SEARCH

SEARCH BY CITATION

Keywords:

  • epsilon aminocaproic acid;
  • antifibrinolytic agent;
  • thrombocytopenia;
  • bleeding;
  • hematologic malignancies

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

BACKGROUND

Despite prophylactic platelet transfusions, bleeding remains a significant problem in thrombocytopenic patients.

METHODS

The antifibrinolytic agent epsilon aminocaproic acid (EACA) was administered to 44 chronically (median duration, 273 days) and severely (platelet count, 8 × 109/L; range, 1 × 109/L- 19 × 109/L) thrombocytopenic patients with hematological malignancies. Prophylactic EACA at a dose of 1 g twice daily was orally administered for a median duration of 47 days (range, 7 days-209 days) until the platelet count recovered to > 30; × 109/L. Platelets were only transfused if bleeding occurred.

RESULTS

While receiving EACA, 59% of the patients did not bleed, 25% had 19 episodes of spontaneously resolving minor bleeding that did not require platelet transfusion, and 16% received a median of 4 platelet transfusions (range, 1 transfusion-8 transfusions) for 1 major traumatic and 9 spontaneous grade 2 to grade 3 bleeding (based on the World Health Organization classification of idiopathic thrombocytopenic purpura). No EACA toxicities were noted, and venous thromboses were not observed.

CONCLUSIONS

EACA is well tolerated and is associated with a low risk of major bleeding in patients with hematological malignancies who are experiencing chronic severe thrombocytopenia. Cancer 2013;119:3784–3787. © 2013 American Cancer Society.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Thrombocytopenia is frequently chronic, severe, and refractory to platelet transfusion in patients with bone marrow failure syndromes and hematological malignancies.[1] Despite prophylactic allogeneic platelet transfusion, maintaining platelet counts within a safe range is often difficult in this patient population, and bleeding complications occur in approximately 20% of patients with acute myeloid leukemia and in up to 58% of hematopoietic stem cell transplant recipients.[2-5] Epsilon aminocaproic acid (EACA) is an orally bioavailable and well-tolerated antifibrinolytic agent that reduces mucosal bleeding associated with fibrinolysis, platelet dysfunction, Von Willebrand disease, and hemophilia.[6, 7] EACA was also associated with a reduction of bleeding in thrombocytopenic hemorrhage in patients with cancer and hematological disorders.[8, 9] In the current study, we administered EACA as a substitute for prophylactic platelet transfusion in 44 transfusion-dependent, severely thrombocytopenic patients with hematological malignancies and nonmalignant disorders and report our experience.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Patients with chronic, transfusion-dependent thrombocytopenia who received prophylactic EACA in the outpatient setting between January 2005 and December 2011 were identified through a computerized database search. After the initiation of EACA, prophylactic threshold-driven platelet transfusion was discontinued and patients received only therapeutic platelet transfusion in case of bleeding, except when a patient was admitted to the inpatient unit. In the inpatient unit, prophylactic platelets were routinely infused when the platelet count was < 10 × 109/L. The number of platelets transfused in the hospital in the absence of bleeding was censored. Patient demographics, diagnosis, treatment, platelet counts, duration of thrombocytopenia, transfusion history, bleeding, and outcomes were captured onto study-specific case report forms. Bleeding was captured regardless of the patient's location (outpatient or hospital unit) and retrospectively scored based on the World Health Organization classification of idiopathic thrombocytopenic purpura: grade 1 indicated petechial bleeding; grade 2 indicated clinically mild blood loss; grade 3 indicated macroscopic blood loss requiring transfusion; and grade 4 indicated retinal, cerebral, or debilitating blood loss. Statistics were descriptive. This retrospective analysis was approved by the Emory University Institutional Review Board.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Characteristics of the 44 patients who received EACA are summarized in Table 1. Approximately 96% of the patients had a hematological malignancy and 2 had a nonmalignant hematological disorder (chronic immune thrombocytopenia and aplastic anemia, respectively). The median age of the patients was 61 years (range, 17 years-82 years). The median platelet count at the time of initiation of EACA was 8 × 109/L (range, 1 × 109/L-19 × 109/L). Before the initiation of EACA, the median duration of thrombocytopenia was 273 days (range, 20 days-1463 days) and patients were transfused 2 to 3 times a week in either the outpatient setting at the study institution or at the referring physician's office, when the platelet count was < 20 × 109/L. The median number of outpatient single-donor platelet units transfused at the study institution for these 44 patients was 78 (range, 7 units-418 units). Thirty patients (68%) had a median of 4 hospitalizations (range, 1 hospitalization-12 hospitalizations) of a median duration of 12 days (range, 4 days-23 days) during the course of treatment with EACA mainly for chemotherapy, but also for the management of neutropenic fever. Approximately 71% had recurrent/refractory disease, whereas 29% of patients had a stable disease or were actively receiving chemotherapy at the time EACA was administered. Ten patients (23%) were refractory to platelet transfusions and had platelet counts continuously < 10 × 109/L.

Table 1. Characteristics of 44 Thrombocytopenic Patients Who Received EACA for the Prevention of Bleeding
CharacteristicNo.
  1. Abbreviations: ALL, acute lymphoblastic leukemia; AML: acute myeloid leukemia; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; CNS, central nervous system; EACA, epsilon aminocaproic acid; ITP, immune thrombocytopenic purpura; MDS, myelodysplastic syndrome.

  2. a

    Traumatic brain injury in a car accident.

  3. b

    One patient had 2 episodes of hematuria.

Median age (range), y61 (17-82)
Male/female ratio29/15
Median platelet counts ×109/L at initiation of EACA (range)8 (1-19)
Patients with platelet refractoriness, no.10 (23%)
Median duration of thrombocytopenia (range), d273 (20-1463)
Diagnosis, no. 
CML9 (21%)
AML14 (32%)
ALL1 (2%)
MDS15 (45%)
CLL1 (2%)
ITP1 (2%)
Lymphoma1 (2%)
Aplastic anemia1 (2%)
Myelofibrosis1 (2%)
Disease status of patients at the time of initiation of EACA 
Active treatment, no.13 (30%)
Recurrent/refractory, no.31 (70%)
Median duration of EACA therapy (range), d47 (7-209)
Patients without bleeding on EACA, no.26 (59%)
Patients with bleeding episodes while receiving EACA, no.18 (41%)
Patients requiring platelet transfusions for bleeds, no.7 (16%)
Grade and location of the 10 bleeding episodes requiring platelet transfusions 
Grade 4: CNSa1
Grade 3: rectal1
Grade 2: hemorrhoids1
Grade 2: hematuriab2
Grade 2: epistaxis1
Grade 2: oral3
Grade 2: vaginal1
Grade and location of the 19 bleeding episodes not requiring platelet transfusions 
Grade 1: epistaxis7
Grade 1: skin bruises4
Grade 1: gingival bleed2
Grade 1: vaginal1
Grade 2: gingival2
Grade 2: vaginal1
Grade 2: epistaxis2
Reason for discontinuing EACA, no. 
Death25 (57%)
Increased platelet count18 (41%)
Hematuria1 (2%)

EACA was prescribed at an oral dose of 1 g twice daily until the sustained, untransfused platelet count was > 30 × 109/L. EACA was not administered to reduce bleeding in these thrombocytopenic patients, but rather was given as an alternative to prophylactic platelet transfusions that were previously administered 2 to 3 times per week. The median duration of the administration of EACA was 47 days (range, 7 days-209 days). Patients were monitored in the outpatient clinic, with a complete blood count obtained at least once a week. While receiving EACA, 7 of the 44 patients (16%) received a median of 4 platelet transfusions (range, 1 transfusion-8 transfusions) to treat 10 bleeding episodes. The median score for these 10 bleeding episodes was 2 (range, 2-4), with 1 patient experiencing a traumatic intracranial hemorrhage secondary to a motor vehicle accident (grade 4) and 1 patient suffering an episode of grade 3 hematochezia from a preexisting rectal ulcer. The other 5 patients experienced 8 mucocutaneous bleeding episodes of grade 2 (hemorrhoid, epistaxis, oral, bladder, and vaginal). Eleven patients (25%) experienced 19 episodes of minor mucocutaneous bleeding (epistaxis, bruises, oral, and vaginal) that resolved spontaneously and did not require platelet transfusions. The median bleeding score for these 19 events was 1 (range, 1-2). It is interesting to note that only 4 of the 10 platelet-refractory patients experienced bleeding episodes that were mucocutaneous (3 episodes of grade 1, 5 episodes of grade 2, and 1 episode of grade 3 bleeding).

EACA was generally well tolerated and no patients discontinued treatment because of intolerance. One patient discontinued EACA due to the onset of hematuria (2%), 18 (41%) due to platelet recovery, and 25 (57%) discontinued EACA due to referral to hospice or death. No patient experienced a venous thromboembolic event or other unexpected events attributable to EACA. No patient died of a bleeding event while receiving EACA.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

In the absence of an intervention that increases platelet production or accelerates platelet recovery, recurrent platelet transfusions remain the only option for patients with severe chronic thrombocytopenia associated with hematological malignancies. This approach necessitates frequent visits to the medical center, is hampered by platelet shortages, and ultimately often leads to alloimmunization and platelet refractoriness.[10] In addition, this approach is ineffective in preventing significant bleeding episodes in 20% to 50% of patients.[3] Based on the mechanism of action of EACA and the effectiveness of this agent in preventing hemorrhages in patients with congenital bleeding disorders,[7] EACA was administered to patients with transfusion-dependent chronic and refractory severe thrombocytopenia. Patients were managed in the outpatient setting despite their severe thrombocytopenia and received EACA as a substitute for prophylactic, threshold-directed platelet transfusion. In our experience, patients reported the rapid disappearance of petechiae and resolution of subcutaneous bleeding shortly after the initiation of EACA. With a median duration of EACA administration of 47 days, but ranging up to 209 days, no major spontaneous bleeding episodes were observed in these patients, whose median platelet counts were 8 × 109/L and for whom no prophylactic platelet transfusions were administered. Two grade 3 to grade 4 bleeding episodes occurred in the setting of a trauma and from a preexisting condition, respectively. Only 16% of the patients received platelet transfusions (median of 4 units) for all but one minor spontaneous bleeding episodes.

The dose of EACA selected for chronic administration (1 g administered twice daily) was based on the dosing schedule commonly used in patients with bleeding disorders, and differs from the package insert that provides dose recommendations for the treatment of acute bleeding episodes. To our knowledge, there are no recommended doses for the chronic administration of EACA. All patients tolerated this empiric dose of EACA and no cases of venous thrombosis were observed.

To the best of our knowledge, the current study is the first to report on the use of an antifibrinolytic for the prevention of thrombocytopenic bleeding. It is possible that patients with stable chronic thrombocytopenia previously managed with platelet transfusion in the outpatient setting may very well represent a selected group of individuals who benefit from prophylaxis with EACA. However, a better understanding of these and other selection biases and the effects of EACA on quality of life are addressed in a currently ongoing randomized phase 2 trial comparing prophylactic EACA with platelet transfusions.

We conclude that EACA is well tolerated and is associated with a low risk of major spontaneous bleeding in patients with hematological disorders who are experiencing severe and refractory thrombocytopenia and not receiving prophylactic platelet transfusion. If this approach is not inferior to platelet transfusion, then the use of antifibrinolytic agents may open the door for the use of newer prophylactic strategies in this patient population.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES