Fresh Frozen Plasma for the Treatment of Hereditary Angioedema Acute Attacks

Rui Tang,Shi Chen,and Hong-yu Zhang＊

1Department of Allergy,2Department of Endocrinology,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences &Peking Union Medical College,Beijing 100730,China

HEREDITARY angioedema (HAE) is a rare autosomal dominant disease with an estimated prevalence of 1∶50 000,characterized by episodic edema of the skin,subcutaneous tissues or mucous membranes.Life may be threatened when laryngeal edema appeared.The disease is due to deficiency of the quantity and/or function of C1 inhibitor (C1INH).HAE can be usually divided into two types.HAE type I is up to 85% of all patients,and there is a deficiency in the amount of C1INH protein.In HAE type II,the circulating C1INH concentration is normal or high,but C1INH not fully functional.1

Treatment for HAE includes prophylaxis and aute attacks.C1INH concentrates,2nanofiltered C1INH,3recombinant C1INH,4kallikrein inhibitor ecanllantide5,and bradykinin B2 receptor antagonist icatibant6are the options for acute attacks of HAE.But at present the abovementioned therapies are unavailable in China and there is also no experience on treatment for acute attacks of HAE.Fresh frozen plasma (FFP) is often used as a source of C1INH to treat acute attacks in the United States.7We first reported a Chinese HAE patient successfully treated with FFP for acute attack in 2009.8In this study,we retrospectively analyzed 2 patients undergoing treatment for HAE at Peking Union Medical College Hospital and 11 patients reported in the medical literatures who received FFP infusion,to determine if there was evidence that FFP infusion was safe and effective for acute attacks of HAE patients.

PATIENTS AND METHODS

Data collection

We retrospectively searched the medical records in Peking Union Medical College Hospital during 2004 and 2010 to identify the patients diagnosed with HAE receiving FFP infusion.All patients were diagnosed according to 2010 international HAE consensus.9Patient having angioedema caused by allergen or medicine was excluded.Meanwhile,we searched PubMed database from 1966 to the present using the following key words∶hereditary angioedema and fresh frozen plasma.We identified relevant articles written in English.

Data analysis

The following information was recorded∶patient’s age,sex,body location of HAE attacks,the dose of FFP infusion,time of beginning to improvement,time to complete remission,complication,C1INH activity,and outcome,to determine the safety and efficacy of FFP infusion for acute attacks of HAE patients.

C1INH activity in FFP was 60 000.Normal range of C1INH activity was 60 000-100 000.10

Statistical analysis

Statistical analysis was performed with SPSS software version 11.0 for Windows.The normally distributed data were presented as mean±SD.Significant differences between the groups were evaluated using Student’st-test.The abnomally distributed data were accessed by median(P25,P75).Significant differences between the groups were compared usingFisher’sexact test.A value ofP＜0.05 was considered statistically significant.

RESULTS

General information

A total of 13 patients (7 male and 6 female) experiencing 16 acute attacks were enrolled.The mean age was 30±17 years old.The mean age of male and female patients was 27±15 and 28±18 years,respectively.There was no significant difference between male and female in the mean age (t=-0.061,P=0.952).One type-Ⅰ and one type-Ⅱ HAE patients were diagnosed in Peking Union Medical College Hospital.Other 11 HAE patients reported in the literature included 4 type-Ⅰand 7 unknown type.10-17The 13 HAE patients received 16 times of FFP infusion(Table 1).

Clinical manifestation

Acute attacks manifested as laryngeal edema for 5 cases,abdominal pain for 5 cases,and facial edema for 3 cases(Table 1).

The mean age of 5 cases experiencing laryngeal edema was 20±5 years old,and that of other 8 cases without laryngeal edema was 35±20 years old (Table 1).So there was a trend the patients suffering from laryngeal edema were younger,although difference was not statistically significant (t=-2.086,P=0.056).

Infusion dose of FFP

The mean dose of FFP infusion was 586±337 mL (Table 1).There was no significant difference between male and female in the dose of FFP infusion (581±259vs.519±451 mL,t=1.322,P=0.209).The FFP dosage was lower in the laryngeal edema group (375±128vs.657±256 mL,t=-2.760,P=0.016).

Adverse events

Symptoms of all cases were improved except 1 because of transfusion reaction.The only adverse event recorded was rash,fever and chilling occurred in 1 case,which were considered to be allergic reaction to FFP infusion.Abdominal pain of 2 cases was exacerbated in the first few minutes of FFP infusion,but the symptom completely disappeared within 1.5 to 2.5 hours of FFP treatment(Table 1).10,13

C1INH activity

There were two records of change of C1INH activity in the literature.10After 400 mL of FFP infusion,C1INH activities in both patients after plasma infusion increased from 10 000 to 26 500 and from 16 000 to 25 000,respectively.

Outcome

The mean time of beginning to improvement was 49±19 minutes for 8 acute HAE attacks (Table 1).

Table 1.Clinical characteristics of patients with HAE undergoing FFP infusion for acute attacks

A total of 7 acute attacks (5 cases) had definite records of remission time without FFP treatment,which was 61.7±27.0 hours.The median of remission time of 10 acute attacks shortened to 3.3 (2.0,12.0) hours after FFP infusion (P＜0.01,Table 1).

DISCUSSION

HAE is a rare autosomal dominant disease,characterized by edema of the skin,subcutaneous tissues or the mucous membranes of the gastrointestinal and upper respiratory tracts.Laryngeal edema occurred in 48%-78%of HAE patients,and the risk for asphyxialdeath was 30%-50%.18The manifestation is similar to the angioedema caused by allergen or medicine,so in the emergency room antihistamines,glucocorticoid or epinephrine is usually administrated to control angioedema,but the upper-mentioned medicines have no effect for angioedema attacks of HAE.

HAE is caused by deficiency in C1INH.C1INH is not only the main regulator of the early steps of the classic complement pathway,but also important inhibitor of kallikrein.C1INH deficiency will activate the classic complement pathway and bradykinin,leading to edema.At present,replacement therapy with C1INH is recommended to treat an acute attack of HAE,but which is unavailable in China.

FFP is separated from the whole blood within 6-8 hours after collection,which can be conserved for 1 year under-18°C.FFP contains all coagulation factors except for platelet,so FFP can be used for treatment of acute attacks of HAE.19We reported FFP infusion as the treatment for acute attacks of HAE in China in 2009.8But it is hypothesized FFP might worsen an acute attack of HAE for it contains potentially harmful substrates.20

Angioedema attacks various organs.In this report,the manifestation of FFP treated cases ranged from abdominal pain to facial angioedema to life-threatening laryngeal edema.The patients with laryngeal edema were younger than those with abdominal pain or facial edema,so the clinical doctor should pay attention to the laryngeal edema among the younger patients.In this cohort,375±128 mL of FFP seemed to be able to achieve an improvement in symptoms of patients with laryngeal edema,meanwhile 657±256 mL of FFP seemed effective for the other cases.So 400-600 mL of FFP seemed enough for acute attacks of HAE.

Improvement in symptom appeared in all cases except one because of transfusion reaction.FFP was an efficacious remedy for every type of exacerbation.And 2 cases reported in the literature suffered from worsening abdominal pain within the first few minutes of FFP infusion for an acute attack,but achieved complete resolutions within 1.5 to 2.5 hours of treatment.10,13We can not identify if the abdominal symptom are due to FFP infusion.

After 49±19 minutes of beginning the infusion,there was a definite improvement.At 3.3 hours of infusion,HAE patients were completely free of laryngeal edema,abdominal pain or facial edema.The remission time was obviously shorter than that of patients without FFP transfusion (61.7±27.0 hours).There was an increase in C1INH activity after the infusion,which indicated that the plasma infusion provided the patients with C1INH,leading to the release of acute attacks.

FFP can induce allergic reaction or virus infection as blood products.The only adverse event recorded was rash,fever and chilling,which were considered to be allergic reaction to FFP,and were easily alleviated with antihistamines.So plasma derived C1INH and recombinant C1INH is required in China to treat acute HAE attacks.

In conclusion,FFP seems to be safe and effective when used for treatment of acute HAE attacks.

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