Anesthesia & Analgesia:
REVIEW ARTICLE: Review Article
Factor V Leiden and Perioperative Risk
Donahue, Brian S. MD, PhD
Department of Anesthesiology, Vanderbilt University, Nashville, Tennessee
Accepted for publication December 3, 2003.
Address correspondence and reprint requests to Brian S. Donahue, MD, 504 Oxford House, Department of Anesthesiology, Vanderbilt University, Nashville, TN 37232. Address e-mail to firstname.lastname@example.org.
Factor V Leiden (FVL) is the most common known inherited cause of thrombophilia; it is present in approximately 5% of the Caucasian population. Although the risk of venous thrombosis associated with this polymorphism in various medical settings is well described, its effect on perioperative risk is only beginning to be explored. Specifically, there are few studies addressing the potential risks of FVL in the surgical population, in which both hemorrhagic and thrombotic complications convey substantial clinical and economic significance. There are speculations and unproven hypotheses regarding FVL in this population, and these there fore high light the need to comprehensively address this issue. This review will describe the physiology of the FVL mutation, briefly clarify its risk in the nonsurgical setting, and assess current data regarding FVL in noncardiac and cardiac surgery. Finally, a summary of current clinical evidence and a plan for more detailed investigation of this potentially significant risk factor will be proposed.
Hypercoagulable states describe a heterogeneous mix of clinical and inherited risk factors for thrombotic events and are significant contributors to adverse patient outcomes. Venous thrombosis is an important cause of morbidity in developed countries and affects approximately 2 individuals per 1000 each year (1–3). Although classic risk factors such as pregnancy, surgery, immobilization, malignancy, and estrogen use continue to be clinically important, many thrombotic episodes remain unexplained (4,5). The role of hypercoagulable states in the pathogenesis and prognosis of cardiovascular disease is established and becoming better understood (6–8).
With regard to venous thrombosis, investigators have recently identified many inherited deficiencies and genetic variants as risk factors (9). Rare inhibitor deficiencies, such as protein C, protein S, and anti-thrombin deficiencies, are easily identified by routine testing, but together they account for only approximately 10%–15% of all cases of venous thrombosis (10). Allelic variants in coagulation factor genes appear to account for a much larger fraction of cases; the prothrombin 20210 G/A polymorphism and factor V Leiden (FVL) (present in approximately 2% and 5% of Caucasians, respectively) account for approximately 50% of cases in the Caucasian population (10).
Today, because genetic testing for inherited thrombophilias is becoming more commonplace, anesthesiologists are likely to see more genetic data listed on preoperative laboratory reports. This often leaves them wondering what effect this should have on perioperative management. FVL is a common inherited prothrombotic risk factor (11) in the Caucasian population; its physiologic significance is well characterized, and its testing is often part of a hematology evaluation for venous thrombosis. Yet the literature on the significance of FVL in the perioperative setting is unclear. The purpose of this review is to summarize the current evidence for FVL as a risk factor for perioperative complications, highlight some unresolved issues, and offer evidence-based recommendations for testing, practice, and future investigations.
FVL: Physiology and Epidemiologic Risk
In the early 1990s, Svensson and Dahlback et al. (12,13) reported their results from population studies of patients with idiopathic venous thrombosis. They initially observed that a specific laboratory abnormality—resistance to activated protein C (aPC)—was present at a much more frequent rate in cases than in controls (14). This led the investigators to search for polymorphisms in regions of the factor V gene that coded for protein C cleavage sites (12). A single base substitution, adenosine for guanosine at position 1691, coded for a glutamine substitution for arginine at amino acid 506 and was identified in almost all of the cases (15). This mutated factor V protein was found to have normal procoagulant function in vitro but was resistant to inactivation by aPC, demonstrating that the mutation was responsible for the observed rate of aPC resistance in the studied population. The mutation was later found to have a carrier rate of 5%–10% in the Caucasian population. It was most common in Scandinavian and northern European ethnicities (16) and was termed factor V Leiden. Figure 1 depicts this role of FVL in the pathway of thrombin generation.
Subsequent epidemiologic studies have reported an increased risk of several thrombotic complications associated with FVL, such as recurrent venous thrombosis (17), cerebral sinus thrombosis (18–20), renal transplant rejection (21), venous thrombosis during pregnancy (22), and various obstetric complications (22–28). There is a much weaker association for FVL and arterial thrombosis or infarction: FVL appears to be principally a venous thrombosis risk factor (29). This may be due to the presence of an endogenous protein C inhibitor in platelets and the more dominant role that platelets play in arterial thrombosis (30–32). Although smaller reports in specific clinical subgroups have described some arterial thrombosis risk (33–41), these findings may reflect a common problem known as publication bias: the bias for studies with positive results to be published compared with studies with negative results, especially when the sample size is smaller (29,42). More comprehensive discussions of the clinical effect of FVL can be found in several excellent recent reviews (9,10,43–46).
The discovery of FVL and its 5% frequency in the Caucasian population marks an important watershed in our understanding of the genetics of thrombophilia (16,47,48). Before its discovery, most epidemiology regarding thrombophilia assumed that hypercoagulable states were monogenetic in origin. That is, a single factor deficiency (such as protein C, protein S, or antithrombin) was believed to be responsible for the observed thrombophilic phenotype. After the discovery of FVL, the understanding that multiple risk factors contribute to a clinical hypercoagulable state began to evolve (10,49). This newer model was more consistent with observations that most patients with FVL are asymptomatic and often must be exposed to an additional risk factor (pregnancy, immobilization, severe illness, or other genetic factors) to manifest the thrombophilic phenotype. This paradigm shift has fostered aggressive pursuits of polymorphism detection and the use of computerized technologies for rapid DNA analysis in an effort to characterize multiple genetic risk factors and their possible interactions (48).
Resistance to the anticoagulant effect of aPC is the hallmark laboratory finding associated with FVL (11), and an understanding of its physiologic significance and the laboratory methodology is crucial. Protein C is converted to its biologically active form, aPC, by the thrombin-thrombomodulin complex on endothelium (50). aPC, together with its cofactor protein S, serves multiple anticoagulant and antiinflammatory functions, one of which is to inactivate factors Va and VIIIa by proteolytic cleavage at specific sites on the substrate proteins. aPC also indirectly increases fibrinolytic activity by decreasing thrombin generation and the subsequent formation of thrombin-activatable fibrinolysis inhibitor (TAFI) (51,52). This role of aPC in supporting fibrinolysis has been demonstrated in animal models of experimental thrombosis (53,54). Other activities of aPC include inhibition of inflammatory cytokine production by activated monocytes, reduction of leukocyte rolling on injured endothelium (a key initial step in leukocyte-mediated inflammation), and inactivation of plasminogen activator inhibitor-1 (55).
Resistance to aPC is measured in a laboratory by comparison of standard clotting times in the presence and absence of aPC. Normal plasma typically clots in approximately 28–35 s when exposed to a contact pathway activator, creating the standard measurement known as “activated partial thromboplastin time” (aPTT). When aPC is added to the plasma, the anticoagulant effect of aPC is revealed by an increase in aPTT, usually by a factor of 2.0 or more: to 70–100 s, for instance. This plasma is said to be sensitive to aPC. When the aPTT for a plasma sample is prolonged by aPC by a measurably lesser extent, such as by a factor of 1.5–1.7 (as is typical for FVL heterozygotes), the plasma is said to exhibit resistance to aPC. Many conditions can produce or influence resistance to aPC (56–61); some of these are listed in Table 1. Although the assay can be modified by using different substances (e.g., tissue factor or Russel viper venom) to initiate in vitro coagulation (62), a contact pathway activator, such as colloidal silica, is usually used as described previously. The aPC resistance assay can also be made very specific for detecting factor V mutations by prediluting the plasma sample with factor V-deficient plasma (60).
FVL is therefore one common cause of resistance to aPC in Caucasians. This is due to the loss of the principal aPC cleavage site, usually present at the arginine residue 506, on the factor V protein. Proteolysis of activated factor V by aPC is usually rapid, but the activated FVL molecule remains intact much longer because aPC cannot cleave it at its principal location (45,52). FVL heterozygosity differs considerably from a 50% factor V deficiency, because in the latter case all circulating factor V still remains sensitive to inactivation by aPC, whereas in the former, half of the factor V is resistant to aPC and is present in amounts sufficient to continue thrombin generation despite the presence of aPC. This represents an important source of increased thrombin formation with FVL, because thrombin production is regulated by factor Va availability (45).
Resistance to aPC is not the only measurable prothrombotic abnormality observed in the plasma of FVL subjects. Additional effects of the FVL mutation on coagulation are listed in Table 2. Increased thrombin generation produces increased activation of TAFI, an important clot-stabilizing enzyme, and FVL subjects have demonstrated increased TAFI activity and lysis-resistant clots in laboratory assays of fibrinolysis (52). Also, the cleavage of factor VIIIa by aPC is normally facilitated by the prior cleavage of factor Va by aPC, a curious anticoagulant function of factor V (45). Hence, because factor Va cleavage by aPC is substantially reduced in the presence of FVL, subsequent cleavage of factor VIIIa is reduced.
The aPC resistance phenotype should be understood as a quantitative phenomenon: some patients are more resistant to aPC than others, and multiple factors (such as those in Table 2) can produce additive effects on aPC resistance (60). Clinical hypercoagulability, evidenced by the risk of venous thrombosis, also appears to be directly related to the degree of aPC resistance (60). For example, whereas patients heterozygous for FVL typically have aPC ratios of 1.6–1.8, rare patients who are homozygous for FVL have aPC ratios of 1.2–1.4. Such patients exhibit a lifetime risk of venous thrombosis that is approximately 5–10 times more than that of FVL heterozygotes, whose risk is approximately 5–10 times that of the noncarrier Caucasian population (9,44,46).
FVL in Noncardiac Surgery
Venous thrombosis often complicates the postoperative course, with a reported frequency as high as 36% even with anticoagulant management (63–65). In patients undergoing noncardiac surgery, many investigators have examined the effect of FVL as a potentially additive risk factor for this complication but have reported almost uniformly negative results (66–68). One of these studies (69) reported that FVL was not associated with an increased risk of postoperative venous thrombosis but was associated with an increased risk of pulmonary embolism. This finding was not confirmed in a large autopsy study of postoperative deaths caused by pulmonary embolism (70). Other authors have found that the risk of venous thrombosis after orthopedic surgery may be increased by the presence of the aPC resistance phenotype, which has multiple causes other than FVL, but the increase in clinically relevant predictive power provided by aPC resistance testing appears to be small (71).
From the current literature, it appears that the risk of venous thrombosis associated with joint replacement surgery and current postoperative management is large enough to overpower the relatively mild effect of FVL. Worth noting is that all patients in these studies received postoperative antithrombotic therapy. Therefore, although the natural history of FVL in the postoperative setting (i.e., in the absence of anti-thrombotic therapy) may not be known, such therapy constitutes standard practice, and routine preoperative screening has not been recommended in this population (72,73).
Negative findings have been reported in other post-surgical populations as well, although fewer studies are available and thrombosis rates are less frequent than for orthopedic surgery. Venous thrombosis after gynecologic surgery (74) was not associated with FVL in a retrospective case-control study, although all subjects had solid tissue malignancies, a condition that may carry more thrombosis risk than FVL and may limit the applicability of these results to other populations. Thromboembolic complications of artificial cardiac valves (75) do not appear to be associated with FVL. The relatively small populations in these studies (74 and 148 subjects, respectively) and the approximately 5% incidence of FVL heterozygosity considerably limit the power to detect differences.
Whether FVL and aPC resistance are risk factors for perioperative arterial thrombosis is an important question, because postoperative ischemia is a serious postoperative complication (76). Unfortunately, the current literature contains studies that are not sufficiently powered to conclusively address this question. Kibbe et al. (77) recently reported their findings from a prospective randomized study of 3 anticoagulation regimens for peripheral artery bypass operations in 244 patients; this study showed no decrease in patency rates associated with FVL. The power of the study may have been improved if all patients had been receiving the same postoperative therapy. Foley et al. (78) reported an increased frequency of aPC resistance and FVL among patients with peripheral vascular disease when compared with the general population, but they did not observe a decrease in long-term graft patency rates among patients with FVL. This study population consisted of only 45 patients, 8 of whom were heterozygous for FVL.
Positive associations in subgroups were reported in a study of 262 patients undergoing peripheral revascularization procedures, in which aPC resistance and FVL were not significant contributors toward a composite thrombotic end point (7). Subgroup analysis revealed significant associations of aPC resistance (observed in 22% of subjects) with early graft occlusion and early thrombotic complications. FVL was associated with early postoperative cerebrovascular events and late peripheral bypass graft occlusion, but the very small sample size (FVL was present in 1 of 3 patients with cerebrovascular events and 2 of 11 patients with late graft occlusion) and lack of adjustment for multiple testing call the validity of these results into serious question. Furthermore, postoperative antithrombotic or antiplate-let therapy (in the form of aspirin, warfarin, or both) was not standardized and was not included as a possible covariate.
As is common with rare catastrophic events, case reports further complicate interpretation of the literature because of their inherent publication bias and the anecdotal nature of the clinical circumstances. Cases of thrombosis after noncardiac surgery have been associated with FVL in both adult (79–81) and pediatric (82) settings and are included here for completeness.
FVL in Cardiac Surgery
Relevance of FVL to Cardiac Surgery
Cardiac surgery is a particularly relevant setting for clarifying genetic hemostatic risks because of the difficulty in predicting which patients are at risk for transfusion (83–85). Postoperative thrombosis can be catastrophic (5–8), and the role of antifibrinolytic drugs in precipitating serious thrombotic events is controversial (86–91). Cardiac surgery patients are major consumers of the nation's blood supply (83,92,93)—a problem that is more than economic, because postoperative transfusion is linked with poorer patient outcomes (94–96). The morbidity and economic considerations of antifibrinolytic drugs and the duration of intensive care unit and hospital stay are also matters of significant importance (95,97–101). Before the current literature regarding FVL and cardiac surgery is outlined, it is important to first emphasize some relevant issues of coagulation physiology in this clinical setting.
Physiologic Disturbances Specific to Cardiac Surgery
The hemostatic and inflammatory disturbances induced by cardiopulmonary bypass (CPB) are complex and produce activation of the inflammatory, complement, coagulation, and fibrinolytic systems. These multiple physiologic processes have been previously reviewed in detail (102–104). In our current understanding, thrombin generation remains central to the activation of the coagulation and fibrinolytic systems (104), and postoperative blood loss and transfusion correlate directly with thrombin generation during CPB (104–108). Platelets, activated by thrombin and CPB, are removed from circulation, and remaining platelets exhibit decreased responsiveness to thrombin (109). Fibrinolysis is activated during CPB by several mechanisms. Kallikrein, produced from contact activation, produces the active two-chain urokinase plasminogen activator (110). Kallikrein also releases bradykinin from high-molecular-weight kininogen, which in turn causes tissue plasminogen activator release from endothelium (111,112). Thrombin also stimulates the release of tissue plasminogen activator, the dominant plasminogen activator during CPB (113,114).
Protein C and Other Anticoagulant Systems During CPB
Thrombin generation during CPB has potential relevance for patients with FVL and aPC resistance, because thrombin produces an anticoagulant effect through the protein C pathway (115–117). Thrombin, bound to thrombomodulin, activates protein C, which inactivates factors Va and VIIIa (118). Levels of total protein C decrease during CPB, probably as a result of hemodilution. Levels of aPC increase during CPB, probably a result of thrombin generation, and increase specifically after release of the aortic cross-clamp (116). Investigators have found correlations between the aPC/total protein C ratio in coronary sinus blood and myocardial performance on the first postoperative day, suggesting an important function of this anticoagulant system in suppressing ischemia-induced inflammatory and cytotoxic effects (116). Earlier findings by the same group suggested that pediatric cardiac surgery patients with low perioperative levels of antithrombin and aPC, as well as patients with resistance to aPC, were at most risk for postoperative central venous thrombosis, an important contributor to early postoperative mortality (117).
Other anticoagulant systems, such as tissue factor pathway inhibitor (TFPI) (119,120), antithrombin (121–123), and heparin cofactor II (124–126), clearly play important roles during CPB, and a thorough discussion of the contribution of each is beyond the scope of this review. Also, evidence suggests important synergistic interactions between anticoagulant pathways in suppressing coagulation system activity (127,128). FVL patients who have experienced thrombosis have TFPI levels 39% less than those without thrombosis (129). Baseline thrombin generation in vitro is increased by the presence of FVL (130), suggesting that low TFPI or anti-thrombin activity may be a particularly substantial thrombosis risk factor in the presence of FVL.
FVL and Hemostasis After Cardiac Surgery
Reports of the hemostatic effect of FVL in the cardiac surgery population are shown in Table 3. Until recently, only one rather small study found a nonsignificant trend toward decreased blood loss among FVL heterozygotes (58). Investigators measured blood product use among 13 cardiac surgery patients with FVL and 13 matched controls and noted only a trend toward decreased consumption of blood products among the FVL subjects.
The question of whether FVL patients are at decreased risk for blood loss was addressed directly in a larger study (135): this was one of the first studies to answer a key issue regarding FVL in the cardiac surgery population. Using multivariate regression techniques to account for known variables that affect surgical hemostasis, researchers found that FVL carriers had an average of 30% less blood loss after CPB. The magnitude of blood sparing associated with FVL was nearly the same as that provided by the antifibrinolytic drugs aprotinin and ε-aminocaproic acid. Furthermore, the chance of not receiving any blood product transfusion during hospitalization was 46% among FVL patients, compared with 28% for noncarriers, a finding that was significant on logistic regression accounting for other known transfusion risks.
FVL and Risks for Thrombosis
Coronary bypass graft occlusion is an important clinical problem and often occurs despite optimal patient management (136,137). The frequency of vein graft occlusion may be as much as 10% within the first 10 days after surgery (138) and as frequent as 26% by the first year (136). More recent studies suggest that the long-term occlusion rate is quite variable among centers but approaches approximately 20% after 3–6 yr (139,140).
The unpredictability of vein graft occlusion has prompted investigators to consider patient-specific factors in the etiology, because prothrombotic states have been known to be risk factors for some time (141). In an earlier study, Eritsland et al. (131) reported their findings from 587 patients enrolled in a randomized trial of fatty acid supplementation and anticoagulant management. In these patients, whose aPC resistance status was known, no association was observed between graft occlusion at 1 yr and resistance to aPC. The relevance of these findings to FVL patients is limited, because these authors used a Russell viper venom time to measure resistance to aPC. This assay was later found to be insensitive in detecting FVL carriers (58,142).
The possible association of FVL with coronary artery bypass (CAB) graft occlusion was addressed by Moor et al. (132) in 1998. These authors performed coronary angiography on a population of 100 men 3 months after elective CAB surgery and reported graft occlusion in 45% of the FVL carriers (5 of 11) and in only 20% (18 of 89) of the noncarriers, a finding of borderline statistical significance (P = 0.06). Of note, all patients in this trial received postoperative aspirin therapy beginning on the day after surgery. These findings are mirrored by a later case report (143) describing complete CAB graft occlusion 1 mo after surgery in a patient with FVL and other prothrombotic risk factors, and successful management with repeat CAB and anticoagulation treatment. Because of the anecdotal nature of this report and the marginal findings in the study by Moor et al., overall conclusions regarding FVL and CAB graft occlusion are provocative, yet unclear: FVL may represent a contributory factor for early graft occlusion, but the magnitude of the effect and the possible interacting factors are unknown. Furthermore, because this study involved only men, the risk of CAB graft occlusion associated with FVL in women or in other populations and the possible interaction with other clinical variables or postoperative management options have not been investigated.
The risk of central venous thrombosis has been reported in a series of 20 affected pediatric patients after congenital heart repairs (117). These authors observed an association of low aPC and antithrombin levels with central vein thrombosis, an important contributor to death in 8 of the 20 patients. Also reported was the observation of resistance to aPC in 2 (17%) of 12 tested patients, a finding of unclear significance. Another underpowered study of FVL in pediatric patients undergoing congenital heart surgery (133) observed central vein thrombosis in 3 of 200 subjects, none of whom was found to carry FVL. However, these populations involved mostly children who had a broad spectrum of cardiac defects, and the surgical interventions consisted of a wide range of procedures. These important considerations limit the applicability of the results to adults or to other cardiac surgery populations.
FVL and Antifibrinolytic Drugs
Although antifibrinolytic therapy is a well studied modality for decreasing the hemorrhagic risk associated with CPB, much controversy has surrounded these drugs because of their possible prothrombotic risk (101,144,145). Attempting to characterize patients who are at risk for thrombosis when exposed to CPB and antifibrinolytic therapy has proven difficult. Aprotinin and the lysine analogs will be considered separately because of substantial differences in their pharmacology.
Because aprotinin is a known inhibitor of aPC, authors have addressed its effect in models of cardiac surgery. Sweeney et al. (58) observed that aprotinin induces resistance to aPC in normal plasma and exacerbates aPC resistance further in the plasma from FVL heterozygotes. The authors hypothesize that this doubly impaired anticoagulant function of aPC in the presence of FVL may account for the thrombosis observed in some clinical studies involving aprotinin. A similar laboratory finding—increased resistance to aPC in FVL plasma treated with aprotinin—was also observed in an ex vivo model of CPB, in which blood specimens from noncarriers and from FVL subjects were circulated in a bypass system (134). These authors used a slightly different aPC resistance assay that relied on activation of the patient's endogenous protein C by a snake venom and activated coagulation by Russel viper venom, a method mentioned previously. However, aprotinin induces a dose-dependent prolongation of aPTT in the absence of aPC (146). The standard cutoff value of 2.0 for the aPC ratio assumes a linear relationship of the aPC response and represents an assumption that may not be valid in the presence of prolonged baseline aPTT. The clinical significance of a decreased aPC ratio in the presence of aprotinin is therefore not clear.
Although these findings contribute to our understanding of the pharmacology of aprotinin, no clinical studies have documented an increased thrombotic risk of aprotinin in FVL patients undergoing cardiac surgery. Moreover, no studies have reported measuring an increase in aPC resistance in the blood of patients during CPB, rather than in blood to which aprotinin has been added in vitro. Many authors (147–149) have concluded that the CAB graft occlusion observed in earlier aprotinin trials was most likely a result of inadequate heparinization due to the use of celite-based activated clotting time, which is artificially prolonged in the presence of aprotinin.
Whether this potentially prothrombotic effect of aprotinin (inhibition of aPC) or the anticoagulant effects of aprotinin predominate in the presence of FVL has been addressed in a well documented case report (150). These authors, using a thromboelastogram technique, reported that aprotinin produced a 30% increase in the r-time (time to initiation of clot formation) and a decrease in the α-angle (rate of clot progression), with no measurable change in the maximum amplitude (a measurement of total clot strength), representing a definite anticoagulant effect of aprotinin. This anticoagulant effect persisted after the addition of either endothelial cells (a source of thrombomodulin to generate aPC) or celite (a contact pathway activator). Because aprotinin attenuates coagulation at multiple enzymatic steps (151), the results are somewhat expected. As the authors point out, these assays involved blood samples to which aprotinin was added, rather than specimens drawn from the patient during aprotinin therapy and CPB. Furthermore, inhibition of aPC by aprotinin occurs at concentrations of ≥500 kallikrein-inhibiting units per milliliter, levels not typically achieved in cardiac surgery (152–154). The authors conclude that although aprotinin can inhibit aPC, the anticoagulant effect of aprotinin appears to predominate in FVL plasma, and they recommend the use of aprotinin in this population when clinically warranted (150).
Tranexamic acid and ε-aminocaproic acid have a much different pharmacologic profile than aprotinin, because their principal effect is inhibition of plasmin and plasminogen activators, whereas aprotinin has inhibitory effects on multiple enzyme systems (102,155). The literature appears void of studies of the thrombotic risks of lysine analogs in the FVL population. However, the possible interaction of FVL, antifibrinolytic therapy, and hypothermic circulatory arrest in precipitating thrombosis was recently highlighted by a startling case report. Authors described two lethal massive thrombotic events occurring after protamine administration in patients undergoing hypothermic circulatory arrest with ε-aminocaproic acid (156). One of these patients was found to be a carrier of FVL. Presurgical screening was proposed, which generated some controversy because of its lack of demonstrated advantage in prospective trials (157). Later, the same group observed another massive thrombotic event in a third patient undergoing hypothermic arrest with ε-aminocaproic acid, who was an obligate carrier of FVL as determined by testing family members (Dr. Linda Shore-Lesserson, Mt. Sinai Medical Center, New York, personal communication, 2002). Although there is an inherent anecdotal nature to these reports, they highlight the importance of balancing the need for definitive evidence against conscientious and prudent medical practice.
Perioperative Risk of FVL: Summary and Unresolved Questions
The following conclusions can be drawn from the current data involving FVL in the perioperative setting:
1. Venous thrombosis after orthopedic or general surgery does not appear to be increased in the presence of FVL heterozygosity when patients are managed according to published protocols involving prophylactic anticoagulation. There is no evidence for altering perioperative management on the basis of the finding of FVL, nor is there evidence to support a role of preoperative screening for FVL or aPC resistance.
2. The role of FVL in arterial thrombosis and infarction after vascular surgery is less clear, but current literature suggests that there may be an increase in risk. On the basis of the literature, preoperative screening for FVL is unlikely to be of benefit, but screening for aPC resistance may identify patients at particular risk for earlier postoperative complications. Prudent recommendations include adherence to guidelines established by the American College of Cardiology/American Heart Association Task Force for management of patients at risk for perioperative ischemia (158), with decisions based on surgical urgency, patient history, clinical predictors, functional capacity, surgical risk, and specific invasive and noninvasive testing.
3. Cardiac surgery patients with FVL are likely to bleed less than noncarriers, and the degree of blood sparing may be equivalent to that associated with antifibrinolytic therapy.
4. Coronary bypass graft occlusion within the first few months after surgery may be increased in the presence of FVL. However, there is no evidence documenting the benefits of any targeted postoperative therapy to maintain graft patency in patients with FVL. Adherence to established guidelines (159) for maintaining graft patency, including the use of arterial conduits, postoperative antiplate-let therapy, antilipid therapy, lifestyle modifications, cardiac rehabilitation, and medical follow-up, may therefore have the greatest benefit in this potentially higher-risk group of patients.
5. The interaction of aprotinin at Hammersmith or half-Hammersmith doses with FVL is characterized mostly by an increase in anticoagulation, not by a hypercoagulable state. Early graft closure in FVL patients in the presence of aprotinin and risk factors for graft thrombosis remains a theoretical possibility without supporting or refuting evidence.
6. Little is reported on lysine analogs in the presence of FVL and CPB. Anecdotal evidence suggests the risk of a hypercoagulable state in the setting of circulatory arrest and profound hypothermia.
Several well conducted clinical studies are necessary to better clarify risk in the clinical situations listed previously. The risk for arterial thrombosis after both vascular surgery and cardiac surgery needs to be addressed in a large-scale, well controlled, prospective trial with sensitive clinical end-points and inclusion of other covariates. Early coronary graft occlusion and the need for repeat revascularization need to be studied as clinical end-points. The possible interaction of FVL with antifibrinolytic drugs, especially the lysine analogs, needs to be characterized. Novel methods of contact pathway inhibition are on the horizon, such as the aprotinin analog DX-88, a potent and specific inhibitor of kallikrein (160). Because kallikrein-induced fibrinolysis is a significant result of CPB (110–112), the potential interaction of this drug with FVL and other prothrombotic genotypes will need to be investigated. Each of these studies needs to include an evaluation of coagulation phenotypes, such as resistance to aPC, impaired fibrinolysis, and thrombin activation, as possible mechanisms by which FVL may be having a clinically apparent effect. Because prospective trials demonstrating the benefit of presurgical genotyping have yet to be performed, most current data do not support either preoperative screening for FVL or modification of anesthetic or surgical management on the basis of preoperative knowledge of a patient's factor V genotype. Genetic testing can be advocated only once the risks of a genotype are known and there is an evidence-based plan for decreasing the associated risks.
1. Oger E. Incidence of venous thromboembolism: a community-based study in Western France—EPI-GETBP Study Group. Groupe d'Etude de la Thrombose de Bretagne Occidentale. Thromb Haemost 2000;83:657–60.
2. Silverstein MD, Heit JA, Mohr DN, et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998;158:585–93.
3. Hansson PO, Welin L, Tibblin G, Eriksson H. Deep vein thrombosis and pulmonary embolism in the general population: ‘The Study of Men Born in 1913’. Arch Intern Med 1997;157:1665–70.
4. Heit JA. Venous thromboembolism epidemiology: implications for prevention and management. Semin Thromb Hemost 2002;28(Suppl 2):3–13.
5. Bauer KA. The thrombophilias: well-defined risk factors with uncertain therapeutic implications. Ann Intern Med 2001;135:367–73.
6. Prandoni P, Bilora F, Marchiori A, et al. An association between atherosclerosis and venous thrombosis. N Engl J Med 2003;348:1435–41.
7. Donaldson MC, Belkin M, Whittemore AD, et al. Impact of activated protein C resistance on general vascular surgical patients. J Vasc Surg 1997;25:1054–60.
8. Daley GQ, Cargill M. The heart SNPs a beat: polymorphisms in candidate genes for cardiovascular disease. Trends Cardiovasc Med 2001;11:60–6.
9. Crowther MA, Kelton JG. Congenital thrombophilic states associated with venous thrombosis: a qualitative overview and proposed classification system. Ann Intern Med 2003;138:128–34.
10. Endler G, Mannhalter C. Polymorphisms in coagulation factor genes and their impact on arterial and venous thrombosis. Clin Chim Acta 2003;330:31–55.
11. Dahlback B. Activated protein C resistance and thrombosis: molecular mechanisms of hypercoagulable state due to FVR506Q mutation. Semin Thromb Hemost 1999;25:273–89.
12. Dahlback B, Hildebrand B. Inherited resistance to activated protein C is corrected by anticoagulant cofactor activity found to be a property of factor V. Proc Natl Acad Sci U S A 1994;91:1396–400.
13. Dahlback B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci U S A 1993;90:1004–8.
14. Svensson PJ, Dahlback B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994;330:517–22.
15. Zoller B, Svensson PJ, He X, Dahlback B. Identification of the same factor V gene mutation in 47 out of 50 thrombosis-prone families with inherited resistance to activated protein C. J Clin Invest 1994;94:2521–4.
16. Dahlback B. New molecular insights into the genetics of thrombophilia: resistance to activated protein C caused by Arg506 to Gln mutation in factor V as a pathogenic risk factor for venous thrombosis. Thromb Haemost 1995;74:139–48.
17. Simioni P, Prandoni P, Lensing AW, et al. Risk for subsequent venous thromboembolic complications in carriers of the prothrombin or the factor V gene mutation with a first episode of deep-vein thrombosis. Blood 2000;96:3329–33.
18. Dulli DA, Luzzio CC, Williams EC, Schutta HS. Cerebral venous thrombosis and activated protein C resistance. Stroke 1996;27:1731–3.
19. de Bruijn SF, Stam J, Koopman MM, Vandenbroucke JP. Case-control study of risk of cerebral sinus thrombosis in oral contraceptive users and in carriers of hereditary prothrombotic conditions: the Cerebral Venous Sinus Thrombosis Study Group. BMJ 1998;316:589–92.
20. Siegert CE, Smelt AH, de Bruin TW. Activated protein C resistance and factor V Leiden mutation are risk factors for cerebral sinus thrombosis. Stroke 1997;28:1291–2.
21. Ekberg H, Svensson PJ, Simanaitis M, Dahlback B. Factor V R506Q mutation (activated protein C resistance) is an additional risk factor for early renal graft loss associated with acute vascular rejection. Transplantation 2000;69:1577–81.
22. Gerhardt A, Scharf RE, Beckmann MW, et al. Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium. N Engl J Med 2000;342:374–80.
23. Wramsby ML, Sten-Linder M, Bremme K. Primary habitual abortions are associated with high frequency of factor V Leiden mutation. Fertil Steril 2000;74:987–91.
24. Dilley A, Austin H, El-Jamil M, et al. Genetic factors associated with thrombosis in pregnancy in a United States population. Am J Obstet Gynecol 2000;183:1271–7.
25. Many A, Elad R, Yaron Y, et al. Third-trimester unexplained intrauterine fetal death is associated with inherited thrombophilia. Obstet Gynecol 2002;99:684–7.
26. Kupferminc MJ, Many A, Bar-Am A, et al. Mid-trimester severe intrauterine growth restriction is associated with a high prevalence of thrombophilia. Br J Obstet Gynaecol 2002;109:1373–6.
27. von Kries R, Junker R, Oberle D, et al. Foetal growth restriction in children with prothrombotic risk factors. Thromb Haemost 2001;86:1012–6.
28. Greer IA. The challenge of thrombophilia in maternal-fetal medicine. N Engl J Med 2000;342:424–5.
29. Juul K, Tybjaerg-Hansen A, Steffensen R, et al. Factor V Leiden: the Copenhagen City Heart Study and 2 meta-analyses. Blood 2002;100:3–10.
30. Sidelmann J, Gram J, Pedersen OD, Jespersen J. Influence of plasma platelets on activated protein C resistance assay. Thromb Haemost 1995;74:993–4.
31. Jane SM, Mitchell CA, Hau L, Salem HH. Inhibition of activated protein C by platelets. J Clin Invest 1989;83:222–6.
32. Prendes MJ, Bielek E, Zechmeister-Machhart M, et al. Synthesis and ultrastructural localization of protein C inhibitor in human platelets and megakaryocytes. Blood 1999;94:1300–12.
33. Szolnoki Z, Somogyvari F, Kondacs A, et al. Evaluation of the interactions of common genetic mutations in stroke subtypes. J Neurol 2002;249:1391–7.
34. Szolnoki Z, Somogyvari F, Kondacs A, et al. Evaluation of the roles of the Leiden V mutation and ACE I/D polymorphism in subtypes of ischaemic stroke. J Neurol 2001;248:756–61.
35. Nestoridi E, Buonanno FS, Jones RM, et al. Arterial ischemic stroke in childhood: the role of plasma-phase risk factors. Curr Opin Neurol 2002;15:139–44.
36. Hiatt BK, Lentz SR. Prothrombotic states that predispose to stroke. Curr Treat Options Neurol 2002;4:417–25.
37. French JK, Van de Water NS, Sutton TM, et al. Potential thrombophilic mutations/polymorphisms in patients with no flow-limiting stenosis after myocardial infarction. Am Heart J 2003;145:118–24.
38. Csaszar A, Duba J, Melegh B, et al. Increased frequency of the C3*F allele and the Leiden mutation of coagulation factor V in patients with severe coronary heart disease who survived myocardial infarction. Exp Clin Immunogenet 2001;18:206–12.
39. Chan AK, deVeber G. Prothrombotic disorders and ischemic stroke in children. Semin Pediatr Neurol 2000;7:301–8.
40. Baranovskaya S, Kudinov S, Fomicheva E, et al. Age as a risk factor for myocardial infarction in Leiden mutation carriers. Mol Genet Metab 1998;64:155–7.
41. Irvine CD, Foley PW, Standen GR, Morse C. Should patients with atherosclerosis or peripheral vascular disease be stratified for factor V Leiden? Blood 1997;90:2114.
42. Scargle J. Publication bias: the “file-drawer” problem in scientific inference. J Sci Exploration 2000;14:91–106.
43. Bloomenthal D, Delisle MF, Tessier F, Tsang P. Obstetric implications of the factor V leiden mutation: a review. Am J Perinatol 2002;19:37–47.
44. Ridker PM. Inherited risk factors for venous thromboembolism: implications for clinical practice. Clin Cornerstone 2002;4:18–30.
45. Nicolaes GA, Dahlback B. Factor V and thrombotic disease: description of a janus-faced protein. Arterioscler Thromb Vasc Biol 2002;22:530–8.
46. Qari M, Abdel-Razeq H, Alzeer A, et al. Recent advances in the diagnosis and treatment of deep vein thrombosis: a regional consensus. Curr Opin Investig Drugs 2003;4:309–15.
47. Zoller B, Garcia de Frutos P, Hillarp A, Dahlback B. Thrombophilia as a multigenic disease. Haematologica 1999;84:59–70.
48. Hooper WC, De Staercke C. Venous thromboembolism: implications for gene-based diagnosis and technology development. Expert Rev Mol Diagn 2002;2:576–86.
49. Mohanty S, Saxena R, Behari M. Risk factors for thrombosis in nonembolic cerebrovascular disease. Am J Hematol 1999;60:239–41.
50. Pescatore SL. Clinical management of protein C deficiency. Expert Opin Pharmacother 2001;2:431–9.
51. Castellino FJ. Gene targeting in hemostasis: protein C. Front Biosci 2001;6:D807–19.
52. Bajzar L, Kalafatis M, Simioni P, Tracy PB. An antifibrinolytic mechanism describing the prothrombotic effect associated with factor V Leiden. J Biol Chem 1996;271:22949–52.
53. Gresele P, Momi S, Berrettini M, et al. Activated human protein C prevents thrombin-induced thromboembolism in mice: evidence that activated protein C reduces intravascular fibrin accumulation through the inhibition of additional thrombin generation. J Clin Invest 1998;101:667–76.
54. Hashimoto M, Watanabe S, Oiwa K, et al. Enhanced thrombolysis induced by argatroban or activated protein C in the presence or absence of staphylokinase, measured in an in vivo animal model using mesenteric arterioles. Haemostasis 2001;31:80–9.
55. Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699–709.
56. Bernardi F, Faioni EM, Castoldi E, et al. A factor V genetic component differing from factor V R506Q contributes to the activated protein C resistance phenotype. Blood 1997;90:1552–7.
57. Williamson D, Brown K, Luddington R, et al. Factor V Cambridge: a new mutation (Arg306→Thr) associated with resistance to activated protein C. Blood 1998;91:1140–4.
58. Sweeney JD, Blair AJ, Dupuis MP, et al. Aprotinin, cardiac surgery, and factor V Leiden. Transfusion 1997;37:1173–8.
59. Clark P, Brennand J, Conkie JA, et al. Activated protein C sensitivity, protein C, protein S and coagulation in normal pregnancy. Thromb Haemost 1998;79:1166–70.
60. Clark P, Walker ID. The phenomenon known as acquired activated protein C resistance. Br J Haematol 2001;115:767–73.
61. Hellgren M. Hemostasis during normal pregnancy and puerperium. Semin Thromb Hemost 2003;29:125–30.
62. Akhtar MS, Blair AJ, King TC, Sweeney JD. Whole blood screening test for factor V Leiden using a Russell viper venom time-based assay. Am J Clin Pathol 1998;109:387–91.
63. Hull RD. New insights into extended prophylaxis after orthopaedic surgery: the North American Fragmin Trial experience. Haemostasis 2000;30(Suppl 2):95–100; Discussion 82–3.
64. Turpie AG. Optimizing prophylaxis of venous thromboembolism. Semin Thromb Hemost 2002;28(Suppl 2):25–32.
65. Strebel N, Prins M, Agnelli G, Buller HR. Preoperative or postoperative start of prophylaxis for venous thromboembolism with low-molecular-weight heparin in elective hip surgery? Arch Intern Med 2002;162:1451–6.
66. Woolson ST, Zehnder JL, Maloney WJ. Factor V Leiden and the risk of proximal venous thrombosis after total hip arthroplasty. J Arthroplasty 1998;13:207–10.
67. Ryan DH, Crowther MA, Ginsberg JS, Francis CW. Relation of factor V Leiden genotype to risk for acute deep venous thrombosis after joint replacement surgery. Ann Intern Med 1998;128:270–6.
68. Philipp CS, Dilley A, Saidi P, et al. Deletion polymorphism in the angiotensin-converting enzyme gene as a thrombophilic risk factor after hip arthroplasty. Thromb Haemost 1998;80:869–73.
69. Wahlander K, Larson G, Lindahl TL, et al. Factor V Leiden (G1691A) and prothrombin gene G20210A mutations as potential risk factors for venous thromboembolism after total hip or total knee replacement surgery. Thromb Haemost 2002;87:580–5.
70. Blaszyk H, Bjornsson J. Factor V leiden and morbid obesity in fatal postoperative pulmonary embolism. Arch Surg 2000;135:1410–3.
71. Lowe GD, Haverkate F, Thompson SG, et al. Prediction of deep vein thrombosis after elective hip replacement surgery by pre-operative clinical and haemostatic variables: the ECAT DVT Study—European Concerted Action on Thrombosis. Thromb Haemost 1999;81:879–86.
72. De Stefano V, Chiusolo P, Paciaroni K, Leone G. Epidemiology of factor V Leiden: clinical implications. Semin Thromb Hemost 1998;24:367–79.
73. Eckman MH, Erban JK, Singh SK, Kao GS. Screening for the risk for bleeding or thrombosis. Ann Intern Med 2003;138:W15–24.
74. Ravin AJ, Edwards RPA, Krohn M, et al. The factor V Leiden mutation and the risk of venous thromboembolism in gynecologic oncology patients. Obstet Gynecol 2002;100:1285–9.
75. Mammo L, Saour JN. Lack of association between factor V Leiden and thromboembolism in patients with prosthetic heart valves. Blood Coagul Fibrinolysis 1999;10:141–4.
76. Grayburn PA, Hillis LD. Cardiac events in patients undergoing noncardiac surgery: shifting the paradigm from noninvasive risk stratification to therapy. Ann Intern Med 2003;138:506–11.
77. Kibbe MR, Hassett AL, McSherry F, et al. Can screening for genetic markers improve peripheral artery bypass patency? J Vasc Surg 2002;36:1198–206.
78. Foley PW, Irvine CD, Standen GR, et al. Activated protein C resistance, factor V Leiden and peripheral vascular disease. Cardiovasc Surg 1997;5:157–60.
79. Mira Y, Todoli T, Alonso R, et al. Factor V Leiden and prothrombin G20210A in relation to arterial and/or vein rethrombosis: two cases. Clin Appl Thromb Hemost 2001;7:234–7.
80. Van Buren SF, Heit JA, Panneton JM, Donohue JH. Iliac arterial thrombosis after inguinal hernia repair. Mayo Clin Proc 2002;77:1361–3.
81. Pruthi RK, Heit JA, Green MM, et al. Venous thromboembolism after hip fracture surgery in a patient with haemophilia B and factor V Arg506Gln (factor V Leiden). Haemophilia 2000;6:631–4.
82. Steiner M, Hodes MZ, Shreve M, et al. Postoperative stroke in a child with cerebral palsy heterozygous for factor V Leiden. J Pediatr Hematol Oncol 2000;22:262–4.
83. Stover EP, Siegel LC, Parks R, et al. Variability in transfusion practice for coronary artery bypass surgery persists despite national consensus guidelines: a 24-institution study—Institutions of the Multicenter Study of Perioperative Ischemia Research Group. Anesthesiology 1998;88:327–33.
84. Magovern JA, Sakert T, Benckart DH, et al. A model for predicting transfusion after coronary artery bypass grafting. Ann Thorac Surg 1996;61:27–32.
85. Liu B, Belboul A, Larsson S, Roberts D. Factors influencing haemostasis and blood transfusion in cardiac surgery. Perfusion 1996;11:131–43.
86. Hocker JR, Saving KL. Fatal aortic thrombosis in a neonate during infusion of epsilon-aminocaproic acid. J Pediatr Surg 1995;30:1490–2.
87. Sopher M, Braunfeld M, Shackleton C, et al. Fatal pulmonary embolism during liver transplantation. Anesthesiology 1997;87:429–32.
88. Pitts TO, Spero JA, Bontempo FA, Greenberg A. Acute renal failure due to high-grade obstruction following therapy with epsilon-aminocaproic acid. Am J Kidney Dis 1986;8:441–4.
89. Sundt TM III, Kouchoukos NT, Saffitz JE, et al. Renal dysfunction and intravascular coagulation with aprotinin and hypothermic circulatory arrest. Ann Thorac Surg 1993;55:1418–24.
90. Saffitz JE, Stahl DJ, Sundt TM, et al. Disseminated intravascular coagulation after administration of aprotinin in combination with deep hypothermic circulatory arrest. Am J Cardiol 1993;72:1080–2.
91. Cosgrove DM III, Heric B, Lytle BW, et al. Aprotinin therapy for reoperative myocardial revascularization: a placebo-controlled study. Ann Thorac Surg 1992;54:1031–6; Discussion 1036–8.
92. Stover EP, Siegel LC, Body SC, et al. Institutional variability in red blood cell conservation practices for coronary artery bypass graft surgery: Institutions of the MultiCenter Study of Perioperative Ischemia Research Group. J Cardiothorac Vasc Anesth 2000;14:171–6.
93. Stover EP, Siegel LC, Hood PA, et al. Platelet-rich plasma sequestration, with therapeutic platelet yields, reduces allogeneic transfusion in complex cardiac surgery. Anesth Analg 2000;90:509–16.
94. Engloren MC, Habib RH, Zacharias A, et al. Effect of blood transfusion on long-term survival after cardiac operation. Ann Thorac Surg 2002;74:1180–6.
95. Engloren M, Arslanian-Engloren C, Steckel D, et al. Cost, outcome, and functional status in octogenarians and septuagenarians after cardiac surgery. Chest 2002;122:1309–15.
96. Moulton MJ, Creswell LL, Mackey ME, et al. Reexploration for bleeding is a risk factor for adverse outcomes after cardiac operations. J Thorac Cardiovasc Surg 1996;111:1037–46.
97. Moskowitz AJ, Rose EA, Gelijns AC. The cost of long-term LVAD implantation. Ann Thorac Surg 2001;71:S195–8; Discussion S203–4.
98. Ray MJ, Brown KF, Burrows CA, O'Brien MF. Economic evaluation of high-dose and low-dose aprotinin therapy during cardiopulmonary bypass. Ann Thorac Surg 1999;68:940–5.
99. Reddy P, Song J. Cost comparisons of pharmacological strategies in open-heart surgery. Pharmacoeconomics 2003;21:249–62.
100. Porte RJ, Leebeek FW. Pharmacological strategies to decrease transfusion requirements in patients undergoing surgery. Drugs 2002;62:2193–211.
101. Henry DA, Moxey AJ, Carless PA, et al. Antifibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 2001;1.
102. Despotis GJ, Avidan MS, Hogue CW Jr. Mechanisms and attenuation of hemostatic activation during extracorporeal circulation. Ann Thorac Surg 2001;72:S1821–31.
103. Hunt BJ, Parratt RN, Segal HC, et al. Activation of coagulation and fibrinolysis during cardiothoracic operations. Ann Thorac Surg 1998;65:712–8.
104. Koster A, Fischer T, Praus M, et al. Hemostatic activation and inflammatory response during cardiopulmonary bypass: impact of heparin management. Anesthesiology 2002;97:837–41.
105. Jobes DR, Aitken GL, Shaffer GW. Increased accuracy and precision of heparin and protamine dosing reduces blood loss and transfusion in patients undergoing primary cardiac operations. J Thorac Cardiovasc Surg 1995;110:36–45.
106. Despotis GJ, Joist JH, Hogue CW Jr, et al. The impact of heparin concentration and activated clotting time monitoring on blood conservation: a prospective, randomized evaluation in patients undergoing cardiac operation. J Thorac Cardiovasc Surg 1995;110:46–54.
107. Despotis GJ, Joist JH, Hogue CW Jr, et al. More effective suppression of hemostatic system activation in patients undergoing cardiac surgery by heparin dosing based on heparin blood concentrations rather than ACT. Thromb Haemost 1996;76:902–8.
108. Despotis GJ, Levine V, Joist JH, et al. Antithrombin III during cardiac surgery: effect on response of activated clotting time to heparin and relationship to markers of hemostatic activation. Anesth Analg 1997;85:498–506.
109. Ferraris VA, Ferraris SP, Singh A, et al. The platelet thrombin receptor and postoperative bleeding. Ann Thorac Surg 1998;65:352–8.
110. Schmaier AH. Contact activation: a revision. Thromb Haemost 1997;78:101–7.
111. Brown NJ, Nadeau JH, Vaughan DE. Selective stimulation of tissue-type plasminogen activator (t-PA) in vivo by infusion of bradykinin. Thromb Haemost 1997;77:522–5.
112. Emeis JJ. Regulation of the acute release of tissue-type plasminogen activator from the endothelium by coagulation activation products. Ann N Y Acad Sci 1992;667:249–58.
113. Valen G, Eriksson E, Risberg B, Vaage J. Fibrinolysis during cardiac surgery: release of tissue plasminogen activator in arterial and coronary sinus blood. Eur J Cardiothorac Surg 1994;8:324–30.
114. Spannagl M, Dooijewaard G, Dietrich W, Kluft C. Protection of single-chain urokinase-type plasminogen activator (scu-PA) in aprotinin treated cardiac surgical patients undergoing cardio-pulmonary bypass. Thromb Haemost 1995;73:825–8.
115. Menges T, Wagner RM, Welters I, et al. The role of the protein C-thrombomodulin system and fibrinolysis during cardiovascular surgery: influence of acute preoperative plasmapheresis. J Cardiothorac Vasc Anesth 1996;10:482–9.
116. Petaja J, Pesonen E, Fernandez JA, et al. Cardiopulmonary bypass and activation of antithrombotic plasma protein C. J Thorac Cardiovasc Surg 1999;118:422–9; Discussion 429–31.
117. Petaja J, Lundstrom U, Sairanen H, et al. Central venous thrombosis after cardiac operations in children. J Thorac Cardiovasc Surg 1996;112:883–9.
118. Gregory SA, Morrissey JH, Edgington TS. Regulation of tissue factor gene expression in the monocyte procoagulant response to endotoxin. Mol Cell Biol 1989;9:2752–5.
119. Kojima T, Gando S, Kemmotsu O, et al. Another point of view on the mechanism of thrombin generation during cardiopulmonary bypass: role of tissue factor pathway inhibitor. J Cardiothorac Vasc Anesth 2001;15:60–4.
120. Adams MJ, Cardigan RA, Marchant WA, et al. Tissue factor pathway inhibitor antigen and activity in 96 patients receiving heparin for cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2002;16:59–63.
121. Levy JH. Pharmacologic preservation of the hemostatic system during cardiac surgery. Ann Thorac Surg 2001;72:S1814–20.
122. Levy JH, Despotis GJ, Szlam F, et al. Recombinant human transgenic antithrombin in cardiac surgery: a dose-finding study. Anesthesiology 2002;96:1095–102.
123. Levy JH, Montes F, Szlam F, Hillyer CD. The in vitro effects of antithrombin III on the activated coagulation time in patients on heparin therapy. Anesth Analg 2000;90:1076–9.
124. Turner-Gomes SO, Mitchell L, Williams WG, Andrew M. Thrombin regulation in congenital heart disease after cardiopulmonary bypass operations. J Thorac Cardiovasc Surg 1994;107:562–8.
125. Gravlee GP. Dermatan sulfate anticoagulation: future replacement for heparin? J Cardiothorac Vasc Anesth 1995;9:237–9.
126. Brister SJ, Buchanan MR. Heparinless cardiopulmonary bypass revisited: a newer strategy to avoid heparin-related bleeding using dermatan sulfate. J Cardiothorac Vasc Anesth 1995;9:317–21.
127. van 't Veer C, Mann KG. Regulation of tissue factor initiated thrombin generation by the stoichiometric inhibitors tissue factor pathway inhibitor, antithrombin-III, and heparin cofactor-II. J Biol Chem 1997;272:4367–77.
128. van 't Veer C, Golden NJ, Kalafatis M, Mann KG. Inhibitory mechanism of the protein C pathway on tissue factor-induced thrombin generation: synergistic effect in combination with tissue factor pathway inhibitor. J Biol Chem 1997;272:7983–94.
129. Van Dreden P, Grosley M, Cost H. Total and free levels of tissue factor pathway inhibitor: a risk factor in patients with factor V Leiden? Blood Coagul Fibrinolysis 1999;10:115–6.
130. van 't Veer C, Kalafatis M, Bertina RM, et al. Increased tissue factor-initiated prothrombin activation as a result of the Arg506 → Gln mutation in factor VLEIDEN. J Biol Chem 1997;272:20721–9.
131. Eritsland J, Gjonnes G, Sandset PM, et al. Activated protein C resistance and graft occlusion after coronary artery bypass surgery. Thromb Res 1995;79:223–6.
132. Moor E, Silveira A, van't Hooft F, et al. Coagulation factor V (Arg506→Gln) mutation and early saphenous vein graft occlusion after coronary artery bypass grafting. Thromb Haemost 1998;80:220–4.
133. Ong BC, Zimmerman AA, Zappulla DC, et al. Prevalence of factor V Leiden in a population of patients with congenital heart disease. Can J Anaesth 1998;45:1176–80.
134. Linden MD, Schneider M, Erber WN. Factor V(LEIDEN) and cardiopulmonary bypass: investigation of haemostatic parameters and the effect of aprotinin using an ex vivo model. Perfusion 2001;16:476–84.
135. Donahue BS, Gailani D, Higgins MS, et al. Factor V Leiden protects against blood loss and transfusion after cardiac surgery. Circulation 2003;107:1003–8.
136. Verstraete M, Brown BG, Chesebro JH, et al. Evaluation of antiplatelet agents in the prevention of aortocoronary bypass occlusion. Eur Heart J 1986;7:4–13.
137. Pfisterer M, Burkart F, Jockers G, et al. Trial of low-dose aspirin plus dipyridamole versus anticoagulants for prevention of aortocoronary vein graft occlusion. Lancet 1989;2:1–7.
138. Alderman EL, Levy JH, Rich JB, et al. Analyses of coronary graft patency after aprotinin use: results from the International Multicenter Aprotinin Graft Patency Experience (IMAGE) trial. J Thorac Cardiovasc Surg 1998;116:716–30.
139. Goldman S, Copeland J, Moritz T, et al. Long-term graft patency (3 years) after coronary artery surgery: effects of aspirin—results of a VA Cooperative study. Circulation 1994;89:1138–43.
140. Campos EE, Cinderella JA, Farhi ER. Long-term angiographic follow-up of normal and minimally diseased saphenous vein grafts. J Am Coll Cardiol 1993;21:1175–80.
141. Zajtchuk R, Collins GJ, Holley PW, et al. Coagulation factors influencing thrombosis of aorta-coronary bypass grafts. J Thorac Cardiovasc Surg 1977;73:309–11.
142. Zehnder JL, Benson RC. Sensitivity and specificity of the APC resistance assay in detection of individuals with factor V Leiden. Am J Clin Pathol 1996;106:107–11.
143. Varela ML, Adamczuk YP, Martinuzzo ME, et al. Early occlusion of coronary by-pass associated with the presence of factor V Leiden and the prothrombin 20210A allele: case report. Blood Coagul Fibrinolysis 1999;10:443–6.
144. Royston D. Pro: aprotinin should be used in patients undergoing hypothermic circulatory arrest. J Cardiothorac Vasc Anesth 2001;15:121–5.
145. Gravlee GP. Con: aprotinin should not be used in patients undergoing hypothermic circulatory arrest. J Cardiothorac Vasc Anesth 2001;15:126–8.
146. Hunt BJ, Segal H, Yacoub M. Aprotinin and heparin monitoring during cardiopulmonary bypass. Circulation 1992;86:II410–2.
147. Jobes DR. Safety issues in heparin and protamine administration for extracorporeal circulation. J Cardiothorac Vasc Anesth 1998;12:17–20.
148. Despotis GJ, Joist JH. Anticoagulation and anticoagulation reversal with cardiac surgery involving cardiopulmonary bypass: an update. J Cardiothorac Vasc Anesth 1999;13:18–29; Discussion 36–7.
149. Feindt P, Seyfert UT, Volkmer I, et al. Celite and kaolin produce differing activated clotting times during cardiopulmonary bypass under aprotinin therapy. Thorac Cardiovasc Surg 1994;42:218–21.
150. Robbins P, Forrest M, Fanning S, Royston D. Use of aprotinin therapy in a patient with factor V Leiden. Anesth Analg 1997;84:694–8.
151. Royston D. High-dose aprotinin therapy: a review of the first five years' experience. J Cardiothorac Vasc Anesth 1992;6:76–100.
152. Espana F, Estelles A, Griffin JH, et al. Aprotinin (trasylol) is a competitive inhibitor of activated protein C. Thromb Res 1989;56:751–6.
153. Taby O, Chabbat J, Steinbuch M. Inhibition of activated protein C by aprotinin and the use of the insolubilized inhibitor for its purification. Thromb Res 1990;59:27–35.
154. Nuttall GA, Fass DN, Oyen LJ, et al. A study of a weight-adjusted aprotinin dosing schedule during cardiac surgery. Anesth Analg 2002;94:283–9.
155. Saleem R, Bigham M, Spitznagel E, Despotis GJ. The effect of epsilon-aminocaproic acid on HemoSTATUS and kaolin-activated clotting time measurements. Anesth Analg 2000;90:1281–5.
156. Fanashawe MP, Shore-Lesserson L, Reich DL. Two cases of fatal thrombosis after aminocaproic acid therapy and deep hypothermic circulatory arrest. Anesthesiology 2001;95:1525–7.
157. Donahue BS. Thrombosis after deep hypothermic circulatory arrest with antifibrinolytic therapy: is factor V leiden the smoking gun? Anesthesiology 2002;97:760–1; author reply 761.
158. Eagle KA, Berger PB, Calkins H, et al. ACC/AHA guideline update for perioperative cardiovascular evaluation for noncardiac surgery: executive summary—a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (committee to update the 1996 guidelines on perioperative cardiovascular evaluation for noncardiac surgery). Anesth Analg 2002;94:1052–64.
159. Eagle KA, Guyton RA, Davidoff R, et al. ACC/AHA guidelines for coronary artery bypass graft surgery: executive summary and recommendations—a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (committee to revise the 1991 guidelines for coronary artery bypass graft surgery). Circulation 1999;100:1464–80.
160. Tanaka KA, Sato N, Szlam F, et al. In vitro effects of DX-88, a novel inhibitor of kallikrein and contact activation. Anesth Analg 2003;96(4S):15.
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