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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgement
  9. References

Summary

Background

Patients with decompensated cirrhosis are at risk for hyperfibrinolysis; this is potentially fatal. ɛ-aminocaproic acid has been used to treat patients with hyperfibrinolysis; however, the data about its benefit in the setting of cirrhosis are minimal.

Aim

To analyse the efficacy of ɛ-aminocaproic acid and its safety in cirrhotic patients with hyperfibrinolysis.

Methods

All patients with an abnormal euglobin lysis time who were admitted to Rancho Los Amigos Medical Center from 1 January 2001 to 31 December 2002 were included in the study. Their medical records were reviewed and analysed.

Results

There were 60 cirrhotic patients with shortened euglobin lysis time. Fifty-two patients received ɛ-aminocaproic acid. Of the 52 patients, seven had one or more bleeding episodes with the subcutaneous or soft tissue bleeding as the most common indication for ɛ-aminocaproic acid use. Of the 37 patients, 34 (92%) had improvement or resolution of their bleeding. Only two (3%) patients had ɛ-aminocaproic acid treatment discontinued because of minor side effects, rash and lightheadedness. There were no thromboembolic complications of treatment.

Conclusions

ɛ-aminocaproic acid was found to be effective and safe for treatment of hyperfibrinolysis in patients with cirrhosis.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgement
  9. References

Patients with decompensated cirrhosis have a high incidence of hyperfibrinolysis, as high as 36% at Rancho Los Amigos Medical Center.1 Hyperfibrinolysis occurs when fibrin breakdown exceeds fibrin formation leading to defective haemostasis. Patients with hyperfibrinolysis normally present with mucocutaneous bleeding and/or haematoma.1 There have been reports of fatal bleeding because of hyperfibrinolysis.2, 3 Hyperfibrinolysis can be conveniently and reliably diagnosed by measuring euglobulin lysis time (ELT).4, 5 A shortened ELT indicates increased plasminogen activation and hyperfibrinolysis. ɛ-aminocaproic acid (EACA), an anti-fibrinolytic agent has been used to treat patients with hyperfibrinolysis; however, the data about its benefit and safety are minimal in patients with cirrhosis. In Rancho Los Amigos Medical Center, patients with decompensated cirrhosis and signs of mucocutaneous bleeding normally have ELT checked. If ELT is shortened, EACA is normally given in order to manage the clinical consequences of hyperfibrinolysis, such as soft-tissue bleeding or haematoma. The objective of the study is to determine the efficacy of EACA and its safety in cirrhotic patients with hyperfibrinolysis.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgement
  9. References

This retrospective study was conducted at the University of Southern California Liver Unit in Rancho Los Amigos Medical Center after approval by the Institutional Review Board. Using a laboratory computer database, patients with abnormal ELT from 1 January 2001 to 30 December 2002 were identified and all patients was included in the study. Abnormal ELT is defined as <120 min. These patients medical records were then reviewed thoroughly and demographic data, clinical diagnosis of liver disease, and ELT were documented. For patients with cirrhosis, the Child-Pugh score on admission was calculated and documented, and for patients with alcoholic hepatitis, the Maddrey score on admission was also calculated and documented. Relevant tests of coagulation, i.e. platelet count, activated partial thromboplastin time (APTT), international normalized ratio (INR), fibrinogen, and D-dimer were recorded. The usage of medications, such as heparin, coumadin, aspirin, non-steroidal anti inflammatory drugs (NSAIDs), vitamin K, and fresh frozen plasma (FFP) were also documented as they may contribute to any bleeding episodes or affect coagulation study. In patients whom EACA treatment was given, the reason for the treatment was searched, and if not clearly indicated in the record any significant bleeding patients suffered is presumed to be the reason. The duration, dosage, route of administration, and side effects of EACA were documented. The clinical progression of every patient was thoroughly reviewed with special attention to the progress of the bleeding, any recurrence, and any new bleeding at different site. The data was then analysed and comparisons between continuous variables were made using Student t-test. Comparison for categorical variables was made using χ2 test. A P-value of <0.05 was considered statistically significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgement
  9. References

There were approximately 1200 admissions to the Liver unit between 1 January 2001 and 30 December 2002 and 60 patients had shortened ELT (<120 min) within this period. The mean age was 49.6 (range: 32–67), and majority were males (73%). All of the patients had cirrhosis; 55 (92%) drank alcohol in excess and 24 of these 55 patients had another coexisting etiology (Table 1). The mean Child-Pugh score calculated from 58 patients (data from two other patients were incomplete) was 12.1 (9–15), and 20 (33%) of the patients had superimposed alcoholic hepatitis with a mean Maddrey score of 62.9 (34–110). These scores indicate severe cirrhosis and severe alcoholic hepatitis. Of the 60 patients, 58 had INR performed, 35 had APTT, 14 had fibrinogen, and nine had D-dimer. The mean INR and APTT was 2.86 (1.1–8) and 48.3 (30–74) respectively. Only one of the 14 patients tested for fibrinogen had a value above 200 and all the patients tested for D-dimer had abnormal values. There were 59 patients with available platelet counts and only two had platelet counts above 150.

Table 1.  Clinical diagnosis of liver disease
Clinical diagnosisNumber of patients (%)
Alcoholic and hepatitis C cirrhosis19 (31.7)
Alcoholic cirrhosis and alcoholic hepatitis17 (28.3)
Alcoholic cirrhosis only14 (23.3)
Alcoholic and hepatitis C cirrhosis with alcoholic hepatitis3 (5)
Alcoholic and hepatitis B cirrhosis2 (3.3)
Cryptogenic cirrhosis2 (3.6)
Hepatitis C cirrhosis1 (1.7)
Non-alcoholic fatty liver cirrhosis1 (1.7)
Drug-induced cirrhosis1 (1.7)

The mean ELT was 60.4 min (15–105). Fifty-two (87%) patients received EACA. The majority (77%) were given 1 g EACA four times a day orally with 60% of them received a loading dose which is normally 4 or 5 g orally. The mean duration of use was 13.4 days but 18 (35%) patients were discharged home on EACA. Of the 52 patients, 37 (71%) received EACA because they had one or more bleeding episodes with subcutaneous or soft tissue bleeding as the most common type. The other 15 patients (29%) had no signs of bleeding but EACA was given because of a very low ELT, decreasing haemoglobin, or prior to an operation/invasive procedure. Table 2 lists the complete indications. Eight (13%) patients did not receive EACA and all of them had no bleeding episode.

Table 2.  Indication for ɛ-aminocaproic acid use and its frequency
IndicationNumber of patients (%)
  1. Total percentage is >100% as two patients have more than one indication.

Subcutaneous/soft tissue bleeding23 (44.2)
Mucosal bleeding6 (11.5)
Haemoperitoneum3 (5.8)
Oesophageal variceal bleeding3 (5.8)
Oesophageal ulcer1 (1.9)
Rectal abscess1 (1.9)
Unidentified lower gastrointestinal bleeding1 (1.9)
Brain haemorrhage1 (1.9)
Low euglobulin lysis time without bleeding9 (17.3)
Given prophylactically prior to an operation/invasive procedures4 (7.7)
Decreasing haemoglobin count without obvious sign of bleeding2 (3.8)

There were no significant differences between patients who had bled compared with those who had no bleeding prior to EACA treatment relative to age, gender, Child-Pugh score, Maddrey score, platelets, INR, and APTT. However, patients who had bleeding had a significantly shortened ELT compared with patients who had no bleeding (Table 3). Comparison was not made for fibrinogen and D-dimer as there was limited data. None of the patients received medications which may contribute to bleeding, such as heparin, coumadin, aspirin, and NSAIDs as the use of these medications in patients with liver disease is strictly restricted in our institution. Thirty-four (57%) of all patients, including 20 (54%) of the 37 patients who had bleeding episode received vitamin K or FFP or both, mostly for increased INR. However, only in one patient who received vitamin K injection had improvement in INR abnormality and hence may contribute to bleeding resolution and only two had multiple infusions of FFP for many days, which may account for improvement of subcutaneous bleeding in the patients.

Table 3.  Comparisons between patients who had bleeding and who had none prior to ɛ-aminocaproic acid treatment
 Patients who had bleeding (n = 37)Patients who had no bleeding (n = 23)
  1. ELT, euglobulin lysis time; APTT, activated partial thromboplastin time; INR, international normalized ratio.

  2. P < 0.05.

Mean age49.2 (34–66)49.7 (32–67)
Gender (M:F) (%)25 (67.6): 12 (32.4)19 (82.6): 4 (17.4)
ELT (mean ± s.d.)52.4 ± 25.6 (15–110)73.2 ± 27.6 (20–105)*
Child-Pugh score12.3 ± 2.2 (8–15)11.9 ± 1.9 (8–15)
Maddrey score61.6 ± 27.4 (35–110)66.6 ± 21.0 (34–88)
Platelet72.1 ± 36.3 (1–150)85.5 ± 51.3 (16–260)
INR2.6 ± 1.2 (1.4–8)3.3 ± 2.4 (1.1–8)
APTT51.1 ± 12.2 (30–70)45.8 ± 10.7 (34–74)

In patients who received EACA for bleeding

Of 37 patients who had bled and received EACA, 34 (92%) had improvement or resolution of their bleeding, two patients (5%) showed no improvement (one with brain haematoma and one with subcutaneous bleeding) and in one patient (3%) the efficacy of EACA cannot be assessed as the patient died within 24 h of initiation of treatment because of liver failure. In the patient who had persistent subcutaneous bleeding, an ELT was repeated and demonstrated only slight improvement (from 20 to 35 min) on EACA. Subsequently the dose of EACA was increased but the patient was transferred to another hospital for liver transplantation before its efficacy can be assessed. Three (8%) patients in this group had new bleeding, one with intracerebral haemorrhage after a fall, one had blood oozing from decubitus ulcers with INR 8.3, which improved after FFP infusion, and one had gum bleeding for 1 day. These three patients initially received EACA for subcutaneous bleeding.

In patients who received EACA for non-bleeding reason

Of the 15 patients who received EACA but had no bleeding, 14 (94%) continued to do well without a bleeding episode while on EACA and one (7%) had melena. The patient who had melena had INR of 4.1 and the source of the bleeding in this patient was not identified because of the patient's grave condition. The patient later died from liver failure complications and infective endocarditis. One patient from this group underwent an amputation and two had extensive dental procedures without experiencing excessive bleeding. The eight patients with abnormal ELT who did not receive EACA also remained well without a bleeding episode.

Sixteen patients had EACA discontinued during hospitalization after resolution of their bleeding and 7 (44%) of the 16 had new bleeding. Sixteen of the 52 patients who received EACA had an ELT repeated while on treatment, 10 (63%) normalized the ELT, three (19%) had improved ELT, and three (19%) did not show any improvement. Nine patients had an ELT repeated after treatment was discontinued. Six (67%) of the nine had recurrent abnormal ELT and the other three (22%) had normal ELT but the test was performed in two within 48 h (EACA could continue its effect during this time). Only two (4%) patients had EACA discontinued because of minor side effects, rash and lightheadedness. There were no thromboembolic complications of treatment.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgement
  9. References

There are several reasons why hyperfibrinolysis often occurs in patients with cirrhosis. First, concentration of tissue plasminogen activator (t-PA) has been found to be increased in cirrhotic patients likely because of reduced hepatic clearance of which subsequently results in increased conversion of plasminogen to plasmin leading to increased fibrin breakdown.6–8 Second, a reduced concentration of α-2 antiplasmin, which inhibits plasmin activity, has also been noted in patients with cirrhosis.9, 10 Third, deficiency of thrombin activatable fibrinolysis inhibitor (TAFI) has been noted in cirrhotic patients as well.10, 11 TAFI is synthesized by liver and upon activation is converted to an enzyme, TAFIa, which then inhibits fibrinolysis.11–13

Our study demonstrated that hyperfibrinolysis occurs more in patients with severe liver disease, which is in agreement with a previous study from our institution and other studies.1–2, 14–15 Patients with liver disease have decreased synthesis of procoagulation factors, as reflected in abnormal INR, related to the severity of liver damage.6 Therefore, patients with severe liver disease are more prone to have bleeding6 and have worse prognosis when bleeding occurs.6, 16 As expected, most of the bleeding is mucocutaneous bleeding or haematoma. But six of 37 (9%) had gastrointestinal bleeding. Two other studies have demonstrated that hyperfibrinolysis increased gastrointestinal bleeding in patients with cirrhosis.2, 17 Therefore, a treatment for hyperfibrinolysis can play an important role in patients with cirrhosis.

ɛ-aminocaproic acid is a synthetic derivative of the amino acid lysine, which has antifibrinolytic activity.18 It binds reversibly to lysine-binding site of plasminogen and subsequently blocks the binding of plasminogen to fibrin and hence preventing fibrin breakdown.18 It has been used for many bleeding conditions and its therapeutic value has been thought to be effective in excessive bleeding after dental extraction in patients with coagulation disorders and excessive bleeding associated with thrombocytopenia.18 It has also been used in patients undergoing cardiopulmonary bypass in cardiac surgery. Hyperfibrinolysis can occur during and after the surgery and it contributes greatly to excessive bleeding.19, 20 EACA reduces the amount of blood loss during this kind of surgery21–24 and EACA was found to be the least costly therapy based on medication costs and transfusion requirement when compared with other antifibrinolytic agents, such as aprotinin and tranexamic acid.24–26 Patients undergoing orthotopic liver transplantation can also suffer excessive bleeding because of intraoperative hyperfibrinolysis in addition to preexisting coagulopathy and possibly hyperfibrinolysis because of cirrhosis.19, 27 EACA use in orthotopic liver transplantation has also been shown to be effective for treatment of fibrinolysis.28

In our study, EACA was also found to be effective for treatment of hyperfibrinolysis in patients with cirrhosis. The majority of the patients (92%) had improvement and resolution of their bleeding on EACA. Moreover, majority of the patients tested had improvement or normalization of their ELT on EACA. Upon discontinuation of EACA, almost half had recurrent bleeding and most had their ELT become abnormal again. Our data also lend further evidence that EACA is safe. Although there have been several case reports of thromboembolic complications with EACA29–31 however, this was not found in our study and another study involving patients with liver disease.28 Moreover, EACA was found to be tolerable with only small minority (4%) had minor side effects in the study. However, occult thrombotic disease could have been present as a systematic search, such as using imaging for deep venous thrombosis, was not performed. The optimal EACA dose for prolonged hyperfibrinolysis, such as in cirrhosis, has not been identified. A loading dose of 4–5 g of EACA, followed by 1 g EACA every 1 h until bleeding stop has been advised for transient hyperfibrinolysis, such as after cardiac bypass, based on in vitro study.32 This regimen is not practical and seems unnecessary for hyperfibrinolysis treatment in cirrhosis without active major bleeding. The dose of 1 g EACA every 6 h with or without a loading dose is effective most of the time in our study; however, it may be prudent to repeat ELT especially in patients who do not show any improvement.

The optimal duration of EACA in patients with cirrhosis is not known. Even though, some patients in our study had recurrent bleeding after discontinuation of EACA, it may seem useful to continue EACA for the duration of hospitalization or until the first follow-up outpatient visit; however, it may not be cost-effective to continue these patients on EACA for longer term nor necessary. A repeat ELT and severity of liver disease can be used to help the decision. Moreover, the safety of long-term use of EACA is unknown. Finally, as our study is a retrospective study, the efficacy of EACA in managing clinical consequences of hyperfibrinolysis in patients with cirrhosis needs to be confirmed in a prospective randomized controlled trial.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgement
  9. References

Hyperfibrinolysis correlates with severity of liver disease. Patients who develop mucocutaneous bleeding or haematoma, may have hyperfibrinolysis and should have an ELT performed. Once hyperfibrinolysis is diagnosed, EACA can be an effective and safe treatment. However, the efficacy of EACA needs to be confirmed in a prospective randomized controlled trial, and additional study is also needed to look at the optimal duration and safety of long-term use of EACA.

Acknowledgement

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgement
  9. References

No external financial support was received for this study.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgement
  9. References
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