Leave a comment

CHAPTER 136 DISORDERS OF FIBRINOLYSIS AND USE OF ANTIFIBRINOLYTIC AGENTS

CHAPTER 136 DISORDERS OF FIBRINOLYSIS AND USE OF ANTIFIBRINOLYTIC AGENTS
Williams Hematology

CHAPTER 136 DISORDERS OF FIBRINOLYSIS AND USE OF ANTIFIBRINOLYTIC AGENTS

FEDOR BACHMANN

Introduction
Pharmacology of Antifibrinolytic Agents

Mode of Action

Pharmacokinetics

Adverse Effects
Clinical Use of Antifibrinolytic Agents

Systemic Hyperfibrin(ogen)olysis

Localized Fibrinolysis with Abnormal Hemostasis

Localized Fibrinolysis with Normal Hemostasis
Chapter References

Under physiologic conditions the finely tuned mechanism of hemostasis, consisting of pro- and anticoagulant and pro- and antifibrinolytic components assures healing of a vascular lesion and subsequent reestablishment of normal blood flow. Excessive local or systemic fibrinolysis shifts this delicate equilibrium toward premature lysis of hemostatic plugs and bleeding.
Cases of primary, systemic hyperfibrinolysis without activation of the coagulation system are rare. They comprise the hereditary deficiencies of a2-plasmin inhibitor and of the plasminogen activator inhibitor-1, advanced liver disease, and some cases of snake bite. Much more common is systemic hyperfibrinolysis that is secondary to the activation of the coagulation system by procoagulant factors, mainly tissue factor (as in metastatic cancer), or by artificial surfaces (as during cardiopulmonary bypass) or heart assist devices. Localized excessive fibrinolysis occurs frequently; typical examples are menorrhagia and prostatectomy. Three antifibrinolytic agents are commonly used. Aprotinin, a serine protease inhibitor, forms 1:1 stoichiometric complexes with kallikrein and plasmin and has successfully been used to reduce bleeding in cardiac surgery and liver transplantation. Epsilon-aminocaproic acid and tranexamic acid exert their antifibrinolytic effect by interfering competitively with the binding of plasmin to C-terminal lysine residues of fibrin. Both drugs have been successfully used in a wide range of conditions, including acute promyelocytic leukemia, liver transplantation, cardiac surgery, the hemophilias, factor XI deficiency, von Willebrand disease, amyloidosis, prostatectomy, and menorrhagia.

Acronyms and abbreviations that appear in this chapter include: AMCA, trans-p-aminomethyl-cyclohexanecarboxylic acid; CSF, cerebrospinal fluid; DIC, disseminated intravascular coagulation; EACA, e-aminocaproic acid (6-amino-hexanoic acid); KIU, kallikrein inhibitor units; OLT, orthotopic liver transplantation; PA, plasminogen activator; PAI, plasminogen activator inhibitor; SAH, subarachnoid hemorrhage; t-PA, tissue-type plasminogen activator; u-PA, urinary-type plasminogen activator.

INTRODUCTION
Already during the formation of a hemostatic plug biochemical mechanisms are initiated to limit the extent of the hemostatic process and to reestablish normal blood flow. To a large extent this is accomplished by localized activation of the plasminogen-plasmin enzyme system, also called fibrinolytic system. To accomplish healing of a vascular lesion without compromising the stability of the hemostatic plug too early, and to limit the activation of the fibrinolytic system to the injured area, a finely tuned mechanism is necessary, consisting of the tissue-type and of the urinary-type plasminogen activators (t-PA and u-PA, respectively), prekallikrein-kallikrein, and the fibrinolytic inhibitors a2-antiplasmin and PAI-1 (see Chap. 116). The regulation of hemostatic and fibrinolytic processes is dynamic, representing the balance achieved between pro- and antihemostatic and pro- and antifibrinolytic mediators (Fig. 136-1). This dynamic balance can be upset if any of the components are inadequate or excessive. Excessive local or systemic activation of coagulation may result in the development of macrovascular thrombi or consumption coagulopathy. Similarly, excessive local or systemic fibrinolytic activity can result in renewed or sustained bleeding. When hemostasis is delayed as a result of either a platelet disorder or a coagulation defect, a bleeding episode may be prolonged or renewed because of the imbalance created between an abnormally slow hemostatic rate and a normal rate of fibrinolysis. For example, bleeding in a hemophilic patient following an injury may cease spontaneously but recur 24 to 48 h later, presumably as the weakened plug is dissolved by a normal fibrinolytic response. In other circumstances hemostasis is normal, but excessive local fibrinolysis may give rise to excessive bleeding, as in primary menorrhagia.1

FIGURE 136-1 Disruption of the balance between the opposing forces of fibrinolysis and antifibrinolysis, leading to bleeding or thrombotic manifestations. Bleeding may result from defective inhibition or excessive activation of fibrinolysis. Conversely, defective activation or excess inhibition of fibrinolysis may result in thrombosis. Therapy with fibrinolytic agents may dissolve a thrombus, but bleeding may complicate the clinical management. Bleeding due to excess fibrinolysis may be improved by antifibrinolytic therapy but may also unmask a thrombotic predisposition. Successful therapy, that is, restoration of effective hemostasis or achievement of thrombolysis without complication, depends critically on selection of the patient to be treated. (Reproduced with permission from Francis and Marder.209)

Antifibrinolytic agents are useful for improving hemostasis in a wide variety of bleeding states.2,3 There are three types of clinical conditions in which antifibrinolytic therapy has been used4: (1) systemic hyperfibrinolysis that follows administration of a therapeutic plasminogen activator or that stems from conditions associated with spontaneous, sustained increases in circulating plasminogen activator or lack of fibrinolytic inhibitors; (2) conditions with impaired hemostasis, e.g., hemophilia A and B; (3) excessive local fibrinolysis, as after prostatectomy where u-PA leads to premature dissolution of the hemostatic plug,5 or as in menorrhagia where high concentrations of t-PA maintain menstrual blood in a fluid phase.1
PHARMACOLOGY OF ANTIFIBRINOLYTIC AGENTS
MODE OF ACTION
The stability of fibrin in the hemostatic plug depends on the availability and proper concentration of platelets, thrombin, plasminogen, thrombin-activatable fibrinolytic inhibitor, a2-antiplasmin, and PAI-1.6,7,8,9 and 10 Antifibrinolytic agents shift the balance toward a more stabilized hemostatic plug. The therapeutic antifibrinolytic agents fall into two categories:

1.
Aprotinin, a 58-residue polypeptide (Mr 6500 Da) isolated from bovine lung parotid gland or pancreas11; it is a powerful inhibitor of trypsin, kallikrein, plasmin, and other serine proteases.12,13 The three-dimensional structure of aprotinin reveals it to be a very compact molecule, probably explaining its resistance to heat, extreme pH, and proteolysis.14 Aprotinin forms a 1:1 stoichiometric complex with several serine proteases. Lys15 of aprotinin forms a covalent bond with the serine residue of the catalytic site of serine proteases.15 The potency of aprotinin is expressed in kallikrein inhibitor units (KIU), where 106 KIU corresponds to 140 mg of the pure inhibitor.16

2.
The synthetic lysine analogs such as 6-amino-hexanoic acid, also known as e-aminocaproic acid (EACA), and tranexamic acid, also known as trans-p-aminomethyl-cyclohexanecarboxylic acid (AMCA), possess the ability to bind to the lysine-binding sites of plasminogen and thus inhibit competitively the binding of plasmin(ogen) to lysine residues on fibrin(ogen).17,18 Subtle differences in the synthetic analogs can markedly affect their inhibitory potential; AMCA has a six- to tenfold higher molar potency than EACA.19 Paradoxically, EACA and AMCA accelerate plasminogen activation in vitro by making plasminogen more susceptible to proteolytic action by its activators.20,21 However, any plasmin molecule that forms cannot bind effectively to fibrin, thereby precluding fibrinolysis.
PHARMACOKINETICS
APROTININ
Aprotinin has to be given intravenously because of gastric inactivation.22 The drug distributes rapidly in the extracellular space, with an apparent distribution volume of 26 liters.23 The kidney appears to be the principal organ of metabolism of aprotinin. Approximately 90 percent of the dose appears in the kidney within the first hours after infusion and remains there for 12 to 14 h. Aprotinin is filtered by the glomeruli and reabsorbed by the proximal tubules, where it is metabolized by renal lysosomes into small peptides or amino acids; from 25 to 40 percent of a single dose is excreted in the urine over 48 h, predominantly as metabolites.23,24 The distribution t½a is between 45 min to 2.5 h and the t½b in the range of 7 to 10 h.4,23
e-AMINOCAPROIC ACID (EACA) AND TRANEXAMIC ACID (AMCA)
EACA is rapidly absorbed from the gastrointestinal tract, with peak plasma levels achieved by 2 h, after which the drug is rapidly excreted by the kidneys. Approximately 80 percent of an intravenous dose is cleared within 3 h,25 but because EACA penetrates virtually the entire extravascular space, urinary excretion can be detected for as long as 12 to 36 h after intravenous administration. EACA is usually given as an intravenous priming dose of approximately 0.1 g per kilogram body weight over 20 to 30 min, followed by either a continuous intravenous infusion at 0.5 to 1 g/h or an equivalent intermittent dose, either orally or intravenously, every 1, 2, or 4 h. The serum half-life of AMCA is similar to that of EACA, approximately 1 to 2 h, and it is also rapidly excreted unchanged in the urine (>90 percent within 24 h).19 When AMCA is used orally, the recommended dose is 25 mg/kg given t.i.d. or q.i.d.; when it is infused intravenously, 10 mg/kg is administered at a rate of 1 ml/min three to four times daily (commercially available ampules contain usually 500 mg/5 ml). AMCA should not be administered simultaneously with penicillin.
ADVERSE EFFECTS
APROTININ
The most common adverse effects of aprotinin are nausea, vomiting, diarrhea, muscle pain, and hypotension.26,27 Allergic adverse effects comprise itching, rash, urticaria, and dyspnea; these are probably due to aprotinin-specific IgG and IgE antibodies.28 Serious side effects such as cardiovascular collapse, bronchospasm, and anaphylactic shock are rare.4,22,24 Nevertheless, the manufacturer recommends an intravenous test dose of 1 ml 10 min prior to the infusion of higher doses of aprotinin (available as infusion bottles of 500,000 KIU/50 ml and of 2,000,000 KIU/200 ml) and administration of an H1 antagonist and an anti-H2 drug such as cimetidine. Other, rare, adverse effects include impaired renal function,29 perioperative myocardial infarction, and occlusion of grafts (reviewed by Robert et al16).
EACA AND AMCA
Both AMCA and EACA are associated with infrequent serious side effects (thrombosis, myonecrosis, hypersensitivity reactions), even with long-term administration. Minor complaints such as nasal stuffiness, abdominal discomfort, nausea, vomiting, diarrhea, conjunctival suffusion, and skin rash have been noted,19 but their significance is questionable because they also occur in control patients in studies evaluating these agents. Myoglobinuria and muscle weakness as reflections of rhabdomyolysis require termination of therapy.30
Serious systemic thrombotic complications, e.g., disseminated intravascular coagulation (DIC), have occurred during antifibrinolytic therapy, but their importance has been exaggerated.31 Antifibrinolytic therapy is most unlikely to produce thrombotic complications unless there is an ongoing or transient thrombogenic stimulus such as in DIC (see Chap. 126). The antifibrinolytic agents do not incite de novo venous thrombus formation. Thus, the incidence of clinical venous thromboembolic disease in a randomized, double-blind study after prostatic surgery was the same in control patients (17 of 256) as in patients treated with EACA (16 of 259),32 and the incidence of a positive radioiodinated fibrinogen uptake test after retropubic prostatectomy was likewise unaffected (28 percent of 32 control patients and 30 percent of 30 patients treated with EACA).33
A small number of cases have been reported in which thrombotic events occurred in association with antifibrinolytic therapy, for example, in patients with metastatic prostatic carcinoma, in septic abortion, or after prolonged cardiopulmonary bypass.2 Presumably the thrombotic process was induced by the underlying lesion or postsurgical condition, and antifibrinolytic therapy prevented the physiologic fibrinolytic response. These devastating clinical events are rarely encountered today, because antifibrinolytic therapy is administered to patients with DIC only when hemorrhage fails to respond to replacement therapy and anticoagulation (see Chap. 126).
Upper urinary tract bleeding, which can complicate hemophilia and hemoglobinopathies,34 can lead to clots in the renal pelvis if the clot-dissolving action of urokinase is neutralized by an antifibrinolytic agent that is excreted in the urine. EACA or AMCA should therefore be avoided in such conditions. It should be noted, however, that induction of thrombosis by EACA or EACA and cryoprecipitate has been used for shrinking hemangiomas in patients with the Kasabach-Merritt syndrome.35
CLINICAL USE OF ANTIFIBRINOLYTIC AGENTS
Table 136-1 lists some common indications for the clinical use of antifibrinolytic agents.

TABLE 136-1 ANTIFIBRINOLYTIC THERAPY WITH EACA OR AMCA IN BLEEDING STATES*

SYSTEMIC HYPERFIBRIN(OGEN)OLYSIS
INHERITED DISORDERS
Hereditary deficiency of either the a2-plasmin inhibitor36,37 or PAI-138,39,40 and 41 may result in a lifelong bleeding disorder, presumably caused by premature lysis of hemostatic plugs at sites of vascular trauma. Inheritance is autosomal, with phenotypic manifestations of bleeding noted in homozygotes. In heterozygotes for a2-plasmin inhibitor deficiency, bleeding has been observed to develop only at an advanced age, when vascular fragility is increased.42 Bleeding may occur after initial hemostasis following surgery but may also be manifested spontaneously, for example, by epistaxis or ecchymoses. Given the permanent nature of the underlying defect (barring correction by gene therapy), treatment should be daily and lifelong in patients with frequent episodes of spontaneous bleeding. The oral administration of fibrinolytic inhibitors such as AMCA has been effective in normalizing hemostatic function.37,40
Isolated cases, and a family exhibiting increased levels of circulating active t-PA without PAI-1 deficiency, have also been described.43,44 In one case increased t-PA levels were associated with what appeared to be an inherited deficiency of a2-plasmin inhibitor; they returned to normal after orthotopic liver transplantation.45
Hereditary angioneurotic edema, due to a deficiency of the C1-inhibitor, leads to the activation of plasminogen and of the complement and the kallikrein-kinin systems during attacks.46,47 and 48 Prophylactic treatment with EACA or AMCA reduces the incidence and severity of attacks.49
FIBRINOLYTIC THERAPY
Infusion of plasminogen activators such as recombinant t-PA, streptokinase, urokinase (u-PA), or anistreplase induces a plasma proteolytic state in which plasminogen is converted to plasmin, a2-plasmin inhibitor is consumed, and the excess free plasmin variably degrades plasma fibrinogen (see Chap. 134). In addition to the desired therapeutic result of thrombolysis and vascular reperfusion, bleeding may result if hemostatic plugs at sites of vascular injury are dissolved. Following cessation of fibrinolytic treatment, the therapeutic plasminogen activators are cleared from the circulation at half-lives of 5 to 40 min,50 after which plasma fibrinogen is regenerated by hepatic synthesis, reaching pretreatment levels at 24 to 36 h. If bleeding occurs during or immediately after treatment, therapeutic efforts at normalizing hemostasis should include correction of plasma fibrinogen with cryoprecipitate and correction of possible platelet dysfunction by platelet transfusion.51 Although the clinical efficacy of fibrinolytic inhibitors has not been proven, these agents should be administered to inhibit residual fibrinolytic activity. Since hypofibrinogenemia persists after thrombolytic therapy for at least 12 h,52 there is a risk of excessive bleeding during surgical trauma such as coronary artery bypass grafting.53,54 Thus, in the TIMI II A study, percutaneous transluminal coronary angioplasty (PTCA) performed immediately after thrombolytic therapy was accompanied by increased bleeding; 20 percent of patients who underwent immediate PTCA required blood transfusions, compared to only 7 percent of patients in whom PTCA was performed 18 to 48 h after thrombolytic therapy for acute myocardial infarction.54
ACQUIRED PATHOLOGICAL CONDITIONS
Disseminated Intravascular Coagulation A number of pathologic states can result in hyperplasminemia, presumably through the release of endothelial cell plasminogen activator in sufficient quantities to overcome natural inhibitors. Such states include heatstroke, hypoxia, brain injury, hypotension, thoracic surgery, and certain neoplasms and may all be associated with hemorrhage. Laboratory examinations reveal shortened euglobulin lysis time; decreased plasminogen, fibrinogen, and a2-plasmin inhibitor levels; and elevated levels of fibrin(ogen) degradation products.55,56,57,58,59,60,61 and 62 Such patients frequently have DIC as well, which can be identified if thrombocytopenia is present. Great caution should therefore be exercised before one uses antifibrinolytic agents in these conditions (see Chap. 126).
Malignancy Many malignant cells synthesize procoagulant components that contribute locally to tumor invasion or metastatic spread and may be associated with systemic hypercoagulable states and thrombotic manifestations.63 The secretion of u-PA or t-PA by ovarian, breast, and prostate adenocarcinoma cells,57,59,64,65,66,67,68,69,70,71,72 and 73 with or without concomitant activation of the clotting cascade, may induce a bleeding state via activation of the fibrinolytic system. The possibility that a procoagulant/thrombotic tendency may coexist with a fibrinolytic/bleeding state in patients with malignancy makes the use of fibrinolytic inhibitors especially difficult, since inhibition of fibrinolysis might unmask a prothrombic state and induce thrombosis and/or DIC. The decision to use fibrinolytic inhibitors should be based on: (1) exclusion of DIC by finding a normal and stable platelet count; (2) failure to arrest bleeding by replacement therapy or local hemostatic measures; and (3) demonstration of enhanced whole blood or euglobulin lysis times.
Acute Promyelocytic Leukemia Promyelocytic leukemia cells produce both tissue factor and urokinase74 and express annexin II that enhances fibrinolysis (see Chap. 114 and Chap. 116). Thus, patients with acute promyelocytic leukemia (APL) have the potential for both thrombotic and hemorrhagic complications, which may be manifested at presentation or after induction of chemotherapy (see Chap. 126). The detection of elevated levels of thrombin-antithrombin (TAT) complexes or prothrombin fragment F1+2 or evidence of plasminogen activation, antiplasmin consumption, and hypofibrinogenemia provide evidence for systemic activation of coagulation and/or fibrinolysis, respectively.75,76,77,78,79,80 and 81 Promyelocytic leukemic cells with the t(15;17) translocation express abnormally high levels of cell-surface annexin II. Annexin II is a calcium-regulated, phospholipid-binding protein on endothelial cells, macrophages, and some tumor cells. It acts as a cell surface receptor for both plasminogen and t-PA. In acute promyelocytic leukemia patients, plasmin is generated at an abnormally high rate because of the overexpression of annexin II, leading to consumption of a2-antiplasmin and excess circulating plasmin.82 This group of patients constitutes a therapeutic dilemma, since either bleeding or thrombotic complications or both may be apparent82,83 and treatment of one manifestation could exacerbate or allow the development of the other. While heparin is clearly indicated for a frank thrombotic occlusion, the evidence for efficacy of heparin as prophylaxis against DIC is equivocal.84 Similarly, there is a difference of opinion as to whether antifibrinolytic therapy is of benefit in preventing bleeding complications, which appear to be more prevalent after initiation of chemotherapy. Whereas a retrospective comparison of 268 patients managed with heparin, fibrinolytic inhibitor, or supportive treatment alone showed no difference in early hemorrhagic death with any management policy,83 a prospective, randomized trial in 12 patients showed a significant reduction in hemorrhage and transfusion requirements with AMCA administration.85 All-trans-retinoic acid, which has been successfully used for the treatment of APL, increased the expression of the urokinase receptor on the surface of APL cells and led to increased plasmin generation, whereas dexamethasone totally suppressed this effect of retinoic acid.74 Thus, there appears to be some logic to adding dexamethasone to the chemotherapeutic regimens used for the treatment of APL.
Liver Disease and Transplantation Increased fibrinolytic activity due to the presence of abnormal quantities of t-PA86 and of u-PA87 is often present in advanced liver disease, presumably due to the failure of hepatic clearance mechanisms,88 but there may also be a component in the blood of cirrhotic patients that stimulates t-PA release from endothelial cells.89 A cohort of 112 cirrhotic patients with esophageal varices who had not exhibited upper gastrointestinal bleeding was followed for a period of 3 years. Among the many clinical and laboratory abnormalities found in these patients, multivariate analysis revealed that hyperfibrinolysis (defined as t-PA activity and D-dimer levels above the mean ± 2 SD of 112 controls) was the only marker predictive of subsequent upper gastrointestinal bleeding.90
During orthotopic liver transplantation (OLT) the euglobulin lysis time greatly shortens and the levels of D-dimer, t-PA antigen and activity, and plasmin/a-plasmin inhibitor complexes increase. These changes are usually most pronounced during reperfusion of the grafted liver.91 Several randomized studies have examined whether the administration of antifibrinolytic agents reduces blood loss and transfusion requirements during OLT. While over 10 nonrandomized studies92 concluded that aprotinin greatly diminishes bleeding and the need for red blood cell, fresh-frozen plasma, and platelet transfusions, one randomized trial comprising 80 patients found that the administration of high-dose aprotinin (2,000,000 KIU initial dose, followed by 500,000 KIU/h) was not useful in reducing bleeding and blood product requirement. The results of this study, however, were unexpected insofar as no attenuation of the D-dimer increase during the surgical procedure was observed.92 Also, the mean number of blood products administered during surgery exceeded 40 units, which probably led to a marked wash-out of aprotinin. Another study randomized 199 patients undergoing OLT to high-dose or low-dose aprotinin prophylaxis. No difference in blood product requirements was found.93 Two double-blind randomized studies evaluated the effect of AMCA in OLT. High doses of 40 mg/kg/h up to a maximum of 20 g reduced the requirement of blood products from 43.5 units in control patients to 20.5 units in the AMCA-treated group (P=0.003),94 whereas twentyfold smaller doses of 2 mg/kg/h had no beneficial effect95 (see Chap. 125).
Cardiopulmonary Bypass Extracorporeal circulation results in activation of the contact phase of the coagulation, fibrinolysis, and complement systems. Neutrophils and platelets become activated as well, and platelets are dysfunctional.96,97,98,99,100 and 101 Correlations of shortened euglobulin clot lysis times with sternotomy, and with serious bleeding after open-heart surgery requiring cardiopulmonary bypass,102 suggest that neutralization of the systemic, hyperfibrin(ogen)olytic state could be beneficial in reducing blood loss. Antifibrinolytic agents attenuate platelet activation, suggesting a potential role for plasmin-mediated platelet activation.103,104
Over 100 studies have been published on the blood-sparing effect of aprotinin, EACA, and AMCA in cardiac surgery, thoracoabdominal aneurysm repair, and lung transplantation, and with use of heart-assist devices. A recent meta-analysis105 reviewed 52 randomized clinical trials of cardiac surgery published between 1985 and 1998 involving the use of aprotinin (n=46) and EACA (n=9). Compared to placebo, the mean reduction of blood losses with high-dose aprotinin (priming dose of 2,000,000 KIU, followed by 500,000 KIU/h) was 53 percent, whereas with low-dose aprotinin (usually about one-third to one-half of the high dose) and with EACA, the mean reduction was 35 percent (P<0.001 throughout). Less bleeding resulted in fewer re-explorations; the reduction with high-dose aprotinin was 75 percent (P<0.001), whereas the reduction with low-dose aprotinin was 54 percent (P=0.048) and the reduction with EACA 58 percent (P=0.13; smaller number of patients). Interestingly, there were fewer strokes occurring with all three treatment schedules (P=n.s.). The incidence of postoperative myocardial infarction and overall mortality was similar in the three treatment and the placebo groups.
Five randomized, double-blind studies were reported comparing AMCA to controls, with reduction in blood losses from 31 to 36 percent.103,106,107,108 and 109 In a more recent trial, three different doses of AMCA (50, 100, or 150 mg/kg) were compared.110 The most cost-effective dose was 100 mg/kg.
In general, comparative trials did not show significant differences in blood loss between low-dose aprotinin and EACA and/or AMCA, but blood loss was lower with high-dose aprotinin.111,112,113,114,115 and 116 The incidence of graft occlusion after coronary artery bypass grafting was slightly but insignificantly increased117,118 or not increased.119
Aspirin exposure within 7 days prior to coronary bypass surgery is associated with an increased rate of reoperation, with large increases in transfusion requirements.120 Aprotinin counterbalances the increased risk of perioperative hemorrhage in such patients.121,122
Of practical importance is the fact that aprotinin, but not EACA, or AMCA prolongs the partial thromboplastin time and the activated clotting time independent of heparin, presumably by an inhibitory effect on kallikrein.123 Thus, patients on cardiopulmonary bypass may appear to acquire a greater anticoagulant effect from heparin than actually exists.
Snake Venoms Patients bitten by some snake or caterpillar species may develop localized or systemic bleeding. Some of these venoms are primarily procoagulants and produce DIC (see Chap. 126), whereas others activate inactive single-chain pro-UK to active two-chain UK124 or directly degrade fibrinogen,125,126,127 and 128 often without influencing the platelet count and the prothrombin time.129 A register of snake venoms lists 67 purified fibrino(geno)lytic venom enzymes and 1 plasminogen activator enzyme.130 Many of these enzymes are zinc-metalloproteinases. Antifibrinolytic agents probably are not useful in controlling bleeding due to these venoms.
LOCALIZED FIBRINOLYSIS WITH ABNORMAL HEMOSTASIS
HEMOPHILIA AND OTHER INHERITED BLEEDING DISORDERS
Replacement therapy is effective in providing normal hemostasis following all types of major surgical procedures in patients with hemophilia. The addition of intravenous antifibrinolytic agents to the regimen reduces bleeding and the requirement for factor VIII or factor IX concentrates, as demonstrated by studies of dental extractions.131,132 Patients with hemophilia undergoing other surgical procedures could be similarly supported by conjoint antifibrinolytic and factor-replacement therapy. Because a hypercoagulable state may occur secondary to administration of some factor IX–rich concentrates,133 their use along with antifibrinolytic agents in factor IX–deficient patients may present a greater risk of thrombotic complication.
Therapy of hemarthroses with small doses of factor VIII administered either early after bleeding or prophylactically to patients with hemophilia is extremely effective. EACA and AMCA do not favorably alter the long-term incidence or severity of hemarthroses in these patients.2,134,135
Hemophiliacs have an increased risk of developing frank renal obstruction secondary to large clots in the renal collecting system when treated with EACA.136,137 Therefore, upper urinary tract bleeding should be managed conservatively for as long as possible, using factor replacement and high fluid intake to maintain a low urinary hematocrit and fibrinogen concentration. If bleeding lasts for weeks and requires blood transfusions, or if surgical intervention is considered, then the benefit relative to risk justifies therapy with antifibrinolytic agents.
Antifibrinolytic therapy has also been found useful following minor oral surgery138 or major surgery139 and in patients with menorrhagia due to von Willebrand disease.139 Use of AMCA efficiently prevents bleeding during or after dental extractions in patients with severe factor XI deficiency (see Chap. 122).
ORAL ANTICOAGULATION THERAPY
A recent review analyzed 26 reports on dental surgical procedures and tooth extractions in patients receiving continuous anticoagulation for a prosthetic cardiac valve or vascular prosthesis.140 The author concluded that oral anticoagulation can be safely continued in such patients with a minimal risk of bleeding. The use of an AMCA mouthwash following oral surgery was effective in reducing the incidence of bleeding episodes (without altering the dosage of anticoagulants), as compared to the bleeding in a randomized control group (1/19 versus 8/20 bleeding episodes, P=0.01).141 The mouth has a high level of fibrinolytic activity due to the presence of t-PA,142 so local inhibition of the activity may explain the efficacy of therapy for controlling bleeding.
THROMBOCYTOPENIA AND THROMBOCYTOPATHIES
Treatment with fibrinolytic inhibitors may ameliorate bleeding in patients with immune thrombocytopenic purpura who have elevated concentrations of tissue plasminogen activator.143 Also, patients with amegakaryocytic, immune-mediated, or dyspoietic thrombocytopenia were reported to benefit from the use of fibrinolytic inhibitors.144,145 and 146 However, in a controlled, double-blinded study of patients with amegakaryocytic thrombocytopenia (platelet count <20×109/liter), the use of AMCA failed to decrease dependence on platelet transfusions or to reduce the incidence of cutaneous bleeding, epistaxis, or gingival hemorrhage.147
AMYLOIDOSIS
Several case reports describe increased levels of t-PA and/or u-PA, accompanied by decreased concentrations of plasminogen and of a2-plasmin inhibitor in patients with amyloidosis and bleeding manifestations.148,149,150,151 and 152 Treatment with EACA or AMCA usually was successful in controlling the bleeding. In a special variety of amyloidosis, the Dutch type of hereditary cerebral hemorrhage, the fibrinolytic activity is not increased, although high t-PA antigen levels and a low fibrinogen concentration are demonstrable.153
KASABACH-MERRITT SYNDROME
Patients with multiple giant hemangiomata (Kasabach-Merritt syndrome) present a particularly difficult problem, with progressive tumor enlargement that often requires extensive, dangerous, and sometimes disfiguring surgery. The variable consumption of platelets and fibrinogen suggests that thrombi are continually formed and dissolved within the hemangioma. Tumor shrinkage, improvement of laboratory evidence of intravascular coagulation, and symptomatic patient improvement have been reported when in situ thrombosis was induced by the administration of EACA, either alone or with concomitant cryoprecipitate infusion.35,154 Local (intra-arterial) administration of EACA plus thrombin has also been successfully utilized as adjunct treatment with systemic cryoprecipitate.155
LOCALIZED FIBRINOLYSIS WITH NORMAL HEMOSTASIS
PROSTATECTOMY
Bleeding after prostatectomy is probably enhanced by the presence in the urine of u-PA, which diffuses into the operative site and dissolves newly formed hemostatic plugs.156 The postoperative blood loss correlated best with the measured u-PA activity in one study.157 Trials of systemic EACA or AMCA therapy after prostatectomy have demonstrated a significant decrease in postoperative blood loss when compared to placebo.158,159 However, the bleeding in control patients usually is more bothersome than dangerous, and antifibrinolytic treatment probably is best applied to patients with excessive bleeding at surgery or immediately afterward. Intravesicular irrigation with EACA has not proved superior to saline irrigation for surgical bleeding, but this approach may be useful for late fibrinolytic hemorrhage, especially in patients with possible DIC.160 Vascular thrombotic side effects in patients treated with antifibrinolytic agents were no greater than those in control groups,32,161 but intravesical clots that require surgical evacuation may complicate the postoperative course.162
RENAL BLEEDING
Antifibrinolytic therapy for prolonged spontaneous bleeding in patients with sickle cell disease and sickle cell trait can be dramatically successful.34 Patients with renal disease who exhibit severe and protracted hematuria after renal biopsy may benefit from treatment with EACA.163 However, there is an increased risk of significant clot formation in the renal collecting system,164,165 which in a small number of patients is large enough to seriously impair renal function.156 In some of these patients a trial with an intraureterally administered thrombolytic agent may be considered.165 The abrupt appearance of extrarenal clot formation is recognized by a combination of clearing of blood from the urine, flank pain, and a nephrogram image on intravenous pyelography without dye excretion into the ureters and bladder.
UTERUS
Excessive uterine bleeding due to a variety of pathologic causes has been associated with increased local fibrinolytic activity.166 Higher uterine t-PA activities were found in endometrial curettage samples obtained during the menstrual phase of the cycle from patients with menorrhagia compared to uterine curettings from women with normal menses.1 Fibrinolytic activity is also increased in most patients after placement of intrauterine devices.167 Double-blind trials of antifibrinolytic therapy show decreased bleeding in patients with menorrhagia3,168,169 or after intrauterine device placement.170,171 Moreover, local release of EACA from fitted silicone rubber sleeves has likewise prevented excessive bleeding associated with such devices.172 Before instituting antifibrinolytic therapy, patients should undergo a complete gynecological, hormonal, and hemostasis evaluation. Menorrhagia is a common presenting symptom in women with von Willebrand disease.173,174 There is no consensus on the best antifibrinolytic dosing regimen. Good results have been obtained with oral AMCA, 15 mg/kg t.i.d or q.i.d during the first 3 to 5 days of the monthly menses, but single doses of 3 to 4 g taken once daily also have been effective.174
The cervix contains a high concentration of t-PA, which contributes to excessive bleeding in some patients after cervical conization. The administration of AMCA was effective in reducing blood loss after such surgery and eliminating delayed bleeding during the first 5 postoperative days.175
GASTROINTESTINAL TRACT
Certain pathologic lesions that cause upper and lower gastrointestinal bleeding have been associated with increased fibrinolytic activity, either within the tissues themselves or in veins draining the affected organ.176 Helicobacter pylori infection is associated with chronic gastritis and gastric and duodenal ulcers. Endoscopic biopsy specimens of patients with H. pylori infection and/or gastric and duodenal ulcers exhibited increased u-PA levels, which were highest in patients with active bleeding. In most studies, however, t-PA concentrations in these biopsies were lower than in normal mucosa. Treatment of H. pylori infection with omeprazole or ranitidine, and clarithromycin and metronidazole resulted in normalization of u-PA and t-PA levels.177,178 and 179
Prospective, controlled clinical trials180,181,182,183 and 184 used AMCA in large groups of patients with upper gastrointestinal bleeding, with clear-cut benefit. In one trial 200 patients with acute upper gastrointestinal hemorrhage were randomized, and there was a significant difference in the requirement for surgical intervention to control bleeding (23 of 97 control patients versus only 7 of 103 AMCA-treated patients) and fewer deaths (two of the AMCA-treated patients, four of the placebo-treated patients all secondary to massive blood loss).180 Benefit was noted in patients with esophageal varices as well as in those with gastric ulcers, gastric erosions, or miscellaneous other bleeding lesions. The favorable clinical results most likely are due to inhibition of local fibrinolysis in the mucosa of the upper gastrointestinal tract.176,182,185
Increased amounts of plasminogen activator are present in the rectal mucosa, and fibrin degradation products are increased in plasma of patients with active ulcerative colitis or Crohn’s disease.186,187 and 188 Clinical trials of systemic antifibrinolytic therapy in these conditions have not shown a clear benefit.2 New approaches, such as the direct administration of an antifibrinolytic agent by enema, may ultimately prove more useful186 without causing systemic inhibition of fibrinolysis.189
A marked increase of fibrinolytic activity, probably due to activation of coagulation, is also observed in hepatosplenic schistosomiasis and may contribute to bleeding from esophageal varices in these patients.190
SUBARACHNOID HEMORRHAGE
The cerebrospinal fluid (CSF) is usually devoid of plasminogen activator activity. After subarachnoid hemorrhage (SAH), increased fibrinolytic activity and elevated concentrations of D-dimers are found in the CSF.191,192 However, levels of active PAI-1, of t-PA/PAI-1 complexes, and of thrombin-antithrombin complexes (a marker of thrombin generation) are also increased in the CSF, particularly in patients with severe forms of SAH and in those with subsequent cerebral infarction and/or poor outcome.193 Elevated fibrinogen, t-PA, PAI-1, and D-dimer levels in the plasma of patients with SAH were significantly correlated with cerebral infarction and poor outcome as evaluated by the Glasgow Outcome Scale.194
Rebleeding occurs in 6 to 20 percent of the at-risk population, usually in the first several weeks after the initial episode and most often on the same day as the initial hemorrhage.195 Over 30 studies have evaluated the effect of EACA or AMCA on rebleeding and outcome. Eight truly randomized controlled trials, comprising a total of 937 patients of whom 476 received antifibrinolytic drugs, 364 placebo, and 97 open control treatment, were recently reviewed by Roos et al.196 Although antifibrinolytic therapy significantly decreased the rebleeding rate, it also clearly induced cerebral ischemia (Table 136-2). Death from all causes, and the incidences of hydrocephalus and dependency, were identical in controls and in patients treated with antifibrinolytic therapy. However, these trials were all conducted at least 10 years ago, when treatment of cerebral ischemia was not common. Modern treatment of cerebral ischemia, comprising an increase in daily fluid intake, hypervolemic hemodilution with albumin (aiming for a hematocrit of about 0.3), and the administration of nimodipine, leads to a marked decrease of cerebral ischemia, even in patients treated with AMCA.197

TABLE 136-2 ANTIFIBRINOLYTIC TREATMENT OF SUBARACHNOID HEMORRHAGE: META-ANALYSIS OF 8 RANDOMIZED TRIALS196

ORTHOPEDIC SURGERY
A few randomized studies have examined whether antifibrinolytic agents reduce blood transfusion requirements in orthopedic surgery without increasing the incidence of postoperative deep venous thrombosis. In two small total hip replacement studies, high-dose intravenous infusion of aprotinin was compared in a double-blind fashion to a placebo infusion. Total blood loss was about 30 percent lower in the aprotinin group, and the occurrence of postoperative DVT was comparable in the two groups.198,199 AMCA reduced total blood losses by about 40 percent in a randomized, double-blind study of total knee arthroplasty.200
TRAUMATIC HYPHEMA
Therapy with antifibrinolytic agents is not unreasonable as a prophylactic measure against the rebleeding from traumatic hyphema, which occurs about 2 to 6 days after the initial injury in as many as 30 percent of patients. Increased local fibrinolytic activity present in circumscribed areas of the eye, specifically in the endothelium of the canal of Schlemm, is likely to contribute to the rebleeding. A favorable effect of antifibrinolytic therapy in preventing secondary bleeding following traumatic hyphema has been reported,201,202,203 and 204 but on follow-up examination at 2 to 6 weeks there was no difference in the final visual acuity compared with that in the control group.205
MUCOUS MEMBRANES
Antifibrinolytic therapy in patients undergoing tonsillectomy and adenoidectomy206 resulted in a significant decrease in blood loss, but this treatment modality is not routinely used. Treatment might reasonably be attempted in patients with unexplained serious postoperative bleeding that requires resuturing or packing, perhaps using packs impregnated with an antifibrinolytic agent.
Oral AMCA has not proved useful for adjunctive therapy of epistaxis in patients requiring hospital admission.207
HEREDITARY HEMORRHAGIC TELANGIECTASIA
In two patients with hereditary hemorrhagic telangiectasia experiencing recurrent epistaxis and gastrointestinal bleeding, treatment with EACA greatly reduced the frequency of bleeding episodes and improved hemoglobin levels from 70 g/liter to around 130 g/liter.208 In other patients EACA has not proved helpful.
CHAPTER REFERENCES

1.
Gleeson NC: Cyclic changes in endometrial tissue plasminogen activator and plasminogen activator inhibitor type 1 in women with normal menstruation and essential menorrhagia. Am J Obstet Gynecol 171:178, 1994.

2.
Sherry S, Marder VJ: Therapy with antifibrinolytic agents, in Hemostasis and Thrombosis: Basic Principles and Clinical Practice, 3rd ed, edited by RW Colman, J Hirsh, VJ Marder, EW Salzman, p 335. Lippincott, Philadelphia, 1994.

3.
Ogston D: Antifibrinolytic Drugs. Chemistry, Pharmacology and Clinical Usage. Wiley, New York, 1984.

4.
Verstraete M: Clinical application of inhibitors of fibrinolysis. Drugs 29:236, 1985.

5.
McNicol GP, Fletcher AP, Alkjaersig N, Sherry S: Impairment of hemostasis in the urinary tract: the role of urokinase. J Lab Clin Med 58:34, 1961.

6.
Collen D: On the regulation and control of fibrinolysis. Thromb Haemost 43:77, 1980.

7.
Bachmann F: Fibrinolysis, in Thrombosis and Haemostasis, edited by M Verstraete, J Vermylen, R Lijnen, J Arnout, p 227. Leuven University Press, Leuven, Belgium, 1987.

8.
Aoki N, Harpel PC: Inhibitors of the fibrinolytic enzyme system. Semin Thromb Hemost 10:24, 1984.

9.
Sprengers ED, Kluft C: Plasminogen activator inhibitors. Blood 69:381, 1987.

10.
Kruithof EKO: Plasminogen activator inhibitors—a review. Enzyme 40:113, 1988.

11.
Kunitz M, Northrop JH: Isolation from beef pancreas of crystalline trypsinogen, trypsin, a trypsin inhibitor and an inhibitor trypsin compound. J Gen Physiol 19:991, 1936.

12.
Rühlmann A, Schramm HJ, Kukla D, Huber R: Pancreatic trypsin inhibitor (Kunitz): II. Complexes with proteinases. Cold Spring Harb Symp Quant Biol 36:148, 1972.

13.
Wiman B: On the reaction of plasmin or plasmin streptokinase complex with aprotinin or a-antiplasmin. Thromb Res 17:143, 1980.

14.
Huber R, Kukla D, Rühlmann A, Steigemann W: Pancreatic trypsin inhibitor (Kunitz): I. Structure and function. Cold Spring Harb Symp Quant Biol 36:141, 1972.

15.
Rühlmann A, Kukla D, Schwager P, Bartels K, Huber R: Structure of the complex formed by bovine trypsin and bovine pancreatic trypsin inhibitor. Crystal structure determination and stereochemistry of the contact region. J Mol Biol 77:417, 1973.

16.
Robert S, Wagner BKJ, Boulanger M, Richer M: Aprotinin. Ann Pharmacother 30:372, 1996.

17.
Anonick PK, Vasudevan J, Gonias SL: Antifibrinolytic activities of a-N-acetyl-L-lysine methyl ester, epsilon-aminocaproic acid, and tranexamic acid. Importance of kringle interactions and active site inhibition. Arterioscler Thromb 12:708, 1992.

18.
Fears R, Greenwood H, Hearn J, et al: Inhibition of the fibrinolytic and fibrinogenolytic activity of plasminogen activators in vitro by the antidotes e-aminocaproic acid, tranexamic acid and aprotinin. Fibrinolysis 6:79, 1992.

19.
Andersson L, Nilsson IM, Nilehn J-E, et al: Experimental and clinical studies on AMCA, the anti-fibrinolytic active isomer of p-aminomethylcyclohexane carboxylic acid. Scand J Clin Lab Invest 2:230, 1965.

20.
Thorsen S, Müllertz S: Rate of activation and electrophoretic mobility of unmodified and partially degraded plasminogen. Effects of 6-aminohexanoic acid and related compounds. Scand J Clin Lab Invest 34:167, 1974.

21.
Takada A, Sugawara Y, Takada Y: Enhancement of the activation of Glu-plasminogen by urokinase in the simultaneous presence of tranexamic acid or fibrin. Haemostasis 1:26, 1989.

22.
Royston D: High-dose aprotinin therapy: a review of the first five years’ experience. J Cardiothorac Anesth 6:76, 1992.

23.
Levy JH, Bailey JM, Salmenperä M: Pharmacokinetics of aprotinin in preoperative cardiac surgical patients. Anesthesiology 80:1013, 1994.

24.
Westaby S: Aprotinin in perspective. Ann Thorac Surg 55:1033, 1993.

25.
McNicol GP, Fletcher AP, Alkjaersig N, Sherry S: The absorption, distribution and excretion of e-aminocaproic acid following oral or intravenous administration to man. J Lab Clin Med 59:15, 1962.

26.
Dietrich W, Barankay A, Hahnel C, Richter JA: High-dose aprotinin in cardiac surgery: three years’ experience in 1,784 patients. J Cardiothorac Vasc Anesth 6:324, 1992.

27.
Bidstrup BP, Harrison J, Royston D, Taylor KM, Treasure T: Aprotinin therapy in cardiac operations: a report on use in 41 cardiac centers in the United Kingdom. Ann Thorac Surg 55:971, 1993.

28.
Dewachter P, Mouton C, Masson C, Gueant JL, Haberer JP: Anaphylactic reaction to aprotinin during cardiac surgery [letter]. Anaesthesia 48:1110, 1993.

29.
Feindt PR, Walcher S, Volkmer I, et al: Effects of high-dose aprotinin on renal function in aortocoronary bypass grafting. Ann Thorac Surg 60:1076, 1995.

30.
Kane MJ, Silverman LR, Rand JH, Paciucci PA, Holland JF: Myonecrosis as a complication of the use of epsilon amino-caproic acid: a case report and review of the literature. Am J Med 85:861, 1988.

31.
Ratnoff OD: Epsilon aminocaproic acid—a dangerous weapon. N Engl J Med 280:1124, 1969.

32.
Vinnicombe J, Shuttleworth KED: Aminocaproic acid in the control of haemorrhage after prostatectomy. Safety of aminocaproic acid—a controlled trial. Lancet 1:232, 1966.

33.
Gordon-Smith IC, Hickman JA, el-Masri SH: The effect of the fibrinolytic inhibitor epsilon-aminocaproic acid on the incidence of deep-vein thrombosis after prostatectomy. Br J Surg 59:522, 1972.

34.
Immergut MA, Stevenson T: The use of epsilon-aminocaproic acid in the control of hematuria associated with hemoglobinopathies. Br J Urol 93:110, 1965.

35.
Warrell RP Jr, Kempin SJ: Treatment of severe coagulopathy in the Kasabach-Merritt syndrome with aminocaproic acid and cryoprecipitate. N Engl J Med 313:309, 1985.

36.
Aoki N, Saito H, Kamiya T, Koie K, Sakata Y, Kobakura M: Congenital deficiency of a2-plasmin inhibitor associated with severe hemorrhagic tendency. J Clin Invest 63:877, 1979.

37.
Aoki N, Sakata Y, Matsuda M, Tateno K: Fibrinolytic states in a patient with congenital deficiency of a2-plasmin inhibitor. Blood 55:483, 1980.

38.
Diéval J, Nguyen G, Gross S, Delobel J, Kruithof EKO: A lifelong bleeding disorder associated with a deficiency of plasminogen activator inhibitor type 1. Blood 77:528, 1991.

39.
Fay WP, Shapiro AD, Shih JL, Schleef RR, Ginsburg D: Complete deficiency of plasminogen-activator inhibitor type 1 due to a frame-shift mutation. N Engl J Med 327:1729, 1992.

40.
Lee MH, Vosburgh E, Anderson K, McDonagh J: Deficiency of plasma plasminogen activator inhibitor 1 results in hyperfibrinolytic breeding. Blood 81:2357, 1993.

41.
Fay WP, Parker AC, Condrey LR, Shapiro AD: Human plasminogen activator inhibitor-1 (PAI-1) deficiency: characterization of a large kindred with a null mutation in the PAI-1 gene. Blood 90:204, 1997.

42.
Ikematsu S, Fukutake K, Aoki N: Heterozygote for plasmin inhibitor deficiency developing hemorrhagic tendency with advancing age. Thromb Res 82:129, 1996.

43.
Aznar J, Estellés A, Vila V, Regañón E, España F, Villa P: Inherited fibrinolytic disorder due to an enhanced plasminogen activator level. Thromb Haemost 52:196, 1984.

44.
Booth NA, Bennett B, Wijngaards G, Grieve JHK: A new life-long hemorrhagic disorder due to excess plasminogen activator. Blood 61:267, 1983.

45.
Humphries JE, Gonias SL, Pizzo SV, Williams ME: Life-long bleeding diathesis: effect of orthotopic liver transplantation. Am J Clin Pathol 102:816, 1994.

46.
Cugno M, Hack CE, de Boer JP, Eerenberg AJM, Agostini A, Cicardi M: Generation of plasmin during acute attacks of hereditary angioedema. J Lab Clin Med 121:38, 1993.

47.
Donaldson VH: Plasminogen activation in hereditary angioneurotic edema. J Lab Clin Med 121:13, 1993.

48.
Nielsen EW, Johansen HT, Høgåsen K, Wuillemin W, Hack CE, Mollnes TE: Activation of the complement, coagulation, fibrinolytic and kallikrein-kinin systems during attacks of hereditary angioedema. Scand J Immunol 44:185, 1996.

49.
Agostoni A, Marasini B, Cicardi M, Martignoni G, Uziel L, Pietrogrande M: Hepatic function and fibrinolysis in patients with hereditary angioedema undergoing long-term treatment with tranexamic acid. Allergy 33:216, 1978.

50.
Marder VJ, Sherry S: Thrombolytic therapy: current status. N Engl J Med 318:1512,1585, 1988.

51.
Coller BS: Platelets and thrombolytic therapy. N Engl J Med 322:33, 1990.

52.
Owen J, Friedman KD, Grossman BA, Wilkins C, Berke AD, Powers ER: Quantitation of fragment X formation during thrombolytic therapy with streptokinase and tissue plasminogen activator. J Clin Invest 79:1642, 1987.

53.
Lee KF, Mandell J, Rankin JS, Muhlbaier LH, Wechsler AS: Immediate versus delayed coronary grafting after streptokinase treatment. Postoperative blood loss and clinical results. J Thorac Cardiovasc Surg 95:216, 1988.

54.
The TIMI Research Group: Immediate vs delayed catheterization and angioplasty following thrombolytic therapy for acute myocardial infarction. TIMI II A results. JAMA 260:2849, 1988.

55.
Takahashi H, Urano T, Takada Y, Nagai N, Takada A: Fibrinolytic parameters as an admission prognostic marker of head injury in patients who talk and deteriorate. J Neurosurg 86:768, 1997.

56.
Westaby S: Coagulation disturbance in profound hypothermia: the influence of anti-fibrinolytic therapy. Semin Thorac Cardiovasc Surg 9:246, 1997.

57.
Okajima K, Kohno I, Soe G, Okabe H, Takatsuki K, Binder BR: Direct evidence for systemic fibrinogenolysis in patients with acquired a2-plasmin inhibitor deficiency. Am J Hematol 45:16, 1994.

58.
Bonnemaison J, Thicoïpe M, Dixmérias F, Guérin V: Coagulopathie évocatrice d’une fibrinolyse primaire après traumatisme crânien avec mort cérébrale. Ann Fr Anesth Reanim 17:275, 1998.

59.
Walther PJ, Gore M, Pizzo SV: Increased releasable vascular plasminogen activator and a bleeding diathesis. Am J Med 77:566, 1984.

60.
Stankiewicz AJ, Crowley JP, Steiner M: Increased levels of tissue plasminogen activator with a low plasminogen activator inhibitor-1 in a patient with postoperative bleeding. Am J Hematol 38:226, 1991.

61.
Hunt BJ, Segal H: Hyperfibrinolysis. J Clin Pathol 49:958, 1996.

62.
Palmer JD, Francis DA, Roath OS, Francis JL, Iannotti F: Hyperfibrinolysis during intracranial surgery: effect of high dose aprotinin. J Neurol Neurosurg Psychiatry 58:104, 1995.

63.
Danø K, Andreasen PA, Grøndahl-Hansen J, Kristensen P, Nielsen LS, Skriver L: Plasminogen activators, tissue degradation, and cancer. Adv Cancer Res 44:139, 1985.

64.
Davidson JF, McNicol GP, Frank GL, Anderson TJ, Douglas AS: Plasminogen-activator-producing tumour. Br Med J 1:88, 1969.

65.
al-Mondhiry H, Manni A, Owen J, Gordon R: Hemostatic effects of hormonal stimulation in patients with metastatic prostate cancer. Am J Hematol 28:141, 1988.

66.
Mannucci PM, Cugno M, Bottasso B, et al: Changes in fibrinolysis in patients with localized tumors. Eur J Cancer 26:83, 1990.

67.
Zacharski LR, Memoli VA, Ornstein DL, Rousseau SM, Kisiel W, Kudryk BJ: Tumor cell procoagulant and urokinase expression in carcinoma of the ovary. JNCI 85:1225, 1993.

68.
De Boer WA, Koolen MGJ, Roos CM, ten Cate JW: Tranexamic acid treatment of hemothorax in two patients with malignant mesothelioma. Chest 100:847, 1991.

69.
Weltermann A, Mitterbauer GJ, Mitterbauer M, et al: Disseminierte intravasale Gerinnung (DIG) und massive Hyperfibrinolyse bei metastasierendem Uteruskarzinom. Beobachtungen über die Beeinflussusng der Gerinnunsstörung durch verschiedene Therapien (ein Fallbericht). Wien Med Wochenschr 110:53, 1998.

70.
Webber MM, Waghray A: Urokinase-mediated extracellular matrix degradation by human prostatic carcinoma cells and its inhibition by retinoic acid. Clin Cancer Res 1:755, 1995.

71.
Loópez-Pedrera C, Jardíó M, del Mar Malagoón MD, et al: Tissue factor (TF) and urokinase plasminogen activator receptor (uPAR) and bleeding complications in leukemic patients. Thromb Haemost 77:62, 1997.

72.
Bennett B, Croll AM, Robbie LA, Herriot R: Tumour cell u-PA as a cause of fibrinolytic bleeding in metastatic disease. Br J Haematol 99:570, 1997.

73.
Meijer K, Smid WM, Geerards S, van der Meer J: Hyperfibrinogenolysis in disseminated adenocarcinoma. Blood Coagul Fibrinolysis 9:279, 1998.

74.
Mustjoki S, Tapiovaara H, Sirén V, Vaheri A: Interferons and retinoids enhance and dexamethasone suppresses urokinase-mediated plasminogen activation in promyelocytic leukemia cells. Leukemia 12:164, 1998.

75.
Bauer KA, Rosenberg RD: Thrombin generation in acute promyelocytic leukemia. Blood 64:791, 1984.

76.
Bennett B, Booth NA, Croll A, Dawson AA: The bleeding disorder in acute promyelocytic leukaemia: fibrinolysis due to u-PA rather than defibrination. Br J Haematol 71:511, 1989.

77.
Avvisati G, ten Cate JW, Sturk A, Lamping R, Petti MG, Mandelli F: Acquired alpha-2-antiplasmin deficiency in acute promyelocytic leukaemia. Br J Haematol 70:43, 1988.

78.
Schwartz BS, Williams EC, Conlan MG, Mosher DF: Epsilon-aminocaproic acid in the treatment of patients with acute promyelocytic leukemia and acquired alpha-2-plasmin inhibitor deficiency. Ann Intern Med 105:873, 1986.

79.
Falanga A, Iacoviello L, Evangelista V, et al: Loss of blast cell procoagulant activity and improvement of hemostatic variables in patients with acute promyelocytic leukemia administered all-trans-retinoic acid. Blood 86:1072, 1995.

80.
Watanabe R, Murata M, Takayama N, et al: Long-term follow-up of hemostatic molecular markers during remission induction therapy with all-trans-retinoic acid for acute promyelocytic leukemia. Keio Hematology-Oncology Cooperative Study Group (KHOCS). Thromb Haemost 77:641, 1997.

81.
Pogliani EM, Rossini F, Casaroli I, Maffe P, Corneo G: Thrombotic complications in acute promyelocytic leukemia during all-trans-retinoic acid therapy. Acta Haematol 97:228, 1997.

82.
Menell JS, Cesarman GM, Jacovina AT, McLaughlin MA, Lev EA, Hajjar KA: Annexin II and bleeding in acute promyelocytic leukemia. N Engl J Med 340:994, 1999.

83.
Rodeghiero F, Avvisati G, Castaman G, Barbui T, Mandelli F: Early deaths and anti-hemorrhagic treatments in acute promyelocytic leukemia. A GIMEMA retrospective study in 268 consecutive patients. Blood 75:2112, 1990.

84.
Goldberg MA, Ginsburg D, Mayer RJ, et al: Is heparin administration necessary during induction chemotherapy for patients with acute promyelocytic leukemia? Blood 69:187, 1987.

85.
Avvisati G, Wouter ten Cate J, Büller HR, Mandelli F: Tranexamic acid for control of haemorrhage in acute promyelocytic leukaemia. Lancet 2:122, 1989.

86.
Booth NA, Anderson JA, Bennett B: Plasminogen activators in alcoholic cirrhosis: demonstration of increased tissue type and urokinase type activator. J Clin Pathol 37:772, 1984.

87.
Himmelreich G, Dooijewaard G, Breinl P, et al: Evolution of urokinase-type plasminogen activator (u-PA) and tissue-type plasminogen activator (t-PA) in orthotopic liver transplantation (OLT). Thromb Haemost 69:56, 1993.

88.
Fletcher AP, Biederman O, Moore D, Alkjaersig N, Sherry S: Abnormal plasminogen-plasmin system activity (fibrinolysis) in patients with hepatic cirrhosis: its cause and consequences. J Clin Invest 43:681, 1964.

89.
Hayashi T, Kamogawa A, Ro S, et al: Plasma from patients with cirrhosis increases tissue plasminogen activator release from vascular endothelial cells in vitro. Liver 18:186, 1998.

90.
Violi F, Basili V, Ferro D, et al: Association between high values of D-dimer and tissue-plasminogen activator activity and first gastrointestinal bleeding in cirrhotic patients. Thromb Haemost 76:177, 1996.

91.
Segal HC, Hunt BJ, Cottam S, et al: Fibrinolytic activity during orthotopic liver transplantation with and without aprotinin. Transplantation 58:1356, 1994.

92.
Garcia-Huete L, Domenech P, Sabaté A, Martinez-Brotons F, Jaurrieta E, Figueras J: The prophylactic effect of aprotinin on intraoperative bleeding in liver transplantation: a randomized clinical study. Hepatology 26:1143, 1997.

93.
Soilleux H, Gillon M-C, Mirand A, Daibes M, Leballe F, Ecoffey C: Comparative effects of small and large aprotinin doses on bleeding during orthotopic liver transplantation. Anesth Analg 80:349, 1995.

94.
Boylan JF, Klinck JR, Sandler AN, et al: Tranexamic acid reduces blood loss, transfusion requirements, and coagulation factor use in primary orthotopic liver transplantation. Anesthesiology 85:1043, 1996.

95.
Kaspar M, Ramsay MA, Nguyen AT, Cogswell M, Hurst G, Ramsay KJ: Continuous small-dose tranexamic acid reduces fibrinolysis but not transfusion requirements during orthotopic liver transplantation. Anesth Analg 85:281, 1997.

96.
McKenna R, Bachmann F, Whittaker B, Gilson JR, Weinberg M Jr: The hemostatic mechanism after open-heart surgery: II. Frequency of abnormal platelet functions during and after extracorporeal circulation. J Thorac Cardiovasc Surg 70:298, 1975.

97.
Harker LA, Malpass TW, Branson HE, Hessel EA II, Slichter SJ: Mechanism of abnormal bleeding in patients undergoing cardiopulmonary bypass: acquired transient platelet dysfunction associated with selective alpha-granule release. Blood 56:824, 1980.

98.
Harker LA: Bleeding after cardiopulmonary bypass. N Engl J Med 314:1446, 1986.

99.
Wachtfogel YT, Kucich U, Hack CE, et al: Aprotinin inhibits the contact, neutrophil, and platelet activation systems during simulated extracorporeal perfusion. J Thorac Cardiovasc Surg 106:1, 1993.

100.
Khuri SF, Valeri CR, Loscalzo J, et al: Heparin causes platelet dysfunction and induces fibrinolysis before cardiopulmonary bypass. Ann Thorac Surg 60:1008, 1995.

101.
Williams GD, Bratton SL, Nielsen NJ, Ramamoorthy C: Fibrinolysis in pediatric patients undergoing cardiopulmonary bypass. J Cardiothorac Vasc Anesth 12:633, 1998.

102.
Kevy SV, Glickman RM, Bernhard WF, Diamond LK, Gross RE: The pathogenesis and control of the hemorrhagic defect in open heart surgery. Surg Gynecol Obstet 123:313, 1966.

103.
Soslau G, Horrow J, Brodsky I: Effect of tranexamic acid on platelet ADP during extracorporeal circulation. Am J Hematol 38:113, 1991.

104.
De Haan J, Van Oeveren W: Platelets and soluble fibrin promote plasminogen activation causing downregulation of platelet glycoprotein Ib/IX complexes: protection by aprotinin. Thromb Res 92:171, 1998.

105.
Munoz JJ, Birkmeyer NJO, Birkmeyer JD, O’Connor GT, Dacey LJ: Is e-aminocaproic acid as effective as aprotinin in reducing bleeding with cardiac surgery? A meta-analysis. Circulation 99:81, 1999.

106.
Horrow JC, Hlavacek J, Strong MD, et al: Prophylactic tranexamic acid decreases bleeding after cardiac operations. J Thorac Cardiovasc Surg 99:70, 1990.

107.
Horrow JC, Van Riper DF, Strong MD, Brodsky I, Parmet JL: Hemostatic effects of tranexamic acid and desmopressin during cardiac surgery. Circulation 84:2063, 1991.

108.
Karski JM, Teasdale SJ, Norman P, et al: Prevention of bleeding after cardiopulmonary bypass with high-dose tranexamic acid. Double-blind, randomized clinical trial. J Thorac Cardiovasc Surg 110:835, 1995.

109.
Horrow JC, Van Riper DF, Strong MD, Grunewald KE, Parmet JL: The dose-response relationship of tranexamic acid. Anesthesiology 82:383, 1995.

110.
Karski JM, Dowd NP, Joiner R, et al: The effect of three different doses of tranexamic acid on blood loss after cardiac surgery with mild systemic hypothermia (32°C). J Cardiothorac Vasc Anesth 12:642, 1998.

111.
Pugh SC, Wielogorski AK: A comparison of the effects of tranexamic acid and low-dose aprotinin on blood loss and homologous blood usage in patients undergoing cardiac surgery. J Cardiothorac Vasc Anesth 9:240, 1995.

112.
Boughenou F, Madi-Jebara S, Massonnet-Castel S, Benmosbah L, Carpentier A, Cousin MT: Antifibrinolytiques et prévention du saignement en chirurgie cardiaque valvulaire. Comparaison de l’acide tranexamique à l’aprotinine à haute dose. Arch Mal Coeur Vaiss 88:363, 1995.

113.
Penta de Peppo A, Pierri MD, Scafuri A, et al: Intraoperative antifibrinolysis and blood-saving techniques in cardiac surgery. Prospective trial of 3 antifibrinolytic drugs. Tex Heart Inst J 22:231, 1995.

114.
Menichetti A, Tritapepe L, Ruvolo G, et al: Changes in coagulation patterns, blood loss and blood use after cardiopulmonary bypass: aprotinin vs tranexamic acid vs epsilon aminocaproic acid. J Cardiovasc Surg 37:401, 1996.

115.
Landymore RW, Murphy JT, Lummis H, Carter C: The use of low-dose aprotinin, epsilon-aminocaproic acid or tranexamic acid for prevention of mediastinal bleeding in patients receiving aspirin before coronary artery bypass operations [letter]. Eur J Cardiothorac Surg 11:798, 1997.

116.
Misfeld M, Dubbert S, Eleftheriadis S, Siemens H-J, Wagner T, Sievers HH: Fibrinolysis-adjusted perioperative low-dose aprotinin reduces blood loss in bypass operations. Ann Thorac Surg 66:792, 1998.

117.
Lemmer JH Jr, Stanford W, Bonney SL, et al: Aprotinin for coronary bypass operations: efficacy, safety, and influence on early saphenous vein graft patency. A multicenter, randomized, double-blind, placebo-controlled study. J Thorac Cardiovasc Surg 107:543, 1994.

118.
Laub GW, Riebman JB, Chen C, et al: The impact of aprotinin on coronary artery bypass graft patency. Chest 106:1370, 1994.

119.
Havel M, Grabenwöger F, Schneider J, et al: Aprotinin does not decrease early graft patency after coronary artery bypass grafting despite reducing postoperative bleeding and use of donated blood. J Thorac Cardiovasc Surg 107:807, 1994.

120.
Bashein G, Nessly ML, Rice AL, Counts RB, Misbach GA: Preoperative aspirin therapy and reoperation for bleeding after coronary artery bypass surgery. Arch Intern Med 151:89, 1991.

121.
Klein M, Keith PR, Dauben H-P, et al: Aprotinin counterbalances an increased risk of peri-operative hemorrhage in CABG patients pre-treated with aspirin. Eur J Cardiothorac Surg 14:360, 1998.

122.
Ivert T, Intonti M, Stain-Malmgren R, Dumitrescu A, Blombäck M: Effects of aprotinin during cardiopulmonary bypass in patients treated with acetylsalicylic acid. Scand Cardiovasc J 32:289, 1998.

123.
Dietrich W, Dilthey G, Spannagl M, Jochum M, Braun SL, Richter JA: Influence of high-dose aprotinin on anticoagulation, heparin requirement, and celite- and kaolin-activated clotting time in heparin-pretreated patients undergoing open-heart surgery. A double-blind, placebo-controlled study. Anesthesiology 83:679, 1995.

124.
Sugiki M, Yoshida E, Anai K, Maruyama M: Activation of single-chain urokinase-type plasminogen activator by a hemorrhagic metalloproteinase, jararafibrase I, in Bothrops jararaca venom. Toxicon 36:993, 1998.

125.
Coll-Sangrona E, Arocha-Piñango CL: Fibrinolytic action on fresh human clots of whole body extracts and two semipurified fractions from Lonomia achelous caterpillar. Braz J Med Biol Res 31:779, 1998.

126.
Lobo de Araujo A, Donato JL, Bon C: Purification from Bothrops lanceolatus (fer de lance) venom of a fibrino(geno)lytic enzyme with esterolytic activity. Toxicon 36:745, 1998.

127.
Du XY, Pan H, Jin Y, Zhu H, Wu XF, Zhou YC: Purification, cDNA cloning and molecular characteristic of a fibrinolytic enzyme from the venom of Agkistrodon acutus. J Nat Toxins 7:159, 1998.

128.
Siigur J, Samel M, Tonismägi K, Subbi J, Siigur E, Tu AT: Biochemical characterization of lebetase, a direct-acting fibrinolytic enzyme from Vipera lebetina snake venom. Thromb Res 90:39, 1998.

129.
Premawardena AP, Seneviratne SL, Gunatilake SB, de Silva HJ: Excessive fibrinolysis: the coagulopathy following Merrem’s hump-nosed viper (Hypnale hypnale) bites. Am J Trop Med Hyg 58:821, 1998.

130.
Markland FS Jr: Snake venom fibrinogenolytic and fibrinolytic enzymes: an updated inventory. Registry of Exogenous Hemostatic Factors of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost 79:668, 1998.

131.
Walsh PN, Rizza CR, Matthews JM, et al: Epsilon-aminocaproic acid therapy for dental extractions in haemophilia and Christmas disease: a double blind controlled trial. Br J Haematol 20:463, 1971.

132.
Sindet-Pedersen S, Stenbjerg S: Effect of local antifibrinolytic treatment with tranexamic acid in hemophiliacs undergoing oral surgery. J Oral Maxillofac Surg 44:703, 1986.

133.
Lusher JM: Thrombogenicity associated with factor IX complex concentrates. Semin Hematol 28:3, 1991.

134.
Rainsford SG, Jouhar AJ, Hall A: Tranexamic acid in the control of spontaneous bleeding in severe haemophilia. Thromb Diath Haemorrh 30:272, 1973.

135.
Bennett AE, Ingram GIC, Inglish PJ: Antifibrinolytic treatment in haemophilia: a controlled trial of prophylaxis with tranexamic acid. Br J Haematol 24:83, 1973.

136.
Prentice CRM, Lindsay RM, Barr RD, et al: Renal complications in haemophilia and Christmas disease. Q J Med 40:47, 1971.

137.
van Itterbeek H, Vermylen J, Verstraete M: High obstruction of urine flow as a complication of the treatment with fibrinolysis inhibitors of haematuria in haemophiliacs. Acta Haematol 39:237, 1968.

138.
Williamson R, Eggleston DJ: DDAVP and EACA used for minor oral surgery in von Willebrand disease. Aust Dent J 33:32, 1988.

139.
Blombäck M, Johansson G, Johnsson H, Swedenborg J, Wabo E: Surgery in patients with von Willebrand’s disease. Br J Surg 76:398, 1989.

140.
Wahl MJ: Dental surgery in anticoagulated patients. Arch Intern Med 158:1610, 1998.

141.
Sindet-Pedersen S, Ramström G, Bernvil S, Blombäck M: Hemostatic effect of tranexamic acid mouthwash in anticoagulant-treated patients undergoing oral surgery. N Engl J Med 320:840, 1989.

142.
Sindet-Pedersen S, Gram J, Jespersen J: Characterization of plasminogen activators in unstimulated and stimulated human whole saliva. J Dent Res 66:1199, 1987.

143.
Hanss M, Ville D, Dechavanne M: Increased plasma tissue-type plasminogen activator levels in patients with chronic thrombocytopenia. Haemostasis 20:341, 1990.

144.
Gardner FH, Helmer RE: Aminocaproic acid. Use in control of hemorrhage in patients with amegakaryocytic thrombocytopenia. JAMA 243:35, 1980.

145.
Bartholomew JR, Salgia R, Bell WR: Control of bleeding in patients with immune and nonimmune thrombocytopenia with aminocaproic acid. Arch Intern Med 149:1959, 1989.

146.
Garewal HS, Durie BG: Anti-fibrinolytic therapy with aminocaproic acid for the control of bleeding in thrombocytopenic patients. Scand J Haematol 35:497, 1985.

147.
Fricke W, Alling D, Kimball J, Griffith P, Klein H: Lack of efficacy of tranexamic acid in thrombocytopenic bleeding. Transfusion 31:345, 1991.

148.
Liebman H, Chinowsky M, Valdin J, Kenoyer G, Feinstein D: Increased fibrinolysis and amyloidosis. Arch Intern Med 143:678, 1983.

149.
Meyer K, Williams EC: Fibrinolysis and acquired alpha-2 plasmin inhibitor deficiency in amyloidosis. Am J Med 79:394, 1985.

150.
Takahashi H, Koike T, Yoshida N, et al: Excessive fibrinolysis in suspected amyloidosis: demonstration of plasmin- a2-plasmin inhibitor complex and von Willebrand factor fragment in plasma. Am J Hematol 23:153, 1986.

151.
Sane DC, Pizzo SV, Greenberg CS: Elevated urokinase-type plasminogen activator level and bleeding in amyloidosis: case report and literature review. Am J Hematol 31:53, 1989.

152.
Liebman HA, Carfagno MK, Weitz IC, et al: Excessive fibrinolysis in amyloidosis associated with elevated plasma single-chain urokinase. Am J Clin Pathol 98:534, 1992.

153.
Haan J, Kluft C, Leebeek FWG, de Bart ACW, Buruma OJS, Roos RAC: Hereditary cerebral hemorrhage with amyloidosis–Dutch type: a study of fibrinolysis. Thromb Haemost 67:16, 1992.

154.
Ortel TL, Onorato JJ, Bedrosian CL, Kaufman RE: Antifibrinolytic therapy in the management of the Kasabach Merritt syndrome. Am J Hematol 29:44, 1988.

155.
Stahl RL, Henderson JM, Hooks MA, Martin LG, Duncan A: Therapy of the Kasabach-Merritt syndrome with cryoprecipitate plus intra-arterial thrombin and aminocaproic acid. Am J Hematol 36:272, 1991.

156.
McNicol GP, Fletcher AP, Alkjaersig N, Sherry S: The use of epsilon-aminocaproic acid, a potent inhibitor of fibrinolytic activity in the management of postoperative hematuria. J Urol 86:829, 1961.

157.
Nielsen JD, Gram J, Holm-Nielsen A, Fabrin K, Jespersen J: Post-operative blood loss after transurethral prostatectomy is dependent on in situ fibrinolysis. Br J Urol 80:889, 1997.

158.
Hedlund PO: Antifibrinolytic therapy with Cyklokapron in connection with prostatectomy. A double blind study. Scand J Urol Nephrol 3:177, 1969.

159.
Vinnicombe J, Shuttleworth KED: Aminocaproic acid in the control of haemorrhage after prostatectomy. A controlled trial. Lancet 1:230, 1966.

160.
Sharifi R, Lee M, Ray P, Millner SN, Dupont PF: Safety and efficacy of intravesical aminocaproic acid for bleeding after transurethral resection of prostate. Urology 27:214, 1986.

161.
Smith RB, Riach P, Kaufman JJ: Epsilon aminocaproic acid and the control of post-prostatectomy bleeding: a prospective double-blind study. J Urol 131:1093, 1984.

162.
Ward MG, Richards B: Complications of antifibrinolysis therapy after prostatectomy. Br J Urol 51:211, 1979.

163.
Haygood TA, Atkins R, Kennedy JA, Cutler RE: Aminocaproic acid treatment of prolonged hematuria following renal biopsy. Arch Intern Med 127:478, 1971.

164.
Pitts TO, Spero JA, Bontempo FA, Greenberg A: Acute renal failure due to high-grade obstruction following therapy with epsilon-aminocaproic acid. Am J Kidney Dis 8:441, 1986.

165.
Wymenga LF, van der Boon WJ: Obstruction of the renal pelvis due to an insoluble blood clot after epsilon-aminocaproic acid therapy: resolution with intraureteral streptokinase instillations. J Urol 159:490, 1998.

166.
Nilsson IM: Local fibrinolysis as a mechanism for haemorrhage. Thromb Diath Haemorrh 34:623, 1975.

167.
Larsson B, Liedholm P, Sjöberg N-O, Åstedt B: Increased fibrinolytic activity in the endometrium of patients using copper-IUD. Contraception 9:531, 1974.

168.
Nilsson L, Rybo G: Treatment of menorrhagia with epsilon aminocaproic acid. A double blind investigation. Acta Obstet Gynecol Scand 44:467, 1965.

169.
Callender ST, Warner GT, Cope E: Treatment of menorrhagia with tranexamic acid. A double-blind trial. Br Med J 4:214, 1970.

170.
Westrom L, Bengtsson LP: Effect of tranexamic acid (AMCA) in menorrhagia with intrauterine contraceptive devices. J Reprod Med 5:154, 1970.

171.
Kasonde JM, Bonnar J: Aminocaproic acid and menstrual loss in women using intrauterine devices. Br Med J 4:17, 1975.

172.
Tauber PF, Kloppel A, Goodpasture JC, Burns J, Ludwig H, Zaneveld LJ: Reduced menstrual blood loss by release of an antifibrinolytic agent from intrauterine contraceptive devices. Am J Obstet Gynecol 140:322, 1981.

173.
Ewenstein BM: The pathophysiology of bleeding disorders presenting as abnormal uterine bleeding. Am J Obstet Gynecol 175:770, 1996.

174.
Ong YL, Hull DR, Mayne EE: Menorrhagia in von Willebrand disease successfully treated with single daily dose tranexamic acid. Haemophilia 4:63, 1998.

175.
Rybo G, Westerberg H: The effect of tranexamic acid (AMCA) on postoperative bleeding after conization. Acta Obstet Gynecol Scand 51:347, 1972.

176.
Cox HT, Poller L, Thomson JM: Gastric fibrinolysis. A possible aetiological link with peptic ulcer. Lancet 1:1300, 1967.

177.
Wodzinski MA, Bardhan KD, Reilly JT, Cooper P, Preston FE: Reduced tissue type plasminogen activator activity of the gastroduodenal mucosa in peptic ulcer disease. Gut 34:1310, 1993.

178.
Götz JM, Ravensbergen JW, Verspaget HW, et al: The effect of treatment of Helicobacter pylori infection gastric mucosal plasminogen activators. Fibrinolysis 10 (suppl. 2):85, 1996.

179.
Herszenyi L, Plebani M, Carraro P, et al: Impaired fibrinolysis and increased protease levels in gastric and duodenal mucosa of patients with active duodenal ulcer. Am J Gastroenterol 92:843, 1997.

180.
Biggs JC, Hugh TB, Dodds AJ: Tranexamic acid and upper gastrointestinal haemorrhage—a double-blind trial. Gut 17:729, 1976.

181.
Barer D, Ogilvie A, Henry D, et al: Cimetidine and tranexamic acid in the treatment of acute upper-gastrointestinal-tract bleeding. N Engl J Med 308:1571, 1983.

182.
Bergqvist D, Dahlgren S, Hessman Y: Local inhibition of the fibrinolytic system in patients with massive upper gastrointestinal hemorrhage. Ups J Med Sci 85:173, 1980.

183.
von Holstein CCSS, Eriksson SBS, Kallén R: Tranexamic acid as an aid to reducing blood transfusion requirements in gastric and duodenal bleeding. Br Med J (Clin Res Ed) 294:7, 1987.

184.
Engqvist A, Broström O, von Feilitzen F, et al: Tranexamic acid in massive haemorrhage from the upper gastrointestinal tract: a double-blind study. Scand J Gastroenterol 14:839, 1979.

185.
Oka K, Tanaka K: Local fibrinolysis of esophagus and stomach as a cause of hemorrhage in liver cirrhosis. Thromb Res 14:837, 1979.

186.
Kondo M, Hotta T, Takemura S, Yoshikawa T, Fukumoto K: Treatment of ulcerative colitis by the direct administration of an antifibrinolytic agent as an enema. Hepatogastroenterology 28:270, 1981.

187.
Van Bodegraven AA, Tuynman HARE, Schoorl M, Kruishoop AM, Bartels PCM: Fibrinolytic split products, fibrinolysis, and factor XIII activity in inflammatory bowel disease. Scand J Gastroenterol 30:580, 1995.

188.
Kjeldsen J, Lassen JF, Brandslund I, Schaffalitzky de Muckadell OB: Markers of coagulation and fibrinolysis as measures of disease activity in inflammatory bowel disease. Scand J Gastroenterol 33:637, 1998.

189.
Almer S, Andersson T, Strom M: Pharmacokinetics of tranexamic acid in patients with ulcerative colitis and in healthy volunteers after the single instillation of 2 g rectally. J Clin Pharmacol 32:49, 1992.

190.
el-Bassiouni NE, el Bassiouny AE, el-Khayat HR, Akl MM, Omran SA: Hyperfibrinolysis in hepatosplenic schistosomiasis. J Clin Pathol 49:990, 1996.

191.
Tsementzis SA, Honan WP, Nightingale S, Hitchcock ER, Meyer CH: Fibrinolytic activity after subarachnoid haemorrhage and the effect of tranexamic acid. Acta Neurochir 103:116, 1990.

192.
Suzuki M, Kudo A, Otawara Y, Doi M, Kuroda K, Ogawa A: Fibrinolytic activity in the CSF and blood following subarachnoid haemorrhage. Acta Neurochir 139:1152, 1997.

193.
Ikeda K, Asakura H, Futami K, Yamashita J: Coagulative and fibrinolytic activation in cerebrospinal fluid and plasma after subarachnoid hemorrhage. Neurosurgery 41:344, 1997.

194.
Peltonen S, Juvela S, Kaste M, Lassila R: Hemostasis and fibrinolysis activation after subarachnoid hemorrhage. J Neurosurg 87:207, 1997.

195.
Kassell NF, Haley EC, Torner JC: Antifibrinolytic therapy in the treatment of aneurysmal subarachnoid hemorrhage. Clin Neurosurg 33:137, 1986.

196.
Roos YBWEM, Vermeulen M, Rinkel GJE, Algra A, van Gijn J: Systematic review of antifibrinolytic treatment in aneurysmal subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry 65:942, 1998.

197.
Vermeij FH, Hasan D, Bijvoet HWC, Avezaat CJJ: Impact of medical treatment on the outcome of patients after aneurysmal subarachnoid hemorrhage. Stroke 29:924, 1998.

198.
Janssens M, Joris J, David JL, Lemaire R, Lamy M: High-dose aprotinin reduces blood loss in patients undergoing total hip replacement surgery. Anesthesiology 80:23, 1994.

199.
Murkin JM, Shannon NA, Bourne RB, Rorabeck CH, Cruickshank M, Wyile G: Aprotinin decreases blood loss in patients undergoing revision or bilateral total hip arthroplasty. Anesth Analg 80:343, 1995.

200.
Hiippala S, Strid L, Wennerstrand M, et al: Tranexamic acid (Cyklokapron) reduces perioperative blood loss associated with total knee arthroplasty. Br J Anaesth 74:534, 1995.

201.
Jerndal T, Frisen M: Tranexamic acid (AMCA) and late hyphaema. A double blind study in cataract surgery. Acta Ophthalmol 54:417, 1976.

202.
McGetrick JJ, Jampol LM, Goldberg MF, Frenkel M, Fiscella RG: Aminocaproic acid decreases secondary hemorrhage after traumatic hyphema. Arch Ophthalmol 101:1031, 1983.

203.
Deans R, Noel LP, Clarke WN: Oral administration of tranexamic acid in the management of traumatic hyphema in children. Can J Ophthalmol 27:181, 1992.

204.
Rahmani B, Jahadi HR: Comparison of tranexamic acid and prednisolone in the treatment of traumatic hyphema. A randomized clinical trial. Ophthalmology 106:375, 1999.

205.
Rahmani B, Jahadi HR, Rajaeefard A: An analysis of risk for secondary hemorrhage in traumatic hyphema. Ophthalmology 106:380, 1999.

206.
Falbe-Hansen J Jr, Jacobsen B, Lorenzen E: Local application of an antifibrinolytic in tonsillectomy. A double-blind study. J Laryngol Otol 88:565, 1974.

207.
White A, O’Reilly BF: Oral tranexamic acid in the management of epistaxis. Clin Otolaryngol 13:11, 1988.

208.
Saba HI, Morelli GA, Logrono LA: Brief report: treatment of bleeding in hereditary hemorrhagic telangiectasia with aminocaproic acid. N Engl J Med 330:1789, 1994.

209.
Francis CW, Marder VJ: Physiologic regulation and pathologic disorders of fibrinolysis, in Hemostasis and Thrombosis. Basic Principles and Clinical Practice, 3rd ed, edited by RW Colman, J Hirsh, VJ Marder, EW Salzman, p 1076. Lippincott, Philadelphia, 1994.
Books@Ovid
Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology

Advertisements

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

%d bloggers like this: