. A., and Frank, M. M.: In preparation. 9 Lundh, B., Laurell, A., Wetterqvist, H., White, T., and Graverus, G.: A case of hereditary angioneurotic oedema, successfully treated by e-amino caproic acid: Studies on C’l esterase inhibitor, C’l activation, plasminogen, and histamine metabolism, Clin. Exp. Immunol. 3: 733, 1968. 10 Frank M. M., Sergent, J. S., Kane, M. A., and Alling, D. W.: Epsilon aminocaproio acid therapy of hereditary angioneurotic edema: A double blind study, N. Engl. J. Med. 286:
808,1972. 11 Alkjaersig, N., Fletcher, A. P., and Sherry, S.: e aminocaproic acid: An inhibitor of plasminogen activation, J. Biol. Chem. 234: 832, 1959. 12 Pence, H. L., Evans, R., Guernsey, L. H., and Gerhard, R. C.: Prophylactic use of epsilon aminocaproic acid for oral surgery in a patient with hereditary angioneurotic edema, J. ALLERGYCLIN. IMMUNOL. 53: 298, 1974. 13 Pickering, R. J., Kelly, J. R., Good, R. A., and Gemurz, H.: Replacement therapy in hereditary angioedema: Successful treatment of two patients with fresh frozen plasma, Lancet 1: 326, 1969. 14 Cohen, G., and Peterson, A.: Treatment of hereditary angioedema with frozen plasma, Ann. Allergy 30: 690, 1972. 16 Rosen, F. A., and Austen, K. F.: The “neurotic edema, ” N. Engl. J. Med. 280: 1356, 1969. 16 Donaldson, V. H.: Therapy of the “neurotic edema, ” N. Engl. J. Med. 286: 835, 1972. 17 Gaither, T. A., Alling, D. W., and Frank, M. M.: A new one-step method for the functional assay of the fourth component (C4) of human and guinea pig complement, J. Immunol. 113: 574, 1974. 18 Hutchinson, J. L., Freeman, S. O., Richards, B. A., and Burgen, A. S. V.: Plasma volume expansion and reactions after infusion of autologous and nonautologous plasma in man, J. Lab. Clin. Med. 56: 734, 1960. 19 Gruber, V. F., and Bergentz, J.: Autologous and homologous fresh human plasma as a volume expander in hypovolemio subjects, Ann. Surg. 165: 41, 1967. 20 Rosen, F. S., Alper, C. A., Pensky, J., Klemperer, M. R., and Donaldson, V. H.: Genetically determined heterogeneity of the Cl esterase inhibitor in patients with hereditary angioneurotic edema, J. Clin. Invest. 50: 2143, 1971.
