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Perioperative Management of Patients With Hereditary Angioedema With Special Considerations for Cardiopulmonary Bypass

Tanaka, Kenichi A. MD, MSc*; Mondal, Samhati MBBS*; Morita, Yoshihisa MD; Williams, Brittney MD*; Strauss, Erik R. MD*; Cicardi, Marco MD

Author Information
doi: 10.1213/ANE.0000000000004710

Abstract

See Article, p 152

Hereditary angioedema (HAE) is a rare autosomal dominant disorder primarily due to deficiency of C1-esterase inhibitor (C1-INH) or dysfunctional C1-INH. The prevalence of HAE is estimated as 1 case per 50,000 in general population without racial or gender differences.1 It causes unpredictable, recurrent angioedema attacks affecting the face, extremities, genitals, bowels, or upper airway. The early documentation of HAE includes one by William Osler in 1888,2 but etiology was unclear until 1963 when Donaldson and Evans3 attributed it to the deficiency of C1-INH. Reduced C1-INH activity intermittently disrupts homeostasis of plasma kallikrein (pKLK)–mediated formation of bradykinin (BK),4 enhancing vascular permeability in subcutaneous (s.c.) and submucosal tissues (Figure).5 The first symptoms typically appear within the second decade of life, and diagnosis is usually made during puberty due to increasing symptoms. Other patients have a significant delay in diagnosis due to later presentations in life or remain undiagnosed due to sporadic attacks. Approximately 30% of patients with HAE were misdiagnosed and treated with surgical interventions and presented to the anesthesiologist and perioperative care team with airway emergencies and shock.6 Indeed, first manifestations of HAE might follow a minor procedure such as dental work or an elective surgery related or unrelated to HAE symptoms.7–9

Figure.
Figure.:
Schemata of pathways regulated by C1-INH and bradykinin formation in hereditary angioedema. C1-INH regulates multiple serine proteases in kallikrein-kinin system (in red), intrinsic coagulation pathway (in green), and classical and MBL complement pathways (in orange). The pathophysiology of hereditary angioedema (in purple) is excess bradykinin formation due to unregulated kallikrein activity in the absence of C1-INH. C1-INH also regulates kallikrein activation by inhibiting activated FXII (XIIa and XIIf). Solid and broken arrows indicate direct and indirect activation process, respectively. ACE indicates angiotensin-converting enzyme; C1-INH, C1-esterase inhibitor; HWMK, high-molecular weight kininogen; MASP, mannose-binding lectin–associated serine protease; MBL, mannose-binding lectin pathway; NO, nitric oxide; PGI2, prostacyclin; Plg, plasminogen; tPA, tissue plasminogen activator; uPA, urokinase; XI, factor XI.

The recent clinical developments of biological and pharmacological therapies have improved acute and chronic care of patients with HAE.10–12 However, there is a paucity of data on preprocedural (short-term) prophylaxis using C1-INH concentrate or other agents in patients with HAE.13–15 Cardiovascular (CV) surgery is often considered as a major stressor to HAE patients due to the use of cardiopulmonary bypass (CPB), which is associated with extensive activation of kallikrein-kinin system (KKS), contact coagulation, and complement pathways.16–23 Similar to other procedures, CPB may act as a trigger for HAE attack, leading to sudden laryngeal edema, upper airway obstruction, and asphyxiation up to 30 hours after the procedure.6 There have been published case reports of HAE patients who underwent CPB, and they provide a useful insight into pathophysiology of KKS activation as well as perioperative C1-INH replacement. The aims of this narrative review are (1) to review pathophysiology of HAE and laboratory testing, (2) to summarize pertinent pharmacological data on the prophylactic and on-demand treatment strategies, and (3) to discuss available clinical data for perioperative management in CV surgery.

PHYSIOLOGICAL ACTIONS OF C1-INH

Serine proteases are trypsin-like enzymes that play crucial and diverse roles in digestion, blood coagulation, fibrinolysis, and immunity, and are tightly regulated by serine protease inhibitors (SERPINs). C1-INH is a glycoprotein encoded by the SERPING1 gene on chromosome 11 (Table 1).24 The deficiency of C1-INH SERPIN can result in the debilitating condition of HAE due to uncontrolled activity of serine protease(s).3,5 C1-INH is synthesized in the liver, and plasma level is normally high (2.5–3.0 µM), but is further elevated by 2- to 3-fold during inflammation.25 This is likely due to different regulatory factor(s) controlling for hepatic C1-INH synthesis, and extrahepatic C1-INH production in monocytes, fibroblasts, macrophages, microglial cells, and endothelial cells in response to increase plasma serine protease activity.28–32

Table 1. - Properties of C1-Esterase Inhibitor
Classification Serine protease inhibitor
Gene/location SERPING1, long arm of chromosome 11 at position 12.1 (11q12.1)
Molecular weight24 ~76 kDa by neutron scattering, ~74 kDa by MS, ~105 kDa by SDS-PAGE
Plasma level25 2.5–3.0 µM, ↑ by 2–3 times during inflammation
Half-life26,27 ~28 h in normal subjects, 30–60 h for pdC1-INH in HAE (variable)
Inhibitor targets C1s, C1r, FXIIa, FXIa, kallikrein, MASP-1, MASP-2, plasmin
Mode of inhibition Irreversible inhibition
Inhibitor targets C1s, C1r, FXIIa, FXIa, kallikrein, MASP-1, MASP-2, plasmin
Pathophysiology ↑ BK formation due to ↑ kallikrein and FXIIa activities in HAE
Abbreviations: BK, bradykinin; C1-INH, C1-esterase inhibitor; FXIa, activated factor XI; FXIIa, activated factor XII; HAE, hereditary angioedema; MASP, mannose-binding lectin–associated serine protease; MS, mass spectrometry; pd, plasma-derived; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; ↑, increased.

As indicated by the name, inhibitory targets of C1-INH include C1s, C1r, and mannose-binding lectin (MBL)–associated serine proteases (MASP) in classical and MBL complement pathways (Figure). Complement depletion is helpful in the diagnosis of HAE, but it does not appear to significantly contribute to HAE symptoms.33 Dysregulation of pKLK activation and activity due to C1-INH deficiency is the key pathomechanism of HAE.5,33 Control of activated FXII (FXIIa) and plasmin may be important in a subset of HAE,34 but coagulation perturbation induced by C1-INH deficiency or after C1-INH replacement is limited.35,36 Glycosaminoglycans (GAGs) are known to modulate activity of other SERPINs such as antithrombin (AT).37 Heparin modestly catalyzes inhibitory actions of C1-INH toward C1s and FXIa, but does not at all impact pKLK or FXIIa inhibitions.38–41 Therefore, heparin prophylaxis does not prevent HAE attacks.42

PATHOPHYSIOLOGY OF HAE

Recurrent acute attacks of HAE are manifested by nonitching, self-limiting edema of s.c. and submucosal tissues in the face, extremities, genitals, bowels, and less frequently in the oropharynx and larynx.1,43 HAE attacks are painful, debilitating, and potentially life-threatening, especially when upper airway obstruction is present.44,45 The frequency and severity of HAE attacks are variable between patients, but a typical pattern follows an initial worsening of edema for 24 hours and a gradual resolution in 3–5 days.

Functional C1-INH activity in most HAE patients is typically 20%–35%, which is lower than the expected from heterozygous deficiency (a single functional gene).26 This is attributed to plasma instability due to C1-INH deficiency46 and increased catabolism of C1-INH27; however, impaired gene regulation cannot be excluded. The incubation of HAE plasma in a plastic tube at 37°C results in a progressive production of BK and a depletion of C4 (Table 2). Indeed, there is a tendency for shorter activated partial thromboplastin time (aPTT) in HAE patients due to rapid activations of FXII and pKLK in the setting of reduced C1-INH regulation.47

Table 2. - Different Types of Angioedema and Diagnostic Information
HAE-I HAE-II HAE-N AAE ACEI-AE
C1-INH function N N N
C1-Ag level N ~ ↑ N N N
C4 level N N N
C1q level N N N N
Additional data and test(s) Family history; genetic test if no family history Genetic test for SERPING1 (optional) Mostly female; genetic test for mutation: FXII, Plg, or angiopoietin Late onset, underlying conditions Exposure to ACE-I
Abbreviations: AAE, acquired angioedema; ACE-I, angiotensin-converting enzyme inhibitor; ACEI-AE, ACE-I–induced angioedema; Ag, antigen; C1, complement 1; C1-INH, C1-esterase inhibitor; C4, complement 4; FXII, factor XII; HAE-I, hereditary angioedema type I; HAE-II, hereditary angioedema type II; HAE-N, hereditary angioedema with normal C1-INH level; N, normal; Plg, plasminogen; ↑, increased; ↓, decreased.

In addition to pKLK, FXII plays a pivotal role in the feedback activation loop between prekallikrein and FXII (Figure). pKLK can sequentially cleave FXIIa into FXIIf, and the latter augments activations of prekallikrein and C1r/C1s.33,46,48,49 Enhanced release of BK cleaved from high-molecular weight kininogen (HMWK) by pKLK is the main pathophysiology of HAE, resulting in localized vasodilation, endothelial permeability change, bronchoconstriction, gut contraction, and pain.1 BK is rapidly degraded (half-life, 7.5 × 10−3 hours) by angiotensin-converting enzyme (ACE, kininase II) and other peptidases.50 ACE is abundant on pulmonary vessels, and plasma BK is rapidly inactivated in pulmonary circulation.51 It has been reported that ACE inhibitor (ACE-I) exacerbates HAE.52–54 Similarly, CPB alone results in a major pulmonary shunt associated with increased plasma BK levels,55 and may unmask subclinical HAE in patients with reduced C1-INH activity. ACE-I–induced angioedema (ACEI-AE) is an important differential diagnosis. ACEI-AE also involves excess BK formation, but C1-INH, C1, and C4 levels are normal and HMWK is not cleaved (Table 2).56 ACEI-AE tends to manifest in the face and upper airway.10

CLASSIFICATIONS OF HAE

The classification of HAE is generally based on quantitative (type I) and qualitative (type II) deficiency of C1-INH (Table 2).1,10,57 Type I HAE (HAE-I) is most common (~85%) and is characterized by low C1-INH antigen (<35%) and inhibitory activity. Type II HAE (HAE-II) (~15%) is due to a functional defect of C1-INH with normal or elevated C1-INH antigen levels. Clinical presentations of HAE-I/II are identical. A minority of HAE present with normal C1-INH activity (HAE-N). Less than 1/3 of HAE-N is attributed to FXII gene mutations with a majority involving threonine-to-lysine substitution (Thre309Lys).58,59 This mutation causes defective glycosylation, enhancing autoactivation, and plasmin-mediated preferential cleavage of FXII to FXIIf (Figure).34,60 Mutation in gene coding for plasminogen, angiopoietin 1, and HMWK are other rare causes of HAE.57 In a relatively large proportion of HAE-N, familiar segregation of angioedema symptom is the only evidence of genetic disease while responsible gene(s) has not been identified (HAE of unknown origin).

DIAGNOSTIC TESTING

There are several key laboratory tests to confirm the diagnosis of HAE (Table 2). Serum C4 is persistently low in 95% of patients even when they are asymptomatic.10,57 C1-INH antigen is quantified by radial immunodiffusion (normal, 19–37 mg/dL), and it is reduced only in HAE-I. Considering low serum C4 in 95% of HAE, and a fewer number of HAE-II cases, the majority of HAE patients can be diagnosed with a combination of clinical history with C1-INH antigen and serum C4 measurements. Functional C1-INH is tested by chromogenic assay (mainly used in Europe) or enzyme-linked immunosorbent assay (ELISA) method (mainly used in the United States).61 Both methods are useful as a confirmatory test of HAE-I/II, particularly in the case of normal or elevated C1-INH antigen (HAE-II). ELISA reports normal (>67%) and equivocal range (41%–67%), while chromogenic assay reports normal (≥74%) or abnormal. Discordant results between chromogenic and ELISA have been reported in a small number of cases.61 Preanalytical decay of C1-INH due to sample preparation, handling, or storage can increase the chance of a false-positive diagnosis.62 Repeat testing in 1–3 months is part of the good laboratory practice to confirm the diagnosis.63

Serum C1q measurement is helpful in the diagnosis of acquired angioedema (AAE) because C1q is usually normal in HAE-I/II. AAE is typically diagnosed in older patients with an underlying condition including lymphoproliferative disorders.63

TREATMENT OF HAE

Prophylactic and on-demand therapies are both important in patients with frequent and moderate-severe HAE attacks. Before 2009, attenuated androgens and antifibrinolytics (tranexamic acid [TXA] or ε-aminocaproic acid [EACA]) were the only prophylactic regimen in the United States,64,65 although antifibrinolytic agents were not very effective.66,67 Danazol increases hepatic synthesis of C1-INH, but it may be unsuitable in pregnant women and children due to hormonal disturbances.

As of 2019, 2 C1-INH products and 1 pKLK inhibitor are available for prophylaxis (Table 3). Long-term prophylaxis might be indicated for those who continue to have more than 12 moderate-severe HAE attacks per year or more than 24 days per year despite the effort to optimize on-demand treatment.68 Short-term (preprocedural) prophylaxis is recommended for all dental, medical, and surgical procedures associated with any mechanical impact to the upper aerodigestive tract.57,68

Table 3. - Therapeutic Agents for Patients With Hereditary Angioedema
Product Prophylaxis On-Demand Treatment
Cynrize Haegarda Takhzyro Berinert Ruconest Kalbitor Firazyr
Shire CSL Behring Shire Dyax CSL Behring Pharming Shire Dyax Shire
FDA approval indication 10/2008 6/2017 8/2018 9/2009 7/2014 1/2009 8/2018
Age ≥6 y old Age ≥12 y or older Age ≥12 y old Age ≥6 y old Age ≥12 y old Age ≥12 y old Age ≥18 y old
Key component Lyophilized pdC1-INH Lyophilized pdC1-INH Lanadelumab-flyo mAb IgG1 κ-light chain Lyophilized pdC1-INH Lyophilized rhC1-INH Ecallantide Icatibant
Source Pooled human plasma Pooled human plasma CHO cell line Pooled human plasma Transgenic rabbit milk Pichia pastoris expression Chemical synthesis
Mode of action ↑C1-INH activity ↑C1-INH activity Kallikrein inhibition ↑C1-INH activity ↑C1-INH activity Kallikrein inhibition BK B2 receptor inhibition
Half-life 56 h 69 h 15 d 18.4 h 2.4 h 2 h 1.4 h
34 h for age 7–11 16.7 h for age 6–13
Dose 1000 IU q3–4 d 60 IU/kg q3–4 d 300 mg q2 wk 20 IU/kg 50 IU/kg for wt <84 kg 30 mg per dose may repeat in 6 h
500 IU q3–4 d (peds) may ↓ to q4 wk 4200 IU for wt ≥84 kg
Maximum dose 4000 IU in 4 h 117 IU/kg q3–4 d N.R. 20 IU/kg 4200 IU ×2 in 24 h 90 mga 90 mg in 24 h or 3.2 mg/kg i.v.
10,000 IU in 1 wk
Injection volume 10 mL for 1000 IU 4 mL for 2000 IU 2 mL for 300 mg 10 mL for 500 IU 14 mL for 2100 IU 3 mL for 30 mg 3 mL for 30 mg
5 mL for 500 IU 6 mL for 3000 IU
Route i.v. s.c. s.c. i.v. i.v. s.c. s.c.
Effects on coagulation tests N.A. N.A. nl ~ ↑ aPTTa N.A. N.A. nl ~ ↑ aPTTa N.A.
Side effects Headache, nausea, rash, vomiting s.c. site reaction, hypersensitivity, nasopharyngitis, dizziness s.c. site reaction, hypersensitivity, elevated transaminase Nausea, diarrhea, vomiting, abdominal pain, vomiting, muscle spasm Headache, nausea, diarrhea Headache, nausea, diarrhea, fever, nasopharyngitis, anaphylaxis (3%) s.c. site reaction, fever, dizziness, nausea, headache, elevated transaminase
Antidrug Ab N.R. N.R. Noninhibitory antidrug Ab reported N.R. Noninhibitory antidrug Ab reported Noninhibitory antidrug Ab reportedb N.R.
Storage 2°C–25°C 2°C–30°C 2°C–8°C 2°C–25°C 2°C–25°C 2°C–8°C 2°C–25°C
Abbreviations: Ab, antibody; aPTT, activated partial thromboplastin time; BK, bradykinin; C1-INH, C1-esterase inhibitor; CHO, Chinese hamster ovarian; FDA, Food and Drug Administration; IgG, immunoglobulin G; i.v.,intravenous; mAb, monoclonal antibody; N.A., not applicable; nl, normal; N.R., not reported; pd, plasma-derived; peds, pediatrics; q, every; rhC1-INH, recombinant human C1-INH; s.c., subcutaneous; wt, body weight.
aElevation to upper normal range without actual bleeding.
bAntibody to ecallantide or Pichia pastoris.

On-demand treatment is administered to reduce edema and associated pain, and shortens the recovery time in patients under acute HAE attacks. Transfusion of fresh frozen plasma (FFP) was the mainstay on-demand therapy in the United States until 2009, but there are currently 3 C1-INH products all for i.v. administration, and 1 pKLK inhibitor and BK B2 receptor antagonist that are given s.c. (Table 3). These newest treatments for HAE have been reviewed and approved by the Food and Drug Administration (FDA, Bethesda, MD) based on the efficacy data derived from the prospective randomized controlled trials (PRCTs). A detailed discussion of the trial results is beyond the scope of this review and available in other literature.10–12 We have reviewed pertinent information regarding prophylactic and on-demand treatment options below.

Prophylaxis

The FDA-approved agents for prophylaxis include 2 plasma-derived (pd) C1-INH products, Cinryze (Shire ViroPharma, Lexington, MA)69 and Haegarda (CSL Behring, Kankakee, IL),70 and lanadelumab-flyo, a humanized pKLK inhibiting monoclonal immunoglobulin (Ig) G1κ antibody (Takhzyro, Shire Dyax Corp, Lexington, MA) (Table 3).

Cinryze is a nanofiltered, lyophilized pdC1-INH product approved for long-term prophylaxis. It is administered 1000 IU i.v. every 3–4 days to adult and pediatric patients (≥12 years old) and a half-dose to children aged between 6 and 11.71 Common side effects include headache, nausea, rash, vomiting, and fever.69 The risk of systemic thromboembolism seems to be low when the dose is below 100 IU/kg twice weekly, and reported systemic thromboembolic events were associated with underlying thrombosis risk factors.69,72

Haegarda is a pasteurized, nanofiltered plasma-derived, lyophilized pdC1-INH product approved for long-term prophylaxis in adult and pediatric patients (≥12 years old).70 It is administered 60 IU/kg s.c. every 3–4 days. The common side effects include injection site pain/erythema, pruritis, rash, hypersensitivity, nasopharyngitis, and dizziness.70

Lanadelumab-flyo (Takhzyro, formerly DX-2930; Shire Dyax Corp) is a lyophilized humanized monoclonal IgG1 κ-light chain.73 Lanadelumab directly inhibits pKLK, reducing the cleavage of HMWK to BK (Figure).74 It has been recently approved for long-term prophylaxis in adult and pediatric patients (≥12 years old). The recommended starting dose is 300 mg s.c. every 2 weeks. Every 4-week dosing interval may be considered for well-controlled HAE patients over 6 months.

On-Demand Treatment

The FDA-approved agents for on-demand use include a pdC1-INH (Berinert; CSL Behring),75 a recombinant human C1-INH (rhC1-INH, Ruconest or Rhucin; Pharming, Bridgewater, NJ),76 a synthetic kallikrein inhibitor ecallantide (Kalbitor, Shire Dyax Corp),77 and a BK B2 receptor antagonist icatibant (Firazyr; Shire, Lexington, MA) (Table 3).

Berinert is identical to Haegarda (CSL Behring) except for the concentration and route of administration. It is approved for i.v. self-administration by an appropriately trained patient or guardian in Europe.78 A weight-based i.v. dose (20 IU/kg) is used for both adult and pediatric patients (≥12 years old) after 2 large PRCTs.79,80 The onset of symptomatic relief seems to be dose-dependent up to 25 IU/kg with pdC1-INH.26

Ruconest is a lyophilized rhC1-INH produced in the milk of transgenic rabbits.81 The amino acid sequence is identical to the pdC1-INH, but a higher degree of glycosylation makes plasma half-life much shorter (2–3 hours).82 A weight-based i.v. dose (50 IU/kg) is used for both adults (<84 kg) and pediatric patients (≥12 years old), a fixed-dose (4200 IU) is used for patients weighing ≥84 kg.83–86 No apparent efficacy difference was found among the C1-INH products (Table 3) despite the different half-lives in the acute treatment. It has been speculated that the optimal clinical efficacy of C1-INH depends on the rapid KKS inhibition rather than the half-life.26

rhC1-INR is contraindicated if a patient has known or suspected allergy to rabbits or rabbit-derived products.76 An immunological response to rhC1-INH is possible, but antidrug antibody formation is seldom reported, and it does not appear to neutralize rhC1-INH function.76 Intravenous administration of pdC1-INH or rhC1-INH is well tolerated, and the most common side effects include headache, nausea, vomiting, and diarrhea, but some of these symptoms may be associated with HAE itself.79,80,87 A potential thromboembolic risk was suggested during an experimental (off-label) use of pdC1-INH (500 IU/kg) during neonatal CPB for the prevention of capillary leakage.88 However, the recent reviews of postmarketing data and clinical trial results did not yield evidence for thromboembolic risk in the indicated uses of pdC1-INH and rhC1-INH.36,72,89

Kalbitor or ecallantide, formerly DX-88, is a lyophilized, synthetic pKLK inhibitor expressed in the Pichia pastoris system.90 Ecallantide directly inhibits pKLK, reducing the cleavage of HMWK to BK (Figure). Ecallantide is approved for acute treatment in patients (≥16 years old).10,91 The approved dosing is 30 mg as 3 separate s.c. injections (total 3 mL), and additional 30 mg dose can be repeated (twice at 6 hours intervals) for the recurrence within 24 hours.77 The bioavailability is excellent (~91%) after s.c. injection, reaching a peak plasma level in 2–3 hours with a mean elimination half-life of 2.0 ± 0.5 hours. Self-administration has not been approved due to the risk of anaphylaxis reported in 1%–3% of patients receiving ecallantide (boxed warning).77 The common side effects are injection site skin reactions, diarrhea, nausea, vomiting, headache, and fever.91–93

Firazyr or icatibant acetate, formerly HOE140, is a lyophilized, selective, competitive antagonist of BK B2 receptor.94 It is approved for the treatment of HAE attacks by self-administration in patients ≥18 years of age.95 Icatibant is administered as a single 30 mg (3 mL) s.c. injection into the skin of abdomen. The bioavailability is excellent (~97%), reaching a peak plasma level in 0.75 hours with a mean elimination half-life of 1.4 ± 0.4 hours. It is not degraded by ACE and other aminopeptidases. Icatibant is well tolerated, and there are no reported cases of systemic anaphylactic reactions or antidrug antibody formation. Most common adverse events are mild-moderate injection site reactions, which are generally transient.96

PERIOPERATIVE CONSIDERATION FOR HAE PATIENTS

The unpredictable nature of HAE makes it difficult to foresee the risk of acute attack during/after surgery and to identify those who may benefit from short-term prophylaxis for surgery.13–15,57,68 Natural course of HAE-I/II patients undergoing nondental, noncardiac surgical procedures (n = 335) were evaluated in 144 patients.9 They were not on long-term (androgen or C1-INH) or short-term prophylaxis before procedure. The HAE type was mainly HAE-I (92%) and there were more female patients (68%). The majority of procedures involved abdomen and appendectomy, possibly due to unrecognized abdominal attack. The documented rate of angioedema was 5.7% (19 of 335), and no HAE attack was explicitly documented in 69.6% (233 of 335). However, the occurrence of angioedema could not be excluded in 24.8%, and the 95% confidence interval (CI) of perioperative angioedema risk was estimated to be 3.5%–35.7%. Postoperative angioedema was mostly reported near the surgical site, but some attacks were in nonsurgical sites. Laryngeal attack was recorded in 3 cases: 2 after adenoidectomy without tonsillectomy and the other after laparoscopy that required a reintubation.9 Dental extraction and adenotonsillectomy are considered as high risk for upper airway edema, and short-term prophylaxis is commonly administered.13–15 CV surgery with CPB is an indication for short-term prophylaxis because of heightened emotional stress and physical trauma, as well as mechanical impact to aerodigestive tracts (endotracheal intubation and intraoperative transesophageal echocardiography). Other potential angioedema risks include underlying conditions of CV patients who are often prescribed with an ACE-I. The latter is an important risk for ACEI-AE (facial and laryngeal edema),97,98 and subclinical HAE and AAE may be unmasked by ACE-I in elderly patients.54,99

SPECIAL CONSIDERATIONS FOR CARDIAC SURGICAL PATIENTS

Initiation of CPB creates a unique condition where heparinized blood comes into direct contact with an artificial surface while pulmonary circulation, a major reserve of ACE, becomes excluded. Enhanced BK formation via KKS activation in contact-activated blood and reduced capacity of BK inactivation occur simultaneously in the early phase of CPB.21,55,100–102 In addition to KKS activation, complement pathways undergo extensive perturbation during and after CPB.16,17,19,20,22,23

Kallikrein Activation During CPB

There is sufficient clinical evidence that has demonstrated the up-regulation of KKS involving FXII during CPB.21,55,100–102 Within 5 minutes after instituting CPB in (non-HAE) CV surgical patients, activities of pKLK and FXIIa are enhanced,100,101 while HMWK level is decreased.102 There is a substantial increase in plasma BK levels in 10–15 minutes of CPB.21,55,100 The rise of BK level is inhibited by aprotinin, a kallikrein inhibitor from bovine lung, but not by a lysine analog, EACA.21 The gradient of BK level (inlet < outlet of the circuit) during CPB supports BK generation on the artificial surface of CPB.55 Exclusion of the lung as a reservoir of ACE during CPB makes BK level continue to rise till the end of CPB,55 and ACE-I treatment further increases BK levels during CPB.21 On resuming the lung ventilation, a significant drop (~60%) in BK level is observed across the lung (right atrium > aorta). These data from non-HAE patients collectively suggest that patients with C1-INH deficiency are at higher risk for hypotensive shock and severe edema in the course of CPB because BK formation is already enhanced.4

Complement Activation During CPB

The activation of complement cascade during CPB involves alternative, classical, and MBL pathways (Figure). The alternative pathway is the predominant mechanism of C3 conversion to C3a (anaphylatoxin) starting immediately after CPB.103 The artificial surface of CPB adsorbs C3 and increases the interaction between C3 and water to form C3H2O. The alternative pathway C3 convertase, C3bBb is formed after factor B binding, and cleavage by factor D. Reperfusion of myocardium and the formation of heparin-protamine complex are considered to be crucial for the classical pathway activation involving the interaction of antibody–antigen complexes (IgG or IgM) with C1-esterase.17,20 C1-INH regulates C1 activation by inhibiting 2 serine proteases, C1r and C1s, which are in the complex with C1q component.104 The classical pathway C3 convertase, C4b2a, is formed after C1-mediated cleavage of C2 and C4 (Figure). The pioneering study of Kirklin et al17 demonstrated the biphasic pattern of C4a generation via classical pathway: the first peak after protamine administration and the delayed peak in 24–48 hours. Their findings have been confirmed in contemporary CPB cases.105 The marker of C3 activation and C1-INH-C1rs complex formation increased from 8 hours after surgery up to 24 hours.105 A similar rise in the C3a level at 8 hours after surgery was also reported in the infants who underwent CPB and developed capillary leak syndrome.106 Elevated C5b-9 (terminal complement complex) and C3bBb levels at the end of CPB continue to decline postoperatively over 24 hours. Delayed classical pathway activation is partly attributed to postoperative elevation of C-reactive protein (CRP), which interacts with C4, triggering classical pathway activation and C3a formation.19 Clinical implications of MBL complement pathway is not fully understood, but existing data suggest it contributes to post-CPB inflammatory state.107 C1-INH is involved in the regulation of MBL pathway by inhibiting MASP-1 and MASP-2 (Figure).108 Taken together, C1-INH function is presumed to be crucial in complement activation via classical pathway following protamine administration and during the recovery phase (24–48 hours).

Clinical Experiences of C1-INH Deficiency in Cardiac Surgery

The literature search (detailed in Supplemental Digital Content 1, Document, http://links.lww.com/AA/D29) for CV surgical cases involving HAE-I/II or AAE yielded 15 reported CV surgical cases including 10 CPB cases in HAE and AAE patients (Table 4).109–123 The majority of patients (n = 13) had HAE-I/II, although types were not explicitly documented in some cases. Attenuated androgens were commonly used as part of preoperative prophylaxis. Five patients were successfully managed with prophylactic plasma transfusion (2–3 units), although posttreatment C1-INH activity was poorly documented.113,115,117,118,123 Most of the patients who received plasma had off-pump CABG, reducing CPB-mediated KKS and complement activations.124 One fatality involved a 74-year-old male with AAE with baseline C1-INH activity of 28%, who developed uncontrollable hemorrhage and pulmonary edema despite plasma transfusion after CPB.122

Table 4. - Case Reports of Hereditary Angioedema in Cardiac Surgery
Reference Type of HAE (Severity) Age
Gender
Procedure CPB Time Intravenous Therapy Antifibrinolytic Therapy Basal C1-INH (mg/dL) Basal C1-INH Activity Post C1-INH Activity Nadir C1-INH Activity Additional Products Adverse Events
Chamaraux-Tran et al109 (2014) HAE type I 81
Female
Aortic valve repl. + CABG 140 min Preop pdC1-INH 1500 IU, repeated once on POD2 TXA 2.5 g bolus + infusion 1.2 g/h 11 26% 80% 42% Danazol 600 mg qd TXA 3 g/d × 2 d No major complication
Marney et al110 (2013) HAE 58
Male
CABG 78 min Preop pdC1-INH 1000 IU; repeated 2000 IU before extubation 16.5 h after surgery TXA 1.5 g bolus + infusion 0.5 g/h 0.75 <1% 32% 20% N.A. No major complication
Saito et al111 (2010) HAE 73
Male
Mitral and tricuspid annuloplasty 339 min Preop pdC1-INH 1000 IU ×2 (evening before surgery and before CPB) N.R. N.R. <25% 70% 66% Danazol 300–600 mg/d No major complication
Bernstein et al112 (2010) HAE type II 51
Male
Redo mitral valve repl. N.R. Preop pd-INH 1000 IU ×2 before cath and 12 h before surgery N.R. N.R. N.R. N.R. N.R. Danazol 400 mg qd No major complication
Shick et al113 (2010) HAE 59
Male
Off-pump CABG N.A. Preop plasma transfusion 2 U; repeated 2 U during grafting; hydrocortisone 100 mg N.R. 10 33% N.R. N.R. Danazol 200 mg bid No major complication
Codispote et al114 (2008) HAE type II 51
Male
Mitral valve repl. 144 min Preop rhC1-INH 1000 IU, repeated once on POD2 N.R. N.R. 20% N.R. N.R. Danazol 200 mg bid Premonition of facial swell before second dose
Pecsi et al115 (2008) HAE 62
Male
Off-pump CABG N.A. Preop plasma transfusion 3 U N.R. 5 84% 94% >68% Danazol 400 mg bid No major complication
Lehman et al116 (2002) HAE type I 48
Male
Off-pump CABG N.A. Preop pdC1-INH 1000 IU 1 h; repeated 1500 IU at closure, then 500 IU q6–8 h ×3 N.R. N.R. <1% 31%–65% 31% Danazol 200 mg tid No major complication
Chaney et al117 (2001) HAE 58
Female
CABG 66 min Preop plasma transfusion 2 U; repeated 2 U (+PLT 1 U) after CPB for bleeding N.R. N.R. N.R. N.R. N.R. Stanozolol 4 mg tid No major complication
Bainbridge et al118 (2001) HAE 45
Male
Off-pump CABG N.A. Preop plasma transfusion 2 U; hydrocortisone 100 mg Aprotinin 1 million KIU (total) N.R. 17% 63%a 50% Stanozolol 6 mg qd No major complication
Alvarez119 (2000) HAE type I 71
N.R.
CABG 51 min Preop rhC1-INH 1000 IU, repeated once before extubation 8 h after surgery N.R. 11 28% N.R. >50% Danazol 200 mg qd No major complication
Castelli et al120 (1997) Acquired 68
Male
CABG >60 min pdC1-INH 1500 IU after CPB/protamine Aprotinin 4 million KIU (total) N.R. <10% N.R. N.R. TXA 0.5 g tid No major complication
Haering & Communale121 (1993) HAE 71
Male
CABG 95 min None N.R. 11 68% N.A. 38% Stanozolol dose N.R. No major complication
Bonser, et al122 (1991) Acquired 74
Male
CABG N.R. Preop hydrocortisone 100 mg; post-CPB plasma transfusion and EACA N.R. 6 28% N.R. N.R. Danazol 200 mg qd Hemorrhage, pulmonary edema, death
Umebayashi et al123 (1987) HAE 7 Female (21 kg) ASD repair N.R. Preop plasma transfusion 3 U N.R. N.R. 12% 32% 26% Danazol 100 mg qd No major complication
Abbreviations: ASD, atrial septal defect; bid, twice a day; BK, bradykinin; C1-INH, C1-esterase inhibitor; CABG, coronary artery bypass grafting; CPB, cardiopulmonary bypass; EACA, ε aminocaproic acid; HAE, hereditary angioedema; KIU, kallikrein inhibitory unit; N.A., not applicable; N.R., not reported; pd, plasma-derived; PLT, platelet concentrate; POD, postoperative day; postop, postoperative; preop, preoperative; qd, every day; rhC1-INH, recombinant human C1-INH; repl., replacement; tid, 3 times per day; TXA, tranexamic acid.
aPresumably due to aprotinin’s C1-inhibitory activity.

Seven patients received C1-INH supplementation before surgery, but posttreatment C1-INH levels significantly varied depending on the baseline activity and the dose of C1-INH (Table 4).109–112,114,116,119 In 1 AAE patient with low C1-INH activity (<10%), C1-INH supplementation was only given after CPB. However, aprotinin was infused over the entire surgery (total, 4 million kallikrein inhibitory unit) and pdC1-INH (1500 IU) was supplemented after protamine administration.120 Aprotinin appeared to have prevented hyperacute KKS and complement activations despite the reduced C1-INH activity as shown in reduced C4a and C3a formations in this case. Aprotinin exerts inhibitory actions toward kallikrein, plasmin, and C1-esterase,125 but it is no longer in clinical use following the voluntary recall in 2007.126

Preoperative Prophylaxis for HAE

Before 2009, none of C1-INH products were available in the United States, and perioperative HAE patients were empirically managed with attenuated androgen, antifibrinolytics, and plasma transfusion.127,128 Short-term prophylaxis with either attenuated androgen or plasma remains as an option when C1-INH concentrate is unavailable.13–15,57,68 Plasma normally contains a high concentration (~3 µM) of C1-INH, but it also contains prekallikrein, HMWK, and FXII, which may exacerbate BK formation in acute attack (Figure). Both FFP and solvent/detergent (S/D)–treated plasma are reported to contain normal levels of C1-INH (85% and 78%, respectively),129 and thus S/D–treated plasma is recommended for improved safety with regard to pathogen transmissions.57,65 Although plasma transfusion of 10 mL/kg (2–4 units per adult) is recommended 1–6 hours before surgery,65 there are no data on the restoration of C1-INH activity using plasma transfusion. An incremental change in C1-INH level is presumably similar to that of AT (normal ~2.7 µM), which is about 2%–3% per unit of plasma (200–250 mL).130 Therefore, plasma transfusion may be impractical to achieve a high target level (>70% or 0.7 IU/mL) in a patient with a low baseline C1-INH level.123 Antifibrinolytic agents and steroids are not recommended for short-term prophylaxis.15,57,68

Table 5. - Perioperative Management of Cardiac Surgical Patients With Hereditary Angioedema
Management Intervention(s)
Preoperative period Prophylaxis multidisciplinary care team • Preoperative consultation with a HAE specialist
• Continuation of prophylactic agents per schedule, if indicated
• Short-term danazol prophylaxis for 5 d before surgery, if applicablea
• Check baseline C1-INH level, if feasible
• Comprehensive plan for C1-INH coverage, surgery/CPB, laboratory monitoring
Intraoperative period C1-INH coverage
Minimization of blood loss/hemodilution
• pdC1-INH 20 IU/kg at <1–6 h preop, or rhC1-INH 50 IU/kg <1 h preop
• Plasma transfusion 10 mL/kg, if C1-INH product unavailable
• Standard dose of heparin i.v.
• Minimize blood loss and hemodilution
• Consider ultrafiltration on CPB to minimize hemodilution and remove BK
• Standard antifibrinolytic therapy (TXA or EACA) for clot stabilization
• Check post-CPB C1-INH level, if feasible
Postoperative Observation and/or treatment • Additional dose of C1-INH after surgery to cover stress and inflammation
• Taper down or stop danazol prophylaxis after 3 days, if applicable
• Careful monitoring for attack in upper airway after extubation for POD 1–3
• Standard thromboprophylaxis, early ambulation
• Check accessibility to acute treatment medication(s) after discharge
• Follow-up after discharge
Abbreviations: BK, bradykinin; C1-INH, C1-esterase inhibitor; CPB, cardiopulmonary bypass; EACA, ε aminocaproic acid; HAE, hereditary angioedema; i.v., intravenous; pd, plasma-derived; POD, postoperative day; postop, postoperative; preop, preoperative; rh, recombinant human; TXA, tranexamic acid.
aIf C1-INH concentrate unavailable or known response to androgens.

Preoperative replacement using pdC1-INH is recommended in 1–6 hours before major surgery (Table 5).57,68 The in vivo recovery of pdC1-INH (Berinert) is estimated to be 2.2%, and thus plasma C1-INH activity goes up by 2.2% per each 1 IU/kg i.v. dose. Theoretically, 1000 IU i.v. increases C1-INH activity about 30% in 80-kg adult (~13 IU/kg), though actual yield is highly variable among HAE patients.131 The reported C1-INH activity following a dose of pdC1-INH (1000–1500 IU i.v., Table 4) seems to be consistent with its pharmacokinetics.109–111,116 Perioperative data on rhC1-INH dosing is limited,114 but a standard 50 IU/kg dose immediately before surgery (<1 hour) is recommended in CV surgery because of the short half-life (2–3 hours), and hemodilution during CPB as discussed below (Table 5).

Intraoperative and Postoperative Considerations

CV surgery and CPB can strongly influence intraoperative C1-INH activity following preoperative replacement. C1-INH level is affected not only by the plasma half-life of each product but also by KKS, contact coagulation, and complement activations after initiation of CPB.16,17,19–23 Ongoing hemorrhage, fluid replacement, and blood administration (other than plasma) can progressively decrease C1-INH activity. Cell salvage recovers erythrocytes but removes most of the plasma proteins.132 C1-INH activity is reduced by 30%–50% from baseline after CPB.109,121,133 Ultrafiltration can be performed during CPB using a hemoconcentrator to remove excess H2O and small proteins including BK (1100 Da).134 C1-INH is not removed by ultrafiltration.111

In the reported cases, postoperative supplementation of pdC1-INH has not been consistently performed. However, it is logical to consider it because low-grade BK formation continues,21 and delayed classical pathway activation occurs in 24–48 hours of surgery.19,107,122 Additional dosing should be considered according to the extent of surgery (eg, prolonged CPB) and patient-specific risk factors (eg, history of laryngeal edema after surgery) in consultation with an HAE treatment specialist. Careful observation after extubation and during recovery on the ward is highly recommended because asphyxiation due to laryngeal edema may occur 4–30 hours after the procedure.135 Accessibility to acute treatment medication(s) and urgent medical facility should be assured before discharge.

Experimental Uses of HAE Therapies in CV Patients

Pathological consequences of pKLK and BK formations during CPB have been postulated to be harmful even in patients without HAE. C1-INH supplementation in non-HAE patients undergoing coronary bypass artery grafting (after myocardial infarction) or congenital heart surgery using CPB has not demonstrated any mortality benefit (Supplemental Digital Content 2, Table 1, http://links.lww.com/AA/D30).133,136 After the recall of aprotinin, ecallantide (Kalbitor, Shire Dyax) was considered as a potential alternative and it was tested against TXA in non-HAE subjects undergoing complex surgery on CPB.137 This study was prematurely terminated after 109 patients were enrolled in each group due to higher 30-day mortality associated with ecallantide. The lack of antiplasmin activity in ecallantide might have contributed to increased erythrocyte transfusion compared to TXA (900 vs 300 mL; P < .001) during 12 hours after surgery.

The B2 receptor stimulation by BK induces a release of tissue plasminogen activator (tPA) from endothelium138 and vasodilatation mediated by nitric oxide and prostacyclin (Figure).139,140 Icatibant (Firazyr) was tested against the placebo and EACA in non-HAE patients (n = 115) undergoing CPB,141 but it failed to modulate tPA or plasminogen activator inhibitor-1 (PAI-1) levels. Only EACA reduced D-dimer levels during and after CPB. The blood product utilization was similar among 3 groups. No improvement in intraoperative blood pressure or vasopressor usage was reported with icatibant.141

Ecallantide and icatibant have been evaluated in ACEI-AE, but neither agent has shown any benefit over placebo in the recovery from upper airway angioedema.142,143

These data collectively suggest distinct BK formation patterns in HAE attacks compared to CPB and ACEI-AE. Fibrin-dependent plasmin formation, not KKS, is the dominant mechanism of CPB-associated fibrinolysis, which can be blocked by TXA or EACA.141

FUTURE PERSPECTIVES

Clinical care of patients with moderate-to-severe HAE has made major progress in the last decade with an armamentarium of therapeutic agents with different classes and routes of administration. Extended observational studies of these drugs, PRCTs of new agents,144 and more research to understand the triggering mechanism(s) for various types of HAE33,34 should allow a more individualized approach to prophylaxis and on-demand treatments in the near future. Although attenuated androgens used to be the only option to modulate C1-INH synthesis in the liver, gene therapies and hepatocyte transplantation are being considered as a feasible and valid alternative.145

CONCLUSIONS

Based on available data and pathophysiological consideration, HAE patients with C1-INH deficiency are at high risk for excess BK formation and activity during CPB due to uncontrolled pKLK activity, and reduced availability of ACE due to the exclusion of lungs from circulation. Pathological activation of classical complement pathway following protamine administration is an additional risk for capillary leakage. Considering a potential for hypotensive shock and severe edema, it is prudent to normalize C1-INH functional plasma levels before surgery, and to avoid critically low C1-INH levels (<38%) throughout the perioperative period. Due to interindividual variability, perioperative C1-INH replacement should be carefully planned with a consultation with HAE specialist, and if available, frequent monitoring of C1-INH is desirable. Further preclinical and clinical studies are warranted to optimize perioperative care of patients with different types of HAE.

ACKNOWLEDGMENTS

The authors dedicate this article to Marco Cicardi, MD, who passed away on August 10, 2019. He was a brilliant clinician-scientist and visionary who has made extraordinary contributions to our present understanding of hereditary angioedema, its classifications, and development of modern therapies.

DISCLOSURES

Name: Kenichi A. Tanaka, MD, MSc.

Contribution: This author helped with conception, design, planning, and writing.

Conflicts of Interest: K. A. Tanaka received research funding (unrelated to C1-esterase inhibitor) from CSL Behring (King of Prussia, PA).

Name: Samhati Mondal, MBBS.

Contribution: This author helped collect the data and write the manuscript.

Conflicts of Interest: None.

Name: Yoshihisa Morita, MD.

Contribution: This author helped collect the data and write the manuscript.

Conflicts of Interest: None.

Name: Brittney Williams, MD.

Contribution: This author helped write the manuscript.

Conflicts of Interest: None.

Name: Erik R. Strauss, MD.

Contribution: This author helped write the manuscript.

Conflicts of Interest: None.

Name: Marco Cicardi, MD.

Contribution: This author helped design, plan, and write the manuscript.

Conflicts of Interest: M. Cicardi has received grants from Shire; consulting fees, honoraria, and support for travel from Shire, Pharming, BioCryst, and CSL Behring.

This manuscript was handled by: Roman M. Sniecinski, MD.

FOOTNOTES

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