Bleeding in a perioperative setting, following trauma or surgery, can arise from numerous causes that include activation of the coagulation, fibrinolytic, and inflammatory pathways; dilutional changes; hypothermia; and surgical factors.1–3 Bleeding may be further exacerbated by the increasing use of multiple agents that affect coagulation, including oral and parenteral anticoagulants and platelet inhibitors. Hemostatic function and coagulation are complex and often altered in by multiple events that occur in the perioperative setting.1–3 As a result, when patients bleed following surgery and trauma, multiple therapeutic approaches are often required in addition to blood transfusion, and procoagulants are now increasingly used to treat bleeding in the perioperative setting. This chapter will focus on the role of procoagulants used in a perioperative setting.
Antifibrinolytic Agents: Lysine Analogs
The two synthetic antifibrinolytic agents available are the lysine analogs epsilon aminocaproic acid (EACA) and tranexamic acid (TXA). These agents competitively inhibit activation of plasminogen to plasmin, an enzyme that degrades fibrin clots, fibrinogen, and other plasma proteins. TXA also inhibits plasmin at higher doses4,5 and most of the efficacy data are reported with TXA. EACA does not consistently reduce transfusion requirements or surgical reexploration, especially in cardiac surgery, where these agents are best characterized.6 Multiple meta-analyses examining the use of antifibrinolytic agents consistently report a decrease in bleeding with use of these agents as measured by chest tube drainage, but data are limited for any conclusions about safety. EACA has been removed from many European countries due to concerns about safety. Most studies reporting the use of antifibrinolytic agents are in cardiac surgical patients, but use in other patients, including orthopedic patients have also been reported. Aprotinin, a polypeptide protease inhibitor will be described later.
A review in cardiac surgical patients compared aprotinin, TXA, and EACA.7 From 49 trials, 182 deaths among 7,439 participants were reported and the relative risk for mortality with aprotinin versus placebo was 0.93. In the 19 trials that included TXA versus placebo, there were 24 deaths in 1,802 patients, yielding a relative risk of mortality of 0.55. To calculate direct estimates of death for aprotinin versus TXA, 13 trials with 107 deaths among 3,537 patients were evaluated. The relative risk was 1.43. Among 1,840 patients, the calculated estimates of death for aprotinin compared directly to EACA yielded a relative risk of 1.49. There was no evidence of an increased risk of myocardial infarction with aprotinin compared with TXA or EACA in either direct or indirect analyses. Compared with placebo or no treatment, all three drugs were effective in reducing the need for red blood cell transfusion. The relative risk of transfusion with use of aprotinin was 0.66; the relative risk of transfusion was 0.70 for TXA and 0.75 for EACA. Aprotinin was also effective in reducing the need for reoperation because of bleeding (RR, 0.48; 95% CI, 0.34–0.67).7
One of the potential complications of TXA is seizures. The incidence of postoperative convulsive seizures at one institution was reported to increase from 1.3% to 3.8% following cardiac surgery, temporally coincident with high-dose TXA.8 In 24 patients who developed perioperative seizures, all had received high doses of TXA intraoperatively ranging from 61 to 259 mg/kg, had a mean age of 69.9 years, and 21 of 24 had undergone open chamber cardiac procedures.8 Additional reports have also noted seizures associated with TXA.9 The ability of TXA to block γ-aminobutyric acid (GABA) receptors in the frontal cortex is the suspected mechanism. Despite the lack of safety data regarding these agents, they are widely used based on the available data on reduction in transfusion and mortality.
Antifibrinolytic agents also have been studied in other procedures, including orthopedic surgery, and all three agents reduce blood loss. Although most of the reported studies included small numbers of patients and lacked sufficient power, larger meta-analysis and more recent data suggest that these agents represent an important adjunct for reducing bleeding and the need for allogeneic transfusions. A recent meta-analysis examined the use of intravenous antifibrinolytics compared with placebo on red blood cell transfusion requirement in orthopedic surgery and the safety of these agents, including venous thromboembolic risk.10 They evaluated 42 randomized trials in total hip and knee arthroplasty, spine fusion, musculoskeletal sepsis or tumor surgery performed up to 2004. There were 22 trials with 1,238 participants for aprotinin, 20 trials with 1,096 participants for TXA, and 3 trials with 141 participants for EACA. Aprotinin and TXA both significantly reduced allogeneic blood transfusions compared to placebo. There was a dose-effect relationship with TXA but EACA did not show any efficacy; antifibrinolytic use was not associated with an increased risk of venous thromboembolic events.
TXA has also been studied in trauma patients and is being used more commonly for this application. Much of this increase in use is based on the Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage (CRASH-2) study, a study of the effects of early administration of TXA on death, vascular occlusive events, and blood transfusion in trauma patients conducted in 274 hospitals in 40 countries. A total of 20,211 adult trauma patients with (or at risk of) significant bleeding were randomly assigned within 8 hours of injury to receive either TXA (loading dose 1 g over 10 minutes then infusion of 1 g over 8 hours) or placebo. The primary outcome was in-hospital death within 4 weeks of injury and was described as bleeding, vascular occlusion (myocardial infarction, stroke, and pulmonary embolism), multiorgan failure, head injury, or other causes. A total of 10,096 patients were allocated to TXA and 10,115 to placebo, of whom 10,060 and 10,067, respectively, were analyzed. All-cause mortality was significantly reduced with TXA (1,463 [14.5%] TXA group vs. 1,613 [16.0%] placebo group; relative risk, 0.91; P = .0035). The risk of death due to bleeding was significantly reduced (489 [4.9%] vs. 574 [5.7%]; relative risk, 0.85; P = .0077).
In the United States, clinicians often use EACA instead of TXA; however, most of the efficacy and safety data with antifibrinolytic use is TXA and not EACA. Further, TXA is also approved in an oral form in the United States for the treatment of heavy menstrual bleeding. The recommended dose for women with normal renal function is two 650-mg tablets taken three times daily (3,900 mg per day) for a maximum of 5 days during monthly menstruation.
Antifibrinolytic Agents: Aprotinin
Aprotinin, a polypeptide serine protease inhibitor, inhibits plasmin and other serine proteases and has had a long history of use in different clinical applications. In cardiac surgery, multiple randomized, placebo-controlled trials reported aprotinin as effective in reducing bleeding and allogeneic transfusions.11,12 However, more recent reports from observational databases13–16 and one randomized study17 have questioned the safety of aprotinin. Following publication of the Blood Conservation Using Antifibrinolytics: A Randomized Trial in a Cardiac Surgery Population (BART) study,17 Bayer Pharmaceuticals removed the drug from the market, although it is still available for compassionate use.18 The U.S. Food and Drug Administration (FDA)18 noted “because . . . aprotinin . . . has been shown to decrease the need for RBC transfusions in patients undergoing CABG surgery, future supplies of [aprotinin] will continue to be available through the company as an investigational drug under a special treatment protocol.” A recent retrospective, single-center cohort study reports on 15,365 cardiac surgical patients of which 1,017 received aprotinin and 14,358 received TXA. They noted aprotinin had a better risk-benefit profile than TXA in high-risk patients, but not in low- to moderate-risk patients and suggested its use in high-risk cases may be warranted.19
On September 21, 2011, Health Canada concluded that the benefits of aprotinin outweigh the risks when used as authorized by Health Canada. Aprotinin is authorized for patients undergoing coronary artery bypass graft (CABG) surgery. The evidence does not suggest any increased risk of death associated with use of this agent. As a result of this assessment, the manufacturer, Bayer Inc, can resume the marketing of aprotinin in Canada. (http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2011/2011_124-eng.php). Health Canada’s decision is based on a comprehensive review of the totality of evidence, which included an evaluation of BART study data, other clinical trial data, postmarket studies, and information from Bayer as well as an Expert Advisory Panel that was convened by Health Canada, and a summary of key findings include the following:
(a) Evidence from clinical trials and postmarket studies continues to support that aprotinin benefits outweigh the risks when it is used as authorized by Health Canada: for basic CABG surgery. (b) Clinical trial data involving aprotinin use as authorized does not show an increased risk of death. (c) Data suggesting an increased risk of death involved use of aprotinin in complex, higher risk surgeries for which it is not authorized, such as valve replacement/repair. The precise nature of this risk remains unclear and merits further study. (d) With respect to the BART study, Health Canada concluded that the study was not designed to reliably determine the risk of death (either within or outside of CABG surgery) relative to the two drugs it was being compared against, and that the increased number of deaths in aprotinin patients could have been due to chance. (e) Health Canada’s review of the BART study revealed that aprotinin prolongs certain measures of blood clotting time differently than other drugs. This effect, if not recognized, can affect how blood clotting is managed during surgery in ways that can increase the risk of blood clots and death.
Protamine
Protamine is a polypeptide containing approximately 70% arginine residues and the only available agent to reverse unfractionated heparin. This basic protein inactivates the acidic heparin molecule via a simple acid–base interaction.20 Protamine does not reverse low-molecular-weight heparin. Most patients receive too much protamine for anticoagulation reversal because plasma levels of heparin decrease over time, and most fixed dose regimens for reversal give protamine based on the initial or total heparin dose and do not account for elimination.
Excess protamine should be avoided when reversing heparin as it can contribute to coagulopathy as shown in Figure 29-1.21 Protamine inhibits platelets and serine proteases involved in coagulation. Data suggests that maintaining heparin levels during cardiopulmonary bypass (CPB) and administering protamine based on the correct dose of circulating heparin reduces postoperative bleeding and the need for hemostatic factors.22 Part of this efficacy may be related to the finding that excess protamine prolongs the activated clotting time (ACT) and causes additional platelet dysfunction. When protamine is dosed based on the exact amount needed to reverse circulating heparin levels, it produces the lowest ACT values.21 Others have also reported lower protamine doses reduce bleeding and transfusion requirements.23
Heparin rebound can occur after initial reversal and is generally observed 2 to 3 hours after the first dose of protamine, when the patient is in the intensive care unit.24 Heparin levels at this time may range from 0.1 to 0.3 IU/mL, equivalent to circulating levels of heparin, based on a 5 L blood volume, of 500 to 1,500 units. Protamine doses of 5 to 15 mg at this time may be effective at reversing heparin rebound rather than the dose of 50 mg commonly administered.25 Studies have evaluated the ROTEM (Durham, NC) assay for determining the need for additional protamine administration and note that most patients do not need additional protamine administration within 30 minutes of initial administration. The ACT is not a sensitive indicator of low heparin concentrations because platelet counts and fibrinogen levels may also affect values.
Protamine can cause adverse reactions including anaphylaxis, acute pulmonary vasoconstriction and right ventricular failure, and hypotension.20 Patients at an increased risk for adverse reactions are sensitized, often from exposure to neutral protamine Hagedorn (NPH), which contains insulin and protamine.20 In a study of 1,551 cardiac surgery patients, the incidence of protamine reactions was 1/50 in insulin–dependent diabetics receiving NPH-insulin and 1/501 among other patients.26 A subsequent prospective study found that reactions occurred in 0.6% (1/160) of patients with NPH-insulin–dependent diabetes.27 Other individuals reported at risk for protamine reactions include patients with vasectomy, multiple drug allergies, and prior protamine exposure.20 Despite the potential for anaphylaxis, there are no currently available alternatives to protamine.
Desmopressin
Desmopressin (DDAVP) is the V2 analog of arginine vasopressin that stimulates the release of ultra large von Willebrand factor (vWF) multimers from endothelial cells.28 vWF mediates platelet adherence to vascular subendothelium by functioning as a protein bridge between glycoprotein Ib receptors on platelets and subendothelial vascular basement membrane proteins. DDAVP shortens the bleeding time of patients with mild forms of hemophilia A or von Willebrand’s disease (VWD).29 The specific surgical patients that might benefit from use of DDAVP are not clear. DDAVP is administered intravenously at a dose of 0.3 mg/kg and should be given over 15 to 30 minutes to avoid hypotension.30 Most studies have not confirmed the early reported efficacy during complex cardiac surgery. There have been 18 trials of DDAVP in 1,295 patients undergoing cardiac surgery that show a small effect on perioperative blood loss (median decrease, 115 mL).31,32 Because critically ill patients are often receiving vasopressin, which also has V2- and V1-mediated effects, there may not be a benefit to adding DDAVP to these patients.
DDAVP is also used to treat VWD; there are multiple types of this deficiency and therapy for each type varies. DDAVP is most useful in in type 3 (typically considered mild); in severe forms of types 1 and 2 VWD, DDAVP is not effective and vWF concentrates are available.33 VWD is the most frequent inherited bleeding disorder and is due to quantitative (types 1 and 3) or qualitative (type 2) defects of vWF.33DDAVP is the treatment for type 1 VWD. In type 3 and in severe forms of types 1 and 2 VWD, DDAVP is not effective and virally inactivated plasma vWF concentrates should be used in bleeding, surgery, and secondary long-term prophylaxis.33
DDAVP should be administered by slow intravenous infusion to avoid hypotension because it stimulates endothelial cells releasing vasoactive mediators in addition to vWF.34,35 Prior reports that DDAVP reduced blood loss and transfusion needs approximately 30% during complex cardiac surgery36–38 have not been confirmed.30,35 There have been 18 trials of DDAVP in 1,295 patients undergoing cardiac surgery that show a small effect on perioperative blood loss (median decrease, 115 mL). Although DDAVP may stimulate release of vWF, its effect is likely minimal compared to multiple other factors involved in hemostasis. Also, DDAVP may be associated with other adverse effects as myocardial infarction was twofold higher compared to placebo with no improvement in clinical outcomes.6 However, in another review evaluating 16 trials of DDAVP in cardiac surgery and in other high-risk operations, the rate of thrombosis did not differ significantly between patients who received DDAVP and patients who received placebo (3.4% vs. 2.7%).39
Fibrinogen
Fibrinogen is a 340-kDa plasma glycoprotein synthesized in the liver and a critical component of effective clot formation.40 It is the substrate of three important enzymes involved in clot formation: thrombin, factor (F) XIIIa, and plasmin as previously reviewed. The half-life is ~3.7 days (range, 3.00 to 4.08 days). For clot formation, thrombin cleaves the fibrinogen molecule, producing a soluble fibrin monomer which polymerizes to form a loose network in trapping red blood cells and a clot begins to form. Cross-linking of the fibrin polymers, induced by FXIIIa, is fundamental to the coagulation process, increasing the elasticity of the clot and its resistance to fibrinolysis. Fibrinogen also acts as the binding site (ligand) for glycoprotein IIb/IIIa receptors, found on the platelet surface, which are responsible for platelet aggregation. These platelets then become enmeshed within the fibrin strands, stabilizing the growing clot, and create the ability to cross-link and expand the clot and seal the bleeding site. During major hemorrhage, hemodilution after blood loss and subsequent volume replacement leads to reduced fibrinogen levels impairing fibrin polymerization and reduces clot stability. Thus, fibrinogen supplementation to restore plasma fibrinogen is key to normalizing clotting function.
Fibrinogen is an underrecognized coagulation factor that is critical for producing effective clot in surgical patients, and data supports hypofibrinogenemia as a predictor of perioperative bleeding.41–43 Normal fibrinogen levels are 200 to 400 mg/dL, although during the third trimester of pregnancy, fibrinogen levels are elevated to greater than 400 mg/dL. While the optimal fibrinogen level needed in a bleeding patient is not known, bleeding increases for each 100 mg/dL decrease in fibrinogen level in parturients.44 Low fibrinogen levels can predict bleeding after prolonged CPB.45,46 Treatment of fibrinogen deficiency is important for survival, and the amount of fibrinogen administered to trauma patients has been positively correlated with reductions in mortality.40
A major problem with managing bleeding is that many transfusion algorithms recommend therapy only when fibrinogen levels are less than 100 mg/dL. It is important to consider that such low levels of fibrinogen can increase laboratory measures of hemostasis including prothrombin time (PT) and partial thromboplastin time (PTT) that may not be corrected with transfusing fresh frozen plasma. In this situation, cryoprecipitate or fibrinogen concentrates are a better option to restore adequate plasma levels (~200 mg/dL) and need to be considered when treating life-threatening bleeding. Fibrinogen can be repleted by cryoprecipitate; 1 unit per 10 kg increases fibrinogen by 50 to 70 mg/dL. In Europe, fibrinogen concentrates are available and cryoprecipitate is not used. A fibrinogen concentrate (RiaSTAP [CSL Behring, King of Prussia, PA]) has just been granted licensing as an orphan drug for treating bleeding in patients with congenital afibrinogenemia or hypofibrinogenemia, but not for patients with dysfibrinogenemia.
Recombinant Coagulation Products
Recombinant proteins are becoming more readily available for managing bleeding, topical hemostasis and for other therapeutic interventions.47,48 Recombinant proteins can also be modified to alter specific characteristics that may be important in therapeutic effects or provide quantities that can be administered supraphysiologically as a therapeutic agent.47,48 Currently, they are used to manage bleeding in hemophilia, VWD, and in patients with acquired antibodies/inhibitors.47
Recombinant Activated Factor VIIa
Recombinant activated factor VIIa (rFVIIa; NovoSeven [Novo Nordisk, Princeton, NJ]) is most widely known and approved for hemophilia patients with inhibitors to treat bleeding but is increasingly used off-label as a prohemostatic agent for life-threatening hemorrhage.49 Recombinant factor VIIa produces a prohemostatic effect by multiple mechanisms that include complexing with tissue factor (TF) expressed at the site of vascular injury to locally produce thrombin and amplify hemostatic activation.50 Circulating FVIIa accounts for approximately 1% of circulating FVII and has no effect until bound with TF.50 An increasing number of publications report the off-label use of rFVIIa in cardiac surgical patients. The therapeutic dose of rFVIIa in nonhemophilia patients has not been established.51 However, guidelines as reported by Goodnough et al.51 and Despotis et al.52 for off-label use in patients with life-threatening hemorrhage are listed in Table 29-1.
Controlled clinical trials report the incidence of thrombotic complications among patients who received rFVIIa was relatively low and similar to that among patients who received placebo (Table 29-2).53However, most case reports giving rFVIIa as rescue therapy include patients who have impaired coagulation, have received multiple transfusions, and are at a high risk for adverse events. The complex role that transfusion therapy has in producing adverse outcomes is emerging in the scientific literature.54–56 A report using the FDA MedWatch database noted thromboembolic events in patients with diseases other than hemophilia in whom rFVIIa was used on an off-label basis and included 54% of the events as arterial thrombosis (e.g., stroke or acute myocardial infarction).57 Venous thromboembolism (mostly, venous 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 rFVIIa may have contributed to the risk of thrombosis.31 Other major issues about rFVIIa include costs and dosing. This drug has also seen widespread use in treating battlefield injuries.
In the most recent cardiac surgical study,58 patients bleeding postoperatively >200 mL per hour were randomized to placebo (n = 68), 40 µg/kg rFVIIa (n = 35), or 80 µg/kg rFVIIa (n = 69). The primary endpoints were the number of patients suffering critical serious adverse events. Secondary endpoints included rates of reoperation, blood loss, and transfusions. Although more adverse events occurred in the rFVIIa groups, they did not reach statistical significance (placebo, 7%; 40 µg/kg, 14%; P = .25; 80 µg/kg, 12%; P = .43). However, after randomization, significantly fewer patients in the rFVIIa group underwent a reoperation because of bleeding (P = .03) or needed allogeneic transfusions (P = .01).58
One of the difficulties in using rFVIIa is that it can normalize elevated international normalized ratio (INR)/PT values without actually correcting the coagulation defect, especially in patients receiving warfarin and other vitamin K antagonists.59 The use of prothrombin complex concentrates (PCCs), including a new four-component PCC recently approved in the United States, offers an important and recommended approach for the urgent reversal of warfarin.
Factor XIII (FXIII)
Plasma FXIII is an important final step in clot formation that stabilizes the initial clot. Several investigators have demonstrated reductions in FXIII during CPB and an inverse relationship between postoperative blood loss and postoperative FXIII levels.60,61 Addition of plasma-derived FXIII (Fibrogammin [CSL Behring, King of Prussia, PA]) at the end of CPB with concurrent antifibrinolytic therapy has reduced postoperative hemorrhage and transfusion requirement in two trials including 22 and 75 patients, respectively.61,62 The addition of 2,500 units FXIII (Fibrogammin [CSL Behring, King of Prussia, PA]) quickly restored the plasma level of FXIII as measured by (Berichrom ≥70 [Dade Behring, Marburg, Germany]) and reduced transfusion requirements. A recombinant FXIII has been recently reported in clinical studies and more studies are underway to evaluate this factor as a therapy to reduce bleeding.60
Prothrombin Complex Concentrates
PCCs are concentrates of coagulation factors that include factors II, VII, IX, and X in variable concentrations.63 Two agents (e.g., KCENTRA/Beriplex P/N [CSL Behring, Marburg, Germany], Octaplex [Octapharma, Vienna, Austria]) are used worldwide for vitamin K antagonist–induced (i.e., warfarin) reversal. KCENTA was recently approved in 2013 in the United States. Other PCCs available in the United States include FEIBA VH (Baxter, Vienna, Austria), Profilnine SD (Grifols, Barcelona, Spain), and Bebulin VH (Baxter, Vienna, Austria). They are approved for use in hemophilia and contain mainly factor IX.63
The three-component and activated PCCs available in the United States are indicated for prevention/control of bleeding in patients with hemophilia B, although they are used extensively off-label for other indications. Only FEIBA contains FVII in an activated form, and Bebulin contains only low levels of FVII.63 In general, it is considered preferable to give a PCC containing all four vitamin K–dependent coagulation factors and the natural anticoagulants antithrombin and activated protein C (APC) for anticoagulation reversal.
Although warfarin reversal in the United States is typically achieved with fresh frozen plasma (FFP),64 most other countries use PCCs.63 PCCs are recommended in guidelines as primary treatment for reversal in patients with life-threatening bleeding and an increased INR when urgent reversal is required. Recombinant factor VIIa can also be considered as an off-label alternative.63,65 Compared with FFP, PCCs provide quicker INR correction, have a lower infusion volume, and are more readily available without crossmatching.63,65 Although there are historical concerns about potential thrombotic risk with PCCs, present-day PCCs are much improved.66
Topical Hemostatic Agents
Topical hemostatic agents are used intraoperatively to promote hemostasis at the site of vascular injury and are classified based on their mechanism of action. They include physical and mechanical agents, caustic agents, biologic physical agents, and physiologic agents.67 The agent to use depends on the type of bleeding, the agent’s specific mechanism of action, its interaction with the environment, and the underlying coagulopathy.67 Absorbable agents include gelatin sponges (Gelfoam [Pfizer, New York, NY]), derived from purified pork skin gelatin that increase contact activation to help create topical clot. Surgicel or Oxycel are oxidized regenerated cellulose that work like Gelfoam (Pfizer, New York, NY). Avitene (Bard Davol, Warwick, RI) is microfibrillar collagen derived from bovine skin. Collagen sponges are available in different commercial forms and are derived from bovine Achilles tendon or bovine skin. Gelatin foam should not be used near nerves or in confined spaces but can be administered topically with thrombin. CoSeal (Baxter, Deerfield, IL) is used where swelling and expansion are not a concern. BioGlue (CryoLife, Kennesaw, GA) has been used in cardiac surgery, but it contains a glutaraldehyde component that cross-links proteins to fix tissues it is applied to.67
Topically applied thrombin preparations are also used extensively. The first available thrombin was derived from bovine plasma (Thrombin JMI [Pfizer, New York, NY]). Bovine thrombin currently should be avoided due to its potential for antibovine thrombin antibody formation and immune-mediated coagulopathy.68 Currently, there are two human thrombins available for clinical use including plasma-derived thrombin (Evithrom [Ethicon, Summerville, NJ]) and recombinant human thrombin RECOTHROM (The Medicines Company, Parsippany, NJ).
Fibrin sealants, also referred to as biologic glue or fibrin tissue adhesives, are component products that combine thrombin (mostly human) and fibrinogen (usually plasma derived).67 The first commercial fibrin sealant, Tisseel, (Baxter, Deerfield, IL) was approved in 1989. Additional fibrin sealants are currently in use and include Crosseal (Ethicon, Summerville, NJ), Evicel (Ethicon, Summerville, NJ) and FloSeal (Baxter, Deerfield, IL). They are packaged with a dual-syringe delivery system that combines the components to form a fibrin clot.67 The thrombin concentration determines the onset and the tensile strength fibrin seal.67 Crosseal (Ethicon, Summerville, NJ) contains human fibrinogen, human thrombin, and TXA. Evicel (Ethicon, Summerville, NJ) does not contain any fibrinolytic inhibitors. Several of these agents have been studied in cardiac surgical patients including FloSeal (Baxter, Deerfield, IL) 69 and is the subject of a recent review.70
Summary
The potential for bleeding in surgical patients represents an ongoing problem for clinicians. The increasing use of anticoagulation agents creates a need for multiple pharmacologic approaches as reviewed in the chapter on anticoagulation. Newer therapies, including purified protein concentrates such as the PCCs and potential recombinant therapies under development, will provide clinicians with the ability to administer key coagulation proteins to treat hemorrhage when standard therapies are ineffective, unavailable, or for other reasons that include no need for crossmatching. Therapy should be multimodal when managing perioperative hemostasis (Fig. 29-2).71Understanding the complex physiology of hemostatic function is an important part of therapy, and procoagulation agents are part of a multimodal approach.
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