【全文发布】《新英格兰杂志》综述全文（中文版）：大量失血的预防与治疗
2010-01-12 09:34:56 AM
全文共分为十部分，请各位战友认领翻译。
第一部分
In a medical setting, surgery is the most common cause of major blood loss, defined as a loss of 20% of total blood olume or more. In particular, cardioascular procedures, lier transplantation and hepatic resections, and major orthopedic procedures including hip and knee replacement and spine surgery, are associated with seere bleeding. Excessie blood loss may also occur for other reasons, such as trauma. Indeed, bleeding contributes to approximately 30% of trauma-related deaths.1 Bleeding in critical locations, such as an intracerebral hemorrhage, may also pose a major clinical challenge.
Seere bleeding often requires blood transfusion. Een when the benefits of transfusion outweigh the risks (e.g., mismatched transfusion, allergic reactions, transmission of infections, and acute lung injury),2 strategies to minimize the use of limited resources such as blood products are essential. The most obious and probably the most effectie strategy is to improe surgical and anesthetic techniques. For example, lier transplantation, a procedure that once required transfusion of large amounts of blood products, now has relatiely small transfusion requirements in most instances.
Ruling out abnormalities of hemostasis in a patient with bleeding is also essential, because such problems can often be corrected by replacing the defectie components of the hemostatic system. Howeer, cases of excessie blood loss in which no surgical cause or abnormalities in hemostasis can be identified require pharmacologic strategies, which can be broadly diided into preoperatie prophylaxis for operations that confer a high risk of bleeding and interentions for massie, refractory bleeding. The medications that hae been most extensiely ealuated as hemostatic agents include the antifibrinolytic lysine analogues aminocaproic acid and tranexamic acid; aprotinin, a boine-deried protease inhibitor; and desmopressin, a synthetic analogue of the antidiuretic hormone that raises the plasma leels of factor III and on Willebrand factor.3 In addition, recombinant actiated factor II appears to be efficacious in an array of clinical situations associated with seere hemorrhage.4 The safety of aprotinin, the most widely used of these agents, has been questioned because of concerns about renal and cardioascular aderse eents.5
Most trials of hemostatic agents hae been designed to assess therapeutic efficacy, but they were not optimally designed to assess potential toxic effects, so definitie safety data are lacking for all hemostatic agents. Many trials of these agents hae used perioperatie blood loss and other measures that are not the most clinically releant end points, and many published trials were not powered to assess more clinically releant outcomes such as mortality or the need for reoperation. We reiew the therapeutic benefits of hemostatic drugs and consider the risk of aderse eents. In particular, we consider thrombotic complications, which constitute a major concern when agents that potentiate hemostasis are administered.
第二部分
Antifibrinolytic Agents
Approximately 5% of patients undergoing cardiac surgery require reexploration because of excessie blood loss; indeed, bleeding during and after cardiac surgery is an established marker of increased morbidity and mortality.6,7,8 Pharmacologic strategies are therefore often used to minimize blood loss during cardiac surgery. Aprotinin (a direct inhibitor of the fibrinolytic enzyme plasmin) is the only drug reported to minimize transfusion requirements in coronary-artery bypass grafting and approed by the Food and Drug Administration (FDA). Aminocaproic acid and tranexamic acid are also used, but they hae not been approed by the FDA for this indication. The mechanism of action of these agents is illustrated in Figure 1. Table 1 lists the most frequently used dosages of antifibrinolytic agents.
Figure 1. Mode of Action of Lysine Analogues (Aminocaproic Acid and Tranexamic Acid).
Actiation of plasminogen by endogenous plasminogen actiators results in plasmin, which causes degradation of fibrin. Binding of plasminogen to fibrin makes this process more efficient and occurs through lysine residues in fibrin that bind to lysine-binding sites on plasminogen (Panel A). In the presence of lysine analogues, these lysine-binding sites are occupied, resulting in an inhibition of fibrin binding to plasminogen and impairment of endogenous fibrinolysis (Panel .
Table 1. Mechanism of Action and Intraenous Doses of Antifibrinolytic Agents Used in Cardiac Surgery to Minimize Blood Loss and Transfusion Requirements.
Efficacy of Antifibrinolytic Agents
After the first study in 1987,9 more than 70 randomized, controlled trials that included from 20 to 796 patients (median, 75) confirmed and established the efficacy of aprotinin for limiting the requirements for transfusion of red cells, platelets, and fresh-frozen plasma in patients undergoing cardiac surgery. We examine in depth four trials chosen for their size and design.
In a study of 796 patients who were randomly assigned to receie aprotinin or placebo during primary coronary-artery bypass grafting, aprotinin was associated with reduced blood loss (mean [±SD], 664±1009 ml, s. 1168±1022 ml in the placebo group). Aprotinin also was associated with a decreased rate of use of any blood product (40%, s. 58% in the placebo group).10 In a randomized, placebo-controlled trial inoling 704 patients, treatment with aprotinin was associated with a decrease in mean perioperatie blood loss (832±50 ml, s. 1286±52 ml in the placebo group) and a reduction in the proportion of patients requiring any transfusion (35% s. 55%).11 Two trials recruited patients who were at increased risk for bleeding because they were undergoing repeat cardiac surgery.12,13 On aerage, patients who receied aprotinin needed between 1.6 and 2 units of blood products, whereas patients who receied placebo needed between 10 and 12 units.12,13 Similar findings with aprotinin hae been reported in many other placebo-controlled trials, with a reduction in perioperatie blood loss ranging from 50 to 1350 ml (median reduction, 400 ml) and a reduction by a factor of 1.5 to 3 in the proportion of patients requiring any transfusion.14,15,16,17,18,19,20,21,22,23,24,25
第三部分
Randomized trials of tranexamic acid or aminocaproic acid are much less numerous than trials of aprotinin.26,27,28,29,30,31 In the largest trial of tranexamic acid, 210 patients were randomly assigned to receie tranexamic acid (at a dose of 10 g) or placebo. Administration of tranexamic acid resulted in a 69% reduction in red-cell transfusions, and the proportion of patients requiring any blood product was 12.5% in the tranexamic acid group as compared with 31.1% in the control group.31
There hae also been meta-analyses and systematic reiews of the efficacy of antifibrinolytic agents.32,33,34,35,36 Table 2 summarizes the results of a Cochrane reiew. As compared with placebo, the use of aprotinin or tranexamic acid, but not of aminocaproic acid, reduced the need for blood transfusion by 30% and saed approximately 1 unit of blood per operation.36 There was no difference in efficacy between low-dose and high-dose regimens of aprotinin (Table 1), whereas the large ariations in dosages of tranexamic acid and aminocaproic acid precluded the ealuation of the relationship between dosage and efficacy. In terms of more clinically releant eents, the relatie risk of reoperation for excessie bleeding was significantly reduced among patients who receied aprotinin, as compared with those who receied placebo, although mortality was not affected. There was a significant reduction in these eents with either tranexamic acid or aminocaproic acid.36
Table 2. Results of the Cochrane Reiew of the Effect of Antifibrinolytic Agents on Clinical Eents among Patients Undergoing Major Surgical Procedures
Thus, the results of controlled trials and reiews indicate that antifibrinolytic drugs are effectie hemostatic agents in cardiac surgery. Reductions in both transfusion requirements and reoperation for bleeding appear to be confirmed by the narrow confidence interals of the odds ratios that are indicators of the relatie risks (Table 2). There are not enough efficacy data to draw definitie conclusions regarding the use of antifibrinolytic agents in other situations.
Safety of Antifibrinolytic Agents
There hae been criticisms that many trials of the efficacy of aprotinin in cardiac surgery were unnecessarily carried out (and reported) after the transfusion-sparing efficacy was unequiocally established and that such studies should hae focused instead on the more cogent and unsettled issue of safety.37,38 Aderse eents, particularly thrombotic complications, are expected when a major regulatory system such as the fibrinolytic system is pharmacologically inhibited; this is especially true in patients undergoing cardiac surgery, because they often hae underlying atherothrombotic disease.
Table 3, which summarizes the risks of complications when antifibrinolytic agents are administered, shows that none of the aderse eents examined was significantly increased.36 Howeer, a few early studies indicated that the use of aprotinin could lead to an increase in cases of postoperatie renal dysfunction, possibly through the inhibition of kallikrein and other endogenous asodilators, with a resultant reduction of renal blood flow.24,39,40
Table 3. Results of the Cochrane Reiew of the Effect of Antifibrinolytic Agents on Aderse Eents among Patients Undergoing Major Surgical Procedures.
第四部分
The risk of serious aderse eents associated with aprotinin was recently highlighted by the results of a nonrandomized, obserational study inoling 4374 patients who underwent electie coronary-artery bypass surgery.5 That study, which compared aprotinin, aminocaproic acid, and tranexamic acid with no treatment, used the propensity-score adjustment method to balance the coariates and thus reduce bias that could arise if sicker patients selectiely receied one agent oer another. The results indicated that, as compared with no treatment, aprotinin (but neither aminocaproic acid nor tranexamic acid) doubled the risk of seere renal failure, increased the risk of myocardial infarction or heart failure by 55%, and was associated with a nearly doubled increase in the risk of stroke or other cerebroascular eents. That study confirmed that the three antifibrinolytic agents reduced blood loss to a similar degree, but aderse eents were much more frequent with aprotinin than with the other agents. Much debate followed the publication of the study,41,42,43,44 which was criticized on the grounds that it was obserational, was carried out in many different countries and institutions, and was poorly controlled with respect to known determinants of outcome such as the use or nonuse of antithrombotic and inotropic drugs, the duration of cardiopulmonary bypass, and the amounts of blood transfused.
Howeer, other recent studies hae also reported aderse renal effects of aprotinin. A reiew of randomized trials conducted from 1991 to 2005 reported that patients who receied aprotinin had a 9% rate of renal failure (defined as the need for dialysis or a postoperatie increase in the serum creatinine leel of at least 2.0 mg per deciliter [176.8 µmol per liter]) and that renal dysfunction (defined as an increase in creatinine of 0.5 to 1.9 mg per deciliter [44.2 to 168.0 µmol per liter]) occurred in 12.9% of patients receiing aprotinin as compared with 8.4% of controls (relatie risk, 1.47; 95% confidence interal [CI], 1.12 to 1.94; P<0.001).41 An obserational surey commissioned by the manufacturer showed similar rates of renal dysfunction and renal failure among 67,000 patients who receied aprotinin.45
Although Mangano et al.5 and the authors of preious systematic reiews report that aminocaproic acid and tranexamic acid appear to be relatiely safe,32,33,34,35,36 the numbers of trials and study participants were much smaller for these drugs than for aprotinin. Thus, confidence with regard to safety issues is not solid, especially with respect to thrombosis. Most important, trials comparing aprotinin with lysine analogues hae been too few and too small.46,47,48,49 An independently funded, randomized clinical trial with three study groups is being conducted in Canada. The Blood Conseration using Antifibrinolytics: A Randomized Trial in a Cardiac Surgery Population (BART) study, which is still enrolling patients, plans to enroll 2970 patients undergoing high-risk cardiac surgery to determine whether aprotinin is superior to aminocaproic acid or tranexamic acid in reducing the risk of massie postoperatie bleeding.50 Secondary end points are mortality from all causes and aderse eents such as cardioascular disease and renal failure.50
第五部分
On the basis of all the data reported thus far, there is abundant, solid eidence that aprotinin reduces perioperatie and early postoperatie blood loss and transfusion requirements in patients undergoing cardiac surgery. Howeer, despite the large number of clinical trials inoling this agent, its effectieness in decreasing the need for reoperation has been reported only in reiews,36 and eidence of its effect on mortality is lacking. It is regrettable that the inexpensie lysine analogues hae been less thoroughly inestigated as of this writing, because it appears likely that these agents are at least as efficacious as aprotinin. The uncertainty about aprotinin's safety remains a substantial concern. Until the results of the Canadian trial are aailable,50 aprotinin remains the hemostatic agent of choice. Howeer, it should be used only when excessie perioperatie and early postoperatie blood loss is predicted (e.g., in the case of a complex operation or special clinical circumstances such as the use of antiplatelet agents).
Eidence of the efficacy of lysine analogues is not as solid as that for aprotinin, so these agents should be used only as a second choice in high-risk cardiac surgery. There is definitely no role for either aprotinin or other hemostatic agents in noncomplex coronary-artery bypass surgery, een though in many cases an off-pump procedure is used, which reduces blood loss and transfusion requirements.51,52 The FDA has warned that it is important to monitor patients receiing aprotinin for renal, cardiac, and brain toxic effects and that aprotinin should be used only when the clinical benefit of reducing blood loss is essential to medical management and outweighs any risk.53
Recombinant Actiated Factor II
Recombinant actiated factor II (rFIIa) is thought to act locally at the site of tissue injury and ascular-wall disruption by binding to exposed tissue factor, generating small amounts of thrombin that are sufficient to actiate platelets4 (Figure 2). The actiated platelet surface can then form a template on which rFIIa directly or indirectly mediates further actiation of coagulation, ultimately generating much more thrombin and leading to the conersion of fibrinogen to fibrin.54,55 Clot formation is stabilized by the inhibition of fibrinolysis due to rFIIa-mediated actiation of thrombin-actiatable fibrinolysis inhibitor.56
Figure 2. Mechanism of Action of Recombinant Factor IIa.
When the essel wall is disrupted, subendothelial tissue factor becomes exposed to circulating blood and may bind factor IIa (Panel A). This binding actiates factor X, and actiated factor X (factor Xa) generates small amounts of thrombin. The thrombin (factor IIa) in turn actiates platelets and factors and III. Actiated platelets bind circulating factor IIa (Panel , resulting in further factor Xa generation as well as actiation of factor IX. Actiated factor IX (factor IXa) (with its cofactor IIIa) yields additional factor Xa. The complex of factor Xa and its cofactor a then conerts prothrombin (factor II) into thrombin (factor IIa) in amounts that are sufficient to induce the conersion of fibrinogen to fibrin.
第六部分
Efficacy of rFIIa
Initially, rFIIa was licensed for the treatment of bleeding in patients with hemophilia who had antibodies inactiating factor III or IX.4 More recently, this agent has been used extensiely in patients with major hemorrhage from surgery, trauma, or other causes.57 A small, controlled clinical trial showed that rFIIa could minimize perioperatie blood loss and transfusion requirements in patients undergoing transabdominal prostatectomy, an operation that is often associated with major blood loss.58 In that trial, 36 patients were randomly assigned to receie a single preoperatie injection of rFIIa (20 or 40 µg per kilogram of body weight) or placebo. Administration of the actie drug resulted in a significant reduction of blood loss (50%) and eliminated the need for transfusion, which was required in approximately 60% of patients who receied placebo.58
Additional studies hae focused on patients undergoing orthotopic lier transplantation. An open-label pilot study inoling six patients showed a marked reduction in transfusion requirements among those who receied a single dose of rFIIa (80 µg per kilogram) as compared with matched historical controls.59 Howeer, a subsequent randomized, placebo-controlled trial ealuating two different doses of rFIIa (60 and 120 µg per kilogram) showed no reduction in transfusion requirements among 182 lier-transplant recipients, although red-cell transfusion was aerted in 8.4% of patients who receied rFIIa but in none of the patients in the placebo group.60 Two randomized, controlled trials of rFIIa (up to 100 µg per kilogram at eery second hour of surgery) in patients with cirrhosis or normal lier function who were undergoing major lier resection did not show a significant effect of rFIIa on either the olume of blood products administered or the percentage of patients requiring transfusion.61,62
In addition, rFIIa was ealuated in a randomized, controlled study inoling 20 patients undergoing noncoronary cardiac surgery requiring cardiopulmonary bypass.63 Administration of rFIIa at a dose of 90 µg per kilogram after discontinuation of bypass significantly reduced the need for blood transfusion (relatie risk of any transfusion, 0.26; 95% CI, 0.07 to 0.90). In addition, a propensity score–matched, case–control study inoling 51 patients with massie blood loss after cardiac surgery showed a significant decrease in blood loss and requirements for blood products after the administration of rFIIa (at a dose of 35 to 70 µg per kilogram).64 In this study, howeer, the incidence of acute renal dysfunction among patients receiing rFIIa was 2.4 times that in the control group, although there were no significant differences between the two groups with regard to other aderse eents.64
Seeral case reports and case series suggest that rFIIa is also useful in reducing major blood loss in patients with trauma.65 A placebo-controlled trial inoling 143 patients with seere blunt trauma showed that three successie doses of rFIIa (200, 100, and 100 µg per kilogram) significantly reduced red-cell transfusion (mean reduction, 2.6 units) and reduced the proportion of patients in whom massie transfusion, defined as more than 20 units of red cells, was required (14% of treated patients s. 33% of controls).66 Howeer, a parallel trial inoling 134 patients with penetrating trauma showed no significant effects.66
第七部分
Studies hae also ealuated rFIIa for the treatment of spontaneous intracranial hemorrhage, a condition for which there is a paucity of effectie therapeutic options.67 A dose-finding trial inoling 400 patients showed that as compared with placebo, rFIIa was associated with a slower increase in the size of intracerebral hematoma. More important, there was a 35% reduction in mortality and an improed disability score at 90 days in patients who receied rFIIa.67 Unfortunately, these promising early results were not confirmed in a subsequent phase 3, randomized, controlled trial inoling 821 patients.68 A preliminary report indicated that there was a significant reduction in the size of the intracerebral hematoma but with no effect on mortality and seere disability on day 90, the primary end point of the study.68 The manufacturer has not sought regulatory approal for rFIIa for the treatment of intracerebral hemorrhage.
This agent has also been studied in patients with bleeding esophageal arices and portal hypertension, a combination that constitutes another major clinical challenge. In a randomized, controlled trial inoling 245 patients with cirrhosis and upper gastrointestinal bleeding (66% of whom had bleeding arices) who were being treated with standard endoscopic and pharmacologic interentions, the administration of rFIIa (eight consecutie doses of 100 µg per kilogram within 30 hours after the initiation of treatment) was not more effectie than placebo with respect to the primary composite end point (failure to control bleeding within 24 hours and failure to preent rebleeding or death within the first 5 days).69 Howeer, in a subgroup of patients with more seere cirrhosis (classified as Child class B or C), rFIIa was associated with a decrease in the proportion of patients reaching the composite end point (8%, s. 23% in the control group; P=0.03). Furthermore, none of the patients treated with rFIIa had rebleeding within 24 hours, whereas rebleeding occurred in 11% of patients in the control group (P=0.01).69
Many case reports and case series hae examined the use of rFIIa in patients with excessie or life-threatening blood loss occurring in an array of clinical settings.57 Howeer, no randomized, controlled clinical trials hae been completed, which is not surprising, gien the difficulty of performing meaningful studies in such heterogeneous situations. Many reports claim that the use of rFIIa resulted in rapid reduction of blood loss or a decrease in transfusion requirements after other therapeutic measures had failed. Although many of these reports appear to be compelling, it is difficult to assess the usefulness of rFIIa properly, since publication bias in case reports and series is likely.
第八部分
Safety of rFIIa
Controlled clinical trials hae shown that the incidence of thrombotic complications among patients who receied rFIIa was relatiely low and similar to that among patients who receied placebo.70 Howeer, most studies of rFIIa inoled patients who had impaired coagulation or who were at low risk for thrombosis. In one trial inoling patients with conditions such as intracerebral hemorrhage and a much higher risk of thrombosis, 7% of patients receiing rFIIa had serious thromboembolic eents — mainly myocardial infarction or ischemic stroke — as compared with 2% of those receiing placebo.67 Midway through this trial, an exclusion criterion changed. Initially, only patients with thrombotic disease within 30 days before enrollment were excluded, but at the midpoint, all patients with any history of thrombotic disease were excluded, which may hae obscured safety concerns associated with the use of rFIIa. A reiew based on the FDA MedWatch database indicated that thromboembolic eents hae occurred in both the arterial and enous systems, particularly in patients with diseases other than hemophilia in whom rFIIa was used on an off-label basis.71 A total of 54% of the thromboembolic eents were arterial thrombosis (in most cases, stroke or acute myocardial infarction); enous thromboembolism (in most cases, enous thrombosis or pulmonary embolism) occurred in 56% of patients. In 72% of the 50 reported deaths, thromboembolism was considered the probable cause. It is not clear to what extent the clinical conditions requiring the use of rFIIa may hae contributed to the risk of thrombosis.71 These findings proide eidence of an increased risk of thrombotic complications that may offset the potential benefit of rFIIa in patients with seere blood loss.
The aailability of rFIIa has expanded the treatment options for acute hemorrhage in patients with conditions other than hemophilia. This agent is not a panacea, but it has efficacy in patients with trauma and excessie bleeding that is resistant to other treatments. Howeer, the promising results obtained so far must be substantiated by confirmatory trials, and studies of the cost-effectieness of this expensie agent are also warranted. The many published cases of dramatic success in patients with arious types of acute hemorrhages, albeit conincing and rewarding for the inoled clinicians, should be iewed with caution in terms of constituting clinically directie eidence. Attempts are being made to improe the potency and efficacy of rFIIa further by engineering the molecule through DNA technology, but clinical trials designed to establish increased efficacy and safety remain to be performed.72,73
第九部分
Other Interentions
Desmopressin was originally deeloped and licensed for the treatment of inherited defects of hemostasis.74,75,76 This drug, gien by slow intraenous infusion at a dose of 0.3 µg per kilogram, acts by releasing ultralarge on Willebrand factor multimers from endothelial cells, leading to an increase in plasma leels of on Willebrand factor and associated factor III and an enhancement of primary hemostasis.77,78 The strongest eidence of efficacy is in the preention and treatment of bleeding in patients with mild hemophilia A and on Willebrand's disease.75,76 In 1986, Salzman et al.79 showed that as compared with placebo, desmopressin reduced blood loss and transfusion requirements by approximately 30% during complex cardiac surgery. Subsequent attempts to reproduce these findings were ariable; most did not confirm the marked benefit originally reported.80,81,82 Oerall, there hae been 18 trials of desmopressin in a total of 1295 patients undergoing cardiac surgery. These trials show a small effect on perioperatie blood loss (median reduction, 115 ml). Seeral reiews suggest that although desmopressin helps to reduce perioperatie blood loss, its effect is too small to influence other, more clinically releant outcomes such as the need for transfusion and reoperation.33,83,84,85 In addition, desmopressin does not reduce blood loss or transfusion requirements during electie partial hepatectomy, another operation often associated with major blood loss.86 A report that desmopressin reduced blood loss associated with posterior spinal surgery for idiopathic scoliosis87 was not confirmed.88,89,90
Although desmopressin can shorten the skin-bleeding time in patients with uremia,91 the current widespread use of recombinant erythropoietin has made this abnormality of hemostasis much less frequent than it was preiously.92 The beneficial effect of erythropoietin on hemostasis is based on the increase in red-cell mass, which affects the blood–fluid dynamics, leading to a more intense interaction between circulating platelets and the essel wall.
Thus, there is little eidence that desmopressin is efficacious in conditions other than mild hemophilia A and on Willebrand's disease. The use of desmopressin in some patients who hae bleeding as a consequence of inherited and acquired defects of platelet function may be considered. This drug has been shown to shorten the skin-bleeding time in patients with cirrhosis of the lier and in those with some types of inherited platelet disorders.93 Howeer, the use of desmopressin for these indications is not supported by sound clinical eidence based on releant end points.94 The most common aderse effects of desmopressin, facial flushing and transient hyponatremia, are usually mild. There hae been reports of arterial thrombotic eents, not only in patients with atherothrombosis but also in patients with bleeding disorders and in a blood donor.95,96,97,98,99,100 A systematic reiew showed that for patients with acute myocardial infarction who underwent cardiac surgery, the frequency of these aderse eents among patients who receied desmopressin was twice that among patients who receied placebo, with no improement in clinical outcomes.33 Howeer, another reiew, ealuating 16 trials of desmopressin in cardiac surgery and in other high-risk operations, showed that the rate of thrombosis did not differ significantly between patients who receied desmopressin and patients who receied placebo (3.4% s. 2.7%).101
第十部分
Hemostatic agents for topical use (particularly "fibrin sealants" composed of human fibrinogen, human or boine thrombin, and in some instances human factor XIII and boine aprotinin) hae been licensed in Europe.102,103 In seeral poorly controlled studies inoling small series of patients, the efficacy of these agents has been reported for indications such as cardioascular and thoracic surgery, lier and spleen lacerations, and bleeding at cannulation sites and suture lines. Methodologically sound clinical trials would be required to show the efficacy and safety of these drugs.
Conclusions
The aailable data broadly indicate that aprotinin, lysine analogues, and rFIIa are potent hemostatic agents but that desmopressin is less efficacious. Aprotinin and lysine analogues are used almost exclusiely for prophylaxis against anticipated major blood loss, whereas rFIIa is used not only to preent but also to treat excessie bleeding. The role of antifibrinolytic agents in the treatment of massie refractory hemorrhage has not been established to date. The choice among hemostatic agents is ultimately based on the clinician's sense of the expected therapeutic efficacy, the safety profile, and the costs — a balance that may ary depending on the characteristics of indiidual patients and specific clinical settings. The use of any drug that potentiates hemostasis ineitably carries a risk of thrombosis, particularly in patients with atherosclerosis or risk factors for thrombosis.
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Preention and Treatment of Major Blood Loss
大量失血的预防与治疗
Pier Mannuccio Mannucci, M.D., and Marcel Lei, M.D., Ph.D.
NEJM,olume 356:2301-2311 May 31, 2007 Number 22
第一部分
In a medical setting, surgery is the most common cause of major blood loss, defined as a loss of 20% of total blood olume or more. In particular, cardioascular procedures, lier transplantation and hepatic resections, and major orthopedic procedures including hip and knee replacement and spine surgery, are associated with seere bleeding. Excessie blood loss may also occur for other reasons, such as trauma. Indeed, bleeding contributes to approximately 30% of trauma-related deaths.1 Bleeding in critical locations, such as an intracerebral hemorrhage, may also pose a major clinical challenge.
在医疗上，手术是大量失血（即丢失总血容量的20%甚至更多的失血）最常见的原因。尤其是心血管手术，肝移植和肝切除术，大型的骨科手术，包括髋关节及膝关节置换术及脊柱手术等，常与大量失血有关。失血过多也可能由外伤等其他原因导致。实际上，出血是大约30%的创伤死亡病例的死亡原因。1关键部位的出血，如脑出血，也临床面临的一项主要挑战。
Seere bleeding often requires blood transfusion. Een when the benefits of transfusion outweigh the risks (e.g., mismatched transfusion, allergic reactions, transmission of infections, and acute lung injury),2 strategies to minimize the use of limited resources such as blood products are essential. The most obious and probably the most effectie strategy is to improe surgical and anesthetic techniques. For example, lier transplantation, a procedure that once required transfusion of large amounts of blood products, now has relatiely small transfusion requirements in most instances.
严重出血往往需要输血。即便是好处大于风险(例如血型不匹配，过敏反应，感染传播，和急性肺损伤)，2作为有限资源，最大限度地减少的血液制品的使用这一策略还是必不可少的。最明显并且也可能是最有效的策略是提高手术和麻醉技术。举例来说，肝移植，这一曾经需要输注大量血液制品的手术，现在相对而言大多数情况下输血需要都已经减少。
Ruling out abnormalities of hemostasis in a patient with bleeding is also essential, because such problems can often be corrected by replacing the defectie components of the hemostatic system. Howeer, cases of excessie blood loss in which no surgical cause or abnormalities in hemostasis can be identified require pharmacologic strategies, which can be broadly diided into preoperatie prophylaxis for operations that confer a high risk of bleeding and interentions for massie, refractory bleeding. The medications that hae been most extensiely ealuated as hemostatic agents include the antifibrinolytic lysine analogues aminocaproic acid and tranexamic acid; aprotinin, a boine-deried protease inhibitor; and desmopressin, a synthetic analogue of the antidiuretic hormone that raises the plasma leels of factor III and on Willebrand factor.3 In addition, recombinant actiated factor II appears to be efficacious in an array of clinical situations associated with seere hemorrhage.4 The safety of aprotinin, the most widely used of these agents, has been questioned because of concerns about renal and cardioascular aderse eents.5
排除出血患者的凝血异常也是必不可少的，由于这种问题往往能通过更换凝血系统有问题的因子予以纠正。不过，没有手术或凝血异常这些原因的大量失血病例，是需要药物治疗的，大致可分为对具有大量出血危险性的手术进行术前预防和大量难以控制的出血的控制。评价最广泛的止血剂包括抗纤维蛋白溶解的赖氨酸类似物氨基己酸和止血酸；抑肽酶,牛源性蛋白酶抑制剂; 以及，去氨加压素，一个能提高血浆III因子和WF因子的合成的抗利尿激素3。 此外，重组活化II在合并严重出血的各种临床情况中似乎也是颇为有效的4。这些药物中使用最广泛的抑肽酶的安全性问题，却因为肾和心血管副作用而一直备受质疑5。
Most trials of hemostatic agents hae been designed to assess therapeutic efficacy, but they were not optimally designed to assess potential toxic effects, so definitie safety data are lacking for all hemostatic agents. Many trials of these agents hae used perioperatie blood loss and other measures that are not the most clinically releant end points, and many published trials were not powered to assess more clinically releant outcomes such as mortality or the need for reoperation. We reiew the therapeutic benefits of hemostatic drugs and consider the risk of aderse eents. In particular, we consider thrombotic complications, which constitute a major concern when agents that potentiate hemostasis are administered.
大多数有关止血药物的试验都是设计用来评估其疗效的，却没有用于评估其潜在毒性作用的优秀设计，所以针对所有这些止血药物的确切的安全数据都较为缺乏。这类药物的大多数试验都使用了围手术期失血和其他并不是与临床最相关终结点的指标，许多发表的试验都没有评估诸如死亡率或二次手术的必要性等与临床更相关的结果。我们回顾了止血药物的治疗效果，也考虑它的不良反应的风险。尤其是着重注意了血栓性并发症，这一使用止血药物加强凝血功能时最常关心的问题。
第一部分编译后：811 字
在医疗上，手术是大量失血（即丢失总血容量的20%甚至更多的失血）最常见的原因。尤其是心血管手术，肝移植和肝切除术，包括髋、膝关节置换、脊柱手术在内的大型骨科手术等，常与大量失血有关。失血过多也可能由外伤等其他原因导致。实际上，出血是大约30%的创伤死亡病例的死亡原因1。关键部位的出血，如脑出血，也临床面临的一项主要挑战。
严重出血往往需要输血。即便是好处大于风险(例如血型不匹配，过敏反应，感染传播，和急性肺损伤) 2，因为其资源的有限性，最大限度地减少血液制品的使用这一策略还是必不可少的。最明显并且也可能是最有效的策略便是提高手术和麻醉技术。举例来说，肝移植，这一曾经需要输注大量血液制品的手术，现在相对而言大多数情况下输血需要都已经减少。
排除出血患者的凝血异常也是必不可少的，这种问题也往往能通过更换凝血系统有问题的因子予以纠正。不过，没有手术或凝血异常这些原因的大量失血病例，是需要药物治疗的，大致可分为对具有大量出血危险性的手术进行术前预防和大量难以控制的出血的介入控制。受到最广泛评价的止血剂包括抗纤维蛋白溶解的赖氨酸类似物氨基己酸和止血酸；抑肽酶,牛源性蛋白酶抑制剂; 以及，去氨加压素，一个能提高血浆III因子和WF因子的合成的抗利尿激素3。 此外，重组活化II因子在合并严重出血的各种临床情况中似乎也是颇为有效的4。这些药物中使用最广泛的抑肽酶的安全性问题，却因为肾和心血管副作用而一直备受质疑5。
大多数有关止血药物的试验都是设计用来评估其疗效的，而却没有用于评估其潜在毒性作用的优秀设计，所以针对所有这些止血药物的确切的安全数据都较为缺乏。这类药物的大多数试验都使用了围手术期失血和其他并不是与临床最相关终结点的指标，许多发表的试验都没有评估诸如死亡率或二次手术的必要性等与临床更相关的结果。我们回顾分析了止血药物的治疗效果，也考虑了不良反应的风险。尤其是着重注意了血栓性并发症这一使用止血药物加强凝血功能时最常关心的问题。
本人认领第八部分，48小时内提交。若超过时间，请其他战友自由认领。
本人认领第十部分，48小时内提交。若超过时间，请其他战友自由认领。
第六部分
Efficacy of rFIIa
重组激活因子（rFIIa）的功效
Initially, rFIIa was licensed for the treatment of bleeding in patients with hemophilia who had antibodies inactiating factor III or IX.4 More recently, this agent has been used extensiely in patients with major hemorrhage from surgery, trauma, or other causes.57 A small, controlled clinical trial showed that rFIIa could minimize perioperatie blood loss and transfusion requirements in patients undergoing transabdominal prostatectomy, an operation that is often associated with major blood loss.58 In that trial, 36 patients were randomly assigned to receie a single preoperatie injection of rFIIa (20 or 40 µg per kilogram of body weight) or placebo. Administration of the actie drug resulted in a significant reduction of blood loss (50%) and eliminated the need for transfusion, which was required in approximately 60% of patients who receied placebo.58
rFIIa最初是被批准用来治疗血友病人的出血，因为其体内具有使因子III或IX失活的抗体。最近，该因子被广泛应用于手术、创伤或其他原因引起的大出血。一个小规模的临床对照试验表明，rFIIa能够使经腹前列腺切除术术中的出血量与输血量降到最低，而通常情况下，此手术一般都会引起大量的出血。此试验中，36个病人随机分为rFIIa组（术前注射rFIIa，20 或 40 µg／kg）与安慰剂组，结果发现，给予rFIIa的病人失血量显著减少（50%），输血量也下降为安慰剂组病人的60%左右。
Additional studies hae focused on patients undergoing orthotopic lier transplantation. An open-label pilot study inoling six patients showed a marked reduction in transfusion requirements among those who receied a single dose of rFIIa (80 µg per kilogram) as compared with matched historical controls.59 Howeer, a subsequent randomized, placebo-controlled trial ealuating two different doses of rFIIa (60 and 120 µg per kilogram) showed no reduction in transfusion requirements among 182 lier-transplant recipients, although red-cell transfusion was aerted in 8.4% of patients who receied rFIIa but in none of the patients in the placebo group.60 Two randomized, controlled trials of rFIIa (up to 100 µg per kilogram at eery second hour of surgery) in patients with cirrhosis or normal lier function who were undergoing major lier resection did not show a significant effect of rFIIa on either the olume of blood products administered or the percentage of patients requiring transfusion.61,62
另有研究集中在肝移植人群。在一项开放式研究中，6名接受了单剂量rFIIa（80µg／kg）的肝移植患者，与配对的病例对照相比，输血量显著减少。但是后来的随机、安慰剂对照研究评估了182名肝移植患者，分别给予两种不同剂量的rFIIa（60和120µg／kg），虽然安慰剂组全部患者都需要输注红细胞，而rFIIa组中有8.4%的病人可以不输，但是输血总量并没有减少。另有两个随机对照试验表明，在肝硬化或正常肝功能患者实施大块肝切除术时运用大剂量的rFIIa（100 µg／kg，术中每两时１次），对于血容量高低或血液制品的需求却都没有明显改善。
In addition, rFIIa was ealuated in a randomized, controlled study inoling 20 patients undergoing noncoronary cardiac surgery requiring cardiopulmonary bypass.63 Administration of rFIIa at a dose of 90 µg per kilogram after discontinuation of bypass significantly reduced the need for blood transfusion (relatie risk of any transfusion, 0.26; 95% CI, 0.07 to 0.90). In addition, a propensity score–matched, case–control study inoling 51 patients with massie blood loss after cardiac surgery showed a significant decrease in blood loss and requirements for blood products after the administration of rFIIa (at a dose of 35 to 70 µg per kilogram).64 In this study, howeer, the incidence of acute renal dysfunction among patients receiing rFIIa was 2.4 times that in the control group, although there were no significant differences between the two groups with regard to other aderse eents.64
另外，一项随机对照研究表明，20名需要心肺分流的非冠状心脏手术的患者，在分流术后给予rFIIa（90µg／kg），输血需求显著下降（任何形式的输血，相对危险度0.26，95%可信区间：0.07-0.90）。另外，一项特性评分配对病例对照研究发现，51名心脏手术大量失血的患者，在给予rFIIa（35-70µg／kg）后，失血量及血液制品的需求明显下降，但是，给予rFIIa的患者其急性肾功能障碍的发生率是对照组的2.4倍，两组间其他的不良反应无统计学差异。
Seeral case reports and case series suggest that rFIIa is also useful in reducing major blood loss in patients with trauma.65 A placebo-controlled trial inoling 143 patients with seere blunt trauma showed that three successie doses of rFIIa (200, 100, and 100 µg per kilogram) significantly reduced red-cell transfusion (mean reduction, 2.6 units) and reduced the proportion of patients in whom massie transfusion, defined as more than 20 units of red cells, was required (14% of treated patients s. 33% of controls).66 Howeer, a parallel trial inoling 134 patients with penetrating trauma showed no significant effects.66
许多的病例报告及病例系列分析提示，rFIIa对于减少创伤患者的大出血也大有裨益。一项包括143名严重钝器伤患者的安慰剂对照研究表明，连续三次给予rFIIa（剂量分别为200, 100, and 100 µg ／kg），能够显著减少红细胞的输注量（平均减少2.6Ｕ），降低需要大量输血（输注红细胞超过20Ｕ）患者的比例（14%S 33%），但是，在另一项包括134名穿透伤患者的平行试验中却没有明显效应。
第七部分
Studies hae also ealuated rFIIa for the treatment of spontaneous intracranial hemorrhage, a condition for which there is a paucity of effectie therapeutic options.67 A dose-finding trial inoling 400 patients showed that as compared with placebo, rFIIa was associated with a slower increase in the size of intracerebral hematoma. More important, there was a 35% reduction in mortality and an improed disability score at 90 days in patients who receied rFIIa.67 Unfortunately, these promising early results were not confirmed in a subsequent phase 3, randomized, controlled trial inoling 821 patients.68 A preliminary report indicated that there was a significant reduction in the size of the intracerebral hematoma but with no effect on mortality and seere disability on day 90, the primary end point of the study.68 The manufacturer has not sought regulatory approal for rFIIa for the treatment of intracerebral hemorrhage.
研究还评价了在自发性颅内出血缺乏其他有效治疗手段时rFIIa的疗效。一项包括400名患者的寻找合适剂量的研究表明，与安慰剂组相比，rFIIa可以缓慢减小颅内血肿的体积，更重要的是，使死亡率下降了35%，90天内的残障评分亦得到改善。不幸的是，这些极具前景的早期结果在接下来包括821名患者的3期随机对照实验中没有得到证实，初期报告指出，rFIIa可以显著减小颅内血肿的体积，但是对初级研究终点（90天）的死亡率及严重致残率并无影响。生产商尚没有着手rFIIa用来治疗颅内血肿的注册审批。
This agent has also been studied in patients with bleeding esophageal arices and portal hypertension, a combination that constitutes another major clinical challenge. In a randomized, controlled trial inoling 245 patients with cirrhosis and upper gastrointestinal bleeding (66% of whom had bleeding arices) who were being treated with standard endoscopic and pharmacologic interentions, the administration of rFIIa (eight consecutie doses of 100 µg per kilogram within 30 hours after the initiation of treatment) was not more effectie than placebo with respect to the primary composite end point (failure to control bleeding within 24 hours and failure to preent rebleeding or death within the first 5 days).69 Howeer, in a subgroup of patients with more seere cirrhosis (classified as Child class B or C), rFIIa was associated with a decrease in the proportion of patients reaching the composite end point (8%, s. 23% in the control group; P=0.03). Furthermore, none of the patients treated with rFIIa had rebleeding within 24 hours, whereas rebleeding occurred in 11% of patients in the control group (P=0.01).69
还有研究探讨了该因子在门静脉高压－食管静脉曲张出血中的作用，此疾病也是临床上常见的又一个难题。在一项随机对照研究中，245名患有肝硬化和上消化道出血（66％的为出血性血管曲张）、且正在接受标准的内窥镜检查和药物治疗的病人，rFIIa治疗组（初次剂量后在30小时内连续给予８次，每次100µg／kg）在初级复合终点时末能控制24小时出血量及5天内的再出血或死亡率，并末优于安慰剂对照组。但是，在更加严重的肝硬化患者中（Child分组B或C），rFIIa可以降低到达复合终点的比例（8% s 23% ，P=0.03），此外，给予rFIIa治疗的患者在24小时内全部没有出现再次出血，而对照组中再出血发生率为11%(P=0.01)。
Many case reports and case series hae examined the use of rFIIa in patients with excessie or life-threatening blood loss occurring in an array of clinical settings.57 Howeer, no randomized, controlled clinical trials hae been completed, which is not surprising, gien the difficulty of performing meaningful studies in such heterogeneous situations. Many reports claim that the use of rFIIa resulted in rapid reduction of blood loss or a decrease in transfusion requirements after other therapeutic measures had failed. Although many of these reports appear to be compelling, it is difficult to assess the usefulness of rFIIa properly, since publication bias in case reports and series is likely.
许多病例报告和病例系列分析还评估了rFIIa在极度严重甚至危及生命的失血患者中的价值。但是，随机对照临床尚末完成，考虑到人群的异质性，实施此项研究的难度较大，这也就不足为奇了。许多报告主张在其他治疗措施无效的情况下，使用rFIIa可使失血量快速下降、输血量显著下降。虽然此类报告大多数都引人关注，但是很可能出现出版偏倚，因此很难准确地评估rFIIa的有效性。
由于这两部分其实是个整体，报告了rFIIa在各种出血性疾病中治疗中的临床试验结果，故我翻译后把他们整合在一起，请各位战友指正。（好多的不太确定的统计学术语，我参考的是园子里的其他高分战友的一些译法，谨向他们表示感谢）
第六七部分（共1519字）
重组激活因子（rFIIa）的功效
rFIIa最初是被批准用来治疗血友病人的出血，因为其体内具有使因子III或IX失活的抗体。最近，该因子被广泛应用于手术、创伤或其他原因引起的大出血。一个小规模的临床对照试验表明，rFIIa能够使经腹前列腺切除术的术中出血量与输血量降到最低，而通常情况下，此手术一般都会引起大量的出血。此试验中，36个病人随机分为rFIIa组（术前注射rFIIa，20 或 40 µg／kg）与安慰剂组，结果发现，给予rFIIa的病人失血量显著减少（50%），输血量也下降为安慰剂组病人的60%左右。
另有研究集中在肝移植人群。在一项开放式研究中，6名接受了单剂量rFIIa（80µg／kg）的肝移植患者，与配对的病例对照相比，输血量显著减少。但是后来的随机、安慰剂对照研究评估了182名肝移植患者，分别给予两种不同剂量的rFIIa（60和120µg／kg），虽然安慰剂组全部患者都需要输注红细胞，而rFIIa组中有8.4%的病人可以不输，但是输血总量并没有减少。另有两个随机对照试验表明，在肝硬化或正常肝功能患者实施大块肝切除术时运用大剂量的rFIIa（100 µg／kg，术中每两时１次），对于血容量高低或血液制品的需求却都没有明显改善。
另外，一项随机对照研究表明，20名需要心肺分流的非冠状心脏手术的患者，在分流术后给予rFIIa（90µg／kg），输血需求显著下降（任何形式的输血，相对危险度0.26，95%可信区间：0.07-0.90）。另外，一项特性评分配对病例对照研究发现，51名心脏手术大量失血的患者，在给予rFIIa（35-70µg／kg）后，失血量及血液制品的需求明显下降，但是，给予rFIIa的患者其急性肾功能障碍的发生率是对照组的2.4倍，两组间其他的不良反应无统计学差异。
许多的病例报告及病例系列分析提示，rFIIa对于减少创伤患者的大出血也大有裨益。一项包括143名严重钝器伤患者的安慰剂对照研究表明，连续三次给予rFIIa（剂量分别为200, 100, and 100 µg ／kg），能够显著减少红细胞的输注量（平均减少2.6Ｕ），降低需要大量输血（输注红细胞超过20Ｕ）患者的比例（14%s 33%），但是，在另一项包括134名穿透伤患者的平行试验中却没有明显效应。
研究还评价了在自发性颅内出血缺乏其他有效治疗手段时rFIIa的疗效。一项包括400名患者的寻找合适剂量的研究表明，与安慰剂组相比，rFIIa可以缓慢减小颅内血肿的体积，更重要的是，使死亡率下降了35%，90天内的残障评分亦得到改善。不幸的是，这些极具前景的早期结果在接下来包括821名患者的3期随机对照实验中没有得到证实，初期报告指出，rFIIa可以显著减小颅内血肿的体积，但是对初级研究终点（90天）的死亡率及严重致残率并无影响。生产商尚没有着手rFIIa用来治疗颅内血肿的注册审批。
还有研究探讨了该因子在门静脉高压－食管静脉曲张出血中的作用，此疾病也是临床上常见的又一个难题。在一项随机对照研究中，245名患有肝硬化和上消化道出血（66％的为出血性血管曲张）、且正在接受标准的内窥镜检查和药物治疗的病人，rFIIa治疗组（初次剂量后在30小时内连续给予８次，每次100µg／kg）在初级复合终点时末能控制24小时出血量及5天内的再出血或死亡率，并末优于安慰剂对照组。但是，在更加严重的肝硬化患者中（Child分组B或C），rFIIa可以降低到达复合终点的比例（8% s 23% ，P=0.03），此外，给予rFIIa治疗的患者在24小时内全部没有出现再次出血，而对照组中再出血发生率为11%(P=0.01)。
许多病例报告和病例系列分析还评估了rFIIa在极度严重甚至危及生命的失血患者中的价值。但是，随机对照临床尚末完成，考虑到人群的异质性，实施此项研究的难度较大，这也就不足为奇了。许多报告主张在其他治疗措施无效的情况下，使用rFIIa可使失血量快速下降、输血量显著下降。虽然此类报告大多数都引人关注，但是很可能出现出版偏倚，因此很难准确地评估rFIIa的有效性。
本人认领第四、九部分，48小时内提交。若超过时间，请其他战友自由认领。
第八部分
Safety of rFIIa
rFIIa的安全性
Controlled clinical trials hae shown that the incidence of thrombotic complications among patients who receied rFIIa was relatiely low and similar to that among patients who receied placebo.70 Howeer, most studies of rFIIa inoled patients who had impaired coagulation or who were at low risk for thrombosis.
临床对照实验显示使用rFIIa的患者凝血方面的并发症略低于或与安慰剂患者组相似。70但是，大多数 rFIIa研究中包含了凝血机能受损或处于形成血栓低风险状态的患者。
In one trial inoling patients with conditions such as intracerebral hemorrhage and a much higher risk of thrombosis, 7% of patients receiing rFIIa had serious thromboembolic eents — mainly myocardial infarction or ischemic stroke — as compared with 2% of those receiing placebo.67
在一项包括诸如颅内出血和高风险血栓形成患者的实验中，有7％使用rFIIa的患者发生严重的栓塞并发症－主要是心肌梗塞或缺血性中风－而在安慰剂组中仅为2％。67
Midway through this trial, an exclusion criterion changed. Initially, only patients with thrombotic disease within 30 days before enrollment were excluded, but at the midpoint, all patients with any history of thrombotic disease were excluded, which may hae
obscured safety concerns associated with the use of rFIIa.
在该实验中途改变了排除标准。最初仅排除了实验登记前30天内发生凝血疾病的患者，但在实验期中点，所有有凝血疾病的患者均被排除在外，以排除与 rFIIa使用安全性之间可能存在的不确定关系。
A reiew based on the FDA MedWatch database indicated that thromboembolic eents hae occurred in both the arterial and enous systems, particularly in patients with diseases other than hemophilia in whom rFIIa was used on an off-label basis.71 A total of 54% of the thromboembolic eents were arterial thrombosis (in most cases, stroke or acute myocardial infarction); enous thromboembolism (in most cases, enous thrombosis or pulmonary embolism) occurred in 56% of patients.
FDA MedWatch数据库的一项评论显示，在动脉和静脉血管中都可发生凝血现象，特别是那些患有除血友病外服用无标签 rFIIa的患者。71共有54％的栓塞发生在动脉（大部分病例为中风或急性心梗）；56％的患者栓塞发生于静脉（大部分病例为静脉血栓或肺梗塞）。
In 72% of the 50 reported deaths, thromboembolism was considered the probable cause. It is not clear to what extent the clinical conditions requiring the use of rFIIa may hae contributed to the risk of thrombosis.71 These findings proide eidence of an increased risk of thrombotic complications that may offset the potential benefit of rFIIa in patients with seere blood loss.
在50例死亡病例中，有72％可能是由于栓塞引起的。目前对在何种临床状况下需要应用rFIIa还不清楚，这也与发生血栓风险有关。71这些发现为凝血并发症的风险上升提供了证据，从而抵消了严重失血患者应用rFIIa的潜在益处。
The aailability of rFIIa has expanded the treatment options for acute hemorrhage in patients with conditions other than hemophilia. This agent is not a panacea, but it has efficacy in patients with trauma and excessie bleeding that is resistant to other treatments. Howeer, the promising results obtained so far must be substantiated by confirmatory trials, and studies of the cost-effectieness of this expensie agent are also warranted.
rFIIa的有效性使其成为除血友病外急性失血患者的一种治疗选择。尽管此药并不是万能的，但对那些对其它治疗无效的外伤和大量出血患者确实是有效地。但是，目前得到的这些有希望的结果必须经确定性实验的证实，而且这种昂贵药物效价比也需研究确认。
The many published cases of dramatic success in patients with arious types of acute hemorrhages, albeit conincing and rewarding for the inoled clinicians, should be iewed with caution in terms of constituting clinically directie eidence. Attempts are being made to improe the potency and efficacy of rFIIa further by engineering the molecule through DNA technology, but clinical trials designed to establish increased efficacy and safety remain to be performed.72,73
目前已有大量不同类型急性出血病例大获成功的病例报告，尽管对于临床医师是可信和有益的，但还是应该依据建立的临床指导性证据谨慎观察。通过DNA技术等分子工程使rFIIa的效力和效应进一步提高的努力一直在进行，但旨在进一步提高有效性和安全性的临床实验还有待开展。72，73
编译后：共675字
第八部分
rFIIa的安全性
临床对照实验显示使用rFIIa的患者凝血方面的并发症略低于或与安慰剂患者组相似。70但是，大多数 rFIIa研究中包含了凝血机能受损或处于形成血栓低风险状态的患者。在一项包括诸如颅内出血和高风险血栓形成患者的实验中，有7％使用rFIIa的患者发生严重的栓塞并发症－主要是心肌梗塞或缺血性中风－而在安慰剂组中仅为2％。67在该实验中途改变了排除标准。最初仅排除了实验登记前30天内发生凝血疾病的患者，但在实验期中点，所有有凝血疾病的患者均被排除在外，以排除与 rFIIa使用安全性之间可能存在的不确定关系。FDA MedWatch数据库的一项评论显示，在动脉和静脉血管中都可发生凝血现象，特别是那些患有除血友病外服用无标签 rFIIa的患者。71共有54％的栓塞发生在动脉（大部分病例为中风或急性心梗）；56％的患者栓塞发生于静脉（大部分病例为静脉血栓或肺梗塞）。在50例死亡病例中，有72％可能是由于栓塞引起的。目前对在何种临床状况下需要应用rFIIa还不清楚，这也与发生血栓风险有关。71这些发现为凝血并发症的风险上升提供了证据，从而抵消了严重失血患者应用rFIIa的潜在益处。
rFIIa的有效性使其成为除血友病外急性失血患者的一种治疗选择。尽管此药并不是万能的，但对那些对其它治疗无效的外伤和大量出血患者确实是有效地。但是，目前得到的这些有希望的结果必须经确定性实验的证实，而且这种昂贵药物效价比也需研究确认。目前已有大量不同类型急性出血病例大获成功的病例报告，尽管对于临床医师是可信和有益的，但还是应该依据建立的临床指导性证据谨慎观察。通过DNA技术等分子工程使rFIIa的效力和效应进一步提高的努力一直在进行，但旨在进一步提高有效性和安全性的临床实验还有待开展。72，73
第八部分修改
rFIIa的安全性
临床对照试验显示使用rFIIa的患者凝血方面的并发症略低于或与安慰剂患者组相似。70但是，大多数 rFIIa研究中包含了凝血机能受损或处于形成血栓低风险状态的患者。在一项包括诸如颅内出血和高风险血栓形成患者的试验中，有7％使用rFIIa的患者发生严重的栓塞并发症－主要是心肌梗塞或缺血性中风－而在安慰剂组中仅为2％。67在该试验中途改变了排除标准。最初仅排除了实验登记前30天内发生凝血疾病的患者，但在试验期中点，所有有凝血疾病的患者均被排除在外，以排除与 rFIIa使用安全性之间可能存在的不确定关系。FDA MedWatch数据库的一项评论显示，在动脉和静脉血管中都可发生凝血现象，特别是那些患有除血友病外服用无标签 rFIIa的患者。71共有54％的栓塞发生在动脉（大部分病例为中风或急性心梗）；56％的患者栓塞发生于静脉（大部分病例为静脉血栓或肺梗塞）。在50例死亡病例中，有72％可能是由于栓塞引起的。目前对在何种临床状况下需要应用rFIIa还不清楚，这也与发生血栓风险有关。71这些发现为凝血并发症的风险上升提供了证据，从而抵消了严重失血患者应用rFIIa的潜在益处。
rFIIa的有效性使其成为除血友病外急性失血患者的一种治疗选择。尽管此药并不是万能的，但对那些对其它治疗无效的外伤和大量出血患者确实是有效地。但是，目前得到的这些有希望的结果必须经确定性试验的证实，而且这种昂贵药物效价比也需研究确认。目前已有大量不同类型急性出血病例大获成功的病例报告，尽管对于临床医师是可信和有益的，但还是应该依据建立的临床指导性证据谨慎观察。通过DNA技术等分子工程使rFIIa的效力和效应进一步提高的努力一直在进行，但旨在进一步提高有效性和安全性的临床试验还有待开展。72，73
实验是指动物为对象
试验是指人为对象
第四部分
抑肽酶相关的严重不良事件最近因一项涉及4 374名行选择性冠状动脉旁路（搭桥）手术患者的非随机化观察性研究受到关注。5 该研究将抑肽酶、氨基乙酸、氨酸和不治疗进行比较，采用倾向评分调整法来平衡协变量，以减少因患者选择性地服用某些药物（而不是另一些药物）而可能导致的偏倚。研究结果表明，与不治疗相比，抑肽酶(但既非氨基己酸又不是氨酸)令严重肾功能衰竭的风险加倍，心肌梗塞或心力衰竭的风险增加了55%，并与中风或其他脑血管事件增加近一倍风险相关。该研究证实，三种抗纤维蛋白溶解药在减少失血上功能类似，但抑肽酶的不良事件比另两种药更频繁。该研究已发表的文章41,42,43,44之所以引发了很多争议，其理由不外如下：该研究为观察性的研究，同时在许多不同的国家和不同的机构进行，未控制某些已知的结局的决定因素进行，如使用或不使用抗凝药或影响收缩力的药物，心肺分流术的持续时间及输血量等。
不过，近来其他一些研究也报道了抑肽酶对肾的不良反应。一项对从1991年至2005年间的随机化试验的回顾显示，9％的服用抑肽酶的患者发生了肾功能衰竭(定义：需进行透析或术后增加血清肌酐水平到至少2.0mg每分升[即176.8 µmol])，12.9%的患者肾功能障碍(定义：增加肌苷0.5-1.9mg每分升[即44.2至168.0µmol每升])，而对照组仅为8.4％(RR1.47，95％可信区间（CI）：1.12-1.94，p<0.001)。41一项受生产厂商委托所进行的观察性调查结果也显示：服用抑肽酶的67 000名患者中发生肾功能衰竭和肾功能障碍的比例（与上）类似。45
虽然Mangano et al.5与以往系统性回顾报告的作者均报道，氨基己酸和止血环酸看起来相对安全,32,33,34,35,36，这些药物的试验和参加者的数量比抑肽酶的少得多。因此，在其安全的信心是不稳固的（意译：不要对其安全性太过信任），尤其是对血栓形成来说。最重要的是，
抑肽酶与赖氨酸类似物进行比较的试验太少，规模也太小。46,47,48,49一项独立赞助的包括三个研究小组的随机临床试验正在加拿大进行中。抗纤维蛋白溶解药用于血液保护:一项在心脏外科手术人群中的随机化试验(BART)现仍在招收病人，计划招收2970例患者，以确定抑肽酶在减少术后大出血风险方面是否优于氨基己酸或氨酸。50次要终点是由各种原因及不良反应事件（如心血管病和肾功能衰竭）等所致的死亡率。50
第九部分
其它干预
去氨基精加压素最初因治疗止血上的遗传缺陷而开发并获得许可证.74 ,75,76该药物通过静脉缓慢滴注给予（浓度为0.3µg/g），从内皮细胞释放超大分子量血管性血友病因子(UL-WF)，从而增加血浆血管性血友病因子及相关因子III并加强了初期止血。77 ,78其有效性的最有力证据是预防和治疗了轻度A型血友病和血管性血友病患者的出血。75 ,76 1986年，Salzman et al.79研究表明：与安慰剂相比，去氨基精加压素在复杂的心脏手术可减少约30％的失血和输血量。79 后来为了再现这些结果而进行的研究结果确不同，其中大多数并未证实原先所报道的明显效果。80,81,82 目前已有总计18项去氨基精加压素在1 295例心脏手术中的作用的试验。这些试验显示，其对手术期间的失血效果甚微（中位数减少，115ml)。多个综述表明，虽然去氨基精加压素有助于减少手术失血，但其效果太小无法对其他与临床更相关的，如输血和再手术的需求等方面产生影响。33 ,83,84,85 此外，去氨基精加压素并不能减少选择性部分肝切除（另一种往往与大出血相关的手术）中的失血或对输血的需求。86一份关于去氨基精加压素可减少原发性脊柱侧弯的脊柱后路手术中失血报告87并未获得证实。88,89,90
虽然去氨基精加压素可缩短尿毒症患者的皮肤出血时间，91目前广泛使用的重组人红细胞生成素使此类出血异常的发生率较前大为减少。92促红细胞生成素对止血有作用主要基于其增加了红细胞量，影响血液流体力学，最终导致循环的血小板和血管壁间更激烈的交互作用。
因此，很少有证据表明去氨基精加压素对除轻度A型血友病和血管性血友病外的疾病有效。可考虑在因遗传性的和后天血小板功能缺陷而出血的患者中使用去氨基精加压素。该药已被证实可缩短肝硬化患者及某些遗传性血小板功能障碍的皮肤出血时间。93不过，在这些适应症中使用去氨基精加压素并无可靠基于相关结局变量的临床证据的支持。94去氨基精加压素最常见的副作用通常是轻度的，包括面部潮红、瞬态低钠血症等。也曾有关于动脉血栓事件的报道，不仅在动脉血栓形成的患者，而且出血功能障碍的患者及捐血者均有。95 ,96,97,98,99,100一项系统性综述结果表明，行心脏手术的急性心肌梗死患者使用去氨基精加压素后发生这些不良事件的频率较接受安慰剂的患者高一倍，而患者的临床结局并无改善。33不过,另一项综述评价16项在心脏外科手术和其他高风险手术中使用去氨基精加压素的试验，接受去氨基精加压素和接受安慰剂的患者的血栓形成率并无显着差别(3.4％与2.7％).101
我认领第二部分
我试着译一下第三、十部分吧.
第十部分：局部应用止血剂(特别是纤维蛋白封闭剂 由冻干人纤维蛋白原、人或牛凝血酶，和在一些实例中的人凝血因子XIII和牛抑酞酶组成)已经在欧洲获得许可。在许多少量对照研究中包括小样本病人，这些药物的有效性在心血管和胸外科、肝脾破裂、套管位置和缝线部位的出血的适应症已经被报道了。对说明这些药物的有效性和安全性，方法合理的临床实验是有必要的。
结论：广泛的有效数据表明抑酶酞，赖氨酸类似物，和rFIIa是有效的止血药，但是去氨基精加压素疗效较小。
抑酶酞，赖氨酸类似物几乎只用于预防预期的大出血，然而rFIIa不仅用于预防而且用于治疗严重的大出血。抗纤维蛋白溶解药在治疗大量顽固性出血的作用尚未阐明，止血药的选择最终依据临床意义，包括：所期望的治疗效果，安全范围，和花费。--这是一个平衡，它可能会因为病人个体特征和特殊的临床背景而变化。使用止血的药物不可避免的带来血栓形成的危险，特别是动脉粥样硬化或有血栓形成危险因素的患者。
我认领第五部分，48小时小时内提交。若超过时间，请其他战友自由认领
On the basis of all the data reported thus far, there is abundant, solid eidence that aprotinin reduces perioperatie and early postoperatie blood loss and transfusion requirements in patients undergoing cardiac surgery.根据目前已报道的数据，有大量可靠的证据表明在心外科手术病人中胰蛋白酶抑制剂能够减少手术期间及早期术后失血量及输血需要量。Howeer, despite the large number of clinical trials inoling this agent, its effectieness in decreasing the need for reoperation has been reported only in reiews,36 and eidence of its effect on mortality is lacking.尽管此方面的临床实验比较多，但是它在减少再次手术的有效性方面只有在综述里有报道，36并且它在病死率方面所起作用缺少证据。It is regrettable that the inexpensie lysine analogues hae been less thoroughly inestigated as of this writing, because it appears likely that these agents are at least as efficacious as aprotinin.遗憾的是价格低廉的赖氨酸类似物没有得到深入的研究，因为它可能和胰蛋白酶抑制剂疗效差不多。The uncertainty about aprotinin's safety remains a substantial concern. 胰蛋白酶抑制剂的安全性的不确定还是一个值得关注的内容。 Until the results of the Canadian trial are aailable,50 aprotinin remains the hemostatic agent of choice. 只有加拿大的实验结果有效，50胰蛋白酶抑制剂仍然是止血剂的精选。Howeer, it should be used only when excessie perioperatie and early postoperatie blood loss is predicted (e.g., in the case of a complex operation or special clinical circumstances such as the use of antiplatelet agents). 但是，只有在手术期间及早期术后有大量失血的倾向时才用（例如，复杂的手术或者是在使用抗血小板因子的特殊临床情况下）。Eidence of the efficacy of lysine analogues is not as solid as that for aprotinin, so these agents should be used only as a second choice in high-risk cardiac surgery. 赖氨酸类似物有效性方面的证据还没有胰蛋白酶抑制剂的坚实可靠，所以在高风险的心外科手术中它们只能作为第二选择。There is definitely no role for either aprotinin or other hemostatic agents in non complex coronary-artery bypass surgery, een though in many cases an off-pump procedure is used, which reduces blood loss and transfusion requirements.在不复杂的冠状动脉旁路(搭桥)手术中不能使用胰蛋白酶抑制剂或其它的止血剂，即使在很多情况下采取停止泵作用以减少失血量和输血输血需要量。51,52 The FDA has warned that it is important to monitor patients receiing aprotinin for renal, cardiac, and brain toxic effects and that aprotinin should be used only when the clinical benefit of reducing blood loss is essential to medical management and outweighs any risk.53 FDA警告对使用胰蛋白酶抑制剂病人的肾脏，心脏及脑毒性的监控非常主要，只有在临床治疗中减少失血带来的利益超过任何风险时才能使用胰蛋白酶抑制剂。
Recombinant Actiated Factor II
重组激活因子Ⅶ
Recombinant actiated factor II (rFIIa) is thought to act locally at the site of tissue injury and ascular-wall disruption by binding to exposed tissue factor, generating small amounts of thrombin that are sufficient to actiate platelets4 (Figure 2). rFIIa 通过与暴露的组织因子结合定位在局部受伤组织和血管壁破裂处， 产生少量足以激活血小板4的凝血酶(见表2)。The actiated platelet surface can then form a template on which rFIIa directly or indirectly mediates further actiation of coagulation, ultimately generating much more thrombin and leading to the conersion of fibrinogen to fibrin.活化的血小板表面形成一个模板，rFIIa通过它直接或间接的介导血凝块的进一步激活，最终产生更多的凝血酶使纤维蛋白原转变为纤维蛋白。54,55通过由rFIIa 介导的溶血酶活性的纤维蛋白溶解抑制剂的激活，从而抑制纤维蛋白溶解作用使血块稳定。Clot formation is stabilized by the inhibition of fibrinolysis due to rFIIa-mediated actiation of thrombin-actiatable fibrinolysis inhibitor.56
Figure 2. Mechanism of Action of Recombinant Factor IIa.
重组激活因子Ⅶ的作用机制
When the essel wall is disrupted, subendothelial tissue factor becomes exposed to circulating blood and may bind factor IIa (Panel A). 血管破裂时，内皮下组织暴露于循环血液并且可能结合IIa 因子。This binding actiates factor X, and actiated factor X (factor Xa) generates small amounts of thrombin. The thrombin (factor IIa) in turn actiates platelets and factors and III. Actiated platelets bind circulating factor IIa 结合物激活X因子，活化的X因子 产生少量凝血酶。凝血酶（IIa 因子）激活血小板，因子和III 因子。活化的血小板结合IIa 因子。(Panel , resulting in further factor Xa generation as well as actiation of factor IX. Actiated factor IX (factor IXa) (with its cofactor IIIa) yields additional factor Xa.导致Xa的产生和IX的激活。活化的IX因子（IXa ）（及其辅助因子IIIa ）产生更多的Xa 因子。The complex of factor Xa and its cofactor a then conerts prothrombin (factor II) into thrombin (factor IIa) in amounts that are sufficient to induce the conersion of fibrinogen to fibrin. Xa因子和其辅助因子a 复合物使一定数量凝血酶原转变为凝血酶，这些凝血酶足够使纤维蛋白原转变为纤维蛋白。
第五部分整理：
根据目前已报道的数据，有大量可靠的证据表明在心外科手术病人中胰蛋白酶抑制剂能够减少手术期间及早期术后失血量及输血需要量。尽管此方面的临床实验比较多，但是它在减少再次手术的有效性方面只有在综述里有报道，36并且它在病死率方面所起作用缺少证据。遗憾的是价格低廉的赖氨酸类似物没有得到深入的研究，因为它可能和胰蛋白酶抑制剂疗效差不多。胰蛋白酶抑制剂的安全性的不确定还是一个值得关注的内容。只有加拿大的实验结果有效，50胰蛋白酶抑制剂仍然是止血剂的精选。但是，只有在手术期间及早期术后有大量失血的倾向时才用（例如，复杂的手术或者是在使用抗血小板因子的特殊临床情况下）。赖氨酸类似物有效性方面的证据还没有胰蛋白酶抑制剂的坚实可靠，所以在高风险的心外科手术中它们只能作为第二选择。在不复杂的冠状动脉旁路(搭桥)手术中不能使用胰蛋白酶抑制剂或其它的止血剂，即使在很多情况下采取停止泵作用以减少失血量和输血输血需要量51,52。53 FDA警告对使用胰蛋白酶抑制剂病人的肾脏，心脏及脑毒性的监控非常主要，只有在临床治疗中减少失血带来的利益超过任何风险时才能使用胰蛋白酶抑制剂。
重组激活因子Ⅶ
rFIIa 通过与暴露的组织因子结合定位在局部受伤组织和血管壁破裂处， 产生少量足以激活血小板4的凝血酶(见表2)。活化的血小板表面形成一个模板，rFIIa通过它直接或间接的介导血凝块的进一步激活，最终产生更多的凝血酶使纤维蛋白原转变为纤维蛋白54,55。通过由rFIIa 介导的溶血酶活性的纤维蛋白溶解抑制剂的激活，从而抑制纤维蛋白溶解作用使血块稳定。56
重组激活因子Ⅶ的作用机制
血管破裂时，内皮下组织暴露于循环血液并且可能结合IIa 因子。IIa 结合物激活X因子，活化的X因子 产生少量凝血酶。凝血酶（IIa 因子）激活血小板，因子和III 因子。活化的血小板结合IIa 因子。导致Xa的产生和IX的激活。活化的IX因子（IXa ）（及其辅助因子IIIa ）产生更多的Xa 因子。Xa因子和其辅助因子a 复合物使一定数量凝血酶原转变为凝血酶，这些凝血酶足够使纤维蛋白原转变为纤维蛋白。
第二部分
抗纤维蛋白降解药物
大约5%的进行了心脏外科手术的病人因为过量失血需要重新检测。实际上，心脏手术后或术中大量出血就预示着致残率和致死率增加。（6，7，8）心脏手术时经常用药理方法减少出血。抑肽酶（纤维蛋白的直接抑制子）是唯一被报道的在冠状动脉绕过移植中减低输血需要的药物，它已经被FDA认证了。氨基己酸 和氨甲环酸也有这方面的应用，但它们没有被FDA认可。这些药物的作用机制在图1中显示。表1列出了抗纤维蛋白降解药物的常用剂量。
图1 赖氨酸类似物的作用模式（氨基己酸 和氨甲环酸）
图中单词翻译：plasminogen 纤维蛋白溶酶原
plasminogen actiator 纤维蛋白溶酶原激活剂
lysine-binding site 赖氨酸结合位点
fibrin 纤维蛋白
fibrin-degradation products 纤维蛋白降解产物
lysine analogue 赖氨酸类似物
纤维蛋白溶酶原被内源性纤维蛋白溶酶原激活剂激活后生成纤维蛋白溶酶。纤维蛋白溶酶可降解纤维蛋白。纤维蛋白溶酶原与纤维蛋白结合使这个作用更有效，并在纤维蛋白溶酶原结合的赖氨酸残基上发生（图A）。当体系中存在赖氨酸类似物时，赖氨酸结合位点被占用，纤维蛋白溶酶原与纤维蛋白的结合被抑制，内源性纤维蛋白降解受破坏（图B）。
表1 抗纤维蛋白降解药物的作用机制和心脏手术中用于减少出血和输血的静脉注射剂量
药物 作用机制 推荐剂量
抑肽酶 直接抑制纤维蛋白溶酶、血浆和组织激肽原酶、胰岛素和激发态凝结因子XII 高剂量（全部，700mg或更多）；低剂量（少于700mg的任何剂量）
麻醉后先用药280mg，术中70mg/h，最后泵入280mg（可选）
氨基己酸 与纤维蛋白溶酶原的赖氨酸结合位点结合，抑制纤维蛋白溶酶与纤维蛋白的结合 全部，10-30g
麻醉后用药1-15g，术中1-2g/h
氨甲环酸 与氨基己酸相同，但每摩尔的作用能力是氨基己酸的10倍 全部，3-10g
麻醉后2-7g，术中20-250mg/h
抗纤维蛋白降解药物的效用
经过1987年9月的最初的研究之后，科学家进行了70多次随机的、有对照组的试验。病例数从20个到796个（平均值是75）。这些试验确证并测定了抑肽酶减少心脏手术病人输入红细胞、血小板或新鲜冷冻血浆的需求的效用。我们根据规模和设计选择了四个试验进行深入研究。
其中一项试验是将796个进行原发性冠状动脉绕过移植病人随机分到抑肽酶组或安慰剂组，结果抑肽酶组血压比安慰剂组的低（664±1009 ml, s. 1168±1022 ml）。抑肽酶也减少了病人使用血液产品的比例（(40%, s. 58%)（10）。在一项随机的、有安慰剂组的包括了704个病例的试验中，抑肽酶与心肺血液流失减少有关（832±50 ml, s. 1286±52 ml），也和输血减少有关（35% s. 55%)（11）。有两项试验招募的是有出血增加危险的病人，他们都是经过了反复的心脏手术（12，13）。每个接受抑肽酶的病人平均需要1.6到2 units的血液产品，安慰剂组病人平均需要10到12 units(12，13)。在很多其它有安慰剂组对照的试验中，抑肽酶的效用都有相似的报道，它能将心肺血液流失减少50到1350ml（平均为400ml），还能将需要输血的病人的比例减少1.5到3个百分点（14,15,16,17,18,19,20,21,22,23,24,25）。
表1.doc (25.5k)
第三部分
Randomized trials of tranexamic acid or aminocaproic acid are much less numerous than trials of aprotinin.26,27,28,29,30,31 In the largest trial of tranexamic acid, 210 patients were randomly assigned to receie tranexamic acid (at a dose of 10 g) or placebo. Administration of tranexamic acid resulted in a 69% reduction in red-cell transfusions, and the proportion of patients requiring any blood product was 12.5% in the tranexamic acid group as compared with 31.1% in the control group.31
有关止血环酸或氨基己酸的随机试验远少于抑肽酶相关的试验。在一项最大的止血环酸试验中，210例患者随机分配接受止血环酸（剂量为10g）或安慰剂。止血环酸组红细胞输注减少69%，且输入任何血制品所占比例为12.5%，与之相比，对照组的这一比例为31.1%。
There hae also been meta-analyses and systematic reiews of the efficacy of antifibrinolytic agents.32,33,34,35,36 Table 2 summarizes the results of a Cochrane reiew. As compared with placebo, the use of aprotinin or tranexamic acid, but not of aminocaproic acid, reduced the need for blood transfusion by 30% and saed approximately 1 unit of blood per operation.36 There was no difference in efficacy between low-dose and high-dose regimens of aprotinin (Table 1), whereas the large ariations in dosages of tranexamic acid and aminocaproic acid precluded the ealuation of the relationship between dosage and efficacy. In terms of more clinically releant eents, the relatie risk of reoperation for excessie bleeding was significantly reduced among patients who receied aprotinin, as compared with those who receied placebo, although mortality was not affected. There was a significant reduction in these eents with either tranexamic acid or aminocaproic acid.36
同样有抗纤溶剂疗效的meta分析与系统回顾。表2总结了循证医学评价结果。与安慰剂组相比，应用抑肽酶或止血环酸，而不是氨基已酸，减少了30%的输血要求且每台手术节约了大约1u血。低剂量与高剂量抑肽酶制剂的疗效没有差别（表1），而止血环酸与氨基已酸剂量的巨大变化导致无法评价其剂量与疗效之间的关系。在更多的临床相关事件方面，与安慰剂相比，使用抑肽酶的患者因过多出血需要再次手术的相对风险明显下降，虽然死亡率未受影响。使用止血环酸或氨基已酸，这些事件明显减少。
Table 2. Results of the Cochrane Reiew of the Effect of Antifibrinolytic Agents on Clinical Eents among Patients Undergoing Major Surgical Procedures
抗纤溶剂对接受大型手术的患者的临床事件的影响的循证医学评价结果
Thus, the results of controlled trials and reiews indicate that antifibrinolytic drugs are effectie hemostatic agents in cardiac surgery. Reductions in both transfusion requirements and reoperation for bleeding appear to be confirmed by the narrow confidence interals of the odds ratios that are indicators of the relatie risks (Table 2). There are not enough efficacy data to draw definitie conclusions regarding the use of antifibrinolytic agents in other situations.
因此，对照试验与回顾结果表明抗纤溶药物是心脏手术有效的止血药。表2中相对风险标志——优势比的可信区间窄证示了减少了输血需求量与因出血而再次手术。关于其它情况下应用抗纤溶药，没有足够的可信的资料得出明确的结论。
Safety of Antifibrinolytic Agents
抗纤溶药的安全性
There hae been criticisms that many trials of the efficacy of aprotinin in cardiac surgery were unnecessarily carried out (and reported) after the transfusion-sparing efficacy was unequiocally established and that such studies should hae focused instead on the more cogent and unsettled issue of safety.37,38 Aderse eents, particularly thrombotic complications, are expected when a major regulatory system such as the fibrinolytic system is pharmacologically inhibited; this is especially true in patients undergoing cardiac surgery, because they often hae underlying atherothrombotic disease.
争议一直不断，在毫不含糊地确定了能够节约输血的疗效之后，不必要地进行及报道了有关心脏手术中抑肽酶疗效的许多试验，而这些研究本该是改为关注更使人信服的和没有确定的安全性问题。当主要调节系统（如纤溶系统）被药物抑制时，预想会出现不良事件，尤其是血栓并发症；这点在接受心脏手术的患者中尤为正确，因为他们常有潜在性动脉粥样硬化性血栓性疾病。
Table 3, which summarizes the risks of complications when antifibrinolytic agents are administered, shows that none of the aderse eents examined was significantly increased.36 Howeer, a few early studies indicated that the use of aprotinin could lead to an increase in cases of postoperatie renal dysfunction, possibly through the inhibition of kallikrein and other endogenous asodilators, with a resultant reduction of renal blood flow.24,39,40
表3，总结了使用抗纤溶剂的并发症风险，显示没有一个已出现的不良事件明显增加。可是，早期少数研究显示应用抑肽酶导致术后肾功能不全例数增加，可能通过抑制激肽释放酶及其它内生血管舒张因子，导致肾血流减少。
Table 3. Results of the Cochrane Reiew of the Effect of Antifibrinolytic Agents on Aderse Eents among Patients Undergoing Major Surgical Procedures.
抗纤溶剂对接受大型手术的患者的不良事件的影响的循证医学评价结果
第三部分编译：（除表格外，共776字）
有关止血环酸或氨基己酸的随机试验远少于抑肽酶相关的试验。在一项最大的止血环酸试验中，210例患者随机分配接受止血环酸（剂量为10g）或安慰剂。止血环酸组红细胞输注减少69%，且输入任何血制品所占比例为12.5%，与之相比，对照组的这一比例为31.1%。
同样有抗纤溶剂疗效的meta分析与系统回顾。表2总结了循证医学评价结果。与安慰剂组相比，应用抑肽酶或止血环酸，而不是氨基已酸，减少了30%的输血要求且每台手术节约了大约1u血。低剂量与高剂量抑肽酶制剂的疗效没有差别（表1），而止血环酸与氨基已酸剂量的巨大变化导致无法评价其剂量与疗效之间的关系。在更多的临床相关事件方面，与安慰剂相比，使用抑肽酶的患者因过多出血需要再次手术的相对风险明显下降，虽然死亡率未受影响。使用止血环酸或氨基已酸，这些事件明显减少。
表 2. 抗纤溶剂对接受大型手术的患者的临床事件的影响的循证医学评价结果
因此，对照试验与回顾结果表明抗纤溶药物是心脏手术有效的止血药。表2中相对风险标志——优势比的可信区间窄证示了减少了输血需求量与因出血而再次手术。关于其它情况下应用抗纤溶药，没有足够的可信的资料得出明确的结论。
抗纤溶药的安全性
争议一直不断，在毫不含糊地确定了能够节约输血的疗效之后，不必要地进行及报道了有关心脏手术中抑肽酶疗效的许多试验，而这些研究本该是改为关注更使人信服的和没有确定的安全性问题。当主要调节系统（如纤溶系统）被药物抑制时，预想会出现不良事件，尤其是血栓并发症；这点在接受心脏手术的患者中尤为正确，因为他们常有潜在性动脉粥样硬化性血栓性疾病。
表3，总结了使用抗纤溶剂的并发症风险，显示没有一个已出现的不良事件明显增加。可是，早期少数研究显示应用抑肽酶导致术后肾功能不全例数增加，可能通过抑制激肽释放酶及其它内生血管舒张因子，导致肾血流减少。
表3. 抗纤溶剂对接受大型手术的患者的不良事件的影响的循证医学评价结果
（缩略图，点击图片链接看原图）
第一部分校对：
In a medical setting, surgery is the most common cause of major blood loss, defined as a loss of 20% of total blood olume or more.
在医疗上，手术是大量失血（即丢失总血容量的20%甚至更多的失血）最常见的原因。
在临床上，手术是大量失血（指失血量超过总血容量的20%及以上）最常见的原因。
bleeding contributes to approximately 30% of trauma-related deaths.
出血是大约30%的创伤死亡病例的死亡原因。
约30%创伤相关的死亡是出血引起的。
Many trials of these agents hae used perioperatie blood loss and other measures that are not the most clinically releant end points
这类药物的大多数试验都使用了围手术期失血和其他并不是与临床最相关终结点的指标
有关这些药物的多数试验是使用围手术期失血与其他标准，这不是与临床最相关终点
第十部分校对：
Hemostatic agents for topical use (particularly "fibrin sealants" composed of human fibrinogen, human or boine thrombin, and in some instances human factor XIII and boine aprotinin) hae been licensed in Europe.
局部应用止血剂(特别是纤维蛋白封闭剂 由冻干人纤维蛋白原、人或牛凝血酶，和在一些实例中的人凝血因子XIII和牛抑酞酶组成)已经在欧洲获得许可。
局部应用的止血药(尤其是由人纤维蛋白原、人或牛凝血酶、某些情况下还有人凝血因子XIII和牛抑肽酶组成的纤维蛋白粘合剂)已经在欧洲获得许可。
The choice among hemostatic agents is ultimately based on the clinician's sense of the expected therapeutic efficacy, the safety profile, and the costs
止血药的选择最终依据临床意义，包括：所期望的治疗效果，安全范围，和花费
止血药的选择最终根据医师对预期疗效的判断、安全性和医疗成本
表1内容
（缩略图，点击图片链接看原图）
结合以上各位战友的翻译、校对，进一步校对（文中下划线部分）(近20处)后全文编译：
在临床上，手术是大量失血（指失血量超过总血容量的20%及以上）最常见的原因，尤其是心血管手术、肝移植及肝切除术、包括髋、膝关节置换、脊柱手术在内的大型骨科手术等，常与大量失血有关。外伤等其他原因也可能导致失血过多。实际上，约30%创伤相关的死亡是出血引起的。关键部位的出血，如脑出血，也是临床面临的一项主要挑战。
严重出血往往需要输血，这种情况下输血即使利大于弊(例如血型不合、过敏反应、感染传播、急性肺损伤) ，最大限度地减少使用有限的资源（如血制品）的策略必不可少。最明显且很可能是最有效的策略就是提高手术和麻醉技巧。例如，肝移植，这一曾经需要输注大量血制品的手术，目前大多数情况下输血量已经相对较小。
排除出血患者的凝血异常也是必不可少的，这种问题也往往能通过替换凝血系统有缺陷的成分予以纠正。不过，没有手术或凝血异常这些原因的大量失血病例，是需要药物治疗的，大致可分为对具有大量出血危险性的手术进行术前预防和大量难以控制的出血的干预治疗。受到最广泛评价的止血剂包括抗纤维蛋白溶解的赖氨酸类似物氨基己酸和止血酸、抑肽酶、牛源性蛋白酶抑制剂、以及去氨加压素（人工合成的抗利尿激素类似物，能提高血浆III因子和WF因子的水平）。 此外，与严重出血相关的一系列临床情况中，重组活化II因子看来颇为有效。这些药物中使用最广泛的抑肽酶的安全性问题，却因为肾和心血管副作用而一直备受质疑。
大多数有关止血药物的试验都是设计用来评估疗效，却没有评估其潜在毒性作用的最佳设计，所以缺乏所有止血药物的权威性安全数据。有关这些药物的多数试验是使用了围手术期失血与其他标准，这不是与临床最相关终点，许多已发表的试验都没有评估诸如死亡率或二次手术的必要性等与临床更相关的结果。我们回顾分析了止血药物的治疗效果，也考虑了不良反应的风险，尤其是着重注意了血栓性并发症这一使用止血药物加强凝血功能时最常关心的问题。
抗纤溶药
大约5%的进行了心脏外科手术的病人因为过量失血需要再次手术。实际上，心脏手术后或术中大量出血就预示着致残率和致死率增加。心脏手术时经常用止血剂减少出血。抑肽酶（纤溶酶plasmin的直接抑制因子）是唯一被报道的、使冠状动脉旁路移植术中输血量减至最小的药物，并且已经得到FDA的批准;也用氨基己酸和氨甲环酸，但FDA没有批准它们的这一适应症。图1显示了这些药物的作用机制。表1列出了抗纤维蛋白降解药物的常用剂量。
图1.赖氨酸类似物的作用模式（氨基己酸和氨甲环酸）
plasminogen 纤维蛋白溶酶原，plasminogen actiator 纤维蛋白溶酶原激活剂，lysine-binding site 赖氨酸结合位点，fibrin 纤维蛋白，fibrin-degradation products 纤维蛋白降解产物，lysine analogue 赖氨酸类似物 。纤维蛋白溶酶原被内源性纤维蛋白溶酶原激活剂激活后生成纤维蛋白溶酶。纤维蛋白溶酶可降解纤维蛋白。纤维蛋白溶酶原与纤维蛋白结合使这个作用更有效，并在纤维蛋白溶酶原结合的赖氨酸残基上发生（图A）。当体系中存在赖氨酸类似物时，赖氨酸结合位点被占用，纤维蛋白溶酶原与纤维蛋白的结合被抑制，内源性纤维蛋白降解受破坏（图B）。
表1 抗纤维蛋白降解药物的作用机制和心脏手术中用于减少出血和输血的静脉注射剂量
抗纤溶药的作用
继1987年首次研究后，70多项随机对照试验中，患者数从20例到796例不等（平均75例），证实并确定了抑肽酶减少心脏手术患者的红细胞、血小板或新鲜冷冻血浆的输入量的作用。我们根据规模和设计选择了四个试验进行深入研究。
一项796例初次行冠状动脉旁路移植术的患者参与的研究中，患者随机分配至抑肽酶组或安慰剂组，结果抑肽酶组失血量较安慰剂组的低（mean [±SD], 分别为664±1009 ml、1168±1022 ml），抑肽酶也减少了血制品的使用率(分别为40%、58%)。在一项704例患者参与的随机安慰剂对照试验中，抑肽酶减少了围手术期失血量（抑肽酶组832±50 ml、安慰剂组1286±52 ml），也减少了患者需要输血的比例（分别为35%、55%)。由于再次心脏手术导致出血风险增加的患者参与的两项试验中，抑肽酶组患者平均需要1.6-2单位的血制品，安慰剂组平均需要10-12单位。在许多其它有安慰剂对照的试验中，报道了抑肽酶相似的作用，使围手术期失血量减少50至1350ml不等（平均减少400ml），需要输血的患者比例减少1.5至3分之一。
有关止血环酸或氨基己酸的随机试验远少于抑肽酶相关的试验。在一项最大的止血环酸试验中，210例患者随机分配接受止血环酸（剂量为10g）或安慰剂。止血环酸组红细胞输注减少69%，且输入任何血制品所占比例为12.5%，与之相比，对照组的这一比例为31.1%。
同样有抗纤溶剂疗效的meta分析与系统回顾。表2总结了循证医学评价结果。与安慰剂组相比，应用抑肽酶或止血环酸，而不是氨基已酸，减少了30%的输血要求且每台手术节约了大约1u血。低剂量与高剂量抑肽酶制剂的疗效没有差别（表1），而止血环酸与氨基已酸剂量的巨大变化导致无法评价其剂量与疗效之间的关系。在更多的临床相关事件方面，与安慰剂相比，使用抑肽酶的患者因过多出血需要再次手术的相对风险明显下降，虽然死亡率未受影响。使用止血环酸或氨基已酸，这些事件明显减少。
表 2. 抗纤溶剂对接受大型手术的患者的临床事件的影响的循证医学评价结果
因此，对照试验与回顾结果表明抗纤溶药物是心脏手术有效的止血药。表2中相对风险标志——优势比的可信区间窄证示了减少了输血需求量与因出血而再次手术。关于其它情况下应用抗纤溶药，没有足够的可信的资料得出明确的结论。
抗纤溶药的安全性
争议一直不断，在毫不含糊地确定了能够节约输血的疗效之后，不必要地进行及报道了有关心脏手术中抑肽酶疗效的许多试验，而这些研究本该是改为关注更使人信服的和没有确定的安全性问题。当主要调节系统（如纤溶系统）被药物抑制时，预想会出现不良事件，尤其是血栓并发症；这点在接受心脏手术的患者中尤为正确，因为他们常有潜在性动脉粥样硬化性血栓性疾病。
表3，总结了使用抗纤溶剂的并发症风险，显示没有一个已出现的不良事件明显增加。可是，早期少数研究显示应用抑肽酶导致术后肾功能不全例数增加，可能通过抑制激肽释放酶及其它内生血管舒张因子，导致肾血流减少。
表3. 抗纤溶剂对接受大型手术的患者的不良事件的影响的循证医学评价结果
抑肽酶相关的严重不良事件最近因涉及一项4374名选择性冠状动脉旁路移植术患者的非随机化观察性研究受到关注。该研究将抑肽酶、氨基乙酸、氨酸和未治疗进行比较，采用倾向评分调整法来平衡协变量，以减少因患者选择性地服用某些药物（而不是另一些药物）而可能导致的偏倚。研究结果表明，与未治疗相比，抑肽酶(但既非氨基己酸又不是氨酸)令严重肾功能衰竭的风险加倍，心肌梗塞或心力衰竭的风险增加了55%，并与中风或其他脑血管事件增加近一倍风险相关。该研究证实，三种抗纤维蛋白溶解药在减少失血上功能类似，但抑肽酶的不良事件比另两种药更频繁。该研究已发表的文章之所以引发了很多争议，其理由不外乎如下：该研究为观察性的研究，同时在许多不同的国家和不同的机构进行，未控制某些已知结局的决定因素进行，如使用或不使用抗凝药或影响收缩力的药物，心肺分流术的持续时间及输血量等。
不过，近来其他一些研究也报道了抑肽酶对肾的不良反应。一项对从1991年至2005年间的随机化试验的回顾显示，9％的服用抑肽酶的患者发生了肾功能衰竭(定义：需进行透析或术后增加血清肌酐水平到至少2.0mg每分升[即176.8 µmol])，12.9%的患者肾功能障碍(定义：增加肌苷0.5-1.9mg每分升[即44.2至168.0µmol每升])，而对照组仅为8.4％(RR1.47，95％可信区间（CI）：1.12-1.94，p<0.001)。一项受生产厂商委托所进行的观察性调查结果也显示：服用抑肽酶的67 000名患者中发生肾功能衰竭和肾功能障碍的比例与上类似。
虽然Mangano等与以往系统性回顾报告的作者均报道，氨基己酸和止血环酸看起来相对安全,这些药物的试验和参加者的数量比抑肽酶的少得多。因此，不要对其安全性太过信任，尤其是对血栓形成来说。最重要的是，
抑肽酶与赖氨酸类似物进行比较的试验太少，规模也太小。一项独立赞助的包括三个研究小组的随机临床试验正在加拿大进行中。抗纤溶药用于血液保护:一项在心脏外科手术人群中的随机化试验(BART)现仍在招收病人，计划招收2970例患者，以确定抑肽酶在减少术后大出血风险方面是否优于氨基己酸或氨酸。次要终点是由各种原因及不良反应事件（如心血管病和肾功能衰竭）等所致的死亡率。
根据目前已报道的资料，有大量可靠的证据表明在心外科手术病人中抑肽酶能够减少围手术期及早期术后失血量及输血需要量。尽管此方面的临床实验比较多，但是它在减少再次手术的有效性方面只有在综述里有报道，并且它在病死率方面所起作用缺少证据。遗憾的是价格低廉的赖氨酸类似物至此仍没有得到深入的研究，它们很可能似乎至少与抑肽酶的疗效相当。抑肽酶的安全性的不确定性还是一个值得关注的内容。直到得到加拿大试验结果为止，仍选择抑肽酶止血，但是，只有在围手术期及早期术后有大量失血的倾向时才用（例如，复杂的手术或者是在使用抗血小板药的特殊临床情况下）。
赖氨酸类似物有效性方面的证据还没有抑肽酶的坚实可靠，所以在高风险的心外科手术中它们只能作为二线选择。在不复杂的冠状动脉旁路手术中不能使用抑肽酶或其它的止血剂，即使在很多情况下采取停止泵作用以减少失血量和输血需要量。 FDA警告对使用胰蛋白酶抑制剂病人的肾、心及脑毒性的监控非常重要，只有在临床治疗中减少失血带来的益处超过风险时才能使用抑肽酶。
重组活化因子Ⅶ
rFIIa 通过与暴露的组织因子结合定位在局部受伤组织和血管壁破裂处， 产生少量足以激活血小板的凝血酶(图2)。活化的血小板表面形成一个模板，rFIIa通过它直接或间接的介导血凝块的进一步激活，最终产生更多的凝血酶使纤维蛋白原转变为纤维蛋白。通过由rFIIa 介导的溶血酶活性的纤溶酶抑制剂的激活，从而抑制纤维蛋白溶解作用，使血块稳定。
图2重组激活因子Ⅶ的作用机制
血管破裂时，内皮下组织暴露于循环血液并且可能结合IIa 因子。IIa 结合物激活X因子，活化的X因子 产生少量凝血酶。凝血酶（IIa 因子）激活血小板，因子和III 因子。活化的血小板结合IIa 因子。导致Xa的产生和IX的激活。活化的IX因子（IXa ）（及其辅助因子IIIa ）产生更多的Xa 因子。Xa因子和其辅助因子a 复合物使一定数量凝血酶原转变为凝血酶，这些凝血酶足够使纤维蛋白原转变为纤维蛋白。
重组活化因子（rFIIa）的作用
rFIIa最初是被批准用来治疗血友病人的出血，因为其体内具有使因子III或IX失活的抗体。最近，该因子被广泛应用于手术、创伤或其他原因引起的大出血。一个小规模的临床对照试验表明，rFIIa能够使经腹前列腺切除术的术中出血量与输血量降到最低，而通常情况下，此手术一般都会引起大量的出血。此试验中，36个病人随机分为rFIIa组（术前注射rFIIa，20 或 40 µg／kg）与安慰剂组，结果发现，给予rFIIa的病人失血量显著减少（50%），输血量也下降为安慰剂组病人的60%左右。
另有研究集中在肝移植人群。在一项开放式研究中，6名接受了单剂量rFIIa（80µg／kg）的肝移植患者，与配对的病例对照相比，输血量显著减少。但是后来的随机、安慰剂对照研究评估了182名肝移植患者，分别给予两种不同剂量的rFIIa（60和120µg／kg），虽然安慰剂组全部患者都需要输注红细胞，而rFIIa组中有8.4%的病人可以不输，但是输血总量并没有减少。另有两个随机对照试验表明，在肝硬化或正常肝功能患者实施大块肝切除术时运用大剂量的rFIIa（100 µg／kg，术中每两时１次），对于血容量高低或血液制品的需求却都没有明显改善。
另外，一项随机对照研究表明，20名需要心肺分流的非冠状心脏手术的患者，在分流术后给予rFIIa（90µg／kg），输血需求显著下降（任何形式的输血，相对危险度0.26，95%可信区间：0.07-0.90）。另外，一项特性评分配对病例对照研究发现，51名心脏手术大量失血的患者，在给予rFIIa（35-70µg／kg）后，失血量及血液制品的需求明显下降，但是，给予rFIIa的患者其急性肾功能障碍的发生率是对照组的2.4倍，两组间其他的不良反应无统计学差异。
许多的病例报告及病例系列分析提示，rFIIa对于减少创伤患者的大出血也大有裨益。一项包括143名严重钝器伤患者的安慰剂对照研究表明，连续三次给予rFIIa（剂量分别为200, 100, and 100 µg ／kg），能够显著减少红细胞的输注量（平均减少2.6Ｕ），降低需要大量输血（输注红细胞超过20Ｕ）患者的比例（14%s 33%），但是，在另一项包括134名穿透伤患者的平行试验中却没有明显效应。
研究还评价了在自发性颅内出血缺乏其他有效治疗手段时rFIIa的疗效。一项包括400名患者的寻找合适剂量的研究表明，与安慰剂组相比，rFIIa可以缓慢减小颅内血肿的体积，更重要的是，使死亡率下降了35%，90天内的残障评分亦得到改善。不幸的是，这些极具前景的早期结果在接下来包括821名患者的3期随机对照实验中没有得到证实，初期报告指出，rFIIa可以显著减小颅内血肿的体积，但是对初级研究终点（90天）的死亡率及严重致残率并无影响。生产商尚没有着手rFIIa用来治疗颅内血肿的注册审批。
还有研究探讨了该因子在门静脉高压－食管静脉曲张出血中的作用，此疾病也是临床上常见的又一个难题。在一项随机对照研究中，245名患有肝硬化和上消化道出血（66％的为出血性血管曲张）、且正在接受标准的内窥镜检查和药物治疗的病人，rFIIa治疗组（初次剂量后在30小时内连续给予８次，每次100µg／kg）在初级复合终点时末能控制24小时出血量及5天内的再出血或死亡率，并末优于安慰剂对照组。但是，在更加严重的肝硬化患者中（Child分组B或C），rFIIa可以降低到达复合终点的比例（8% s 23% ，P=0.03），此外，给予rFIIa治疗的患者在24小时内全部没有出现再次出血，而对照组中再出血发生率为11%(P=0.01)。
许多病例报告和病例系列分析还评估了rFIIa在极度严重甚至危及生命的失血患者中的价值。但是，随机对照临床尚末完成，考虑到人群的异质性，实施此项研究的难度较大，这也就不足为奇了。许多报告主张在其他治疗措施无效的情况下，使用rFIIa可使失血量快速下降、输血量显著下降。虽然此类报告大多数都引人关注，但是很可能出现出版偏倚，因此很难准确地评估rFIIa的有效性。
rFIIa的安全性
临床对照试验显示使用rFIIa的患者凝血方面的并发症略低于或与安慰剂患者组相似。但是，大多数 rFIIa研究中包含了凝血机能受损或处于形成血栓低风险状态的患者。在一项包括诸如颅内出血和高风险血栓形成患者的试验中，有7％使用rFIIa的患者发生严重的栓塞并发症－主要是心肌梗塞或缺血性中风－而在安慰剂组中仅为2％。在该试验中途改变了排除标准。最初仅排除了实验登记前30天内发生凝血疾病的患者，但在试验期中点，所有有凝血疾病的患者均被排除在外，以排除与 rFIIa使用安全性之间可能存在的不确定关系。FDA MedWatch数据库的一项评论显示，在动脉和静脉血管中都可发生凝血现象，特别是那些患有除血友病外服用无标签 rFIIa的患者。共有54％的栓塞发生在动脉（大部分病例为中风或急性心梗）；56％的患者栓塞发生于静脉（大部分病例为静脉血栓或肺梗塞）。在50例死亡病例中，有72％可能是由于栓塞引起的。目前对在何种临床状况下需要应用rFIIa还不清楚，这也与发生血栓风险有关。这些发现为凝血并发症的风险上升提供了证据，从而抵消了严重失血患者应用rFIIa的潜在益处。
rFIIa的有效性使其成为除血友病外急性失血患者的一种治疗选择。尽管此药并不是万能的，但对那些对其它治疗无效的外伤和大量出血患者确实是有效地。但是，目前得到的这些有希望的结果必须经确定性试验的证实，而且这种昂贵药物效价比也需研究确认。目前已有大量不同类型急性出血病例大获成功的病例报告，尽管对于临床医师是可信和有益的，但还是应该依据建立的临床指导性证据谨慎观察。通过DNA技术等分子工程使rFIIa的效力和效应进一步提高的努力一直在进行，但旨在进一步提高有效性和安全性的临床试验还有待开展。
其它干预措施
去氨基精加压素最初因治疗止血上的遗传缺陷而开发并获得许可证.该药物通过静脉缓慢滴注给予（浓度为0.3µg/g），从内皮细胞释放超大分子量血管性血友病因子(UL-WF)，从而增加血浆血管性血友病因子及相关因子III并加强了初期止血。其有效性的最有力证据是预防和治疗了轻度A型血友病和血管性血友病患者的出血。1986年，Salzman等的研究表明：与安慰剂相比，去氨基精加压素在复杂的心脏手术可减少约30％的失血和输血量。后来为了再现这些结果而进行的研究结果确不同，其中大多数并未证实原先所报道的明显效果。目前已有总计18项去氨基精加压素在1295例心脏手术中的作用的试验。这些试验显示，其对手术期间的失血效果甚微（中位数减少115ml)。多个综述表明，虽然去氨基精加压素有助于减少手术失血，但其效果太小无法对其他与临床更相关的，如输血和再手术的需求等方面产生影响。此外，去氨基精加压素并不能减少选择性部分肝切除（另一种往往与大出血相关的手术）中的失血或对输血的需求。一份关于去氨基精加压素可减少原发性脊柱侧弯的脊柱后路手术中失血报告87并未获得证实。
虽然去氨基精加压素可缩短尿毒症患者的皮肤出血时间，目前广泛使用的重组人红细胞生成素使此类出血异常的发生率较前大为减少。促红细胞生成素对止血有作用主要基于其增加了红细胞量，影响血液流体力学，最终导致循环的血小板和血管壁间更激烈的交互作用。
因此，很少有证据表明去氨基精加压素对除轻度A型血友病和血管性血友病外的疾病有效。可考虑在因遗传性的和后天血小板功能缺陷而出血的患者中使用去氨基精加压素。该药已被证实可缩短肝硬化患者及某些遗传性血小板功能障碍的皮肤出血时间。不过，在这些适应症中使用去氨基精加压素并无可靠基于相关结局变量的临床证据的支持。去氨基精加压素最常见的副作用通常是轻度的，包括面部潮红、瞬态低钠血症等。也曾有关于动脉血栓事件的报道，不仅在动脉血栓形成的患者，而且出血功能障碍的患者及捐血者均有。一项系统性综述结果表明，行心脏手术的急性心肌梗死患者使用去氨基精加压素后发生这些不良事件的频率较接受安慰剂的患者高一倍，而患者的临床结局并无改善。不过,另一项综述评价16项在心脏外科手术和其他高风险手术中使用去氨基精加压素的试验，接受去氨基精加压素和接受安慰剂的患者的血栓形成率并无显着差别(3.4％与2.7％)。
局部应用的止血药(尤其是由人纤维蛋白原、人或牛凝血酶、某些情况下还有人凝血因子XIII和牛抑肽酶组成的纤维蛋白粘合剂)已经在欧洲获得许可。在几个控制不佳的小样本患者参与的研究中，已报道了这些药物的作用，其适应症为心血管及胸科手术、肝脾破裂、套管位置和缝线部位的出血。需要方法合理的临床试验证明这些药物的有效性和安全性。
结论
已有的资料显示抑酶酞、赖氨酸类似物、rFIIa是有力的止血药，但是去氨基精加压素疗效较小。抑酶酞、赖氨酸类似物几乎专用于预防预期的大出血，然而rFIIa不仅用于预防而且用于治疗严重的大出血。抗纤溶药在治疗大量难治性出血方面的地位至今尚未阐明，止血药的选择最终根据医师对预期疗效的判断、安全性和医疗成本来确定，这是一个权衡过程，它可能会因为患者个体特征和特殊临床背景而变化。使用止血的药物不可避免的带来血栓形成的风险，特别是动脉粥样硬化或有血栓形成风险因素的患者。
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