Anesthesia & Analgesia:
Cardiovascular Anesthesiology: Review Article
Etiology and Assessment of Hypercoagulability with Lessons from Heparin-Induced Thrombocytopenia
Sniecinski, Roman M. MD*; Hursting, Marcie J. PhD†; Paidas, Michael J. MD‡; Levy, Jerrold H. MD, FAHA*
Continued Medical Education
From the *Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia; †Clinical Science Consulting, Austin, Texas; and ‡Department of Obstetrics and Gynecology, Yale School of Medicine, New Haven, Connecticut.
Jerrold H. Levy is Section Editor of Hemostasis and Transfusion Medicine for the Journal. The manuscript was handled by Charles W. Hogue, Jr., Associate Editor-in-Chief for Cardiovascular Anesthesiology, and Dr. Levy was not involved in any way with the editorial process or decision.
Conflicts of Interest: See Disclosure at the end of the article.
Reprints will not be available from the author.
Address correspondence to Jerrold H. Levy, MD, FAHA, Emory Hospital, 1364 Clifton Rd., Atlanta, GA 30322. Address e-mail to firstname.lastname@example.org.
Accepted September 21, 2010
Published ahead of print November 16, 2010
Hypercoagulability, or thrombophilia, is a condition associated with an abnormally increased tendency toward blood clotting. Affected individuals are prone to developing venous or arterial thrombosis and often require thromboprophylaxis. Hypercoagulability can be generally classified as either an inherited or acquired condition. Patients with an inherited thrombophilia have genetic variances that alter the quality or quantity of proteins involved with hemostasis. Hypercoagulability may also be acquired and develop as an exaggeration of normal physiologic responses to major tissue injury, or an abnormal response to various prothrombotic clinical factors. Careful assessment for hypercoagulability is important because effective management strategies, often involving anticoagulation, may be available. Heparin-induced thrombocytopenia is an example of an acquired hypercoagulable state that has been well studied and, when recognized, responds to appropriate therapy. In this article, we review the etiology, risks, and assessment of thrombophilia, with emphasis on the clinical lessons learned from heparin-induced thrombocytopenia.
There is a delicate balance between 2 competing forces intravascularly. The coagulation system ensures that bleeding does not continue indefinitely after vascular injury. At the same time, this system is balanced by thromboresistant forces that use anticoagulant proteins to regulate clot formation and fibrinolytic proteins to remove clots once vascular injury has been repaired. The proper balance between these systems must be maintained to ensure blood fluidity.
Hypercoagulability, also known as thrombophilia, pre/prothrombotic state, or “vulnerable blood,” is a condition in which blood clots more readily than normal. It is the result of tilting the normal equilibrium of procoagulant and thromboresistant forces in favor of coagulation.1 Although arterial and venous thrombi were once thought to be distinct problems, patients with hypercoagulability can be at risk for both, and it has been suggested that the condition represents a spectrum of diseases rather than separate clinical entities.2–4 Clinicians, particularly those in the operating room, are usually concerned about the risk of bleeding in patients; however, hypercoagulability is also a potential cause of adverse outcomes but is often overlooked.5,6
Risk factors for hypercoagulability are broadly classified as either inherited or acquired.7 Effects are exerted by either increasing procoagulant activity or decreasing anticoagulant or fibrinolytic activity and both can act synergistically. These risk factors have an important role in the development of disease and it is estimated that 80% of patients with venous thrombosis have an underlying risk factor.8 Because of this increased risk, hypercoagulable patients are often treated prophylactically with anticoagulation therapy, which clinicians need to consider.9,10
Herein, we review the inherited and acquired risk factors for hypercoagulability, their clinical impact, and approach to diagnosis. Additionally, we discuss the diagnosis and treatment of heparin-induced thrombocytopenia (HIT), which offers representative lessons in the management of a potentially catastrophic hypercoagulable state.
INHERITED RISK FACTORS
Patients with inherited hypercoagulability are particularly prone to venous thromboembolic events that occur early in life, and even in utero.11–14 Some conditions, such as inherited antithrombin deficiency, have been recognized for decades,15 whereas others, prothrombin G20210A mutation, for example, have only recently been identified.16,17 With the help of genetic testing, variants that contribute to hypercoagulability are continually being discovered.18 The inherited risk factors described herein are grouped according to whether they enhance procoagulant effects, reduce natural anticoagulation, impair fibrinolysis, or have some other unique effect. Figure 1 presents an overview of the coagulation/fibrinolytic pathways and where each inherited risk factor has an effect.
Enhancement of Procoagulant Effects
For venous thrombosis, the most common inherited risk factors are factor V Leiden and prothrombin G20210A mutation, present respectively in approximately 5% and 2% of Caucasians.19,20 The factor V Leiden gene mutation leads to an amino acid substitution that renders the activated procoagulant factor V resistant to cleavage (and thus inhibition) by activated protein C. The thrombotic risk for individuals with factor V Leiden, compared with individuals lacking the mutation, is increased approximately 3-fold in heterozygotes, 18-fold in homozygotes, and 9-fold overall.21,22 Individuals who are heterozygous for the prothrombin G20210A mutation have increased messenger RNA stability for the protein and thus higher plasma levels of prothrombin. This results in an approximate 3-fold increased risk of venous thrombosis, relative to individuals lacking the mutation.16,22 Approximately 7% of patients diagnosed with venous thrombosis have this prothrombin variant.23 Individuals who are homozygous for the G20210A mutation are extremely rare, with only 70 cases (patient age: neonate to 74 years) published before 2006.24 Factor V Leiden and prothrombin G20210A can be found together in some individuals.25
The association of factor V Leiden and prothrombin G20210A with arterial thrombosis is controversial. However, a large meta-analysis showed a small yet significant association of each with myocardial infarction (respective per-allele relative risks, 1.2 and 1.3).26 Prothrombin G20210A has also been linked to a 5-fold–higher incidence of thrombotic cerebrovascular disease,27 and, when combined with the factor XIII Leu34 polymorphism, which leads to increased levels of the clot-stabilizing protein factor XIII, there is a 12-fold–higher risk of myocardial infarction.28
Fibrinogen abnormalities can result in hypercoagulability by causing levels to be too high (hyperfibrinogenemia) or causing structural variants that are less susceptible to breakdown (dysfibrinogenemia). Individuals in the highest tercile of plasma fibrinogen concentration have nearly twice the risk of arterial thrombosis as do those in the lowest tercile.29 Additionally, stroke patients with initial fibrinogen levels ≥450 mg/dL have poorer functional outcomes.30 Hyperfibrinogenemia also increases the risk for venous thrombosis, although to a smaller extent.31,32 Dysfibrinogenemias, although often associated with bleeding diatheses, can also cause hypercoagulability if the resulting fibrin molecules fail to inhibit thrombin or are less susceptible to cleavage by plasmin.33,34 This condition is frequently present in patients who develop chronic thromboembolic pulmonary hypertension after acute thromboembolism.35
Other prothrombotic risk factors include elevated levels of specific coagulation factor levels, as well as von Willebrand factor. Factor VIII, an acute phase reactant, is increased in up to 25% of patients with unexplained venous thrombosis.36 Independent of inflammatory markers, however, an increased factor VIII level remains a risk factor for venous thrombosis and arterial vascular events.37,38 In a large, nested case-control study, elevated levels of factor XI were associated with an increased risk of venous thromboembolism (odds ratio, 1.8; 95% confidence interval, 1.3–2.7).39 von Willebrand factor is involved with platelet adhesion, and the risk of myocardial infarction is approximately 3-fold greater in individuals with levels in the highest quartile compared with the lowest quartile.40
Reduction of Natural Anticoagulation
Protein C and protein S are vitamin K–dependent proteins that inhibit the activated procoagulant factors V and VIII. Inherited qualitative or quantitative deficiencies of these natural anticoagulants are strong genetic risk factors for venous thrombosis, increasing the risk at least 5- to 10-fold.41–43 Homozygous protein C deficiency often results in fatal thrombosis in the newborn.44
Antithrombin, formerly referred to as antithrombin III, is a serine protease inhibitor with a particularly strong affinity for thrombin in the presence of heparin-like glycosaminoglycans on the endothelium or exogenously administered heparin.45 Heterozygous antithrombin-deficient patients typically have thrombin inhibition of only 50% of normal and are at increased risk for thrombotic events.46 Similar to protein C–deficient individuals, being homozygous for the trait is almost always fatal in the newborn or in utero. Although congenital deficiencies in these natural coagulants are rare (≤0.2% in the general population),47 they may also be acquired from certain clinical conditions, as discussed below.
Tissue factor pathway inhibitor neutralizes both factors VIIa and Xa. A very low level of tissue factor pathway inhibitor is an independent risk factor for myocardial infarction, with an estimated 7-fold increase in events among individuals in the lowest 10th percentile, and polymorphisms of the protein may be associated with increased risk of venous thrombosis.40,48 Associations have been equivocal between thrombosis and polymorphisms/deficiencies of other natural anticoagulants such as thrombomodulin, endothelial protein C receptor, or heparin cofactor II.48,49
Reduction of Fibrinolysis
Lipoprotein (a) is a serum lipoprotein that has high homology with plasminogen and competitively inhibits fibrinolysis. Levels of lipoprotein (a) are highly heritable, and genome-wide linkage studies have identified genomic regions that influence its concentration.50 Plasma lipoprotein (a) levels >300 mg/L are significantly associated with venous thromboembolism (odds ratio, 2.1), and increased levels are also considered a risk factor for cardiovascular disease.51,52
Plasminogen activator inhibitor-1 (PAI-1) is a serpin that down-regulates fibrinolysis. A deletion/insertion (4G/5G) polymorphism in its gene promoter region correlates with higher plasma levels.53 In a meta-analysis of published data (22 articles) regarding the PAI-1 4G/5G polymorphism, the 4G mutation was associated with a significant increase in risk of venous thromboembolism, but only in patients having another genetic risk factor for hypercoagulability (per-allele odds ratio, 1.833; 95% confidence interval, 1.325–2.536).54 However, when only studies of patients with a nongenetic risk factor for venous thromboembolism were considered, insignificant results were obtained, suggesting that the polymorphism is only important in patients with other predisposing genetic defects. Elevated levels of tissue plasminogen activator, which paradoxically may reflect impaired fibrinolysis because of assay methodologies in use, are associated with a 2- to 3-fold increased risk of myocardial infarction and thrombotic stroke.48,54,55 Inherited deficiencies of plasminogen and polymorphisms affecting plasma levels of thrombin-activatable fibrinolysis inhibitor are reported, yet their associations with thrombotic risk remain unclear and complex.56
Other Inherited Conditions
Hyperhomocysteinemia has been linked to increased arterial or venous thrombosis, perhaps via endothelial damage; however, results are variable and some data suggest that elevated plasma levels of homocysteine may be a response to ischemic events.57,58 Polymorphisms in the gene for methylene tetrahydrofolate reductase, an enzyme involved in homocysteine metabolism, may lead to hyperhomocysteinemia.59 Hyperhomocysteinemia may also be acquired in individuals with folic acid deficiency.
Polymorphisms for a variety of platelet glycoproteins, including Ib/IX (von Willebrand factor receptor), Ia/IIa (collagen receptor), and IIb/IIIa (fibrinogen receptor), have been described. Study results of platelet glycoprotein genetic variants have been inconsistent regarding association with thrombosis, although some suggest a link with cardiovascular risk.5,48 Genome-wide association studies have already identified 11 risk alleles explaining 20% of the heritability of myocardial infarction or coronary artery disease, and particular attention is now being given to better characterizing loci related to platelet function, number, or volume.60
ACQUIRED RISK FACTORS
Acquired risk factors are often transient, yet may confer higher thrombotic risk than genetic polymorphisms. Similar to inherited factors, some acquired conditions enhance procoagulant forces (e.g., HIT) whereas others decrease levels of natural anticoagulants (e.g., antiphospholipid antibodies). However, most acquired risk factors are likely multifactorial and have mechanisms that remain to be fully characterized. We have grouped the acquired risk factors into broad categories of disease states, clinical scenarios, and pharmacologic causes. How the major acquired risk factors affect the coagulation and fibrinolytic systems is presented in Figure 2.
Various antiphospholipid antibodies, including lupus anticoagulants, anticardiolipin antibody, and anti–β 2 glycoprotein I antibody, are associated with increased risk of venous or arterial thrombosis.61–63 Literature review indicates that the presence of lupus anticoagulants confers an odds ratio of 8.6 to 10.8 for arterial thrombosis, 4.1 to 16.2 for venous thrombosis, 5.7 to 7.3 for any thrombosis, and 3 to 4.8 for recurrent miscarriage and fetal death.62,64 Potential mechanisms explaining hypercoagulability with antiphospholipid antibodies include down-regulation of thrombomodulin expression, increased tissue factor expression, and impairment of the protein C anticoagulant pathway.65 Antiphospholipid antibody may be induced during acute infection or inflammation and be short-lived, i.e., detectable for 2 to 3 months; however, in some patients, persistent or pathologic antibodies develop in response to infection.13,66,67 Patients with thrombosis (arterial or venous) or repeated pregnancy loss plus antiphospholipid antibody detected on at least 2 occasions at least 12 weeks apart meet diagnostic criteria for antiphospholipid syndrome.68 This syndrome is a well-established risk factor for recurrent thrombotic events, and indefinite anticoagulation is often recommended.47,69,70
Although liver and kidney disease are more frequently viewed as risks for bleeding, both can also contribute to hypercoagulability. In cirrhosis, protein C, protein S, antithrombin, and plasminogen levels are all decreased.71 Although procoagulant factors are also lower because of impaired synthesis, prothrombin levels tend to be proportionately higher, setting up the potential for a hypercoagulable state. Additionally, endothelial dysfunction, particularly in the pulmonary and portal vasculature, increases platelet aggregation and promotes activation of coagulation.72 It has been known for years that in nephrotic syndrome, fibrinogen synthesis is increased and antithrombin levels are below normal.73,74 Similar to liver disease, there is also a component of endothelial dysfunction, particularly in the renal vasculature, which contributes to the 35% overall incidence of renal vein thrombosis.75
Many conditions associated with blood stasis, such as immobility from paralysis or low intracardiac flow caused by heart failure, are considered risk factors for hypercoagulability. Although abnormal blood flow is one of the classic components of Virchow triad, it alone does create thrombosis. The importance of Virchow's other 2 factors, vessel wall abnormalities and dysfunctional blood constituents, is just starting to be appreciated at the molecular level. The so-called “metabolic syndrome,” which includes abdominal obesity, hypertension, elevated glucose, and unfavorable cholesterol levels, is associated with endothelial dysfunction and increased platelet aggregation.76 Patients with heart failure have reduced nitric oxide release from the endothelium, promoting platelet aggregation.77 Cancer cells release microparticles that promote fibrin deposition.78 Even advancing age, although hardly considered a disease state, is associated with procoagulant changes including elevated fibrinogen,79 increased factor VII,80 impaired fibrinolytic activity,81 and increased platelet aggregation.82 Clearly, these factors represent complex interactions that are just beginning to be understood.
Although there is an obvious need for hemostasis after tissue injury caused by trauma or surgery, hypercoagulability can occur during the healing process. In the absence of preventive therapy, thrombosis will occur in up to 50% of patients who undergo surgery, particularly orthopedic surgery, and up to 60% of trauma patients.83,84 Levels of tissue factor in circulation as well as that exposed on the affected endothelium increase.85,86 Disseminated intravascular coagulation can occur after severe tissue damage and is both a bleeding and thrombotic condition. Although disseminated intravascular coagulation promotes thrombin generation and fibrin deposition, the fibrinolytic system is severely impaired because of high levels of PAI-1.87,88 Furthermore, in trauma patients who receive no anticoagulant prophylaxis, markers of thrombin generation increase within 24 hours of the injury and stay increased for approximately 5 days, without an early, compensatory increase in tissue factor pathway inhibitor.84 This has led to the recent recommendation that all surgical patients, with the exception of ambulatory patients undergoing minor procedures or those patients at high bleeding risk, receive anticoagulant thromboprophylaxis with drugs other than aspirin alone.9
Cardiac surgery using cardiopulmonary bypass (CPB) results in a wide range of hematologic insults. In addition to consumptive and hemodilutional losses of procoagulant factors, anticoagulant factors become low as well.89,90 After prolonged CPB, transfusion of hemostatic blood products is typical, but this can result in excessive thrombin generation and many case reports in the literature describe catastrophic thromboses after platelet, cryoprecipitate, and protamine administration.91 Given the possibility of hypercoagulability, hemostatic drugs should probably be used with caution in patients with other known risk factors for thrombophilia (see below).
The use of oral contraceptives or hormone replacement therapy is associated with increased risk of thrombosis.3,92 The prothrombin 20210A mutation or factor V Leiden may increase risk for atherothrombotic cardiovascular disease in women receiving estrogen replacement therapy.93 Estrogen intake may lead to an acquired protein S deficiency and hence decreased natural anticoagulation. Normal pregnancy, a hyperestrogenic state, is associated with decreased free protein S antigen, with mean levels in the second and third trimester of 39% and 31%, respectively.94
The lysine analogs tranexamic acid and aminocaproic acid are antifibrinolytics frequently used in cardiac surgery that competitively inhibit plasminogen activator and noncompetitively inhibit plasmin. Thrombotic events, including retinal artery or vein obstruction (tranexamic acid) and glomerular capillary thrombosis (aminocaproic acid), are reported after therapy, and patients with a history of thromboembolic disease appear at increased risk.95 Aprotinin, a broad-spectrum serine protease inhibitor with antifibrinolytic effects, was recently removed from marketing (still available for compassionate use), and further analysis of the Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART) is underway.96
The hemostasis-enhancing drugs desmopressin acetate and recombinant factor VIIa (rFVIIa) are frequently used for prevention or treatment of bleeding in various settings, but these agents may contribute to hypercoagulability in some patients. Desmopressin, a vasopressin analog, stimulates release of procoagulant (factor VIII and von Willebrand factor), thromboresistant (tissue plasminogen activator), and vasodilatory (prostacyclin) factors from the endothelium. This agent is a treatment of choice for many patients with von Willebrand disease, mild hemophilia A, some congenital platelet function defects, and uremia.97 There have been reports of thrombotic events after infusion of desmopressin, and the Food and Drug Administration (FDA) recommends using the drug with caution in patients predisposed to thrombosis.98,99 In one meta-analysis, desmopressin was associated with a 2.4-fold greater risk of perioperative myocardial infarction, with minimal reduction in perioperative bleeding.100 The risk of thrombotic sequelae with rFVIIa is relatively low in its licensed indications, i.e., treatment of bleeding in patients having hemophilia A or B with inhibitors, acquired hemophilia, or congenital factor VII deficiency; or prevention of bleeding in surgical interventions or invasive procedures in the same patient types.101 However, rFVIIa has also been used off-label extensively in patients with refractory, life-threatening bleeding not in those categories. Across 13 studies of rFVIIa therapy for coagulopathy secondary to anticoagulant therapy, cirrhosis, or severe traumatic injury, thrombotic adverse events occurred in 6.0% of rFVIIa-treated patients (45 of 748 patients) and 5.3% of placebo-treated patients (23 of 430 patients) (P = 0.57).102 In a study in patients with massive postpartum hemorrhage, rFVIIa therapy reduced maternal mortality and no thromboembolic events were reported.103 Nevertheless, close monitoring of rFVIIa-treated patients for signs or symptoms of thrombosis is warranted.
Fibrin sealant (a widely used, multicomponent system of fibrinogen and thrombin), bovine thrombin, and recombinant human thrombin are topical aids to tissue adhesion and hemostasis, but may lead to life-threatening thromboembolic events if administered intravascularly.104 Furthermore, exposure to bovine thrombin during cardiovascular surgery has been linked to the development of antiphospholipid antibodies that are associated with thrombotic risk.105,106
Acquired antithrombin deficiency may result from heparin therapy. In 250 patients administered heparin during and after percutaneous coronary intervention, the mean decrease in antithrombin activity was 7.5% during the 1- or 2-hour procedure and 4% between the end of the procedure and the next morning, and the level remained significantly less than normal until heparin had been discontinued for ≥20 hours.107 Heparin therapy leads to the hypercoagulable condition of HIT in approximately 1% to 5% of patients administered unfractionated heparin and <1% of patients administered low-molecular-weight heparin.108 Approximately 8% of heparin-treated patients experience a nonimmune-mediated, asymptomatic transient decrease in the platelet count (sometimes known as “HIT type I”); however, the term “HIT” now preferably refers to the hypercoagulable state. HIT is strongly associated with venous and arterial thrombosis (odds ratio, 12–37) and is more fully discussed below as an example of acquired hypercoagulability.109
ASSESSMENT OF HYPERCOAGULABILITY
Clinical suspicion is paramount in assessing a patient's risk of hypercoagulability. Whereas most perioperative physicians readily uncover risks for bleeding, risks for thrombosis are less sought after. A careful personal and family history of thrombosis or fetal loss and a thorough review of pharmacologic factors that predispose to hypercoagulability should be taken. What must be realized is that, although any single risk factor might not lead to a thromboembolic event, risks are cumulative and patients with an inherited risk at baseline can experience poor outcomes when placed in clinical situations that can also result in acquired risks. For example, a patient with factor V Leiden may be asymptomatic, but when exposed to antifibrinolytics and prolonged CPB, catastrophic thrombosis can result.110,111
Unfortunately, screening for inherited risk factors is problematic because of their infrequent prevalence in the general population. In mathematical modeling using even the highest level of testing specificity, there would likely be at least 1 to 4 false positives for every true positive result, and the ratio could be as high as 100:1.112 Therefore, indiscriminate testing in unselected individuals, even after a first episode on a deep venous thrombosis, is not recommended.113 In general, testing for inherited risk factors is only recommended for young patients with unprovoked or recurrent thromboembolism or patients with arterial thrombosis who do not have known atherosclerotic disease. Consensus guidelines for testing various conditions are summarized in Table 1.
Testing for acquired hypercoagulability is also problematic. As demonstrated in Figure 2, acquired conditions can exert their effects at many different points along the coagulation– fibrinolysis cascades. Therefore, any laboratory testing should be tailored to the patient's clinical situation. General laboratory markers of a persistent hypercoagulable state include elevated levels of prothrombin fragment 1.2, thrombin-antithrombin complexes, plasmin-antiplasmin complexes, fibrinopeptide A, fibrin monomer, and D- dimer.114,115 Among these, D-dimer is arguably the best studied for routine clinical application, and clinical trial data support its utility for determining the need for prolonged anticoagulation in patients with unprovoked venous thromboembolism.116,117 Soluble P selectin and measurement of thrombin generation show promise as biomarkers of a prothrombotic state but require additional prospective testing.118
Of course, the ideal test for hypercoagulability would allow clinicians to assess a patient's risk of thrombosis before it actually happened. Unfortunately, 2 of the most frequently ordered plasma tests, prothrombin time and activated partial thromboplastin time, have failed to show any correlation with thrombotic events in orthopedic, trauma, or general surgery patients.119–121 This is not surprising because each provides only limited information on stages of clot formation and none on platelet function or fibrinolytic activity. One whole blood assay that provides a comprehensive view of the clotting and fibrinolytic pathways is thromboelastography (TEG®). Both TEG® and rapid-TEG® (which differs by the addition of tissue factor) have gained interest for the evaluation of hypercoagulability.122–125 However, a recent review of the literature found that the test's predictive accuracy for postoperative thrombotic events was “highly variable,” in part because of the lack of reference standards.126 More studies using TEG® with respect to hypercoagulability seem warranted.
HIT: AN ACQUIRED HYPERCOAGULABLE STATE
Overview and Pathogenesis
HIT is an adverse reaction to heparins that leads to an increase in thrombotic risk. Although the odds ratio for thrombosis in HIT depends in part on how the thrombocytopenia is assessed, i.e., absolute platelet count <150 × 109/L (odds ratio, 37) versus 50% relative decrease in platelet count beginning after 5 days of heparin (odds ratio, 12), the risk is comparable to, if not greater than, that associated with lupus anticoagulants and the more common inherited hypercoagulable states.127 Regardless, HIT provides a good example to illustrate the clinical approach to diagnosis and management of prothrombotic states.
HIT is unique as a hypercoagulable state in that it paradoxically occurs during (or soon after) therapy with an anticoagulant, specifically heparins. The paradox is explained by the pathogenesis of HIT in which procoagulant forces are substantially enhanced via immune-mediated mechanisms.128,129 In HIT, antibodies to a complex of heparin and platelet factor 4 (PF4) bind to the platelet surface and induce platelet activation. Activated platelets release PF4, which furthers complex formation, releasing microparticles that increase generation of thrombin, which in turn activates more platelets. This cycle contributes to thrombocytopenia and thrombosis. Antibody-mediated endothelial injury contributes further to the hypercoagulable state. Bleeding is a rare complication in HIT, consistent with its hypercoagulable nature. Recent data suggest that HIT may be a misplaced immune-host defense, mimicking immunity against repetitive antigens such as seen in microbial defense.130 The risk of HIT for various patient populations is summarized in Table 2. There may be an increased risk with the use of bovine versus porcine heparin.131
Like all hypercoagulable states, the evaluation for HIT must begin with suspicion. HIT should be suspected whenever the platelet count decreases ≥50% within 5 to 14 days after heparin introduction, even if the patient is no longer receiving heparin.10 In patients with recent (<100 days) previous heparin exposure, a more rapid onset (<24 hours) of thrombocytopenia may occur, often in association with acute systemic reactions.132 In a patient acquiring HIT after CPB, the platelet count either may not increase after 3 to 4 days (i.e., the time by which CPB-related thrombocytopenia would have typically resolved) or may decrease 3 to 4 days after bypass.133 Less frequently, the onset of HIT may be delayed up to 20 days and manifest after the patient has been discharged from the hospital.134 The thrombocytopenia of HIT is usually moderately severe (median nadir, 50 to 70 × 109/L), although a relative 50% decrease in platelet count is more indicative of HIT than the absolute count. Other causes of thrombocytopenia, including sepsis, mechanical destruction via intraaortic balloon pump, or another drug-induced thrombocytopenia, should be considered and excluded.
HIT may first be suspected after a thrombotic event such as deep venous thrombosis, pulmonary embolism, myocardial infarction, stroke, or limb artery occlusion.135 Hemorrhagic-like skin lesions at heparin injection sites, systemic symptoms such as hypotension or flushing after heparin administration, and heparin resistance (i.e., related to PF4 release leading to heparin binding) should also prompt suspicion. Venous events predominate over arterial events, except in cardiac surgery patients.136 Approximately 38% to 76% of affected patients have a thromboembolic complication within a month, typically within the first few days.137 Nearly 10% of patients with HIT and thrombosis lose a limb, and mortality is approximately 20% to 30%.138
Laboratory testing is recommended when HIT is suspected, although results may not be available for hours to days, so it is useful to estimate the pretest probability using the “4 Ts” system. The exact scoring method is reviewed elsewhere, but involves the criteria of thrombocytopenia, timing of platelet count decline, thrombosis, and other causes for low platelets.139 The resultant score seems most useful for excluding HIT. Antigenic immunoassays for the heparin-PF4 antibodies are frequently used and have a >90% sensitivity, but poor specificity because they also detect nonplatelet-activating antibodies. With immunoassays for heparin-PF4 antibodies, the optical density may be more informative than a simple positive or negative result because a higher optical density (e.g., at least >1.0) is associated with increased likelihood of a strongly positive serotonin release assay (see below) and with an increased thrombotic risk in HIT.140 Whereas heparin-PF4 immunoassays typically detect immunoglobulin (Ig)G, IgA, and IgM classes, assays for only the IgG class have become commercially available and may improve clinical specificity for HIT. However, overdiagnosis of HIT can still occur if a positive immunoassay result alone is considered confirmatory of HIT, irrespective of the clinical scenario.141
Functional assays such as the serotonin release assay have greater sensitivity (95%) and specificity (95%) than immunoassays, but are technically demanding and usually performed only as a confirmatory test. Most patients with HIT elicit a strong positive result (i.e., at least >50% release, where >20% is considered positive) with the serotonin release assay.142 Still, not all heparin-PF4 antibodies have platelet-activating capabilities, and most seropositive patients do not develop HIT. In a study of cardiac surgery patients receiving unfractionated heparin postoperatively, heparin-PF4 antibodies were detected by immunoassay in 50% of the patients, platelet-activating heparin-PF4 antibodies were detected by serotonin release assay in 20%, and HIT occurred in 1%.143 This illustrates that, similar to all hypercoagulable states, clinician awareness and judgment are paramount in diagnosis.
When HIT with or without thrombosis is strongly suspected, all heparins should be discontinued and a fast-acting, nonheparin anticoagulant should be initiated promptly, without delay for laboratory confirmation.10 Heparin cessation alone is inadequate treatment because of the persistent hypercoagulability and increased thrombotic risk for at least a month. Three anticoagulants, each a direct thrombin inhibitor, are FDA approved for use in HIT patients in the noninterventional setting (lepirudin, argatroban) or during percutaneous coronary intervention (argatroban, bivalirudin). Additionally, danaparoid (a heparinoid unavailable in the United States) and fondaparinux (a selective factor Xa inhibitor) have been suggested as alternative anticoagulants, although neither is FDA approved in this setting.10 Warfarin should be avoided during acute HIT because it is slow acting and also because its earlier reduction of protein C and protein S levels, as compared with factor X, factor IX, and prothrombin levels, may actually promote thrombosis.
The direct thrombin inhibitors are routinely monitored using the activated partial thromboplastin time or, at higher levels of anticoagulation, activated clotting time. In historical controlled studies, lepirudin and argatroban each significantly reduced adverse outcomes, particularly new thrombosis, in patients with HIT.144 Lepirudin is renally cleared, and doses should be reduced in patients with renal impairment. Patients often develop antilepirudin antibodies and, rarely, patients reexposed to lepirudin have anaphylactoid reactions.10 Argatroban is hepatically metabolized, and doses should be reduced in patients with hepatic impairment or conditions associated with hepatic hypoperfusion. Argatroban profoundly prolongs the prothrombin time/international normalized ratio, and published approaches to monitor the transition from argatroban to warfarin should be followed.10 Retrospective data suggest that bivalirudin at doses much less than those used during coronary intervention may be effective and safe in patients with HIT in the noninterventional setting; however, no prospective study has been published. Bivalirudin is cleared by renal and enzymatic mechanisms, and doses should be reduced in renal impairment.
HIT during pregnancy, although rare, poses unique risks because of the potential adverse fetal effects.145 For treating HIT in a woman who is pregnant, reported experience is sparse for the direct thrombin inhibitors (lepirudin, argatroban) and is also limited, yet encouraging, for danaparoid and fondaparinux.146–151 Each of these alternative anticoagulants is a pregnancy category B drug.
The data on alternative anticoagulants during cardiac surgery are sparse. Because HIT antibodies have a relatively short half-life, the ideal situation is to delay elective cardiac surgery until heparin-PF4 antibody assays are negative, which should occur after 3 months.10,132 The operation can then proceed with heparin anticoagulation and protamine reversal during the operative period only, with alternative anticoagulants used for pre- and postoperative management as needed.10 If cardiac surgery cannot be delayed, use of an alternative anticoagulation is recommended. Small case series of CPB with lepirudin and argatroban have been reported,152,153 although bivalirudin has been studied more extensively for this purpose.154,155 Bivalirudin also seems to have become the anticoagulant of choice for off-pump cardiac surgery, with reduced dosing comparable to that used in the cardiac catheterization laboratory.156,157
The optimal duration of alternative, nonheparin anticoagulant therapy has not been established. Consideration should be given to providing treatment for at least a month in HIT patients without thrombosis and 3 to 6 months in HIT patients with thrombosis.137,158 Warfarin may be initiated after adequate parenteral nonheparin anticoagulation is achieved and the platelet count is >150 × 109/L, and warfarin and parenteral anticoagulation should be overlapped until a therapeutic international normalized ratio is achieved for at least 2 consecutive days.10 In a patient with current or previous HIT, heparin should be avoided at least as long as heparin-PF4 antibodies are detectable by a sensitive assay.
Physicians in the operating room are acutely aware of the dangers of excessive bleeding, but thrombotic complications, which can be equally as devastating, are often ignored. Hypercoagulability can be inherited or acquired and, as shown in Figure 3, significantly increase the risk of thrombosis. The first step in improving management of these situations is to make perioperative physicians aware of these risks, which we have attempted to do in this review. Careful, watchful assessment for hypercoagulability is important because effective management strategies, often involving anticoagulation, may be available. HIT is one such hypercoagulable state that can be successfully diagnosed and treated now that there is a strong awareness of it. In the future, it is likely that new inheritable risk factors will be identified by genome-wide analyses, the mechanism(s) by which acquired risk factors exert their effects will be better elucidated, and management strategies, possibly involving newer antithrombotic drugs, for hypercoagulability will be refined.
1. Martinelli I, Bucciarelli P, Mannucci PM. Thrombotic risk factors: basic pathophysiology. Crit Care Med 2010;38:S3–9
2. Franchini M, Mannucci PM. Venous and arterial thrombosis: different sides of the same coin? Eur J Intern Med 2008; 19:476–81
3. Lowe GD. Common risk factors for both arterial and venous thrombosis. Br J Haematol 2008;140:488–95
4. Lowe GD. Arterial disease and venous thrombosis: are they related, and if so, what should we do about it? J Thromb Haemost 2006;4:1882–5
5. Chan MY, Andreotti F, Becker RC. Hypercoagulable states in cardiovascular disease. Circulation 2008;118:2286–97
6. Kfoury E, Taher A, Saghieh S, Otrock ZK, Mahfouz R. The impact of inherited thrombophilia on surgery: a factor to consider before transplantation? Mol Biol Rep 2009;36: 1041–51
7. Mannucci PM. Laboratory detection of inherited thrombophilia: a historical perspective. Semin Thromb Hemost 2005;31:5–10
8. Whitlatch NL, Ortel TL. Thrombophilias: when should we test and how does it help? Semin Respir Crit Care Med 2008;29:25–39
9. Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, Colwell CW. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008;133:381S–453S
10. Warkentin TE, Greinacher A, Koster A, Lincoff AM. Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008; 133:340S–80S
11. Paidas MJ. Thrombosis and regulation of the trophoblast at the maternal interface. Thromb Res 2009;124:387–8
12. Paidas MJ, Ku DH, Langhoff-Roos J, Arkel YS. Inherited thrombophilias and adverse pregnancy outcome: screening and management. Semin Perinatol 2005;29:150–63
13. Goldenberg NA. Thrombophilia states and markers of coagulation activation in the prediction of pediatric venous thromboembolic outcomes: a comparative analysis with respect to adult evidence. Hematology Am Soc Hematol Educ Program 2008:236–44
14. Parker RI. Thrombosis in the pediatric population. Crit Care Med 2010;38:S71–5
15. Egeberg O. Inherited antithrombin deficiency causing thrombophilia. Thromb Diath Haemorrh 1965;13:516–30
16. Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3′-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996;88:3698–703
17. Rosendaal FR, Vos HL, Poort SL, Bertina RM. Prothrombin 20210A variant and age at thrombosis. Thromb Haemost 1998;79:444
18. Bezemer ID, Bare LA, Doggen CJ, Arellano AR, Tong C, Rowland CM, Catanese J, Young BA, Reitsma PH, Devlin JJ, Rosendaal FR. Gene variants associated with deep vein thrombosis. JAMA 2008;299:1306–14
19. De Stefano V, Chiusolo P, Paciaroni K, Leone G. Epidemiology of factor V Leiden: clinical implications. Semin Thromb Hemost 1998;24:367–79
20. Rosendaal FR, Doggen CJ, Zivelin A, Arruda VR, Aiach M, Siscovick DS, Hillarp A, Watzke HH, Bernardi F, Cumming AM, Preston FE, Reitsma PH. Geographic distribution of the 20210 G to A prothrombin variant. Thromb Haemost 1998;79:706–8
21. Juul K, Tybjaerg-Hansen A, Schnohr P, Nordestgaard BG. Factor V Leiden and the risk for venous thromboembolism in the adult Danish population. Ann Intern Med 2004;140:330–7
22. Gohil R, Peck G, Sharma P. The genetics of venous thromboembolism: a meta-analysis involving approximately 120,000 cases and 180,000 controls. Thromb Haemost 2009;102:360–70
23. Hillarp A, Zoller B, Svensson PJ, Dahlback B. The 20210 A allele of the prothrombin gene is a common risk factor among Swedish outpatients with verified deep venous thrombosis. Thromb Haemost 1997;78:990–2
24. Bosler D, Mattson J, Crisan D. Phenotypic heterogeneity in patients with homozygous prothrombin 20210AA genotype: a paper from the 2005 William Beaumont Hospital Symposium on Molecular Pathology. J Mol Diagn 2006;8:420–5
25. Kabukcu S, Keskin N, Keskin A, Atalay E. The frequency of factor V Leiden and concomitance of factor V Leiden with prothrombin G20210A mutation and methylene tetrahydrofolate reductase C677T gene mutation in healthy population of Denizli, Aegean region of Turkey. Clin Appl Thromb Hemost 2007;13:166–71
26. Ye Z, Liu EH, Higgins JP, Keavney BD, Lowe GD, Collins R, Danesh J. Seven haemostatic gene polymorphisms in coronary disease: meta-analysis of 66,155 cases and 91,307 controls. Lancet 2006;367:651–8
27. Bick RL. Prothrombin G20210A mutation, antithrombin, heparin cofactor II, protein C, and protein S defects. Hematol Oncol Clin North Am 2003;17:9–36
28. Butt C, Zheng H, Randell E, Robb D, Parfrey P, Xie YG. Combined carrier status of prothrombin 20210A and factor XIII-A Leu34 alleles as a strong risk factor for myocardial infarction: evidence of a gene-gene interaction. Blood 2003;101:3037–41
29. Maresca G, Di Blasio A, Marchioli R, Di Minno G. Measuring plasma fibrinogen to predict stroke and myocardial infarction: an update. Arterioscler Thromb Vasc Biol 1999;19:1368–77
30. del Zoppo GJ, Levy DE, Wasiewski WW, Pancioli AM, Demchuk AM, Trammel J, Demaerschalk BM, Kaste M, Albers GW, Ringelstein EB. Hyperfibrinogenemia and functional outcome from acute ischemic stroke. Stroke 2009;40:1687–91
31. van Hylckama Vlieg A, Rosendaal FR. High levels of fibrinogen are associated with the risk of deep venous thrombosis mainly in the elderly. J Thromb Haemost 2003;1:2677–8
32. Tsai AW, Cushman M, Rosamond WD, Heckbert SR, Polak JF, Folsom AR. Cardiovascular risk factors and venous thromboembolism incidence: the longitudinal investigation of thromboembolism etiology. Arch Intern Med 2002;162:1182–9
33. Martinez J. Congenital dysfibrinogenemia. Curr Opin Hematol 1997;4:357–65
34. Mosesson MW. Dysfibrinogenemia and thrombosis. Semin Thromb Hemost 1999;25:311–9
35. Morris TA, Marsh JJ, Chiles PG, Magana MM, Liang NC, Soler X, Desantis DJ, Ngo D, Woods VL Jr. High prevalence of dysfibrinogenemia among patients with chronic thromboembolic pulmonary hypertension. Blood 2009;114:1929–36
36. O'Donnell J, Tuddenham EG, Manning R, Kemball-Cook G, Johnson D, Laffan M. High prevalence of elevated factor VIII levels in patients referred for thrombophilia screening: role of increased synthesis and relationship to the acute phase reaction. Thromb Haemost 1997;77:825–8
37. O'Donnell J, Mumford AD, Manning RA, Laffan M. Elevation of FVIII: C in venous thromboembolism is persistent and independent of the acute phase response. Thromb Haemost 2000;83:10–3
38. Bank I, van de Poel MH, Coppens M, Hamulyak K, Prins MH, van der Meer J, Veeger NJ, Buller HR, Middeldorp S. Absolute annual incidences of first events of venous thromboembolism and arterial vascular events in individuals with elevated FVIII:c: a prospective family cohort study. Thromb Haemost 2007;98:1040–4
39. Cushman M, O'Meara ES, Folsom AR, Heckbert SR. Coagulation factors IX through XIII and the risk of future venous thrombosis: the Longitudinal Investigation of Thromboembolism Etiology. Blood 2009;114:2878–83
40. Morange PE, Simon C, Alessi MC, Luc G, Arveiler D, Ferrieres J, Amouyel P, Evans A, Ducimetiere P, Juhan-Vague I. Endothelial cell markers and the risk of coronary heart disease: the Prospective Epidemiological Study of Myocardial Infarction (PRIME) study. Circulation 2004;109:1343–8
41. Rosendaal FR, Reitsma PH. Genetics of venous thrombosis. J Thromb Haemost 2009;7:301–4
42. Griffin JH, Evatt B, Zimmerman TS, Kleiss AJ, Wideman C. Deficiency of protein C in congenital thrombotic disease. J Clin Invest 1981;68:1370–3
43. Schwarz HP, Fischer M, Hopmeier P, Batard MA, Griffin JH. Plasma protein S deficiency in familial thrombotic disease. Blood 1984;64:1297–300
44. Takamiya O, Kinoshita S, Niinomi K, Yoshioka K. Protein C in the neonatal period. Haemostasis 1989;19:45–50
45. Marciniak E. Antithrombin III and heparin inactivation in thrombin involving reactions. Thromb Haemost 1977; 38:486–93
46. Patnaik MM, Moll S. Inherited antithrombin deficiency: a review. Haemophilia 2008;14:1229–39
47. Moll S. Thrombophilias: practical implications and testing caveats. J Thromb Thrombolysis 2006;21:7–15
48. Franchini M, Veneri D, Salvagno GL, Manzato F, Lippi G. Inherited thrombophilia. Crit Rev Clin Lab Sci 2006;43:249–90
49. Uitte de Willige S, Van Marion V, Rosendaal FR, Vos HL, de Visser MC, Bertina RM. Haplotypes of the EPCR gene, plasma sEPCR levels and the risk of deep venous thrombosis. J Thromb Haemost 2004;2:1305–10
50. Lopez S, Buil A, Ordonez J, Souto JC, Almasy L, Lathrop M, Blangero J, Blanco-Vaca F, Fontcuberta J, Soria JM. Genome-wide linkage analysis for identifying quantitative trait loci involved in the regulation of lipoprotein a (Lpa) levels. Eur J Hum Genet 2008;16:1372–9
51. de la Pena-Diaz A, Izaguirre-Avila R, Angles-Cano E. Lipoprotein Lp(a) and atherothrombotic disease. Arch Med Res 2000;31:353–9
52. Marcucci R, Liotta AA, Cellai AP, Rogolino A, Gori AM, Giusti B, Poli D, Fedi S, Abbate R, Prisco D. Increased plasma levels of lipoprotein(a) and the risk of idiopathic and recurrent venous thromboembolism. Am J Med 2003;115:601–5
53. Tsantes AE, Nikolopoulos GK, Bagos PG, Bonovas S, Kopterides P, Vaiopoulos G. The effect of the plasminogen activator inhibitor-1 4G/5G polymorphism on the thrombotic risk. Thromb Res 2008;122:736–42
54. van der Bom JG, de Knijff P, Haverkate F, Bots ML, Meijer P, de Jong PT, Hofman A, Kluft C, Grobbee DE. Tissue plasminogen activator and risk of myocardial infarction: The Rotterdam Study. Circulation 1997;95:2623–7
55. Ridker PM, Hennekens CH, Stampfer MJ, Manson JE, Vaughan DE. Prospective study of endogenous tissue plasminogen activator and risk of stroke. Lancet 1994;343:940–3
56. Martini CH, Brandts A, de Bruijne EL, van Hylckama Vlieg A, Leebeek FW, Lisman T, Rosendaal FR. The effect of genetic variants in the thrombin activatable fibrinolysis inhibitor (TAFI) gene on TAFI-antigen levels, clot lysis time and the risk of venous thrombosis. Br J Haematol 2006;134:92–4
57. den Heijer M, Koster T, Blom HJ, Bos GM, Briet E, Reitsma PH, Vandenbroucke JP, Rosendaal FR. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med 1996;334:759–62
58. den Heijer M, Rosendaal FR, Blom HJ, Gerrits WB, Bos GM. Hyperhomocysteinemia and venous thrombosis: a meta-analysis. Thromb Haemost 1998;80:874–7
59. Frederiksen J, Juul K, Grande P, Jensen GB, Schroeder TV, Tybjaerg-Hansen A, Nordestgaard BG. Methylenetetrahydrofolate reductase polymorphism (C677T), hyperhomocysteinemia, and risk of ischemic cardiovascular disease and venous thromboembolism: prospective and case-control studies from the Copenhagen City Heart Study. Blood 2004;104:3046–51
60. Ouwehand WH. The discovery of genes implicated in myocardial infarction. J Thromb Haemost 2009;7:305–7
61. Galli M, Barbui T. Antiphospholipid syndrome: definition and treatment. Semin Thromb Hemost 2003;29:195–204
62. Galli M, Luciani D, Bertolini G, Barbui T. Anti-beta 2-glycoprotein I, antiprothrombin antibodies, and the risk of thrombosis in the antiphospholipid syndrome. Blood 2003;102:2717–23
63. Galli M, Luciani D, Bertolini G, Barbui T. Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature. Blood 2003;101:1827–32
64. Galli M, Barbui T. Antiphospholipid antibodies and thrombosis: strength of association. Hematol J 2003;4:180–6
65. Todorova M, Baleva M. Some recent insights into the prothrombogenic mechanisms of antiphospholipid antibodies. Curr Med Chem 2007;14:811–26
66. Avcin T, Toplak N. Antiphospholipid antibodies in response to infection. Curr Rheumatol Rep 2007;9:212–8
67. Uthman IW, Gharavi AE. Viral infections and antiphospholipid antibodies. Semin Arthritis Rheum 2002;31:256–63
68. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, Derksen RH, De Groot PG, Koike T, Meroni PL, Reber G, Shoenfeld Y, Tincani A, Vlachoyiannopoulos PG, Krilis SA. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295–306
69. Khamashta MA, Cuadrado MJ, Mujic F, Taub NA, Hunt BJ, Hughes GR. The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med 1995;332:993–7
70. Crowther MA, Ginsberg JS, Julian J, Denburg J, Hirsh J, Douketis J, Laskin C, Fortin P, Anderson D, Kearon C, Clarke A, Geerts W, Forgie M, Green D, Costantini L, Yacura W, Wilson S, Gent M, Kovacs MJ. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med 2003;349:1133–8
71. Mammen EF. Coagulation abnormalities in liver disease. Hematol Oncol Clin North Am 1992;6:1247–57
72. Budhiraja R, Tuder RM, Hassoun PM. Endothelial dysfunction in pulmonary hypertension. Circulation 2004;109:159–65
73. Kendall AG, Lohmann RC, Dossetor JB. Nephrotic syndrome: a hypercoagulable state. Arch Intern Med 1971;127:1021–7
74. Kauffmann RH, Veltkamp JJ, Van Tilburg NH, Van Es LA. Acquired antithrombin III deficiency and thrombosis in the nephrotic syndrome. Am J Med 1978;65:607–13
75. Llach F. Hypercoagulability, renal vein thrombosis, and other thrombotic complications of nephrotic syndrome. Kidney Int 1985;28:429–39
76. Franchini M, Targher G, Montagnana M, Lippi G. The metabolic syndrome and the risk of arterial and venous thrombosis. Thromb Res 2008;122:727–35
77. Kubo SH, Rector TS, Bank AJ, Williams RE, Heifetz SM. Endothelium-dependent vasodilation is attenuated in patients with heart failure. Circulation 1991;84:1589–96
78. Prandoni P, Falanga A, Piccioli A. Cancer and venous thromboembolism. Lancet Oncol 2005;6:401–10
79. Kannel WB, Wolf PA, Castelli WP, D'Agostino RB. Fibrinogen and risk of cardiovascular disease: The Framingham Study. JAMA 1987;258:1183–6
80. Ofosu FA, Craven S, Dewar L, Anvari N, Andrew M, Blajchman MA. Age-related changes in factor VII proteolysis in vivo. Br J Haematol 1996;94:407–12
81. Gleerup G, Winther K. The effect of ageing on platelet function and fibrinolytic activity. Angiology 1995;46:715–8
82. Kasjanovova D, Balaz V. Age-related changes in human platelet function in vitro. Mech Ageing Dev 1986;37:175–82
83. Platt A. Can you recognize a patient at risk for a hypercoagulable state? JAAPA 2008;21:20–6
84. Selby R, Geerts W, Ofosu FA, Craven S, Dewar L, Phillips A, Szalai JP. Hypercoagulability after trauma: hemostatic changes and relationship to venous thromboembolism. Thromb Res 2009;124:281–7
85. Gando S. Tissue factor in trauma and organ dysfunction. Semin Thromb Hemost 2006;32:48–53
86. Kageyama K, Nakajima Y, Shibasaki M, Hashimoto S, Mizobe T. Increased platelet, leukocyte, and endothelial cell activity are associated with increased coagulability in patients after total knee arthroplasty. J Thromb Haemost 2007;5:738–45
87. van Hinsbergh VW, Bauer KA, Kooistra T, Kluft C, Dooijewaard G, Sherman ML, Nieuwenhuizen W. Progress of fibrinolysis during tumor necrosis factor infusions in humans: concomitant increase in tissue-type plasminogen activator, plasminogen activator inhibitor type-1, and fibrin(ogen) degradation products. Blood 1990;76:2284–9
88. Biemond BJ, Levi M, Ten Cate H, Van der Poll T, Buller HR, Hack CE, Ten Cate JW. Plasminogen activator and plasminogen activator inhibitor I release during experimental endotoxaemia in chimpanzees: effect of interventions in the cytokine and coagulation cascades. Clin Sci (Lond) 1995;88:587–94
89. Zaidan JR, Johnson S, Brynes R, Monroe S, Guffin AV. Rate of protamine administration: its effect on heparin reversal and antithrombin recovery after coronary artery surgery. Anesth Analg 1986;65:377–80
90. Okita Y, Takamoto S, Ando M, Morota T, Yamaki F, Matsukawa R, Kawashima Y. Coagulation and fibrinolysis system in aortic surgery under deep hypothermic circulatory arrest with aprotinin: the importance of adequate heparinization. Circulation 1997;96:II-376–81
91. Sniecinski R, Szlam F, Chen EP, Bader SO, Levy JH, Tanaka KA. Antithrombin deficiency increases thrombin activity after prolonged cardiopulmonary bypass. Anesth Analg 2008;106:713–8
92. Rosendaal FR, Van Hylckama Vlieg A, Tanis BC, Helmerhorst FM. Estrogens, progestogens and thrombosis. J Thromb Haemost 2003;1:1371–80
93. Glueck CJ, Wang P, Fontaine RN, Sieve-Smith L, Lang JE. Estrogen replacement therapy, thrombophilia, and atherothrombosis. Metabolism 2002;51:724–32
94. Paidas MJ, Ku DH, Lee MJ, Manish S, Thurston A, Lockwood CJ, Arkel YS. Protein Z, protein S levels are lower in patients with thrombophilia and subsequent pregnancy complications. J Thromb Haemost 2005;3:497–501
95. Ide M, Bolliger D, Taketomi T, Tanaka KA. Lessons from the aprotinin saga: current perspective on antifibrinolytic therapy in cardiac surgery. J Anesth 2010;24:96–106
96. Fergusson DA, Hebert PC, Mazer CD, Fremes S, MacAdams C, Murkin JM, Teoh K, Duke PC, Arellano R, Blajchman MA, Bussieres JS, Cote D, Karski J, Martineau R, Robblee JA, Rodger M, Wells G, Clinch J, Pretorius R. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med 2008;358:2319–31
97. Franchini M. The use of desmopressin as a hemostatic agent: a concise review. Am J Hematol 2007;82:731–5
98. Crowther MA, Warkentin TE. Managing bleeding in anticoagulated patients with a focus on novel therapeutic agents. J Thromb Haemost 2009;7:107–10
99. Sanofi-Aventis. DDAVP® injection (desmopressin acetate): prescribing information. Bridgewater, NJ: Sanofi-Aventis, 2007
100. Levi M, Cromheecke ME, de Jonge E, Prins MH, de Mol BJ, Briet E, Buller HR. Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints. Lancet 1999;354:1940–7
101. Novo Nordisk Inc. NovoSeven® RT, coagulation factor VIIa (recombinant) room temperature stable: prescribing information. Princeton, NJ: Novo Nordisk Inc, 2008
102. Levy JH, Fingerhut A, Brott T, Langbakke IH, Erhardtsen E, Porte RJ. Recombinant factor VIIa in patients with coagulopathy secondary to anticoagulant therapy, cirrhosis, or severe traumatic injury: review of safety profile. Transfusion 2006;46:919–33
103. Hossain N, Shamsi T, Haider S, Soomro N, Khan NH, Memon GU, Farzana T, Ansari S, Triche EW, Kuczynski E, Lockwood CJ, Paidas MJ. Use of recombinant activated factor VII for massive postpartum hemorrhage. Acta Obstet Gynecol Scand 2007:1–7
104. Spotnitz WD, Prabhu R. Fibrin sealant tissue adhesive: review and update. J Long Term Eff Med Implants 2005;15:245–70
105. Fastenau DR, Wagenknecht DR, Hormuth DA, McIntyre JA. Left ventricular assist system recipients exposed to bovine thrombin preparations have a higher frequency of antiphospholipid antibodies than nonexposed recipients. ASAIO J 2001;47:537–40
106. Su Z, Izumi T, Thames EH, Lawson JH, Ortel TL. Antiphospholipid antibodies after surgical exposure to topical bovine thrombin. J Lab Clin Med 2002;139:349–56
107. Matthai WH Jr, Kurnik PB, Groh WC, Untereker WJ, Siegel JE. Antithrombin activity during the period of percutaneous coronary revascularization: relation to heparin use, thrombotic complications and restenosis. J Am Coll Cardiol 1999;33:1248–56
108. Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood 2005; 106:2710–5
109. Warkentin TE, Levine MN, Hirsh J, Horsewood P, Roberts RS, Gent M, Kelton JG. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 1995;332:1330–5
110. 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
111. Shore-Lesserson L, Reich DL. A case of severe diffuse venous thromboembolism associated with aprotinin and hypothermic circulatory arrest in a cardiac surgical patient with factor V Leiden. Anesthesiology 2006;105:219–21
112. Favaloro EJ, McDonald D, Lippi G. Laboratory investigation of thrombophilia: the good, the bad, and the ugly. Semin Thromb Hemost 2009;35:695–710
113. Baglin T, Gray E, Greaves M, Hunt BJ, Keeling D, Machin S, Mackie I, Makris M, Nokes T, Perry D, Tait RC, Walker I, Watson H. Clinical guidelines for testing for heritable thrombophilia. Br J Haematol 2010;149:209–20
114. Rosenberg RD, Bauer KA. Thrombosis in inherited deficiencies of antithrombin, protein C, and protein S. Hum Pathol 1987;18:253–62
115. Stegnar M, Vene N, Bozic M. Do haemostasis activation markers that predict cardiovascular disease exist? Pathophysiol Haemost Thromb 2003;33:302–8
116. Zhu T, Martinez I, Emmerich J. Venous thromboembolism: risk factors for recurrence. Arterioscler Thromb Vasc Biol 2009;29:298–310
117. Palareti G, Cosmi B, Legnani C, Tosetto A, Brusi C, Iorio A, Pengo V, Ghirarduzzi A, Pattacini C, Testa S, Lensing AW, Tripodi A. D-dimer testing to determine the duration of anticoagulation therapy. N Engl J Med 2006;355:1780–9
118. Pabinger I, Ay C. Biomarkers and venous thromboembolism. Arterioscler Thromb Vasc Biol 2009;29:332–6
119. Radl R, Kastner N, Aigner C, Portugaller H, Schreyer H, Windhager R. Venous thrombosis after hallux valgus surgery. J Bone Joint Surg Am 2003;85-A:1204–8
120. Milic DJ, Pejcic VD, Zivic SS, Jovanovic SZ, Stanojkovic ZA, Jankovic RJ, Pecic VM, Nestorovic MD, Jankovic ID. Coagulation status and the presence of postoperative deep vein thrombosis in patients undergoing laparoscopic cholecystectomy. Surg Endosc 2007;21:1588–92
121. Park MS, Martini WZ, Dubick MA, Salinas J, Butenas S, Kheirabadi BS, Pusateri AE, Vos JA, Guymon CH, Wolf SE, Mann KG, Holcomb JB. Thromboelastography as a better indicator of hypercoagulable state after injury than prothrombin time or activated partial thromboplastin time. J Trauma 2009;67:266–75
122. Kashuk JL, Moore EE. The emerging role of rapid thromboelastography in trauma care. J Trauma 2009;67:417–8
123. Kashuk JL, Moore EE, Sabel A, Barnett C, Haenel J, Le T, Pezold M, Lawrence J, Biffl WL, Cothren CC, Johnson JL. Rapid thrombelastography (r-TEG) identifies hypercoagulability and predicts thromboembolic events in surgical patients. Surgery 2009;146:764–72
124. Hvitfeldt Poulsen L, Christiansen K, Sorensen B, Ingerslev J. Whole blood thrombelastographic coagulation profiles using minimal tissue factor activation can display hypercoagulation in thrombosis-prone patients. Scand J Clin Lab Invest 2006;66:329–36
125. Mahla E, Lang T, Vicenzi MN, Werkgartner G, Maier R, Probst C, Metzler H. Thromboelastography for monitoring prolonged hypercoagulability after major abdominal surgery. Anesth Analg 2001;92:572–7
126. Dai Y, Lee A, Critchley LA, White PF. Does thromboelastography predict postoperative thromboembolic events? A systematic review of the literature. Anesth Analg 2009;108:734–42
127. Warkentin TE, Heddle NM. Laboratory diagnosis of immune heparin-induced thrombocytopenia. Curr Hematol Rep 2003;2:148–57
128. Kelton JG. The pathophysiology of heparin-induced thrombocytopenia: biological basis for treatment. Chest 2005;127:9S–20S
129. Levy JH, Tanaka KA, Hursting MJ. Reducing thrombotic complications in the perioperative setting: an update on heparin-induced thrombocytopenia. Anesth Analg 2007; 105:570–82
130. Greinacher A. Heparin-induced thrombocytopenia. J Thromb Haemost 2009;7:9–12
131. Francis JL, Palmer GJ III, Moroose R, Drexler A. Comparison of bovine and porcine heparin in heparin antibody formation after cardiac surgery. Ann Thorac Surg 2003;75:17–22
132. Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med 2001;344:1286–92
133. Pouplard C, May MA, Regina S, Marchand M, Fusciardi J, Gruel Y. Changes in platelet count after cardiac surgery can effectively predict the development of pathogenic heparin-dependent antibodies. Br J Haematol 2005;128:837–41
134. Rice L, Attisha WK, Drexler A, Francis JL. Delayed-onset heparin-induced thrombocytopenia. Ann Intern Med 2002;136:210–5
135. Greinacher A, Farner B, Kroll H, Kohlmann T, Warkentin TE, Eichler P. Clinical features of heparin-induced thrombocytopenia including risk factors for thrombosis: a retrospective analysis of 408 patients. Thromb Haemost 2005;94:132–5
136. Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia and cardiac surgery. Ann Thorac Surg 2003;76:2121–31
137. Hirsh J, Heddle N, Kelton JG. Treatment of heparin-induced thrombocytopenia: a critical review. Arch Intern Med 2004;164:361–9
138. Warkentin TE, Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Med 1996;101:502–7
139. Lo GK, Juhl D, Warkentin TE, Sigouin CS, Eichler P, Greinacher A. Evaluation of pretest clinical score (4 T's) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost 2006;4:759–65
140. Warkentin TE, Sheppard JI, Moore JC, Sigouin CS, Kelton JG. Quantitative interpretation of optical density measurements using PF4-dependent enzyme-immunoassays. J Thromb Haemost 2008;6:1304–12
141. Lo GK, Sigouin CS, Warkentin TE. What is the potential for overdiagnosis of heparin-induced thrombocytopenia? Am J Hematol 2007;82:1037–43
142. Warkentin TE. Platelet count monitoring and laboratory testing for heparin-induced thrombocytopenia. Arch Pathol Lab Med 2002;126:1415–23
143. Warkentin TE, Sheppard JA, Horsewood P, Simpson PJ, Moore JC, Kelton JG. Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood 2000;96:1703–8
144. Greinacher A, Volpel H, Janssens U, Hach-Wunderle V, Kemkes-Matthes B, Eichler P, Mueller-Velten HG, Potzsch B. Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopenia: a prospective study. Circulation 1999;99:73–80
145. Aijaz A, Nelson J, Naseer N. Management of heparin allergy in pregnancy. Am J Hematol 2001;67:268–9
146. Huhle G, Geberth M, Hoffmann U, Heene DL, Harenberg J. Management of heparin-associated thrombocytopenia in pregnancy with subcutaneous r-hirudin. Gynecol Obstet Invest 2000;49:67–9
147. Ekbatani A, Asaro LR, Malinow AM. Anticoagulation with argatroban in a parturient with heparin-induced thrombocytopenia. Int J Obstet Anesth 2010;19:82–7
148. Young SK, Al-Mondhiry HA, Vaida SJ, Ambrose A, Botti JJ. Successful use of argatroban during the third trimester of pregnancy: case report and review of the literature. Pharmacotherapy 2008;28:1531–6
149. Schindewolf M, Mosch G, Bauersachs RM, Lindhoff-Last E. Safe anticoagulation with danaparoid in pregnancy and lactation. Thromb Haemost 2004;92:211
150. Magnani HN. An analysis of clinical outcomes of 91 pregnancies in 83 women treated with danaparoid (Orgaran). Thromb Res 2010;125:297–302
151. Gerhardt A, Zotz RB, Stockschlaeder M, Scharf RE. Fondaparinux is an effective alternative anticoagulant in pregnant women with high risk of venous thromboembolism and intolerance to low-molecular-weight heparins and heparinoids. Thromb Haemost 2007;97:496–7
152. Koster A, Hansen R, Kuppe H, Hetzer R, Crystal GJ, Mertzlufft F. Recombinant hirudin as an alternative for anticoagulation during cardiopulmonary bypass in patients with heparin-induced thrombocytopenia type II: a 1-year experience in 57 patients. J Cardiothorac Vasc Anesth 2000;14:243–8
153. Martin ME, Kloecker GH, Laber DA. Argatroban for anticoagulation during cardiac surgery. Eur J Haematol 2007;78:161–6
154. Dyke CM, Smedira NG, Koster A, Aronson S, McCarthy HL II, Kirshner R, Lincoff AM, Spiess BD. A comparison of bivalirudin to heparin with protamine reversal in patients undergoing cardiac surgery with cardiopulmonary bypass: the EVOLUTION-ON study. J Thorac Cardiovasc Surg 2006;131:533–9
155. Huebler M, Koster A, Buz S, Boettcher W, Hetzer R, Kuppe H, Dyke CM. Cardiopulmonary bypass for complex cardiac surgery using bivalirudin anticoagulation in a patient with heparin antibodies. J Card Surg 2006;21:286–8
156. Koster A, Spiess B, Jurmann M, Dyke CM, Smedira NG, Aronson S, Lincoff MA. Bivalirudin provides rapid, effective, and reliable anticoagulation during off-pump coronary revascularization: results of the “EVOLUTION OFF” trial. Anesth Analg 2006;103:540–4
157. Smedira NG, Dyke CM, Koster A, Jurmann M, Bhatia DS, Hu T, McCarthy HL II, Lincoff AM, Spiess BD, Aronson S. Anticoagulation with bivalirudin for off-pump coronary artery bypass grafting: the results of the EVOLUTION-OFF study. J Thorac Cardiovasc Surg 2006;131:686–92
158. Arepally GM, Ortel TL. Clinical practice: heparin-induced thrombocytopenia. N Engl J Med 2006;355:809–17
159. Warkentin TE. Clinical picture of heparin-induced thrombocytopenia. In: Warkentin TE, Greinacher A, eds. Heparin-Induced Thrombocytopenia. 4th ed. New York: Informa Healthcare USA, 2007:21–66
160. Van Cott EM, Laposata M, Prins MH. Laboratory evaluation of hypercoagulability with venous or arterial thrombosis. Arch Pathol Lab Med 2002;126:1281–95
Dr. Hursting has received consultancy fees from GlaxoSmithKline. Dr. Paidas has received research support from GTC Biotherapeutics, Novo Nordisk, Celera, and Lundbeck; honoraria from GTC Biotherapeutics, Novo Nordisk, CSL Behring, Talecris, and Lundbeck; and consulting fees from Talecris. Dr. Levy has received research support from Eisai, GlaxoSmith Kline, and Novo Nordisk. Dr. Sniecinski has no financial disclosures to make.
This article has been cited 1 time(s).
Journal of Cardiothoracic and Vascular AnesthesiaLeft Ventricular Thrombus During Cardiopulmonary Bypass as the Primary Manifestation of Heparin-Induced ThrombocytopeniaJournal of Cardiothoracic and Vascular Anesthesia
© 2011 International Anesthesia Research Society
What does "Remember me" mean?
By checking this box, you'll stay logged in until you logout. You'll get easier access to your articles, collections,
media, and all your other content, even if you close your browser or shut down your
To protect your most sensitive data and activities (like changing your password),
we'll ask you to re-enter your password when you access these services.
What if I'm on a computer that I share with others?
If you're using a public computer or you share this computer with others, we recommend
that you uncheck the "Remember me" box.
Data is temporarily unavailable. Please try again soon.
Readers Of this Article Also Read