What Is a Hemostatic Agent?

Hemostasis is defined as "blocking bleeding or bleeding through blood vessels or other parts of the body." Hemostasis improves hemostasis by improving the initial hemostatic process, stimulating fibrin formation or inhibiting fibrinolysis. Although the main method of hemostasis is infusion of platelets and coagulation factors, due to the decreasing supply of blood products and the need to consider the treatment methods already implemented, pharmaceutical preparations are still important supplements. The pharmacological effect of various hemostatic agents is to treat and prevent bleeding by preventing or reversing existing or acquired coagulation defects in patients with various problems.

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Hemostasis is defined as "blocking bleeding or bleeding through blood vessels or other parts of the body." Hemostasis improves hemostasis by improving the initial hemostatic process, stimulating fibrin formation or inhibiting fibrinolysis. Although the main method of hemostasis is infusion of platelets and coagulation factors, due to the decreasing supply of blood products and the need to consider the treatment methods already implemented, pharmaceutical preparations are still important supplements. The pharmacological effect of various hemostatic agents is to treat and prevent bleeding by preventing or reversing existing or acquired coagulation defects in patients with various problems.

Drug Name

Hemostatic

Whether prescription drugs

Non-prescription drugs

Athletes use with caution

Use with caution

Whether to include health insurance

Not included

Due to the increasing use of drugs that inhibit platelet and thrombin function in cardiovascular medicine, including clopidox, low molecular weight heparin, fondaparinux, melagatran, it is difficult for clinicians to reverse bleeding with standard treatments. See Table 1 for pharmacological effects and treatment methods of hemostatic agents. The potential use of newer therapeutic agents, including recombinant activating factor VIIa, is also being considered as a treatment for refractory bleeding.

Aprotinin is a serine protease inhibitor that can suppress a broad spectrum of proteases including fibrinolytic enzymes, trypsin, kallikrein, chymotrypsin, activated protein c, and thrombin. Aprotinin has been studied in cardiovascular surgery, and other studies including plastic surgery and liver transplantation have also reported aprotinin. Aprotinin is the only FDA-approved medical treatment to reduce blood transfusions in coronary artery bypass grafting (CABG) and combined heart-lung bypass (CPB). Multiple studies including nearly 45 studies in more than 7,000 patients have reported efficacy of aprotinin. Some of the small and well-designed design studies in the literature report adopt a meta-analysis approach. In high-risk, repetitive coronary bypass patients, a variety of studies have reported that aprotinin is effective in reducing blood loss and blood transfusion requirements. Although a retrospective analysis of earlier studies suggests high risk factors for myocardial infarction (MI) and end-of-transplant closure, two other prospective studies include Levy and colleagues' study of repetitive CABG patients and Alderman and his The concurrent study of patients with initial CABG did not support earlier reports. In a study of 287 patients with repetitive CABG surgery, there were important differences in exposure to whole blood products, in (high dose: aprotinin 2.2 ± 0.4U; low dose: aprotinin, 3.4 ± 0.9U; Blank group: 5.1 ± 0.9U; placebo: 10.3 ± 1.4U) There was no difference in the incidence of myocardial infarction between the treatment groups. Furthermore, an analysis of drug strategies in cardiac surgery reports that aprotinin can reduce mortality by a factor of two compared to the placebo group (probably (OR), 0.55; 95% confidence interval (CI) 0.34- 0.90) and reduce the frequency of repeated surgical explorations (OR, 0.37; 95% CI, 0.25-0.55). Any hemostatic agent that can reduce the need for bleeding and transfusion can significantly affect transplantation. Aprotinin is the only preparation that has been tested in multiple studies. There were no significant differences in graft patency in any of the three studies after surgery. Alderman and colleagues report the effects of aprotinin on transplant patency, myocardial infarction, and blood loss in patients undergoing the first combination of CABG and CPB.

Patients were randomly assigned to receive aprotinin (n = 436) or placebo (n = 434). Transplant angiography was performed postoperatively. Electrocardiograms, myocardial enzymes, and blood loss and supplementation were all evaluated. Aprotinin reduced pleural fluid by 43% (p <0.0001) and 49% red blood cell transfusion requirement (p <0.0001) in 796 estimable patients. Aprotinin was estimated in 703 saphenous vein transplant patients Occlusions occurred in 15.4% of the enzyme-treated group and 10.9% of the placebo group. (P = 0.03) After adjusting for risk factors associated with venous graft occlusion, the risk ratio for the aprotinin and placebo group decreased from 1.07 to 1.05 (90% CI, 0.6-1.8). These factors included women, Lack of prior aspirin treatment and distal vascular quality. In the United States, there is no difference in transplant patency. Occlusion occurred in 9.4% of the aprotinin group and 9.5% of the placebo group (p = 0.72). In Denmark and Israel, patients there had more adverse characteristics, with an occlusion rate of 23% in the aprotinin group and 12.4% in the placebo group (p = 0.01). Aprotinin did not affect the incidence of myocardial infarction (suppression Peptidase, 2.9%; placebo, 3.8%) or lethality (aprotinin, 1.4%; placebo, 1.6%)

Miller and his collaborators report the hemostatic and economic effects of using aprotinin in children undergoing repeated cardiac surgery and CPB. The effect of reducing the blood product input, shortening the skin healing time and shortening the time in the intensive care unit and hospital stay in the aprotinin treatment group, and more importantly, the cost of the high-dose group patients finally reduced by an average of nearly $ 2500.

Meta analysis

Levi and his collaborators report on the three most commonly used pharmacological strategies to reduce peripheral blood loss (aprotinin, lysine analogs, (aminocaproic acid and tranexamic acid), and desmopressin) Meta analysis of all randomized, controlled experiments. Studies include clinical trials reporting at least one clinically relevant outcome (mortality, thoracotomy, rate of patients receiving blood transfusions, or myocardial infarction) in addition to peripheral blood loss. In addition, an independent meta-analysis was used to study complex heart surgery. They identified 72 trials that met admission criteria (8409 patients). With aprotinin, the mortality rate was reduced by almost two times compared to the placebo group (OR, 0.55; 95% CI, 0.34-0.90). Aprotinin and lysine analogs reduced the frequency of surgical repeat exploration. (OR, 0.37; 95% CI, 0.25-0.55; and OR, 0.44; 95% CI, 0.22-0.90) These two treatments also significantly reduced the proportion of patients receiving any allogeneic blood transfusion. Aprotinin did not increase the risk of myocardial infarction. Levi and his colleagues have suggested that pharmacological strategies to reduce blood loss during cardiac surgery, especially with aprotinin and lysine analogues, also reduce mortality, the need for thoracotomy and the patients receiving blood transfusions. proportion. In a recent International Study of Meta-analysis of Perioperative Blood Transfusions (ISPOT), they performed 45 experiments in 5805 patients, demonstrating that aprotinin reduces the need for allogeneic blood transfusions during cardiac surgery. Combined with all doses of aprotinin, the total relative ratio is 0.31 (range, 0.25-0.39; p = 0.0006)

Aprotinin has been extensively evaluated in multiple double-blind, placebo-controlled, multicenter studies on cardiac and orthopedic surgery, and it is the only agent approved to reduce bleeding in CABG surgery in the United States. From studies in the United States, aprotinin does not increase the risk of myocardial infarction, graft occlusion, stroke or renal insufficiency, and may actually reduce the risk of stroke. The mechanism in this regard is complex, but aprotinin has anti-inflammatory properties due to its complex series of protease inhibition. Like other peptides, aprotinin is at risk for allergic reactions, and it is not only dangerous for the first contact. Danger may occur for the time after the first contact. Aprotinin is also safe and effective in reducing blood loss in many plastic surgery procedures. Due to tissue damage and contact activation in a large number of plastic surgery operations, a large number of studies have explored the effectiveness and safety of aprotinin. Furthermore, these patients are an important model to assess the side effects of hemostatic agents due to the potential dangers of thrombotic complications during plastic surgery, including deep vein thrombosis.

Tranexamic acid

-Aminocaproic acid (EACA) and tranexamic acid (TA) are synthetic lysine analogs to inhibit plasminogen and / or plasmin-mediated fibrinolysis. TA is ten times more potent than EACA, and the anti-fibrinolytic capacity of lysine analogs has been studied in cardiac surgery and cardiopulmonary bypass surgery by studying preventative blood loss prevention and reducing bleeding. A recent meta-analysis of 12 randomized trials of patients undergoing cardiac surgery showed that TA reduced the proportion of patients receiving heterologous red blood cell transfusions. In the same meta-analysis, only three studies (118 patients) showed that EACA was appropriate and the relative comparison was not significant. Unfortunately, there are very few prospective studies analyzing data on the safety of these formulations. No increase in myocardial infarction was found in the ISPOT's meta-analysis that included 12 heart experiments, but these were only retrospective analyses that were not carefully designed for safety. Although from the experimental data of the randomized control group, EACA is quite limited. A combined analysis of four cardiac surgeries (548 patients in total) showed a significant increase in one myocardial infarction (OR, 2.5; 95% CI, 1.06-5.86; p = 0.035). In noncardiac surgery, three randomized controlled trials evaluated TA in plastic surgery. All showed a significant reduction in the need for blood transfusions, and did not indicate any increase in deep vein thrombosis (DVT) or pulmonary thrombosis. The proportion was 97 in the TA group, 6 patients with thrombosis (6.2%), and 94 in the placebo group, 9 patients with thrombosis (9.6%) (OR, 0.71; 95% CI, 0.26--1.96; p = 0.51) . Three trials of preventive use of TA to reduce blood loss in patients undergoing liver transplantation did not find any complications of thrombosis in the TA group or the control group. Although thrombosis of the main blood vessels is common in patients with liver disease, because fibrinolytic status is usually self-limiting in liver transplant patients, there is still a view that EACA exaggerates this tendency. Kang and his colleagues gave EACA to 20 patients undergoing liver transplantation, compared to the rate of thrombosis (3.9%) in 77 of the control group. No thrombus was observed in this experiment. Munoz and his colleagues performed a meta-analysis of 52 randomized clinical trials published from 1985 to 1998, which included the use of EACA (n = 9) and aprotinin (n = 46) in cardiac surgery. The original results included loss of whole blood, red blood cell transfusion rate and total volume, repeat detection rate, stroke rate, myocardial infarction, and mortality. Unfortunately, the results of EACA are five times that of aprotinin, and most EACA researchers are patients who report a first CABG operation with little bleeding. The authors reported significant reductions after all postoperative infusions of EACA (a 61% reduction from the placebo group) and high-dose aprotinin (62% reduction). In these studies, data from patients treated with aprotinin included a series of repeated sternotomy, valvular surgery, and more complex patients, while the EACA-treated group was a small number of patients with initial CABG surgery. Although the two drugs are similar in reducing the rate of repeated exploration, aprotinin must be used in high doses. Finally, most of the methods used to study the incidence of side effects in EACA-treated patients are not consistent with the rigorous evaluation methods of clinical trials initiated by the FDA to evaluate the safety of aprotinin.

Desmopressin is used to prevent and treat bleeding or moderate disease in patients with VWD

Coagulation drugs are used to control bleeding problems in patients with hemophilia, VWD, or inhibitors that require anti-hemophilia factors including anti-hemophilia factor concentrates, F IX concentrates, FVIIa and F IX. Although these drugs are specifically modified to serve patients with hemophilia, they can also be used to control the acute bleeding phase during cardiovascular and non-cardiovascular surgery. The most reported are recombination that is activated by FVIIa (rFVIIa; NovoSeven, Novo Nordisk, Princeton, New Jersey), improved for the treatment of hemorrhagic conditions in patients with hemophilia with inhibitors, and Life-threatening, uncontrollable blood loss promotes hemostasis. In the pre-hemostatic phase, the effect of rFVIIa is regulated by forming complexes with tissue factor (TF). TF is a transmembrane glycoprotein expressed in subendothelial cells after tissue damage. FVIIa in the circulation accounts for about 1% of circulating FVII and is inactive. It is activated after binding to TE and activates FX to FXa, leading to the formation of thrombin (FIIa) and the formation of fibrin and PLT. RFVIIa has been shown to give patients with multiple hemostatic disorders with many different effects including excess thrombosis on the surface of activated PLTs and localized wounds. Many cases report that patients with dysfunction of hemostatic factors and PLTs, whether congenital or acquired, have been treated with rFVIIa during cardiovascular and non-cardiovascular surgery when life-threatening and uncontrollable bleeding occurs. Although rFVIIa has been reported to treat a variety of coagulopathy, it is now being improved to treat inhibitors of hemophilia. Although 90 ug / Kg is the initial dose for treating hemophilia, lower doses of 30-45 ug / Kg have been reported to be more effective for surgical patients. We need further research to evaluate the dose, safety, and efficacy of perioperative rFVIIa use.

Hemostasis enhances hemostasis through multiple mechanisms including improving the initial process of coagulation, promoting thrombosis and / or fibrin formation, or preventing fibrinolysis. Although coagulation factors are the backbone of treatment methods, drugs are also an important adjuvant therapy. For example, blood products are becoming increasingly scarce. New long-acting anticoagulants and PLTs inhibitors are increasingly used, and alternatives need to be considered. Therapies are used to treat difficult-to-control bleeding, and preventive treatment for such bleeding is no longer effective. Aprotinin has been widely studied for prophylactic administration, which is of great value in terms of safety and efficacy. Lysine analog fibrinolytic inhibitors have also been extensively studied and have been shown to be effective together with TA. Only a very small amount of safety-related data relates to these drugs. DDAVP can increase VWF and is often used as a hemostatic agent, but there is little data to show that this effect is effective, especially for the treatment of major bleeding during cardiac surgery. Because in vivo coagulation occurs via TF and FVII (a), rFVIIa has developed into a hemostatic precursor, and numerous reports indicate that in uncontrolled clinical experimental studies of severe and complex coagulation defects, life-threatening, uncontrollable bleeding It works. The more widespread use of this drug for bleeding in patients without significant coagulation defects is the subject of today's clinical studies.