Types

Hereditary angioedema (HAE) - genetic deficiency of C1-INH (11q11-q13.1)
  • Type 1 (85%) - Low C1-INH level resulting in decreased function
  • Type 2 (15%) - Normal C1-INH level, but enzyme defective resulting in decreased function
  • Type 3 (Rare) - Similar to type 1 and 2 HAE clinical presentation, except for normal C1-INH levels and function.
    • Estrogen dependent, seen primarily in women (but also men), and often triggered by pregnancy or exogenous estrogen administration, facial swelling predominant.
    • Dominant inheritance, usually later age of onset (typically 2nd decade), and a subset of patients have a mutation in factor XII (Thr309Lys or Thr309Arg) that possibly increases its activity as an initiator of bradykinin formation
    • Zuraw: without a definitive test to rule-in type 3 HAE it is necessary to have a clear personal and family history of recurrent angioedema, recognizing that there is the possibility of missing the diagnosis in some patients

HAE3 dx criteria.png
HAE with normal c1inh comparison.png
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Acquired angioedema (AAE) - acquired deficiency of C1-INH
  • Type 1 (paraneoplastic) - Associated with B-cell lymphoproliferative diseases (lymphoma, monoclonal gammopathy of unknown significance or MGUS)
    • Low C1INH and C1q caused by increased consumption of C1-INH by neoplastic lymphatic tissue, and activation of classical complement pathway
    • Autoantibody to C1-INH may also be present and cause decreased C1-INH function
  • Type 2 (autoimmune) - Defined by presence of an autoantibody (IgG but occasionally IgA, IgM) against the C1-INH protein; patients usually otherwise healthy or may have AAE type 1.
    • Autoantibody inactivates C1-INH function, therefore C1-INH level (but not function) may be normal

Note
  • Late age of onset (older adults, elderly) and low C1q help differentiate AAE from HAE


Diagnosis

  • In general, abnormal testing for HAE should be repeated
  • Cicardi: it is mandatory to screen for C1-INH deficiency in all patients with non-histaminergic AE without urticaria, including those who become symptomatic during ACE inhibitor or estrogen treatment (because these conditions can induce underlying/silent HAE)

Lab Tests

  • C4 level- Low when level is <50% of normal value
    • Measurement of C4 levels is a cost-effective screening test to rule out HAE but false negatives/positives can occur
    • C4 is almost always <50% of normal in HAE types 1 and 2 but in rare cases the C4 level is normal between attacks (Zuraw)
      • <10% with HAE type 1 or 2 will have C4 >12 mg/dL, levels >12 make HAE 1/2 diagnosis very unlikely
    • C4 should virtually always be low during an attack of HAE
    • Low C4 level found in up to 2% of the healthy general population due to a partial genetic deficiency and is typically not associated with disease
    • Low C4 found in 15% of patients with SLE (in addition to characteristic autoantibodies, clinical symptoms, etc.) and also cryoglobulinemia
  • C4d:C4 ratio- High ratio seen in HAE.
    • C4 level measures the total C4 level (intact C4 + cleaved/activated C4 aka C4d)
    • Addition of the C4d measurement to C4 quantifies the level of ongoing activation rather than just the total level of C4, which is highly variable from person to person
  • C2 level - May be low during acute attack of HAE, normal between attacks
  • C1-INH level and function - Low when level or function <50-60% of normal value
    • When both C1-INH and C4 are <50% of normal values, diagnosis of HAE type 1 is established without need for further testing. If C1-INH level is normal but C4 is low, obtain C1-INH function.
    • C1-INH function is best obtained using a chromogenic assay (the common alternative ELISA/EIA may be less sensitive; chromogenic assay widely used in Europe but not the USA)
      • Measurement of C1-INH function with a hemolytic complement assay is the most accurate test but is technically difficult to perform and not readily available
    • In infants, C1-INH level/function correspond to 70/61.8% of adult values initially and increase to normal level by age 6-12 months (too early testing may lead to a false diagnosis)
    • In pregnant patients, C1-INH level decreases due to plasma volume expansion, and patients with eclampsia/preeclampsia have lower levels during the third trimester. These levels return to normal after delivery and should be repeated at that time to confirm diagnosis.
  • C1q level- Low in patients with AAE (Type 1 and 2) due to consumption related to underlying autoimmune disease or malignancy
  • Factor XII genotyping for Thr309Lys or Thr309Arg mutation associated with HAE type 3 - Available from National Jewish and Gene Dx; utility of this test is controversial due to mixed studies
    • Riedl: if positive in a person with suggestive clinical symptoms, this finding is strong supportive evidence of HAE type 3
  • C3 level - expected to be normal
  • CH50 - not useful for HAE
  • Anti-C1-INH antibody - present in AAE type 2 (sometimes may be present in AAE type 1)
  • Anti-C1q antibody - patients with HUVS typically have auto-antibodies to C1q, and can develop angioedema
  • C1INH (aka SERPING1) gene analysis - Available from GeneDx, detects 99% of mutations in C1INH gene resulting in HAE
    • Most C1 inhibitor HAE families have "private mutations" (each family has its own mutation), and more than 300 different mutations have been associated with genetic C1INH deficiency
    • No mutation in C1INH is found in 8-10% of HAE cases
    • Can help distinguish de novo (negative family history) HAE from AAE
    • Prenatal testing (via amniocentesis at 16-18 weeks or chorionic villus sampling at 10-12 weeks) can be done but may not be practical:
      • May assist in genetic counseling if you demonstrate identical mutation in affected parent and fetus, however note that identical mutations may be associated with substantially different phenotypes
      • Mutation may not be a valid indication for terminating pregnancy because it may cause a non-fatal, manageable disease in the offspring, the severity of which can not be predicted in advance


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AE complement profiles.png

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Obtaining Accurate Complement Studies

  • Complement deteriorates at room temperature in serum or fluid; samples should be brought to the laboratory as soon as possible. Separate serum from clot and freeze below -60°C within 2 hours of specimen collection. Failure to process the specimen in this manner may lead to falsely decreased C1INH function.
  • ADx lab at National Jewish recommends collecting plasma with EDTA because it will help block ex-vivo activation of complement or coagulation enzymes that may lead to an artificially low measurement of C1INH function
  • Complement studies must be performed when the patient is not receiving treatment, because therapies can alter results
    • For patients treated with C1 inhibitor or fresh frozen plasma, at least 1 week should be allowed
    • For patients on androgen therapy, 3 weeks are necessary
  • The diagnosis of HAE requires consistent results from at least two sets of complement studies, ideally separated in time by one month or more
  • Falsely low C1-INH function can result from "cold activation" of the inhibitor, which can occur when a sample is frozen for extended period of time. C4 should be normal if cold activation has taken place. Antigenic levels of complement components, including C1-INH, are more reliable. Studies should be done with fresh or freshly frozen serum that has not been standing for more than four hours.



Diagnostic Algorithm

2010 International Consensus Algorithm
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2012 WAO Guideline Algorithm
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HAE Management


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Avoidance of Triggers

  • Avoid known triggers
  • Avoid ACE-inhibitors in all patients with HAE
  • For female contraception, estrogens should be avoided because they are known to upregulate activation of the kallikrein-bradykinin system and can exacerbate HAE. Barrier methods, progesterone, and IUD are preferred, and progesterone could provide a therapeutic benefit:
Progestin contraception for HAE.png

Algorithm

HAE_patient_management.png


Treatments

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Drug
Mechanism
Dose
Approximate Cost
Notes
Danazol (Danocrine)
50, 100, 200 mg capsules
Antigonadotropic agent; increases production of C1INH.
Adult:
  • Short-term prophylaxis for minor procedure: 2.5-10 mg/Kg/d, maximum 600 mg/d for 5 days prior and 2-5 days after event
  • Long term prophylaxis: ≤200 mg/day, use lowest effective dose (including alternate day or 2-3 times/week regimens)
  • Acute attack: some patients on androgens can abort attacks by doubling their prophylaxis dose at the first signs or prodrome of an attack.
30 x 50 mg: $53
30 x 100 mg: $69
30 x 200 mg: $111
  • Caution with carbamazepime and warfarin. Caution in renal, hepatic, or cardiac insufficiency and seizure disorders; hepatitis and benign hepatic adenoma have been observed with long-term therapy (>10 y); thromboembolic events and pseudotumor cerebri reported; androgenlike effects, including weight gain, acne, hirsutism, edema, hair loss, voice changes, and menstrual disturbances, occur.
  • Monitoring: LFTs, lipid profile, CBC, and UA q6 months. For adults with a dose of ≤200 mg/d: annual liver/spleen ultrasound. In prepubertal patients or adults with doses >200 mg/d: liver/spleen ultrasound q6 months and annual α-fetoprotein.
  • Pregnancy category X. Androgen contraindications also include lactation, cancer, hepatitis, and childhood (until puberty finished). Short term prophylaxis may be used during third trimester of pregnancy or in children if C1INH replacement not available.
  • Prophylaxis with attenuated androgens should be stopped 2 months before attempted conception due to risk of abnormalities in fetus. If patient becomes pregnant, AA should be discontinued and family informed about risk of fetal abnormalities.
ε-aminocaproic acid (Amicar)
500, 1000 mg tablets
0.25 g/mL oral solution
Lysine analog that inhibits fibrinolysis via inhibition of plasminogen activator substances and antiplasmin activity.

Half-life is 1-2 hours. Peak effect occurs within 2 hours
Adult:
  • Acute attack: 8 g q4h IV, then 16 g/d
  • Maintenance: 6-10 g/d PO

Pediatric:
  • 8-10 g/d PO
  • Not recommended in newborns
30 x 500 mg: $103
  • Caution in cardiac, hepatic, or renal disease; adverse effects are postural hypotension, thrombosis, and muscular pain and weakness due to risk of rhabdomyolysis; caution in patients with upper urinary tract bleeding; caution with rapid infusions; do not administer with factor IX complex concentrates or anti-inhibitor coagulant complexes.
  • Antifibrinolytics have not been associated with excess thrombosis or myocardial infarction in controlled trials but there are case reports of thrombosis in patients with hypercoagulable states so it is prudent to use them cautiously if there is a family history of thrombophilia or active thromboembolic disease.
  • Monitor CK and aldolase levels, UA, LFT, and renal function q6 months.
  • Antifibrinolytics may not be as effective as androgen therapy in HAE but may be useful in acquired angioedema.
  • Pregnancy category C. Prophylaxis with antifibrinolytics should be discontinued days before attempting to conceive.
Tranexamic acid (Cyklokapron, Lysteda)
500, 650 mg tablets
Inhibits fibrinolysis by displacing plasminogen from fibrin.
Adult:
  • Acute attack: Up to 8 g PO/IV
  • Long term prophylaxis: 20-50 mg/Kg/d div. bid or tid, maximum 3-6 g/day

Pediatric:
  • 12-25 mg/Kg/dose (not to exceed 1.5 g) PO tid/qid
60 x 500 mg: $70
  • Caution in renal impairment; adverse effects are not common but include headaches, nausea, abdominal pain, and diarrhea; risk of rhabdomyolysis but less than in aminocaproic acid; evidence of tumor formation in retina and liver found in experimental animal models after long-term use; although no evidence has supported these findings in humans.
  • Antifibrinolytics have not been associated with excess thrombosis or myocardial infarction in controlled trials but there are case reports of thrombosis in patients with hypercoagulable states so it is prudent to use them cautiously if there is a family history of thrombophilia or active thromboembolic disease.
  • Monitoring: CK, UA, LFT and renal function q6 months; annual ophthalmology check for eye pressure, baseline ophthalmology exam before long term use.
  • Antifibrinolytics may not be as effective as androgen therapy in HAE but may be useful in acquired angioedema.
  • Mostly used for prophylaxis in children before Tanner 5 puberty or if not wanting to risk androgen prophylaxis
  • Pregnancy category B. Prophylaxis with antifibrinolytics should be discontinued days before attempting to conceive.
Fresh frozen plasma (FFP)
1 unit (~400 mL)
Replacement of deficient or dysfunctional endogenous C1INH.

Blood product: after a unit of blood is drawn, cell components (WBC/RBC/ platelets) removed by centrifugation and remaining portion is frozen.
Adolescent/adult:* Acute attack: 1-2 units (400-800 mL) IV
  • Short term prophylaxis for major procedure: 1-2 units (400-800 mL) IV 1-6 hours before procedure + danazol short term prophylaxis

Pediatric:
  • Acute attack or short term prophylaxis: 10 mL/Kg

  • Anecdotal reports of worsening angioedema.
  • Universal precautions for blood-borne infection.
Nanofiltered human C1INH (Cinryze)
500 unit vial
Replacement of deficient or dysfunctional endogenous C1INH.
Adolescent/adult:
  • Abdominal or facial attacks (off-label): 20 U/Kg IV, infusion rate ≤4 mL/min
  • Short term prophylaxis for major procedure: 10-20 U/Kg IV 1-6 hours before procedure
  • Long term prophylaxis: 1000 U IV over 10 min q3-4 days
500 unit vial: $2340
70 Kg patient: $9360 (4 vials) for acute treatment, $243,360 per year for biweekly prophylaxis.
  • Severe hypersensitivity may occur and result in urticaria, chest tightness, wheezing, hypotension, and/or anaphylaxis; thrombotic events have been reported with high doses .20 U/Kg; as with all products derived from human blood, universal precautions for infection transmission should be used; common adverse effects (ie, >5%) include URTIs, sinusitis, rash, and headache.
  • Pregnancy category C.
Human C1INH (Berinert)
500 unit vial
Replacement of deficient or dysfunctional endogenous C1INH.

Half-life 18.4 ± 3.5 hours
Adolescent/adult ≥13 years old acute attack:
  • 20 U/Kg IV, infusion rate ≤4 mL/min
500 unit vial: $850
70 Kg patient = $3400 (4 vials)
  • Made from human plasma and may contain infectious agents, eg, viruses and, theoretically, Creutzfeldt-Jakob disease (CJD). Hyper-sensitivity reactions may occur and result in urticaria, chest tightness, wheezing, hypotension, and/or anaphylaxis; thrombotic events have occurred with high doses >20 U/Kg; common adverse effects (>4%) include nausea, vomiting, diarrhea, dysgeusia, abdominal pain, muscle spasms, and headache; may increase severity of pain associated with HAE.
  • Pregnancy category C. It is not known whether Berinert is excreted in human milk.
Recombinant human C1INH (Ruconest, Rhucin)
Replacement of deficient or dysfunctional endogenous C1INH.

Secreted in transgenic rabbit’s milk; identical amino acid sequence to endogenous human C1INH
Adult:
  • 50 U/Kg IV
N/A
  • Likely to be similar to plasma-derived C1INH except there is no risk of human blood-borne infection.
  • Patients should be screened for allergic sensitization to rabbit dander prior to use because hypersensitivity reactions in rabbit-allergic patients are reported.
Icatibant (Firazyr)
30 mg (3 mL) syringe
Bradykinin B2 receptor antagonist

Following subcutaneous administration, the absolute bioavailability is 97%. The time to maximum concentration is ~0.5 hours. The half-life is 1-2 hours. Mainly eliminated by liver metabolism with less than 10% of the dose eliminated in the urine as unchanged drug.
Adult (≥18 years old) acute attack:
  • 30 mg SQ
  • In case of insufficient relief or recurrence of symptoms, a second dose can be given after 6 hours, if the second dose produces insufficient relief or if symptoms recur, a third doe can be given after a further 6 hours. No more than 3 injections should be given in a 24 hour period.
N/A
  • Special precautions: In ischemic heart disease, a deterioration of cardiac function and a decrease in coronary blood flow could theoretically arise from antagonism of bradykinin B2 receptor. Caution when administering to patients with acute ischemic heart disease or unstable angina pectoris. In addition, caution should be observed in the administration of icatibant to patients in the weeks following a stroke. Although there is evidence to support a beneficial effect of B2 receptor blockade immediately following a stroke, there is a theoretical possibility that icatibant may attenuate the positive late phase neuroprotective effects of bradykinin.
  • Most common adverse reaction is self-limited erythema, swelling, warm sensation, burning, itching, and cutaneous pain at the injection site.
  • Icatibant should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus, (e.g for treatment of potentially life threatening laryngeal attacks). It is unknown whether icatibant is excreted in human breast milk but it is recommended that breastfeeding women should not breastfeed for 12 hours after treatment.
Ecallantide (Kalbitor)
3 x 10 mg (1 mL) syringes
Plasma kallikrein inhibitor. Ecallantide binds to plasma kallikrein and blocks its binding site, inhibiting the conversion of HMW kininogen to bradykinin.

Produced by yeast (P. pastoris).
Maximum plasma concentration was observed approximately 2-3 hours post-dose. Ecallantide is a small protein and renal elimination has been demonstrated.
Adolescent/adult ≥16 years old acute attack:
  • 30 mg given as three 10 mg SQ injections.
  • If attack persists, additional 30 mg may be given within a 24 hour period (at least 4 hours after initial dose).
  • The site for each injection may be in the same or different locations (abdomen, thigh, upper arm). Sites should be separated by 5 cm and away from the anatomical site of attack.

Pediatric acute attack (off-label):
  • 10-20 mg given as 1-2 10 mg SQ injections
30 mg: $7950
  • FDA blackbox warning for anaphylaxis: occurred in 3.9% of treated patients. Given the similarity in hypersensitivity symptoms and acute HAE, monitor patients closely for hypersensitivity reactions.
  • Patients may develop antibodies to ecallantide. Rates of seroconversion increase with exposure In the Kalbitor HAE program, 7.4% of patients seroconverted to anti-ecallantide antibodies. Neutralizing antibodies to ecallantide were determined in vitro to be present in 4.7% of patients. Anti-ecallantide and anti-P. pastoris IgE antibodies were also detected. Patients who seroconvert may be at a higher risk of a hypersensitivity reaction. The long-term effects of antibodies to ecallantide are not known.
  • The most common adverse reactions occurring in ≥3% of treated patients and greater than placebo are headache, nausea, diarrhea, pyrexia, injection site reactions, and nasopharyngitis.
  • Pregnancy category C.


HAE Acute Attack Treatment (WAO 2012)

WAO attack tx.png

  • All attacks that result in debilitation/dysfunction and/ or involve the face, the neck, or the abdomen should be considered for on-demand treatment. Treatment of attacks affecting the upper airways is mandatory.
  • Oral antifibrinolytics are not to be used as on-demand treatment
  • For children and in pregnant/lactating women, only C1INH or plasma is recommended (limited experience with icatibant and ecallantide)
  • All patients should have on-demand treatment for 2 attacks and should carry their treatment at all times


HAE Prophylaxis

Treatment Overview

Long term HAE prophylaxis agents.png

Short Term Prophylaxis Strategy

  • 2010 International Consensus Guideline:
HAE_short_term_algo.png
*10-20 U/Kg or 1000 IU

  • WAO 2012: short-term prophylaxis with C1INH replacement should be considered before surgeries, especially dental/intraoral surgery, where endotracheal intubation is required, where upper airway or pharynx is manipulated, and before bronchoscopy or endoscopy
    • Androgens (danazol, stanozolol) may be used when the surgery-related risk is relatively low and when C1INH is not available; efficacy of tranexamic acid for this purpose seems to be low

Long Term Prophylaxis Strategy

HAE_prophylaxis_recs.png
  • 2010 International Consensus Guideline:

HAE_long_term_algo.png
  • WAO 2012 Guideline:
    • Plasma-derived C1INH concentrate 2 times/week, with dose and/or frequency adjusted for optimum control, with on-demand therapy (C1-INH concentrate, ecallantide, or icatibant) available for breakthrough attacks
      • Vaccination with hepatitis A and B, serologies to hepatitis A/B/C, hepatitis E, HIV, human T-lymphotropic virus, and parvovirus should be done before initiation of C1INH long-term prophylaxis and once annually
    • Prophylaxis with androgens is effective but complicated by adverse effects
      • Before the initiation of long-term with androgens, check CBC, UA, LFTs, lipid profile, assessment of cardiac risk factors, and liver ultrasound
      • Every 6 months and for up 6 months after stopping therapy, monitor CBC, UA, lipid profile, LFTs, and blood pressure with annual liver ultrasound



AAE Management (Cicardi)

  • Treatment of underlying disease may result in biochemical/clinical remission. If AAE diagnosed, evaluate for underlying disorders with the following studies:
    • CBC, electrolytes, BUN, creatinine, LFTs
    • LDH
    • Urinalysis
    • Serum protein electrophoresis (SPEP) and immunofixation
    • Serum free light chain assay
    • CXR, abdominal ultrasound (vs. CT chest/abdomen) to screen for lymphadenopathy/masses
    • All age-appropriate cancer screening tests
    • Other
      • Hem/Onc consult
      • If workup negative, screen yearly with CBC, SPEP, CXR, abdominal ultrasound
  • Acute treatment
    • Even in AAE, intubate if airway is threatened (e.g. stridor) as deaths have occurred due to AAE
    • First line treatment is C1-INH concentrate, usually 20 U/Kg
      • No established therapeutic alternative to C1-INH for life-threatening attacks
      • AAE patients have 3000 U of C1-INH immediately available and treat attacks with 1500 U (repeating or trying alternative drug class if ineffective)
      • May become resistant to treatment and require increasingly larger doses over time than HAE
        • Resistance to C1-INH may be due to autoantibody-mediated rapid catabolism
    • Ecallantide and icatibant are good alternative for patients with slow or no response to C1-INH
    • If no other option, FFP 2 units (or 10-15 mL/Kg if there is concern about volume overload) q2-4 hours until there is clinical improvement
    • Antihistamines, steroids, epinephrine are generally not effective however they are low risk and may be used if diagnosis of AAE attack is questionable

  • Prophylaxis
    • Avoid estrogens, ACE inhibitors, tamoxifen
    • Antifibrinolytics - more effective than androgens in AAE patient, may be considered first choice drug for AAE prophylaxis
      • e.g. Tranexanic acid 3 g PO QD with consideration for warfarin for patients with increased risk of thromboembolism who need long term prophylaxis
    • Androgens - frequently resistant, e.g. Danazol 200 mg PO TID x 1 month then tapering to lowest effective dose
    • Little rationale for C1-INH prophylaxis due to infrequent attacks and risk of inducing resistance


HAE Type 3 Management (Zuraw 2012)

  • Due to lack of studies, no firm recommendations regarding the treatment of HAE with normal C1INH replacement can be made
    • Angioedema attacks in patients with HAE with normal C1INH do not respond to either corticosteroids or antihistamines, even at high doses
    • Prophylactic use of androgens, tranexamic acid, or progestins have shown promising results in some but not all patients
    • There is relatively little experience regarding the efficacy of on-demand C1INH, icatibant, or ecallantide in HAE with normal C1INH; however, anecdotal reports suggest that each of these agents may be beneficial


References