Page 2590 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 159 Hematologic Problems in the Surgical Patient 2307

fibrinolytic enzymes in the digestive tract, and a metaanalysis found Aprotinin
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reductions in recurrent bleeding, need for surgery, and mortality.
However, improvements in the efficacy of other medical and endo- Aprotinin is a polypeptide extracted from bovine lung that inhibits
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scopic treatments have limited the use of these drugs in this setting, the action of serine proteases, including plasmin and kallikrein. In
although they are still useful for some patients with underlying bleed- addition to its antifibrinolytic activity, aprotinin is also thought to
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ing disorders. The urinary tract is also rich in plasminogen activa- preserve platelet function and have antiinflammatory effects, both of
tors, and some clinical trials comparing tranexamic acid or which may be mediated by inhibition of protease-activated receptors
aminocaproic acid with placebo in patients undergoing prostatectomy expressed on platelets, vascular endothelium, and neutrophils. 68
have shown reduced blood loss, but not a reduced need for transfu- The bulk of clinical experience with aprotinin was in cardiac
sion or decreased mortality. 36 surgery. In a large number of trials prophylactic administration of
The largest experience with aminocaproic acid in surgical patients aprotinin improved hemostasis and reduced requirements for transfu-
is in those undergoing cardiac and orthopedic surgery. Older meta- sion of red blood cells, platelets, and fresh-frozen plasma in patients
analyses have consistently shown that prophylactic treatment of undergoing cardiopulmonary bypass. 35,39,43 A large metaanalysis of
cardiac surgery patients with aminocaproic acid results in a 30%–40% such trials demonstrated decreased mortality with aprotinin and a
reduction in postoperative bleeding, without an increase in throm- reduced incidence of repeat thoracotomy, without any increased risk
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boembolic complications. 41,54-56 Similar results have been shown with for perioperative myocardial infarction. Furthermore, another
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tranexamic acid. Other metaanalyses have shown that aminocaproic metaanalysis showed a lower incidence of stroke in cardiac surgery
acid and tranexamic acid are effective in reducing surgical blood loss patients treated with high-dose aprotinin. 70
but have yielded inconsistent results in their capacity to reduce Although there is abundant evidence that aprotinin reduces blood
transfusion requirements. 42,57 A wide variety of dosing schedules may loss and transfusion requirements in cardiac surgery patients, an
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partly explain these heterogeneous results. A recent meta-analysis observational study in patients undergoing elective coronary revascu-
showed that both agents were effective in reducing blood loss and larization surgery revealed that aprotinin increased the risk of renal
transfusion requirements in those undergoing cardiac surgery. 58 failure, myocardial infarction, heart failure, stroke, or encephalopathy.
A number of studies have demonstrated that antifibrinolytic In that study, aminocaproic acid and tranexamic acid reduced blood
agents reduce blood loss in orthopedic surgery. A meta-analysis of 43 loss to a similar extent as aprotinin without an increase in adverse
randomized controlled trials in total hip and knee arthroplasty, spine events. The same investigators subsequently reported that aprotinin
fusion, musculoskeletal infection, or tumor surgery found that use was associated with increased long-term mortality after coronary
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aprotinin and tranexamic acid significantly reduced the number of artery bypass graft surgery. A second observational study confirmed
patients requiring transfusion, with a dose-effect relationship sug- the increased risk of postoperative renal dysfunction, without the
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gested for tranexamic acid. A meta-analysis of 11 clinical trials associated elevated risk of myocardial or cerebrovascular events
involving total hip replacement found that the use of tranexamic acid however. 72
significantly reduced intraoperative blood loss and transfusion A database analysis of over 30,000 children undergoing congenital
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requirements, without any increase in VTE or other complications. heart operations found no difference in postoperative mortality, need
A recent double-blind, randomized, placebo-controlled trial demon- for dialysis, or length of stay in patients who received aprotinin versus
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strated that intraoperative treatment with tranexamic acid was also those who did not. The Blood Conservation Using Antifibrinolytics
effective for reducing the need for transfusion in patients undergoing in a Randomized Trial (BART) randomly assigned 2331 cardiac
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retropubic prostatectomy. Therefore many centers routinely admin- surgery patients to aprotinin, tranexamic acid, or aminocaproic acid.
ister tranexamic acid to patients undergoing elective joint arthroplasty The study was terminated early because of an excess of deaths in the
to reduce blood loss and decrease the need for transfusion, and some aprotinin group, and the drug was subsequently withdrawn from the
centers also use it in patients undergoing urologic procedures. market in both Europe and the United States. Although the European
Antifibrinolytics, particularly tranexamic acid, have also been Medicines Agency subsequently lifted this ban in 2012, the use of
studied in the treatment of trauma patients, in whom 30% of deaths aprotinin is limited, and tranexamic acid is preferred.
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are attributed to hemorrhage. A landmark trial, Clinical Randomi-
sation of an Antifibrinolytic in Significant Haemorrhage 2 (CRASH-
2), evaluated the safety and efficacy of tranexamic acid in the setting Recombinant Factor VIIa
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of trauma. This randomized, placebo-controlled, multinational trial
that included more than 20,000 trauma patients demonstrated a rFVIIa is licensed in the United States only for the prevention and
significant reduction in all-cause mortality and death because of treatment of bleeding in hemophilia patients with factor VIII or
bleeding in the treatment group. More severely injured patients and factor IX inhibitors, patients with acquired hemophilia, and in those
those treated within 3 hours of injury derived the greatest benefit, with congenital factor VII deficiency. This drug is believed to induce
and there was no difference in the rate of vascular occlusive events hemostasis at local sites of tissue injury through enhancement of
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between the two groups. Tranexamic acid is now incorporated into thrombin generation on the surface of thrombin-activated platelets.
trauma clinical practice guidelines and treatment protocols. 64 rFVIIa also activates thrombin activatable fibrinolysis inhibitor,
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Two randomized controlled trials have shown that high-dose which in turn stabilizes the clot by inhibiting fibrinolysis. The use
tranexamic acid significantly reduces surgical blood loss and transfu- of rFVIIa in the management of hemophilia and factor VII deficiency
sion requirements in liver transplant recipients. 65,66 A metaanalysis is reviewed in Chapters 135–137.
identified 23 studies with a total of 1407 liver transplant patients who rFVIIa is often used for a variety of off-label indications, such as
received aminocaproic acid, tranexamic acid, or aprotinin compared to control refractory bleeding after surgery or major trauma and to
with each other or with controls/placebo. This review found that prevent bleeding in surgeries where blood loss is expected to be
tranexamic acid and aprotinin reduced transfusion requirements excessive (see box on Off-Label Use of rFVIIa). A prospective, mul-
without any increased risk for hepatic artery thrombosis, VTE, or ticenter, randomized, controlled trial that included 143 patients with
perioperative mortality. 67 blunt trauma and 134 patients with penetrating trauma found that
Aminocaproic acid and tranexamic acid are not without risks. in the group with blunt trauma, three successive doses of rFVIIa
There are case reports of thrombosis associated with both aminoca- significantly decreased red blood cell transfusion (mean reduction of
proic acid and tranexamic acid. However, no significant increase in 2.6 units) and decreased by approximately half the number of patients
thrombotic complications has been observed when the drugs have requiring massive transfusion (more than 20 units of red blood
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been used in patients undergoing cardiac, liver transplantation, or cells). Although similar trends were observed in the patients with
orthopedic surgery. 37,39,59,61,68 Furthermore, when used in doses penetrating trauma, the differences were not statistically significant.
exceeding 80 mg/kg, tranexamic acid has been associated with con- In spite of the reduction in the need for blood products, there was
vulsive seizures in patients undergoing cardiac surgery. 66,69 no survival benefit. After these initial encouraging reports of the use