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Educated Hand Publishing LLC 
“The Science Behind the Art” 
Volume 6 - No. 3 2018 

Anesthesia eJournal - Online
ISSN 2333-2611

Page 12

Prophylaxis and Treatment of Hereditary Angioedema With Fresh Frozen Plasma: 
A Synthesis and Narrative Review

Meredith Mosier, RN, BSN, RRNA1

J. Dru Riddle, PhD, DNP, CRNA2

Affiliation:
1. School of Nurse Anesthesia Texas Christian University, Fort Worth, TX.  The author was a student at the time of writing.

2. Assistant Professor of Professional Practice, School of Nurse Anesthesia Harris College of Nursing and Health Sciences, Texas Christian University, Fort Worth, TX

Funding/Conflict of Interest Disclosure: 
None 

KEYWORDS:  angioedema, fresh frozen plasma, surgery

INTRODUCTION
Rapid intervention by a skilled team of clinicians is required when angioedema occurs in the operative setting. Hereditary 
angioedema (HAE), acquired angioedema (AAE), and angiotensin-converting enzyme (ACE) inhibitor-induced angioedema 
are 3 types of bradykinin-mediated angioedema.1 Patients susceptible to bradykinin-mediated angioedema may experience 
a precipitating event before an acute episode occurs.1 Airway instrumentation, upper airway trauma resulting from airway 
instrumentation, surgery, and psychologic or physiologic stress experienced by the patient may precipitate an exacerbation 
of angioedema.1 However, exacerbations can also occur in the absence of a triggering event.1 Patients at risk for bradyki-
nin-mediated angioedema are susceptible to airway compromise during or immediately after surgery. For susceptible patients, 
anesthetists should anticipate an exacerbation resulting in potential airway compromise. If a patient undergoing surgery is 
known or suspected to be at risk for bradykinin-mediated angioedema, prophylactic measures can be taken.2 Pharmacologic 
prophylactic options include fresh frozen plasma (FFP), C1 esterase inhibitor (C1-INH), and androgen therapy.1 

The present review aimed to answer the PICO question, In patients with a known history of or suspected susceptibility to 
HAE, does the administration of FFP compared with no infusion of FFP affect the occurrence or severity of angioedema 
postoperatively? This synthesis presents search strategies for the topic and reviews 6 articles (Appendix A) pertaining to the 
above PICO question. 

Abstract
Patients with angioedema who experience an acute exacerbation may die if their symptoms are not treated promptly. 
Airway compromise can occur if proper precautions are not taken. Surgical patients with hereditary angioedema should 
undergo prophylactic treatment before surgical procedures to decrease the risk of an exacerbation. A literature search was 
performed using the Embase (Elsevier), CINAHL (EBSCO), Health Source: Nursing/Academic Edition (EBSCO), and 
MEDLINE (National Library of Medicine) databases. Six articles were found that discussed administration of fresh fro-
zen plasma (FFP) for treatment or prophylaxis against angioedema exacerbations. Synthesis of the evidence suggests that 
use of FFP as a sole prophylaxis or treatment for angioedema is inappropriate. FFP can be used as part of a multimodal 
treatment plan for prophylaxis against angioedema if a C1 esterase inhibitor is not available. 

AEJ



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Volume 6 - No. 3 2018 Page 13

SEARCH METHODOLOGY
Two structured searches were conducted. The Embase database 
(Elsevier) was searched by using the search terms “fresh frozen 
plasma,” “angioneurotic edema,” and “anesthesia” combined with 
the Boolean operator “AND.” The search was limited to articles 
published between 2000 and 2016. Twenty-three articles were re-
trieved and 3 were selected for analysis.1,3,4 The second search was 
conducted of the CINAHL (EBSCO), Health Source: Nursing/
Academic Edition (EBSCO), and MEDLINE (National Library 
of Medicine) databases within the EBSCOhost platform search 
engine. The search terms “angioedema,” “fresh frozen plasma,” and 
“surgery” were combined with the Boolean operator “AND.” This 
search was limited to articles in English and retrieved 16 results. 
Three articles were selected for review.5,6,7 In total, 6 articles were 
selected that best related to the stated PICO question. The select-
ed articles were classified according to the Joanna Briggs Institute 
Levels of Evidence.8 A PRISMA flow diagram of the search is 
shown in Appendix B.9 
REVIEW OF THE LITERATURE
Limited quality research exists regarding FFP prophylaxis against 
an acute HAE episode during the operative course. HAE is an 
uncommon condition and, if an exacerbation occurs, it can be 
life-threatening.7 The rarity and severity of HAE exacerbations 
make opportunities to conduct clinical trials almost nonexistent. 
The existent body of research therefore consists of case studies. 
Two retrospective chart reviews, 1 expert opinion article, and 3 
case reports were selected as the best evidence for inclusion. 
Macbeth et al reviewed the medical records of 24 patients with 
bradykinin-mediated angioedema who received general anesthe-
sia.1 The researchers searched for evidence of prior airway com-
promise, frequency of angioedema episodes, prophylactic treat-
ment before surgery, and perioperative management. They also 
conducted a literature search of the MEDLINE database and 
located 19 case reports and 2 case series that described patients 
with angioedema who underwent general anesthesia. Macbeth et 
al included data from the results of their database search in their 
discussion. 
We classified Macbeth et al’s study as a level of evidence 3.b 
cohort study.8 Although Macbeth et al1 analyzed the largest 
amount of data compared with the other articles included here, 
their work had some weaknesses. The authors occasionally arrived 
at conclusions through speculation. For example, they speculated 
that, although the complication risk for patients who did not 
receive prophylaxis was low at 5.7%, using prophylaxis would 
further reduce the incidence of angioedema perioperatively.1 They 
also proposed that infusions of FFP could exacerbate an acute 
episode of angioedema because of the additional complement 
components FFP contains besides C1-INH. No source was cited 
to support this claim and it was stated that, because FFP contains 
complement components, it should be used as prophylaxis before 
surgery if no other treatment option is available.1 
Prematta and colleagues5 reviewed the medical records of all pa-
tients from their institution who were diagnosed with HAE and 
received FFP from their institution’s blood bank. Twenty-three 
cases were compiled. Only 2 of these cases involved the use of 
FFP as prophylaxis before surgery. These 2 patients did not have 
an acute HAE exacerbation postoperatively and the authors con-
cluded that FFP is an effective treatment for surgical prophylaxis 

against HAE. The authors identified weaknesses in their review 
and pointed out that no control group existed. Thus, there was no 
way to be certain that infusions of FFP prevented an HAE ex-
acerbation. The amount of FFP administered to each patient was 
not consistent. The number and timing of doses varied among the 
patients discussed in the review. We classified this retrospective 
study as a level of evidence 3.b cohort study.8 
Szema and colleagues3 authored guidelines for the preoperative 
and intraoperative management of patients with HAE. This arti-
cle was a level 5.b expert consensus.8 The authors used literature 
retrieved from PUBMED to construct the guidelines.3 They 
suggested giving 3 units each day before a surgical procedure and 
checking serum C1 and C4 esterase inhibitor levels after the first 
and second doses. The authors suggested transfusing 2 units of 
FFP intraoperatively. Recommendations were graded based on 
the strength of supporting evidence. Recommendations based 
on evidence from randomized controlled trials (RCTs) were not 
provided because no RCTs were located.
Shick et al6 wrote a case study, level of evidence 4.d,8 concern-
ing a patient with HAE who underwent coronary artery bypass 
grafting (CABG). The patient’s care team determined that 
CABG without cardiopulmonary bypass (off-pump CABG, or 
OP-CABG) would be most appropriate.6 The care team chose 
this technique in an effort to minimize the risk of activation of 
complement cascade. The patient was given 2 units of FFP before 
incision and 2 units of FFP intraoperatively. The patient was later 
extubated in the intensive care unit (ICU) without complication 
and discharged home 6 days after admission. Several measures 
were taken to prevent an acute exacerbation of HAE during the 
operative period, including an increased danazol dose preoper-
atively, use of the OP-CABG technique, and infusions of FFP.6 
The patient was also premedicated with intravenous doses of 
diphenhydramine, ranitidine, and hydrocortisone. These drugs 
have shown little benefit in patients with HAE suffering an acute 
exacerbation.1 The role of FFP infusion as prophylaxis against an 
acute HAE exacerbation cannot be absolutely determined from 
the evidence contained in the study. 
Mihailovic et al4 authored a case study that described a patient 
with HAE who underwent CABG on cardiopulmonary bypass. 
We assigned the study a level of evidence 4.d.8 The patient was 
prescribed danazol 3 days preoperatively. On the day of surgery, 
the patient received 2 doses of FFP 2 hours preoperatively and 
received 4 doses of FFP before successful extubation in the ICU.4 
The authors also used other prophylactic methods in addition 
to infusions of FFP. They reported that infusions of FFP raised 
the patient’s plasma levels of C1-INH and were instrumental in 
preventing an HAE exacerbation. However, FFP cannot be solely 
credited for preventing the exacerbation, and the extent that FFP 
contributed to prophylaxis cannot be determined when other 
prophylactic measures are taken. 
A case study written by Cifuentes and colleagues7 examined 
FFP as a treatment option for exacerbation of angioedema. The 
researchers reported the case of a patient with undiagnosed HAE 
who underwent orthognathic surgery.7 The authors reported that 
the patient developed severe facial and upper airway edema on 
postoperative day 1. The patient was emergently intubated and 
received 2 units of FFP as a treatment for angioedema. The pa-
tient experienced a 10% reduction in edema 12 to 14 hours after 
the infusion and remained intubated for 24 hours. Subsequently, 



Anesthesia eJournal          www.anesthesiaejournal.com
Volume 6 - No. 3 2018 Page 14

the patient was extubated without complication and discharged 
2 weeks later. This case did not describe the prophylactic use of 
FFP, but it did describe a rare scenario that may be encountered 
in the surgical arena. 
SYNTHESIS
The research studies reviewed are inconclusive related to the value 
of FFP in HAE prophylaxis because in all cases the investiga-
tors used multiple prophylactics. We did not identify any clinical 
trials investigating the effect of FFP on HAE. Administration of 
FFP as a treatment for acute exacerbations does not lend itself 
to clinical trial studies because occurrences are rare. When signs 
and symptoms of HAE occur, the situation is acute and re-
quires immediate, multimodal prophylactic measures to treat the 
condition. The use of FFP as the sole treatment in a clinical trial 
or withholding FFP to establish a placebo group is not appropri-
ate. HAE can be life-threatening, so when signs and symptoms 
appear, multiple therapeutic techniques should be used. Patients 
in the cases studied received other prophylactic measures besides 
FFP infusions, including attenuated androgens, histamine antag-
onists, and corticosteroids. 
It has been determined that HAE exacerbations result from 
deficiency of C1-INH and subsequent overproduction of 
bradykinin.1 The overproduction of bradykinin may lead to 
vascular permeability and HAE exacerbation.1 Researchers have 
concluded that exogenous C1-INH is a valuable component in 

treatment and prophylaxis against HAE exacerbations. The Food 
and Drug Administration approved Cinryze (complement C1 
esterase inhibitor) in 2008 for use as a routine prophylaxis against 
HAE,3 but the drug is not widely available. Because FFP is more 
readily available at hospitals in the United States than exogenous 
C1-INH, FFP has become a mainstay of treatment to be admin-
istered in conjunction with additional prophylactic measures.
CONCLUSION
The information presented represents the best evidence available 
concerning the use of prophylactic FFP to prevent HAE exacer-
bations. The PICO question, In patients with a known history of 
or suspected susceptibility to HAE, does the administration of 
FFP compared with no infusion of FFP affect the occurrence or 
severity of angioedema postoperatively, cannot be definitively an-
swered. All the above studies included prophylactic measures such 
as administration of danzolol preoperatively, administration of 
antifibrinolytics, or administration of antihistamines in addition 
to FFP. The effect of administration of FFP without additional 
prophylactic measures on the occurrence or severity of angioede-
ma cannot be determined from the evidence cited. 
Acknowledgments
This review was conducted in partial fulfillment of the require-
ments for the Doctor of Nursing Practice degree at the School of 
Nurse Anesthesia at Texas Christian University.



REFERENCES
1. MacBeth LS, Volcheck GW, Sprung J, Weingarten TN. Preoperative course in patients with hereditary or acquired angioedema. 

J Clin Anesth. 2016;34:385-391. doi:10.1016/j.jclinane. 2016.05.010.
2. Levy JH, Freiberger DJ, Roback J. Hereditary angioedema: current and emerging treatment options. Anesth Analg.

2010;110(5):1271-1280. doi:10.1213/ANE.0b013e3181d7ac98.
3. Szema AM, Paz G, Merriam L, Stellaccio F, Jen J. Modern preoperative and intraoperative management of hereditary

angioedema. Allergy Asthma Proc. 2009;30:338–342. doi:10.2500/aap.2009.30.3225.
4. Mihailovic S, Volas L, Arezina Mihailovic A. Hereditary angioedema type II: perioperative management of coronary artery

bypass graft surgery: 4AP2‐2. Eur J Anaesthesiol. 2012;29:55. 
5. Prematta M, Gibbs JG, Pratt EL, Stoughton TR Craig TJ. Fresh frozen plasma for the treatment of hereditary angioedema. 

Ann Allergy Asthma Immunol. 2007;98(4):383-388. doi:10.1016/S1081-1206(10)60886-1.
6. Shick V, Sanchala V, McGoldrick K, Tartaglia JJ, Nelson J, Fleisher AJ. Perioperative management of a patient with hereditary

angioedema during off-pump coronary artery bypass graft surgery. J Clin Anesth. 2010;22(4):282-284. doi:10.1016/j.
jclinane.2009.04.007.

7. Cifuentes J, Palisson F, Valladares S, Jerez D. Life-threatening complications following orthognathic surgery in a patient with
undiagnosed hereditary angioedema. J Oral Maxillofac Surg. 2013;71(4):e185-e188. doi:10.1016/j.joms.2012.11.023.

8. Levels of Evidence and Grades of Recommendation Working Party. New JBI levels of evidence. The Joanna Briggs Institute
Web site. http://joannabriggs.org/assets/docs/approach/ JBI-Levels-of-evidence_2014.pdf. Published October 2013. 
Accessed April 20, 2016.

9. Moher D, Liberati A, Tetzlaff J, Altman DG. The PRISMA Group. Preferred Reporting Items for Systematic Reviews and
Meta-Analyses: The PRISMA Statement. PLoS Med. 2009;6(7):e1000097. doi:10.1371/journal.pmed1000097.

Summary of Key Points

Hereditary angioedema (HAE) is a rare disease but can have life-threatening consequences when an exacerbation occurs. Situations in 
which patients with HAE are at risk for an exacerbation include airway instrumentation, upper airway trauma resulting from airway 
instrumentation, and psychologic or physiologic stress experienced by the patient. Knowledge of treatment options is paramount for 
anesthesia providers. 

• Angioedema requires rapid intervention, including securing the airway and pharmacologic interventions to decrease severity of
angioedema. 

• Prophylaxis should be considered in patients with HAE undergoing surgery.
• HAE exacerbations result from deficiency of C1 esterase inhibitor (C1-INH) and subsequent overproduction of bradykinin.
• FFP contains C1-INH. 
• FFP may have some value in treating or preventing HAE exacerbations if the FDA-approved complement C1 esterase inhibitor

(Cinryze) is not available.

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Appendix A: Annotated Bibliography Table

Author and Year Joanna Briggs 
Institute Level of 

Evidence

Methodology No. of Subjects Major Findings, Conclusions

Prematta et al, 2007 3.B Cohort Study Reviewed literature and 
patient records to evaluate 
efficacy of FFP in treatment 
or prophylaxis of HAE exac-
erbation. 

N=23 case 
reports of FFP 
being used as 
treatment or 
prophylaxis for 
HAE 

FFP does not worsen acute exacer-
bation of HAE. FFP is an effective 
surgical prophylaxis agent and 
treatment for acute exacerbations.

MacBeth et al, 2016 3.B Cohort Study Retrospective review of med-
ical records and review of pub-
lished case reports of patients 
with bradykinin-mediated 
angioedema who underwent 
general anesthesia with airway 
manipulation.

N=24 medi-
cal records of 
patients who 
had bradyki-
nin-mediated 
angioedema and 
received general 
anesthesia 

Plasma-derived C1-INH should 
be administered 1 hour before 
surgery and repeated daily after a 
major procedure until there is no 
remaining risk for exacerbation. 
FFP should be used only if no oth-
er treatment option is available.

Szema et al, 2009 5.B Expert Con-
sensus

Reviewed literature regard-
ing airway management and 
angioedema etiology and 
prophylaxis. Developed guide-
lines for managing patients 
with HAE preoperatively and 
intraoperatively. 

None stated Preoperative protocol for manage-
ment of patients with hereditary 
angioedema developed. 

Mihailovic et al, 2012 4.D Case Study One case was presented 
involving a patient with HAE 
undergoing CABG surgery. 
Patient did not develop an-
gioedema postoperatively.

N=1 Patient was successfully extubated 
without exacerbation of HAE. 
Patient received danazol 200 mg 
twice a day preoperatively, 2 doses 
of FFP preoperatively, and 4 doses 
of FFP after surgery and before 
extubation.

Shick et al, 2010 4.D Case Study One case was presented con-
cerning a patient with HAE 
undergoing off-pump CABG 
surgery. This patient did not 
develop angioedema postop-
eratively.

N=1 The patient received 2 units of FFP 
before incision and 2 additional 
units of FFP intraoperatively. 
Patient received other prophylactic 
treatment measures as well. The 
patient was successfully extubated 
in the intensive care unit.

Cifuentes et al, 2013 4.D Case Study One case was presented 
involving a patient with un-
diagnosed HAE who under-
went orthognathic surgery and 
developed facial and airway 
edema. 

N=1 The patient developed severe 
facial and upper airway edema on 
postoperative day 1 that required 
endotracheal intubation. The 
patient’s edema improved after 
administration of FFP, and the 
patient was discharged from the 
hospital 2 weeks after extubation.  

Abbreviations: C1-INH, C1 esterase inhibitor; CABG, coronary artery bypass grafting; FFP, fresh frozen plasma; HAE, hereditary 
angioedema.



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Volume 6 - No. 3 2018 Page 17

PRISMA 2009 Flow Diagram 

Records identified through Embase 
database searching 

(n = 23) 

Sc
re

en
in

g 
In

clu
de

d 
El

ig
ib

ili
ty

 
Id

en
tif

ica
tio

n 

Records identified through CINAHL, 
Health Source, MEDLINE 

(n = 16) 

Records after duplicates removed 
(n = 39) 

Records screened 
(n = 39) 

Records not addressing 
PICO (n = 33) 

Full-text articles 
addressing PICO 

(n = 6) 

Full-text articles excluded, 
with reasons 

(n = 0) 

Studies included in 
synthesis 

(n = 6) 




