Epsilon-aminocaproic Acid Therapy Research Articles

Epsilon Aminocaproic Acid Pretreatment Provides Neuroprotection Following Surgically Induced Brain Injury in a Rat Model.

Neurosurgical procedures can damage viable brain tissue unintentionally by a wide range of mechanisms. This surgically induced brain injury (SBI) can be a result of direct incision, electrocauterization, or tissue retraction. Plasmin, a serine protease that dissolves fibrin blood clots, has been shown to enhance cerebral edema and hemorrhage accumulation in the brain through disruption of the blood brain barrier. Epsilon aminocaproic acid (EAA), a recognized antifibrinolytic lysine analogue, can reduce the levels of active plasmin and, in doing so, potentially can preserve the neurovascular unit of the brain. We investigated the role of EAA as a pretreatment neuroprotective modality in a SBI rat model, hypothesizing that EAA therapy would protect brain tissue integrity, translating into preserved neurobehavioral function. Male Sprague-Dawley rats were randomly assigned to one of four groups: sham (n = 7), SBI (n = 7), SBI with low-dose EAA, 150 mg/kg (n = 7), and SBI with high-dose EAA, 450 mg/kg (n = 7). SBI was induced by partial right frontal lobe resection through a frontal craniotomy. Postoperative assessment at 24 h included neurobehavioral testing and measurement of brain water content. Results at 24 h showed both low- and high-dose EAA reduced brain water content and improved neurobehavioral function compared with the SBI groups. This suggests that EAA may be a useful pretherapeutic modality for SBI. Further studies are needed to clarify optimal therapeutic dosing and to identify mechanisms of neuroprotection in rat SBI models.

8. Hereditary angioedema

Hereditary angioedema is an episodic swelling disorder with autosomal dominant inheritance. Attacks are characterized by brawny, self-limited, nonpruritic edema of the deep dermal layers of the skin that most often involve the hands and feet. They usually begin in childhood and become more severe after puberty. Patients also have episodic attacks of severe abdominal pain caused by edema of the gastrointestinal mucosa. Swelling attacks are life threatening when they involve the airway. Estrogens exacerbate attacks, and in some patients attacks are precipitated by trauma or psychologic stress. The disease is caused by a mutation in one of the 2 copies of the gene for the plasma protein C1 inhibitor, with the product of 1 gene unable to control generation of bradykinin. Eighty-five percent of patients have low antigenic levels of C1 inhibitor, and 15% have normal levels of poorly functioning protein. Most patients have decreased plasma complement protein C4 levels. Impeded androgens and, less frequently, epsilon-aminocaproic acid are currently the mainstays of chronic treatment. These agents or fresh frozen plasma are also used for prophylaxis. At this time, acute therapy is mostly supportive. There are currently ongoing multiple trials of new therapeutic agents. In half a century, a life-threatening disease has become one that is manageable and rarely causes death.

Efficacy of serum therapy on the treatment of rats experimentally envenomed by bristle extract of the caterpillar Lonomia obliqua: Comparison with epsilon-aminocaproic acid therapy

Large number of accidents caused by contact with Lonomia obliqua caterpillars, with hemorrhagic complications, have occurred in southern Brazil. Based on Venezuelan expertise to treat Lonomia achelous envenomation, the use of the antifibrinolytic drug epsilon-aminocaproic acid (EACA) has been indicated to treat L. obliqua envenomation, although no evidence has been presented to justify its use. Specific antivenom (antilonomic serum (ALS)) that neutralizes toxins that cause envenomation was developed. To compare the effectiveness of such treatments, rats were injected i.d. with the bristle extract of L. obliqua caterpillars and treated 15 min, 1 and 6 h after with saline, ALS, EACA, or with both ALS and EACA. ALS elicited fibrinogen recovery and normalization of thrombin time (TT), prothrombin time (PT) and activated partial thromboplastin time (APTT), independent of when it was administered; however, hematocrit was decreased in the group treated later. Saline or EACA-treated groups presented neither fibrinogen recovery nor normalization of hemostatic parameters. A high death rate was observed in the group treated with EACA 15 min after the envenomation. Prolongation of TT and APTT observed in the group treated with EACA and ALS indicated that this association gave no benefit in relation to the group treated solely with ALS. The results presented herein suggest that ALS is the only effective treatment for envenomation caused by contact with Lonomia obliqua caterpillars and indicate that EACA should not be administered in the initial phase of envenomation.

Ischemic Colitis Associated with Epsilon-Aminocaproic Acid Therapy

Ischemic Colitis Associated with Epsilon-Aminocaproic Acid Therapy

Quantitative assessment of fibrinogen cross-linking by epsilon aminocaproic acid in patients with end-stage liver disease.

Analysis of the effectiveness of antifibrinolytic therapy for liver transplant recipients is hampered by lack of quantitative assays for assessing drug effects. We adapted chemical engineering tools used in polymerization studies to quantify fibrinogen cross-linking by plasma from liver transplant patients obtained before and after epsilon aminocaproic acid (EACA) therapy. A target fluorescein isothiocyanate-fibrinogen (FITC-fibrinogen) molecule was constructed; it fluoresces in a quantifiable pattern when in solution, and undergoes cross-linking in the presence of plasmin inhibitors. Cross-linking quenches the fluorescent signal, and the quenching is a quantifiable endpoint. Thus fluorescence from this reporter molecule can be used to assess functional improvement in fibrinogen cross-linking as a result of antifibrinolytic therapies, and it is sensitive to picomolar amounts of plasmin inhibitors and activators. Cross-linking of FITC-fibrinogen by patient plasma, before and after EACA therapy, was assessed using fluorescence spectrometry. Fluorescence patterns from FITC-fibrinogen indicated no significant cross-linking of the target fibrinogen as a consequence of EACA in posttreatment plasma. When the fibrinogen-FITC target was assayed without plasma in the presence of EACA at concentrations that bracket therapeutic levels (100 and 400 microg/ml), significant fluorescence quenching (target FITC-fibrinogen cross-linking) was achieved. These results suggest that fibrinogen-FITC fluorescence is sensitive enough to detect EACA activity in clinically relevant ranges, but that EACA given in usual doses is insufficient to promote fibrinogen cross-linking in patients with end-stage liver disease.

Plasma proteinase inhibitor activity and hemostasis tests in children with nephrotic syndrome. Effect of prednisone alone and prednisone plus epsilon-aminocaproic acid treatment regimens: a preliminary report.

Neutrophil-derived proteinases cause glomerular injury by proteolysis of the glomerular basement membrane and alterations in glomerular metabolism. Recently, a marked elevation of the plasma elastase complex with alpha1-proteinase inhibitor (alpha 1-PI) both in the acute phase and during remission of nephrotic syndrome (NS) compared with age-matched controls was reported. In experimental immune-mediated glomerulonephritis epsilon-aminocaproic acid (EACA) significantly reduced albuminuria, and it was suggested that this may be linked with the antiproteolytic activity of the drug. We studied plasma antithrombin III (AT-III), alpha 1-PI, alpha 2-antiplasmin (alpha 2-A), alpha 2-macroglobulin (alpha 2-M) activity, and some blood coagulation and fibrinolysis tests in children with frequently relapsing prednisone-responsive NS. Also, the effect of prednisone alone (Group I, n = 9) and prednisone plus EACA (Group II, n = 10) treatment regimens on the studied parameters was estimated. All investigations were performed on admission to the hospital and after approximately 13 days of prednisone alone therapy (Group I), as well as before the administration of prednisone plus EACA and 24 hours after the last dose of EACA, ie, after approximately 5 days of treatment (Group II). Prednisone was administered at the usual dose of approximately 2 mg/kg/d and EACA was given orally at the doses of 72 to 230 mg/kg of body weight per day for 3 to 10 days. In the acute phase of disease, NS patients (n = 19) were shown to have a statistically significant decrease of plasma AT-III (16.4 +/- 4.7 vs. 21.9 +/- 2.5 IU/mL) and alpha 1-PI (1.28 +/- 0.6 vs. 1.97 +/- 0.34 IU/mL) activity, as well as a marked increase in plasma alpha 2-M activity (14.96 +/- 5.81 vs. 9.6 +/- 1.6 IU/mL), and fibrinogen concentration (5.51 +/- 1.78 vs. 2.96 +/- 0.34 g/L) compared to the age-matched controls; no significant changes in plasma alpha 2-A activity, plasminogen concentration, euglobulin clot lysis time, activated partial thromboplastin time (APTT), or thromboplastin time were noted. In children treated with prednisone alone, a marked increase in plasma AT-III (by 76%, P < 0.001) and alpha 2-A (36%, P < 0.019) activity, and a significant decrease of the plasma fibrinogen concentration (6.07 +/- 1.66 vs. 3.17 +/- 1.64 g/L, P < 0.001), and APTT (45.1 +/- 7.6 vs. 33.8 +/- 4.4 s, P < 0.001) were found. Prednisone plus EACA therapy resulted in a significant increase in plasma AT-III activity (by 53%, P < 0.003), whereas plasma fibrinogen concentration and APTT remained unchanged. However, statistically significant differences between the pre- and posttreatment plasma AT-III, alpha 1-PI, and alpha 2-A activities in these patients were observed. There was also a relationship between EACA dose and the percentage change in plasma alpha 2-A activity. In a few patients receiving prednisone plus EACA regimen, side effects that included purulent rhinitis, pharyngitis, increases in body temperature, loose stools, and an approximately 20% to 30% decrease in systolic and diastolic arterial blood pressure were observed. Thus, although the prednisone plus EACA treatment regimen seems to offer new therapeutic possibilities in some patients with NS, it should not be used in acute phase of the disease.

Adjuvant use of e-aminocaproic acid (Amicar) in the endovascular treatment of cranial arteriovenous fistulae

We report our experience with the use of the antifibrinolytic agent epsilon-aminocaproic acid (EACA), Amicar, as an adjuvant to endovascular treatment of cranial arteriovenous fistulae. We also review applications of antifibrinolytic agents to neurovascular disorders and discuss the mechanism of action, dosing strategy, contraindications, and possible complications associated with the use of EACA. We identified 13 patients with cranial arteriovenous fistulae (five direct carotid cavernous fistulae [CCF], seven dural arteriovenous fistulae [DAVF], and one vein of Galen malformation) who received EACA as an adjunct to endovascular treatment. In all cases embolic coils were the primary embolic agent. We reviewed the modes of initial endovascular therapy and angiographic findings immediately thereafter and the response to EACA. Two direct CCF and two DAVF were completely thrombosed on follow-up angiography, and two DAVF demonstrated diminished flow after EACA therapy. Seven fistulae did not respond to EACA. Four of eight tightly coiled fistulae thrombosed, while none of five loosely coiled fistulae thrombosed. None of four cases with a residual fistula separate from the coil mass underwent thrombosis with EACA, while four of nine cases without a separate fistula thrombosed. There was no morbidity related to EACA therapy. EACA may thus be useful as an adjunct to endovascular treatment of cranial arteriovenous fistulae. Loose or incomplete coil packing of the fistula predicts a poor response to EACA therapy.

OBSTRUCTION OF THE RENAL PELVIS DUE TO AN INSOLUBLE BLOOD CLOT AFTER EPSILON-AMINOCAPROIC ACID THERAPY: RESOLUTION WITH INTRAURETERAL STREPTOKINASE INSTILLATIONS

Purpose We demonstrate the effectiveness of intraureteral streptokinase instillations for the resolution of an insoluble blood clot in the renal pelvis. Materials and Methods A patient with renal adenocarcinoma had prolonged hematuria related to involvement of the “pyelum” by the tumor. An insoluble blood clot obstruction of the left renal collecting system developed as a consequence of epsilon aminocaproic acid therapy, which was treated with low dose streptokinase through a ureteral catheter. Results Complete resolution of the clot and obstruction occurred within 3 days of therapy. Conclusions This relatively simple approach should be used for the treatment of obstruction before radical surgery is performed.

Reducing the risk of rebleeding before early aneurysm surgery: a possible role for antifibrinolytic therapy.

Previous studies on the initial nonoperative management of aneurysmal subarachnoid hemorrhage (SAH) demonstrated that antifibrinolytic therapy reduced the risk of rebleeding by approximately 50%; however, prolonged antifibrinolytic treatment was associated with an increase in the incidence of hydrocephalus and delayed ischemic deficit. When early surgical intervention became routine for ruptured aneurysms, the use of antifibrinolytic therapy diminished. However, early surgery is generally performed in the first several days after SAH and the risk of rebleeding remains until the aneurysm is obliterated. Based on a review of the literature, the authors formed two hypotheses: 1) the high-dose intravenous administration of epsilon-aminocaproic acid (EACA), an antifibrinolytic agent, might reduce the risk of recurrent hemorrhage in the interval between SAH and early surgical intervention, and 2) a short course of EACA might not produce the increase in complications previously associated with its prolonged administration. The use of preoperative high-dose EACA therapy was evaluated in 307 patients to determine its safety and efficacy in reducing the incidence of rebleeding before early aneurysm surgery. All patients were admitted within 3 days of their SAH and were classified as Hunt and Hess Grades I to III. Only four patients (1.3%) suffered a recurrent hemorrhage. This compares favorably to the rebleeding rate of 5.7% reported for the early surgery group in the International Cooperative Study on the Timing of Aneurysm Surgery. The incidence of hydrocephalus or symptomatic vasospasm was not unduly elevated in patients receiving preoperative EACA. Thirty-five patients (11.4%) needed temporary cerebrospinal fluid drainage during their hospitalization and, overall, 8.8% required a ventriculoperitoneal shunt. The mean age of the patients who required a shunt was nearly 10 years older than the general study population. Seventy-one patients (23%) developed symptomatic vasospasm and 8.1% suffered a stroke. This study indicates that a brief course of high-dose EACA is safe and may be beneficial in diminishing the risk of rebleeding in good-grade patients prior to early surgical intervention. Further investigation is planned based on these promising results.

Long-Term Treatment of C1 Inhibitor Deficiency With ɛ-Aminocaproic Acid in Two Patients

Most patients who have hereditary angioedema receive treatment with androgens or impeded androgens. epsilon-Aminocaproic acid (EACA) is another treatment for C1 inhibitor deficiency. In two patients with angioedema and attacks of abdominal pain due to C1 inhibitor deficiency, long-term treatment with EACA (for more than 2 decades in one of them) was associated with a substantial decrease in the frequency and severity of episodes. One patient had definite hereditary angioedema, and the other had probable hereditary angioedema but the family history was negative for the disease. The EACA therapy caused no major side effects.

Hemostasis in malignancy

Hemostatic abnormalities are present in a majority of patients with metastatic cancer. These abnormalities can be categorized as 1) increased platelet aggregation and activation, 2) abnormal activation of coagulation cascade, 3) release of plasminogen activator, and 4) decreased hepatic synthesis of anticoagulant proteins like Protein C and antithrombin III. The abnormal activation of coagulation cascade is mediated through release of Tissue Factor, Factor X activators, and other miscellaneous procoagulants from the plasma membrane vesicles of tumor cells. Macrophages of a tumor-bearing host also produce increased amounts of Tissue Factor. Production of Factor X activators and macrophage Tissue Factor is decreased by warfarin. The ability of the tumor cells to produce platelet-aggregating activity and plasminogen activator parallels their metastatic potential in animal and experimental systems. These studies also show that antiplatelet agents and antibodies against plasminogen activator can suppress the metastatic process. One or more laboratory abnormalities of hemostasis can be shown in up to 95% of patients with metastatic cancer. These abnormalities, however, are unable to predict subsequent development of thromboembolic or hemorrhagic complications. Clinical complications occur in 9-15% of the patients in the form of thrombotic or hemorrhagic disorders. The therapy of tumor-related coagulopathy should be guided by its clinical expression. Subclinical DIC should not be treated. Coumadin is generally ineffective for therapy of thrombosis in cancer patients. There is no consensus regarding the use of heparin in acute promyelocytic leukemia (APL). The defibrination in APL may be from disseminated intravascular coagulation as well as systemic fibrinolysis, as shown by decreased alpha 2 antiplasmin levels. In such cases, epsilon aminocaproic acid plus heparin therapy may be of benefit.

Cerebral sinus thrombosis as a potential hazard of antifibrinolytic treatment in menorrhagia.

We describe a 42-year-old woman who developed superior sagittal and left transverse sinus thrombosis associated with prolonged epsilon-aminocaproic acid therapy for menorrhagia. This antifibrinolytic agent has been used in women with menorrhagia to promote clotting and reduce blood loss. Although increased risk of thromboembolic disease has been reported during treatment with epsilon-aminocaproic acid, cerebral sinus thrombosis has not been previously described. Careful use of epsilon-aminocaproic acid therapy is recommended.

Intraocular Pressure Increase Associated With Epsilon-Aminocaproic Acid Therapy for Traumatic Hyphema

We treated five patients receiving epsilon-aminocaproic acid who demonstrated sudden and accelerated clot dissolution with accompanying increases in intraocular pressure 24 to 96 hours after discontinuing treatment. All of these patients required additional ocular hypotensive medications and one patient required anterior chamber washout for persistently increased intraocular pressure. These findings suggest that certain patients with hyphema may be at risk for significant intraocular pressure increases following cessation of epsilon-aminocaproic acid therapy.

Quantitative determination of plasma fibrinolytic activity in patients with ruptured intracranial aneurysms who are receiving epsilon-aminocaproic acid: relationship of possible complications of therapy to the degree of fibrinolytic inhibition.

Fifty-two patients were each given a constant infusion of 1.5 g of epsilon-aminocaproic acid (EACA) per hour after subarachnoid hemorrhage (SAH) from an intracranial aneurysm. Each patient's available plasminogen activity (APA), a measure of plasma fibrinolytic activity, was determined by fluorometric assay before and during EACA treatment. Five categories of potential EACA complications were identified: rebleeding, cerebral vasospasm, hydrocephalus, thrombosis, and miscellaneous (bleeding time prolongation, thrombocytopenia). The APA of the 37 patients with complications was significantly higher than that of the 15 without complications. Four patients suffered rebleeding episodes and had significantly higher APA levels during EACA therapy when compared to all other patients, i.e., those with and without other complications. Patients with vasospasm, hydrocephalus, and thrombotic complications also had significantly higher APA levels during EACA therapy compared to patients without complications. The latter may be simply a reflection of the activation of fibrinolytic activity that occurs after SAH. It is apparent from these studies that, after the initiation of EACA treatment, a maximal steady state inhibition of fibrinolytic activity is not achieved for 2 days and, after the cessation of EACA therapy, normal fibrinolytic activity is not restored for a period of 3 to 4 days. In addition, patients with thrombotic events may show persistently low serum plasminogen activity after discontinuance of EACA therapy, probably due to continuing thrombosis and consumption of plasminogen. These results indicate that patients with recurrent preoperative aneurysmal hemorrhage while on EACA therapy may have inadequate fibrinolytic inactivation, and this may be an important factor contributing to rebleeding episodes.(ABSTRACT TRUNCATED AT 250 WORDS)

Successful treatment of skeletal hemangioma and kasabach-merritt syndrome with aminocaproic acid: Is fibrinolysis “defensive”?

A young man presented with a disabling skeletal hemangioma. Fibrinolysis seemed to be a major component of coagulopathy and persisted after steroid therapy and irradiation of the lesions. Three weeks after therapy with epsilon-aminocaproic acid, there was dramatic alleviation of pain and eventual disappearance of laboratory evidence of fibrinolysis. Epsilon-aminocaproic acid therapy was discontinued. The patient remained free from symptoms and coagulopathy. There was evidence of new bone formation nine months later. Fibrinolysis may be a primary or sustaining feature of hemangioma. Epsilon-aminocaproic acid may be beneficial in the treatment of selected patients with these lesions.

A method for monitoring antifibrinolytic therapy in patients with ruptured intracranial aneurysms.

A rapid fluorometric assay technique has been utilized to assess the degree of fibrinolytic inhibition in 20 patients with ruptured intracranial aneurysms treated with epsilon-aminocaproic acid (EACA). This method quantitates the available plasminogen activity (APA) of plasma, and has proven to be a reliable means of monitoring antifibrinolytic therapy. Determination of the plasma APA also permits correlation of the level of fibrinolytic activity with putative complications of EACA therapy. Normal control plasma APA was 3.1 +/- 0.7 CTA units/ml, but in patients with subarachnoid hemorrhage (SAH), pretreatment fibrinolytic activity was supranormal at 3.78 +/- 0.88 CTA units/ml. During continuous intravenous administration of EACA (1.5 gm/hr) in patients with SAH, the plasma fibrinolytic activity was decreased to 0.9 +/- 0.31 CTA units/ml. A case described which examplifies the use of this assay. In addition, an approach to monitoring antifibrinolytic therapy using the plasma APA is proposed.

Lack of functional recovery from spinal cord trauma following dimethyl-sulphoxide and epsilon amino caproic acid therapy in dogs

The spinal cords of 20 normal dogs were exposed via dorsal laminectomies at L1 and damaged with a direct impact force of 440 g cm. One hour later treatment with dimethylsulphoxide (DMSO) was started on 10 dogs and with epsilon amino caproic acid (EACA) on the other 10 dogs. Administration of the DMSO ceased at 41 h after trauma and EACA at 49 h. The results showed that neither drug had a significant beneficial effect on the functional recovery of the spinal cords, when compared to a control group of similarly traumatised dogs.

Recurrent subarachnoid hemorrhage associated with aminocaproic acid therapy and acute renal artery thrombosis

Epsilon aminocaproic acid (EACA) has been used to prevent rebleeding in patients with subarachnoid hemorrhage (SAH). Although this agent does decrease the frequency of rebleeding, several reports have described thrombotic complications of EACA therapy. These complications have included clinical deterioration and intracranial vascular thrombosis in patients with SAH, arteriolar and capillary fibrin thrombi in patients with fibrinolytic syndromes treated with EACA, or other thromboembolic phenomena. Since intravascular fibrin thrombi are often observed in patients with fibrinolytic disorders, EACA should not be implicated in the pathogenesis of fibrin thrombi in patients with disseminated intravascular coagulation or other "consumption coagulopathies." This report describes subtotal infarction of the kidney due to thrombosis of a normal renal artery. This occlusion occurred after EACA therapy in a patient with SAH and histopathological documentation of recurrent SAH. The corresponding clinical event was characterized by marked hypertension and abrupt neurological deterioration.

Ocular Enucleation in a Patient with Severe Classic Hemophilia a

A 27-year-old man with severe classic hemophilia A (antihemophilic globulin level: 1.5% of normal) had blunt trauma to his left eye that produced a corneoscleral laceration with prolapse of the intraocular contents. His left eye was enucleated under management with factor VIII replacement. This consisted of sufficient cryoprecipitate to increase the calculated circulating factor VIII level to 125%, sufficient factor VIII every 12 hours to increase peak postinfusion levels from 100 to 120%, and to maintain minimum levels of 30% immediately before infusion. Because he had developed a gingival hematoma when he was placed on epsilon amino caproic acid after only one day of factor VIII replacement following extraction of mandibular molars, we continued the high level of factor VIII replacement for five days and then began antifibrinolytic epsilon amino caproic acid therapy. His surgical and postoperative course were uneventful on this regimen.

Carcinoma of bladder masked by epsilon aminocaproic acid therapy

Uncontrolled EACA (epsilon aminocaproic acid) therapy for hematuria was responsible for the formation of an insoluble fibrin cast within the bladder. The causefo the bleeding was found to be unsuspected carcinoma of the bladder. Repeated and thorough urologic investigation is mandatory in all instances of continued hematuria, and therapy with EACA is contraindicated unless a specific fibrinolytic defect is proved.