Surgery and Hemostasis

Thrombotic Signals as a Result of Surgery

Initiators of coagulation include TF and other cytokines, particularly tumor necrosis factor-α and interleukin-6 if inflammation or infection is present. These cytokines rapidly accelerate the extrinsic system. Tissue destruction and TF release also occur in medical situations such as myocardial infarction (MI), sepsis, and malignancy (see Chapters 13 and 23 ). During the first several hours following surgery or significant trauma, there is an increase to approximately twice normal in circulating tissue plasminogen activator (tPA) levels and a rapid decrease toward normal levels by the end of the first 24 hours. Beginning approximately 2 hours after trauma, levels of plasminogen activator inhibitor type 1 (PAI-1) begin to rapidly rise, approaching levels 4 to 5 times normal, and then gradually decrease over a day or so—only to have a secondary peak at approximately day 7. During that period, these high levels of PAI-1 dampen the fibrinolytic system, a process that has been termed “fibrinolytic shutdown.” Of interest, it has been observed that warfarin administration dampens the increase in the PAI-1 reflex and thus may attenuate fibrinolytic shutdown, which could explain, in part, its net antithrombotic effect.

While thrombin is being generated, antithrombin III is consumed as it neutralizes thrombin by forming thrombin:antithrombin III complexes. Antithrombin III levels acutely can become severely reduced during surgery, particularly with trauma and especially after burns.

Levels of these mediators fluctuate rapidly and their degree of perturbation as measured by static laboratory tests will be a function not only of the type, degree, and duration of trauma but also of the timing of blood sample collection. Experimental evidence in reproducible trauma in animals validates that graduated degrees of trauma result in graduated degrees of hypercoagulability.

Shock and stasis often follow trauma. Stasis and venodilation may be induced in surgery by various anesthetic agents. General anesthetics cause more systemic venostasis than do local anesthetics used in epidural anesthesia. General anesthesia is associated with higher levels of PAI-1 generation 24 hours after the surgery and a higher incidence of thrombosis when compared in a controlled manner with patients undergoing the same procedure using epidural anesthesia. These higher levels of PAI-1 correlated well with subsequent thrombosis. Hamer and colleagues demonstrated that venous stasis is associated with hypoxia in venous valve pockets and may account in part for these pockets serving as loci of thrombosis generation. In endothelial cell cultures, hypoxia is associated with release of P-selectin from the endothelial cells, which may contribute to local inflammation. Comerota and colleagues studied the degree of venodilation of arm veins in patients undergoing total hip replacement. In patients who experienced a postoperative deep vein thrombosis (DVT), the mean degree of venous dilation was 29% over presurgical diameters, whereas the mean dilation of those who did not experience DVT was only 12%. All patients who experienced more than 20% dilation of their arm veins experienced a DVT. Venodilation created “microtears” in the endothelial lining that exposed underlying collagen and may very well have served as the nidus or trigger for thrombosis associated with surgery.

The pathophysiology of venous thrombosis and its relationship to the postsurgical inflammatory response have been characterized even further. This inflammatory response—previously best described as a cytokine “storm”—begins within hours after surgery and gives rise to a hypercoagulable state marked by several cellular processes, including the release of circulating microparticles (MPs), which have a multitude of effects on endothelial function. MPs are vesicles of ubiquitous origin, derived from the membranes of activated or apoptotic cells such as platelets, erythrocytes, leukocytes, endothelial cells, and even tumor cells. They are present in normal human blood but are increased in response to several disease states in addition to trauma and surgery. Their various roles in inhibiting and promoting inflammation, thrombosis, and angiogenesis depend on the stimulus triggering their formation and are defined by their cell of origin. Although platelet-derived MPs have generally been accepted to be the most abundant subtype, there has been growing interest in other cellular-derived MPs. This includes endothelial-derived MPs that have the ability to express surface phosphatidylserine and bind annexin V, forming a prothrombotic complex (especially in environments such as surgery) that further drive the generation of procoagulant enzymes, as well as those derived from activated monocytes, which appear to be the primary source of TF-bearing MPs (TF + MPs), which have been hypothesized to trigger thrombosis at sites of activated endothelium. Supporting the importance of other cellular-derived MPs is the observation of the induction of TF + MP release from activated monocytes by heparin–platelet factor 4 antibody complexes, which may serve as the initiating factor for thrombosis in heparin-induced thrombocytopenia.

Inferior vena cava (IVC) ligation models have been instrumental in helping us understand the role of MPs in venous thrombosis. Animal models have demonstrated increased leukocyte-derived MPs in mice genetically engineered to have high expression of circulating P-selectin, which was particularly notable after thrombosis was induced by IVC ligation. In comparison with their wild-type (WT) counterparts, these genetically engineered mice demonstrated a 50% increase in thrombus mass (TM) at day 2 and a 57% increase in TM on day 6. In contrast, the P-selectin knockout (KO) animals demonstrated the lowest TM, as well as the least amount of procoagulant MPs. Interestingly, investigators hypothesize that these thrombotic effects could not be due to elevated levels of P-selectin alone, because supplemental P-selectin in WT mice did not generate TM to the levels noted in the genetically engineered animals. In addition, the thrombotic mass in the genetically engineered animals did not completely revert to the levels seen in WT mice with the addition of P-selectin receptor antagonist or the P-selectin receptor antibody. This led to the hypothesis that in certain disease states (including injury induced during surgical intervention), selectins are expressed on the surface of endothelial cells and platelets, leading to MP formation and recruitment into areas of developing thrombosis furthering clot propagation. Ramacciotti and colleagues also examined MPs in a mouse IVC ligation model and demonstrated that re-injection of MPs in addition to IVC ligation leads to higher thrombus weight than does IVC ligation alone, with older MPs producing higher thrombus weight than do younger MPs. Finally, these investigators demonstrated direct correlation of MP concentration and TF activity, all supporting the notion of the important role that MPs play in amplification of thrombus formation.

To highlight and better define the impact that MPs have on endothelial function in the setting of surgical stress, Fu and colleagues isolated MPs from patients with valvular heart disease (VHD), before and after cardiac surgery with CPB, and compared them with age-matched healthy subjects. Not only did they demonstrate significantly higher levels of MPs in the VHD patients in comparison with the healthy controls at baseline; these levels were even higher postoperatively and appeared to contribute to significant impairment of endothelium-dependent vasodilation (as demonstrated through a number of in vitro physiologic testing). Of particular interest is the demonstration of MP effects on decreasing nitric oxide production and increasing superoxide anion generation (via uncoupling of endothelial nitric oxide synthase); effects that were enhanced even further after surgical intervention and which continued on 72 hours post surgery. The authors concluded that the higher level of MPs from VHD patients may contribute to the hemodynamic instability and physiologic abnormalities that are often seen in patients following such surgery, and that interventions such as cardiac surgery with CPB may generate the production of more harmful MPs that contribute to even further vascular dysfunction. Other studies have suggested that higher levels of circulating endothelial-derived MPs can be seen in certain higher-risk populations undergoing surgical interventions (i.e., obese and elderly) and may—in the future—be used to predict patients who are more susceptible to impaired recovery from surgery or even perioperative complications including, but not limited to, VTE.

Although the previous studies serve as just a few of the many examples of investigator-initiated efforts that have paved the way to our better appreciation of the vast contributions MPs have on vascular biology, challenges remain regarding the lack of standardization and reference controls to allow for reproducibility of such data among various centers. In addition, efforts remain ongoing to accurately measure and observe the effects of MPs in vivo (primarily limited to murine models), which will hopefully allow for a better understanding of all of their contributions to human biology. As our knowledge grows, the role of MPs as important markers of active thrombosis or increased risk for thrombosis during surgical interventions will likely expand. MPs, in the future, may even serve as potential targets to minimize surgical inflammation and the subsequent risks of postoperative VTE. Current theories of surgically induced hypercoagulability are listed in Box 34.2 .

Various other situations and events might have an impact on the effects of surgery on hemostasis and thrombosis. As alluded earlier, in major orthopedic surgery, epidural anesthesia seems to result in comparatively less hypercoagulability than does general anesthesia. The use of tourniquets in total knee replacement seems to lessen the hypercoagulability while increasing the net fibrinolysis in that operation when compared with not using a tourniquet. Boldt and colleagues deduced that there was no net difference between use of normal saline or lactated Ringer solution as replacement strategies with respect to input on hemostasis. CABG procedures appear less hypercoagulable when performed on-pump rather than off-pump, according to Quigley and colleagues. The use of hetastarch was found to be associated with increased post-CABG hemorrhage in a dose-response manner. Mild hypothermia (32° C to 36° C) did not affect hemostasis in one study, but more severe and prolonged hypothermia, as well as acidosis, grossly impeded hemostasis (see Chapter 40 ). In a randomized trial, normothermic off-pump CABG resulted in less hemorrhage and fewer transfused blood products than did relative hypothermia. It is of interest that harboring the gene for factor V Leiden mutation is correlated with decreased blood loss in CPB.

White and associates have prepared an interesting database regarding varying degrees of apparent hypercoagulability of various surgical procedures, demonstrating the higher incidence of thrombosis following vascular, orthopedic, and central nervous system parenchymal surgeries compared with a lower incidence following minor orthopedic, urologic, and head and neck surgery cases.

Prophylaxis Against Thrombosis

Prophylaxis against DVT and pulmonary embolism (PE) is discussed in Chapters 16 and 35 , as well as thoroughly reviewed in a 2012 consensus. The role of mechanical and similar adjuncts in prophylaxis against VTE verifies their use. Westrich demonstrated that intermittent pneumatic compression (IPC) in total knee replacement surgery was, in their hands, more effective than low-molecular-weight heparin (LMWH) and far more effective than ASA alone in reducing both DVT and PE. However, they did note only a 33% compliance rate with patients for whom IPC was prescribed. Several have demonstrated not only the effectiveness of IPC and similar devices but also the additive effect of this methodology with chemical (heparin) prophylaxis. The efficacy is theoretically due to a decrease in cross-sectional area of capacitance veins, thus generating both an increase in linear blood flow as well as protection of venous valve competency. There are clinical data supporting the theory that IPCs work in part by release of endogenous tPA. In addition, because the vein wall is less distended, one might speculate a decrease in microtears in the venous wall.

Although there has been a general and increasing acceptance of chemical prophylaxis in surgical patients, there remains a reticence on the part of some neurosurgeons for understandable fear of possible additional risk of hemorrhage. For many indications, IPC is probably effective. However, for neurosurgical patients who have additional risk factors for VTE (i.e., prior VTE, tumors [benign or malignant], advanced age, longer duration of surgery, head trauma, spinal cord injury, and paresis), there has been a growing body of literature investigating the risk:benefit ratio of pharmacologic prophylaxis to address the reported high incidence (up to 25%) of VTE in this particular patient population. In summary, these studies have indicated that not only is pharmacologic prophylaxis itself safe but, when combined with IPC, it adds to the efficacy of VTE prophylaxis either without an additional risk of hemorrhage or with a small amount of increased risk that such risk of hemorrhage was balanced by the decrease in overall morbidity and mortality from VTE. In addition, successful use of VTE prophylaxis avoids the concern for much higher and longer dosage of therapeutic anticoagulation should a VTE occur.

In one small study involving only patients undergoing brain tumor surgery, LMWH prophylaxis given preoperatively resulted in 5 of 46 patients judged to have experienced intracranial hemorrhage. However, in many of the neurosurgical studies, prophylactic doses of anticoagulation were typically initiated within 24 hours of completion of surgery. The overall benefit of pharmacologic prophylaxis in the neurosurgical population was confirmed in a meta-analysis which relied on postoperative LMWH prophylaxis trials, with none of the deaths considered to be related to prophylactic anticoagulation. In another study involving a mixed population of cranial and spine surgical patients, the addition of pharmacologic prophylaxis in the form of subcutaneous heparin at 5000 units twice daily to standard mechanical prophylaxis led to an approximately 43% relative risk (RR) reduction in VTE compared with the use of mechanical prophylaxis alone. This risk reduction was primarily seen in the form of lower extremity DVT (rather than PE), a majority of which were detected within the first week of surgery. Importantly, there was no associated increased risk of hemorrhagic complications.

rFVIIa has been used in some neurosurgical cases with recalcitrant hemorrhage, although a comprehensive systematic review of off-label rFVIIa use (which primarily focused on randomized controlled trials examining outcomes in patients with intracerebral hemorrhage) showed no improvement in mortality with use of rFVIIa across a range of doses. There also appeared to be an increase in arterial thromboembolism seen, in particular, with medium- and high-dosed rFVIIa use.

There is considerable debate regarding the need for VTE prophylaxis in patients undergoing laparoscopic surgery, with arguments for it and against it. In patients with prior VTE, prophylaxis seems indicated and rational. The reduction in net tissue damage afforded by laparoscopic surgery seems counterbalanced by the effects of the use of pneumoperitoneum and the Trendelenburg position.

The coagulation challenges associated with two surgical procedures, cardiopulmonary bypass surgery (CPB) and orthotopic liver transplantation (OLT) , are multiple with many various abnormalities noted; however, more likely than not, the changes leading to significant hemorrhage are mediated by surges of endogenous tPA resulting in a brisk hyperfibrinolytic state.

Cardiopulmonary Bypass Surgery

The effects of CPB on blood have been thoroughly reviewed. Although platelet defects have been ascribed to CPB, these are mostly multiple, minor, and transient. These aberrations are produced, in part, by partial activation of platelets coming in contact with the nonbiological material of the CPB pump and oxygenator apparatus, as well as binding and agglutination of platelets to such material. Platelet glycoprotein Ib (GpIb) is decreased on these platelets, but it is doubtful whether this change itself is sufficient to cause a significant hemostatic challenge. Hemorrhage may be serious enough to result in re-exploration in 3% to 7% of cases of CABG and is associated with a 30% increase in mortality.

Patients with acute coronary syndrome (ACS) are frequently administered antiplatelet agents because of their efficacy. However, because of clinical uncertainty regarding the timing of necessary operative intervention, patients frequently may be taken to the surgery suite while being administered such agents. Currently, major society guidelines provide conflicting recommendations regarding dosing of ASA or timing of discontinuation prior to surgery. A systematic review and meta-analysis demonstrated an increased risk of bleeding (defined as requiring transfusion and/or re-exploration) but with an observed decrease in the risk of MI (44% reduction) with the use of preoperative ASA in patients within 7 days of CABG. In an exploratory analysis, there was no increase in bleeding in those patients who received low-dose ASA (defined as a total daily dose of <160 mg), yet the protective effects against MI appeared to be maintained.

Recently, a large randomized controlled trial highlighted the uncertainty of the benefit of continued ASA therapy. The ATACAS Investigators examined more than 2000 patients who were considered at increased risk for major complications, either related to age or coexisting conditions, who underwent CABG. Patients were randomly assigned to receive 100 mg of ASA or placebo, 1 to 2 hours prior to elective CABG after ASA had been discontinued for at least 4 days. Importantly, a majority of the patients underwent on-pump (i.e., with CPB) CABG, which is known for its potential deleterious effects on platelet activation and coagulation system regulation. The results of this trial showed no significant effect of ASA therapy on thrombotic complications or death, nor the risk of surgical bleeding, need for transfusion, or need for reoperation. Although antifibrinolytic therapy was used in half of the patients (part of the 2 × 2 factorial design of the study), no significant interaction between the effects of ASA and TXA with regards to death, thrombotic complications, or major hemorrhage was seen. Still, a subsequent published systematic review (which included the data derived by the ATACAS investigators) surmised that, although studies were not consistent in demonstrating an increased bleeding risk with preoperative ASA, it appeared the risk:benefit ratio continues to support its use, with beneficial outcomes with regards to improved vein graft patency and reduction in perioperative MI. There also appeared to be the potential minimization of bleeding risks with lower doses of ASA and use of modern blood conservation techniques.

Exposure to clopidogrel within 3 days of CABG results in excessive postoperative bleeding and reoperation ; therefore its use ideally should be withheld prior to elective or semielective CABG. Based on the results of the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) trial, which demonstrated that bleeding complications were generally associated with patients undergoing CABG within 5 days of clopidogrel exposure, current guidelines recommend to discontinue thienopyridines 5 to 7 days before cardiac procedures when clinical circumstances allow for this. However, many critiques cite that this recommendation is based on weak levels of evidence (ad hoc analysis of a subgroup of patients from the CURE trial) and did not address bleeding due to off-pump CABG surgery, which is proposed to potentially have fewer bleeding complications. A retrospective, cohort study suggested that a full 3-day delay may be an alternative for this patient population, with comparable intraoperative and postoperative blood losses when compared with the control group without preoperative clopidogrel exposure. This is also supported by updated clinical practice guidelines. However, clopidogrel exposure within 72 hours of surgery was associated with increased blood loss and blood product transfusion.

Over the years, the development of new platelet inhibitors alleviated concerns regarding the up to 30% prevalence of clopidogrel nonresponders but highlighted ongoing uncertainty about timing of antiplatelet therapy discontinuation prior to CABG. Prasugrel, a thienopyridine derivative, which binds irreversibly to the P2Y12-receptor, provides a higher degree of platelet inhibition than does clopidogrel. In the first large phase 3 trial involving prasugrel (TRION-TIMI 38), patients with moderate- to high-risk ACSs scheduled to undergo percutaneous intervention were randomized to receive prasugrel or clopidogrel. Although composite death from cardiovascular causes, nonfatal MI, or nonfatal stroke was significantly reduced in patients treated with prasugrel, these patients also experienced significantly more bleeding complications, platelet transfusion, and surgical re-exploration for bleeding. This was particularly noted in the patients proceeding to CABG who experienced a 4 times higher rate of major bleeding than those treated with clopidogrel (13.4% vs. 3.2%). In spite of this, there was still improved survival with prasugrel compared with clopidogrel in CABG patients seen in the subset analysis of the TRITON-TIMI 38 CABG (all-cause mortality was 2.31% in the prasugrel group compared with 8.67% in the clopidogrel cohort).

To better understand the risks and benefits of preoperative use of clopidogrel, prasugrel, and the newest antiplatelet agent (ticagrelor), a large meta-analysis was conducted of more than 50,000 patients with coronary artery disease who underwent surgery (to include CABG) with or without one of the antiplatelet agents (often with concurrent use of ASA). Clopidogrel use was associated with a 2.5-fold increased risk of reoperation for bleeding in patients undergoing CABG in comparison with those patients who discontinued clopidogrel at least 5 days prior to surgery or who were not treated with clopidogrel at all. In addition, the use of preoperative clopidogrel increased the risk for death 1.47-fold in CABG surgery but did not diminish the risk for major adverse cardiovascular events. Similarly, preoperative prasugrel use appeared to increase the risk for death (4.7% mortality rate compared with 0.9% in those with preoperative prasugrel withdrawal). Interestingly, preoperative ticagrelor use did not appear to increase the risk for mortality. As a result, current guidelines (ACCF/AHA, ESC) recommend delaying elective CABG for 5 or more days after the last dose of clopidogrel or ticagrelor and 7 or more days after the last dose of prasugrel, given its longer off-set time.

Drugs that block the platelet glycoprotein IIb-IIIa (GPIIb/IIIa) platelet receptor (see Chapter 21 ) are used in patients with ACS, a population that may undergo emergent CABG with CPB and attendant extra risk for hemorrhage. Following abciximab, the GPIIb/IIIa receptor blocker with the longest half-life, a 12-hour hiatus after the last infusion is recommended. Because abciximab is very tightly bound to platelet membranes, with negligible amounts of unbound circulating abciximab in the plasma, use of platelet transfusions is rational for preparation of patients requiring emergent surgery before 12 hours have lapsed since the last abciximab infusion. Short-acting IV GPIIB/IIIa inhibitors (eptifibatide or tirofiban) should be discontinued for at least 2 to 4 hours before surgery to limit blood loss.

There is considerable growing opinion that the amount of bleeding encountered in CABG may be of less total clinical outcome significance than the total amount of blood products transfused and that increased use of blood products seems to be associated with less favorable long-term outcome. For instance, in an ASA study, although ASA patients received blood slightly more often, they were transfused the same amounts yet had better oxygenation and shorter ventilation times than patients off ASA for the week preceding CABG surgery. Interestingly, another study demonstrated that perioperative red blood cell transfusion was the single factor most reliably associated with increased risk of postoperative morbidity following CABG, with each unit of red cells transfused associated with incrementally increased risk for adverse outcomes. More recently, the Transfusion Requirements in Cardiac Surgery (TRiCS) III study demonstrated that even in cardiac surgery patients who were considered at moderate to high risk of death, a restrictive transfusion strategy (defined as a hemoglobin cutoff of 7.5 g/dL) was noninferior to a liberal approach (defined as a hemoglobin cutoff of 9.5 g/dL) with respect to adverse cardiovascular and renal events.

Current guidelines recommend maintenance of dual antiplatelet therapy (DAPT) for up to 12 months after percutaneous coronary intervention, followed by lifelong therapy with ASA. Although two trials demonstrated reductions in ischemic events in patients with ACS treated with DAPT beyond 1 year, this came at the expense of an increased risk of major bleeding. Efforts are underway to identify those patients at high risk for ischemic complications, yet low risk for bleeding, who would benefit the most from this approach. As a result, it is not unusual to encounter a patient who is already on maintenance DAPT and is also requiring urgent revascularization where a 5- to 7-day waiting period is not feasible. In response to this clinical dilemma, there has been a growing popularity in using point-of-care testing for platelet adenosine diphosphate responsiveness to identify clopidogrel nonresponders who are candidates for early operative intervention.

When excessive hemorrhage in CPB patients was believed to be caused primarily by acquired platelet defects, many studies examined the efficacy of routine use of DDAVP in managing those defects. DDAVP was not uniformly efficacious in reducing mortality, re-exploration, and blood use and may have even contributed to a twofold risk of perioperative acute myocardial infarction (AMI) ( Table 34.3 ). These data suggest that hemorrhage in the majority of CPB patients is not primarily due to a platelet defect or at least a platelet defect that could be reversed by the administration of DDAVP. DDAVP should not be used routinely in CPB patients but used only when it is apparent that a patient is hemorrhaging, and then it should be given in the routine dosage (0.3 µg/kg intravenously). This approach may minimize hemorrhage in patients taking ASA prior to their surgery.

Similarly the routine nonspecific use of platelet transfusions, as well as fresh frozen plasma (FFP) infusion, is not indicated. Indeed, using the large aprotinin database, Spiess and coauthors demonstrated that use of platelet transfusions was associated with multiple types of poor outcome, including infection, vasopressor use, stroke, and death.

Meta-analysis of six studies found neither rationale for nor reduction in blood loss with routine prophylactic use of FFP in CABG. Similarly, in another systematic review and meta-analysis of 37 studies, plasma transfusion was associated with either no benefit or with increased mortality in other surgical and nonsurgical settings (excluding trauma). Autotransfusion of shed blood during CABG using cell saver techniques was found in a randomized trial to be safe, resulting in no apparent clinical or laboratory aberrations while decreasing significantly the use of any homologous transfused blood or blood products. Two studies comparing preoperative use of LMWH with unfractionated heparin in ACS patients undergoing CABG demonstrated more re-exploratory surgery for hemorrhage and a higher transfusion rate for those patients receiving LMWH.

There is now general consensus that the majority of excessive bleeding following CPB is due to the surge of endothelial-derived tPA that occurs during rewarming of the patient, which temporally correlates with coming off the CPB apparatus and closure of the mediastinum. Until that time, circulating levels of tPA are not particularly high because the surge does not begin until the rewarming phase. Of interest, patients who undergo cardiothoracic surgery without CPB do not experience this tPA surge. Patients undergoing “off-pump” CABG do not lose as much blood as those “on-pump,” and use of ASA off-pump did not increase shed blood.

Re-exploration to assess hemorrhage is necessary in 3% to 7% of cases following CPB, and 67% of the time a specific bleeding site responding to local measures is found. Of interest, Pelletier found for the 33% of cases in which they did not find a surgical or anatomic correctable reason for hemorrhage, most hemorrhage simply stopped as though the re-exploration itself had a net hemostatic effect. Studying their hypothesis, various coagulation components of shed mediastinal blood were measured and compared with systemic levels in the same patient. The fibrinogen and α ₂ -plasmin inhibitor levels were both significantly lower ( P = .05), whereas the levels of PAI-1 and fibrin degradation products (FDPs) were both significantly higher ( P = .05) in the shed mediastinal blood than in systemic blood. They used these data as evidence for increased fibrinolytic activity primarily within the mediastinal cavity itself and that drainage via exploration may have eliminated self-perpetuating local hyperfibrinolysis. Khalil and colleagues have reproduced similar findings and additionally showed the efficacy of the installation of aprotinin into the pericardial sac.

Aprotinin, EACA, and TXA exert their primary procoagulant effects by blocking the action of plasmin, thereby greatly impeding fibrinolysis. Because aprotinin is of bovine origin, it could be expected to cause immunologic reactions, including anaphylaxis. Dietrich and colleagues studied 248 cases of re-exposure to aprotinin and found a 3% incidence of adverse reactions, which typically occurred on initiation of aprotinin administration and were characterized by an acute fall in blood pressure. All survived the reaction. Only 1.5% of patients experienced adverse reaction on re-exposure if more than 6 months had lapsed since their last exposure. Patients who had had re-exposure within 6 months had a reaction rate of 4.5%. However, after the preliminary data from the BART trial demonstrated a trend toward increased all-cause mortality in patients receiving aprotinin, the US Food and Drug Administration and Bayer Pharmaceuticals Corporation agreed to suspend marketing and distribution of the drug in November 2007, with withdrawal from world markets in May 2008. Subsequent analysis, including the Cochran Collaborative, summarized the efficacy and safety of aprotinin in all types of surgery. Although aprotinin was slightly more effective in comparison with placebo in reducing the need for RBC transfusion and reoperation due to bleeding, it resulted in a significant increase in the risk of death (relative risk [RR] 1.39, 95% confidence interval [CI] 1.02 to 1.89) and a nonsignificant increased risk of MI (RR 1.11, 95% CI 0.82 to 1.50) when compared directly with either or both of the lysine analogues, TXA and EACA. Between 2011 and 2012, Bayer was again allowed to market the drug in Canada and Europe following a critique of the BART trial by Canada's health regulatory body (Health Canada). Currently, aprotinin availability is limited to Canada, the United Kingdom, Sweden, and the Netherlands, although other European countries are likely to follow, with strict monitoring under the Nordic Aprotinin Patient Registry. It is still used in fibrin sealant preparations. Current STS/SCA guidelines still favor the use of the lysine analogues for perioperative blood loss management and blood conservation efforts, with a class IIIa recommendation against its routine use. See Chapter 28 for additional details.

Although operative and postoperative hemorrhage experienced in modern CABG surgery is largely controlled by advances in technical skills, cell saver techniques, improved equipment, and the use of antifibrinolytic agents, occasionally hemorrhage can be significant. Based on prior data that plasma fibrinogen deficiency occurs earlier than any other clotting factor deficiency in the setting of major blood loss treated with red blood cell and fluid resuscitation, a few investigators sought to evaluate the effect of fibrinogen concentrate in patients undergoing cardiac surgery. This included a randomized placebo-controlled trial involving 120 patients with intraoperative bleeding, who were administered either fibrinogen concentrate vs placebo, in addition to a standard transfusion protocol. The results showed no difference in intraoperative blood loss with targeted fibrinogen concentrate infusion but suggested an increase in adverse events including stroke, transient ischemic attack, MI, and death. Several small series have reported late use of “last-effort” recombinant activated factor VII (rFVIIa) to control hemorrhage with apparent efficacy, although thrombotic events have been reported. In a randomized controlled trial, Gill and colleagues demonstrated that the off-label use of rFVIIa in cardio­thoracic surgery patients undergoing CPB was feasible as rescue therapy in actively hemorrhaging patients, with reduction in need for reoperation and RBC transfusions. However, mortality was not significantly different in the rFVIIa-treated groups, with a trend toward a higher rate of serious adverse events, particularly stroke, in the patients receiving rFVIIa. As such, the risk:benefit ratio of the off-label use of rFVIIa in this setting remains to be determined. A systematic review of the few available controlled trials with use of rFVIIa in these off-label situations suggests a less favorable outlook than what was initially envisioned.

Orthotopic Liver Transplantation

OLT historically has been complicated by massive hemorrhage and heavy demands on the transfusion service. In recent years, our understanding of the hemorrhagic nature of OLT has increased to the point that effective therapy has greatly reduced both the incidence and severity of hemorrhage, as well as impact on the blood bank (see Chapter 36 ).

OLT often is performed in patients with profound deterioration of their hemostatic system, even preoperatively, given the role of the liver in coagulation, thrombosis, and fibrinolysis. The platelet count is often low because of hypersplenism. Accordingly, it previously had been regarded that these preoperative changes were the primary cause(s) of hemostatic failure in OLT.

Our understanding of hemostatic failure has been assisted by dividing OLT into four phases: the preoperative, anhepatic, and reperfusion phases, with a convalescent phase occurring in the week or two following the transplantation. The hemostatic changes characteristic of OLT have been described by many.

In brief summary, the patient has impaired hemostasis that deteriorates during the anhepatic phase because there is not even an impaired liver attempting to clear activated coagulation products or any released tPA. During the reperfusion phase, the surge of tPA results from washout from the donor liver following anastomosis with the recipient. This release of tPA is enhanced by shock, acidemia, and probably hypothermia. It is also during this phase that hemorrhage can become excessive. Those using thromboelastography (TEG) were instrumental in the discovery of reperfusion hyperfibrinolysis. In the convalescent period from postoperative days 1 through 14, procoagulant factors appear to replenish faster than anticoagulant factors. This may, in part, explain acute hepatic artery thrombosis that, should it happen, does so in this period.

Historically, several groups infused aprotinin (using 2 million KIU as a loading dose followed by 500,000 KIU every hour until skin closure) at the time of reperfusion, noting marked decreases in blood loss and transfusion requirements of red cells, FFP, and platelets. Patients who did not require transfusion of any blood product increased from 17% in patients not receiving aprotinin to 39% in those who did receive aprotinin. Although some studies have shown no benefit using the same aprotinin regimen, a double-blind study supported the use of aprotinin in OLT. Although subsequent studies showed a significant increase in the prevalence of fibrinolysis during OLT since the commercial withdrawal of aprotinin, there has been no increase in transfusion requirements with the use of other antifibrinolytic agents, including TXA or EACA. In addition, there was a suggestion of a trend toward improved graft and patient survival in those patients receiving EACA.

In OLT patients who experienced hemorrhage despite all surgical and pharmacologic corrective efforts, rFVIIa seemed effective in a small number of patients over a broad range of rFVIIa dosage. However, rFVIIa was not effective in reducing blood loss when prophylactically administered to OLT patients. Despite a prior publication deeming rFVIIa use as “appropriate” following failure of all routine measures, a subsequent systematic review showed no benefit on mortality with the use of rFVIIa. Demonstration of excessive mortality in patients undergoing OLT who received platelet transfusions has also been published, with a large part of their extra mortality found to be associated with an increase in acute lung injury.