Vascular Medicine and Endovascular Interventions - part 3 pot

59 5 Thrombophilia* John A. Heit, MD [Table 5.1]); thrombophilia may also be inherited (Table 5.2). This concept is important because disease susceptibil- ity does not imply an absolute requirement for primary or secondary prevention or for treatment. In most persons with a thrombophilia, thrombosis does not develop. Thus, thrombophilia(s) must be considered in the context of other risk factors for incident thrombosis or predictors of recur- Introduction Symptomatic thrombosis is caused by dysregulation of the normal hemostatic response to vessel wall “injury” that occurs with exposure to a clinical risk factor (e.g., surgery, trauma, or hospitalization for acute medical illness). Ves- sel wall injury may be anatomic (e.g., venous endothelial microtears within vein valve cusps due to stasis or rupture of a lipid-rich atherosclerotic plaque) or “non-anatomic” (e.g., cytokine-mediated endothelial expression of adhe- sion molecules or downregulation of thrombomodulin expression, related to the “acute infl ammatory response”). However, the vast majority of persons exposed to a clini- cal risk factor do not have development of symptomatic thrombosis. We now recognize that clinical thrombosis is a multifactorial and complex disease that becomes mani- fest when a person with an underlying predisposition to thrombosis (“thrombophilia[s]”) is exposed to additional risk factors. Emerging evidence suggests that individual variation in the regulation of the procoagulant, anticoagu- lant, fi brinolytic, and acute infl ammation or innate immu- nity pathways most likely accounts for the development of clinical thrombosis in exposed persons. Thrombophilia is defi ned as a predisposition to throm- bosis. Thrombophilia is not a disease per se, but may be as- sociated with a disease (e.g., cancer), with drug exposure (e.g., oral contraceptives), or with a specifi c condition (e.g., pregnancy or post partum—“acquired thrombophilia” *Portions of this manuscript have been previously published in Heit JA. Venous thromboembolism: disease burden, outcomes and risk factors. J Thromb Haemost. 2005;3:1611-7. Used with permission. Supported in part by research grants HL66216, HL83141, HL83797, and RR19457 from the National Institutes of Health and research grant TS1255 from the Centers for Disease Control and Prevention, United States Public Health Service; and by Mayo Foundation. © 2007 Society for Vascular Medicine and Biology Table 5.1 Acquired or Secondary Thrombophilia Defi nite causes of thrombophilia Active malignant neoplasm Chemotherapy ( L-asparaginase, thalidomide, antiangiogenesis therapy) Myeloproliferative disorders Heparin-induced thrombocytopenia and thrombosis Nephrotic syndrome Intravascular coagulation and fi brinolysis/disseminated intravascular coagulation Thrombotic thrombocytopenic purpura Sickle cell disease Oral contraceptives Estrogen therapy Pregnancy/postpartum state Tamoxifen and raloxifene therapy (selective estrogen receptor modulator) Antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibody, anti–β2-glycoprotein-1 antibody) Paroxysmal nocturnal hemoglobinuria Wegener granulomatosis Probable causes of thrombophilia Infl ammatory bowel disease Thromboangiitis obliterans (Buerger disease) Behçet syndrome Varicose veins Systemic lupus erythematosus Venous vascular anomalies (Klippel-Trénaunay syndrome) Progesterone therapy Infertility treatments Hyperhomocysteinemia Human immunodefi ciency virus infection Dehydration Vascular Medicine and Endovascular Interventions 60 most clinical studies have failed to show a consistent asso- ciation between thrombophilia and myocardial infarction or stroke. Unfortunately, no single laboratory assay or simple set of assays can identify all thrombophilias. Consequently, a battery of complex and potentially expensive assays is usually required. Many of the analytes measured in the laboratory are affected by other conditions (e.g., warfa- rin decreases protein C and S levels), such that the cor- rect interpretation of the results can be complicated and always requires clinical correlation. Detailed descriptions of the known thrombophilias are included in this chapter, as well as information on special coagulation laboratory interpretation. • The predominant clinical manifestation of throm- bophilia is VTE Indications for Thrombophilia Testing: Why Should I Test for Thrombophilia? There are no absolute indications for clinical diagnostic thrombophilia testing. Potential relative indications could include the following: – Selected screening of populations that are potentially “enriched” for thrombophilia (e.g., asymptomatic or symptomatic family members of patients with a known familial thrombophilia, especially fi rst-degree relatives); – Selected screening of populations at increased risk for thrombosis (e.g., before pregnancy, use of oral contracep- tion or estrogen therapy, before high-risk surgery, or dur- ing chemotherapy with angiogenesis inhibitors); – Testing of symptomatic patients with an incident throm- botic event (e.g., incident VTE, stillbirth or another com- rent thrombosis, when estimating the need for primary or secondary prophylaxis, respectively. With rare exceptions, the therapy for acute thrombosis is no different for persons with and without a recognized thrombophilia. • Thrombophilia is a predisposition or susceptibility to thrombosis • Thrombophilia is not a disease, but may be associated with a disease, drug exposure, or a condition, or may be inherited • When estimating the need for primary or secondary prophylaxis, thrombophilia(s) must be considered in the context of other risk factors for incident thrombosis or predictors of recurrent thrombosis, respectively • With rare exceptions, therapy for acute thrombosis is the same for those with and without a recognized throm- bophilia Thrombophilia may present clinically as one or more of several thrombotic manifestations or “phenotypes” (Table 5.3). The predominant clinical manifestation of throm- bophilia is venous thromboembolism (VTE). Although it is biologically plausible to hypothesize that patients with atherosclerotic arterial occlusive disease and an underly- ing thrombophilia who have an atherosclerotic plaque rupture are more likely to have a symptomatic thrombosis, Table 5.2 Hereditary (Familial or Primary) Thrombophilia Defi nite causes of thrombophilia Antithrombin III defi ciency Protein C defi ciency Protein S defi ciency Activated protein C resistance Factor V Leiden mutation Prothrombin G20210A mutation Homocystinuria Probable causes of thrombophilia Increased plasma factors I (fi brinogen), II (prothrombin), VIII, IX, and XI Hyperhomocysteinemia Dysfi brinogenemia Hypoplasminogenemia and dysplasminogenemia Hypofi brinolysis Reduced protein Z and Z-dependent protease inhibitor Reduced tissue factor pathway inhibitor Possible causes of thrombophilia Tissue plasminogen activator defi ciency Increased plasminogen activator inhibitor levels Methylene tetrahydrofolate reductase polymorphisms Factor XIII polymorphisms Increased thrombin-activatable fi brinolysis inhibitor Table 5.3 Clinical Manifestations of Thrombophilia Defi nite manifestations Purpura fulminans (neonatalis or adult) Superfi cial or deep vein thrombosis, pulmonary embolism Thrombosis of “unusual” venous circulations (cerebral, hepatic, mesenteric, and renal veins; possibly arm, portal, and ovarian veins; not retinal vein or artery) Warfarin-induced skin necrosis Possible manifestations Arterial thrombosis (stroke, acute myocardial infarction) (Recurrent) fetal loss Intrauterine growth restriction Stillbirth Severe gestational hypertension (preeclampsia) Abruptio placentae CHAPTER 5 Thrombophilia 61 plication of pregnancy, incident arterial thrombosis in a young person without other arterial disease); – Testing of symptomatic patients with recurrent throm- bosis, “idiopathic” thrombosis, thrombosis at a young age (e.g., ≤40 years for venous thrombosis, ≤50 years for arteri- al thrombosis) or thrombosis in unusual vascular territory (e.g., cerebral vein, portal vein, hepatic vein, mesenteric vein, or artery). With the exception of general population screening, which is not recommended, all of these potential indica- tions are controversial and must be considered in the con- text of the clinical presentation. Counseling and Screening Asymptomatic Family Members Thrombophilia testing, especially genetic testing, of asymptomatic family members should be done with cau- tion. Family members (and patients) should receive genetic counseling before genetic testing, and such testing should only be performed after obtaining consent. Counseling should include the reasons for testing, such as the potential for avoiding clinical thrombosis by risk factor modifi cation or prophylaxis (both for the family member as well as his or her children), and the reasons for not testing, such as stigmatization and mental anguish, the potential effect on obtaining personal health insurance or employment, and the possibility of non-paternity. Thrombophilia testing should only be done if the re- sults are likely to change medical management. The risk of idiopathic (“unprovoked”) thrombosis associated with a thrombophilia, although increased, is still insuffi - cient to warrant chronic primary prophylaxis (e.g., war- farin anticoagulation therapy), even for thrombophilias with high penetrance (e.g., antithrombin defi ciency or homozygous factor V Leiden carriers) with the possible exception of paroxysmal nocturnal hemoglobinuria. Thus, primary “prophylaxis” typically involves either avoidance or modifi cation of risk exposure or specifi c prophylactic measures if such exposures are unavoid- able. When counseling a family member (or patient) regard- ing the risk of thrombosis associated with a thrombophilia, it is most useful to provide the “absolute” risk or incidence of thrombosis among persons with that particular throm- bophilia. For example, the relative risk of VTE among women who are factor V Leiden carriers and using oral contraceptives is increased about 30-fold; however, the incidence is only about 300 per 100,000 woman-years, or about 0.3% per woman-year. Thus, the absolute risk pro- vides information on both the baseline risk of VTE (about 10-46 per 100,000 woman-years for women of reproduc- tive age) as well as the relative risk (about 30 for female factor V Leiden carriers using oral contraceptives). Estimation of the absolute risk of thrombosis should especially account for the effect of age on the baseline inci- dence of VTE. For example, among women of perimeno- pausal age (50-54 years), the incidence of VTE is 123 per 100,000 woman-years, which increases exponentially with increasing age (Fig. 5.1). Among female factor V Leiden carriers of perimenopausal age, the relative risk of VTE associated with hormone therapy may be increased 7- to 15-fold. However, whereas the relative risk for VTE is less with the use of hormone therapy than with use of oral con- traceptives, the absolute risk is substantially higher (≈900- 1,800 per 100,000 woman-years, ≈1%-2% per woman-year) because of the increased incidence with age. Given recent studies questioning the benefi t of postmenopausal hor- mone therapy, most women likely would choose to avoid such therapy if they were known to be factor V Leiden car- Fig. 5.1 Annual incidence of venous thromboembolism by age and sex. (From 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. Used with permission.) Vascular Medicine and Endovascular Interventions 62 riers. Thus, it may be relatively cost-effective to perform thrombophilia screening of an asymptomatic perimeno- pausal or postmenopausal woman with a known family history of thrombophilia who is considering hormone therapy. Primary Prevention of Incident VTE Primary prevention of VTE, either by risk factor modifi ca- tion or by appropriate prophylaxis for patients at risk, is essential to improve survival and prevent complications. However, despite improved prophylaxis regimens and more widespread use of prophylaxis, the overall incidence of VTE has been relatively constant at about 1 per 1,000 since 1979. To avoid or modify risk or appropriately target prophy- laxis, patients at risk for VTE must fi rst be identifi ed. In the absence of a central venous catheter or active cancer, the incidence of VTE among children and adolescents is very low (<1 per 100,000 for age ≤15 years). The inci- dence increases exponentially after age 50 years, eventu- ally reaching about 1,000 per 100,000 for persons aged 85 years or older. The incidence of VTE increases signifi cantly with age for both idiopathic and secondary VTE, which suggests that the risk associated with advancing age may be due to the biology of aging rather than simply to an increased exposure to VTE risk factors with advancing age. The incidence is slightly higher for women during childbearing years and for men after age 50 years. The in- cidence of VTE also varies by race. Compared with white Americans, black Americans have a 30% higher incidence and Asian and Native Americans have up to a 70% lower incidence; Hispanics have an incidence intermediate be- tween whites and Asian Americans. Additional independent risk factors for VTE are shown in Table 5.4. Compared with persons in the community, hospitalized patients have a greater than 150-fold in- creased incidence of acute VTE. The population-attribut- able risk provides an estimate of the burden of disease in the community that is attributable to a particular risk factor. For example, the risk factors of hospitalization and nursing home residence together account for almost 60% of all incident VTE events occurring in the community. Thus, hospital confi nement provides an important oppor- tunity to substantially decrease VTE incidence. Of note, hospitalization for medical illness and surgery account for almost equal proportions of VTE (22% and 24%, respec- tively), which emphasizes the need to provide prophylaxis to both of these risk groups. • Primary “prophylaxis” involves either avoidance or modifi cation of risk exposure or specifi c prophylactic measures if such exposures are unavoidable • Compared with persons in the community, hospitalized patients have a greater than 150-fold increased incidence of acute VTE • Hospitalization for medical illness and surgery account for almost equal proportions of VTE (22% and 24%, respectively), which emphasizes the need to provide prophylaxis to both of these risk groups The risk among surgical patients can be further stratifi ed on the basis of patient age, type of surgery, and presence of active cancer. The incidence of postoperative VTE is increased for surgical patients aged 65 years and older. High-risk surgical procedures include neurosurgery, major orthopedic surgery of the leg, renal transplantation, cardiovascular surgery, and thoracic, abdominal, or pelvic surgery for malignancy. After controlling for age, type of surgery, and cancer, additional independent risk factors for incident VTE after major surgery include increasing body mass index, intensive care unit confi nement for more than 6 days, immobility, infection, and varicose veins. The risk from surgery may be less with neuraxial (spinal or epidural) anesthesia than with general anesthesia. Independent risk factors for incident VTE among pa- tients hospitalized for acute medical illness include in- creasing age and body mass index, active cancer, neuro- logic disease with extremity paresis, immobility, fracture, and prior superfi cial vein thrombosis. Active cancer ac- counts for almost 20% of incident VTE events occurring in the community. VTE risk among patients with active cancer can be further stratifi ed by tumor site, presence of distant metastases, and active chemotherapy. Although all of these patients are at risk, the risk appears to be higher for pancreatic cancer, lymphoma, malignant brain tumors, Table 5.4 Independent Risk Factors for Deep Vein Thrombosis or Pulmonary Embolism Baseline characteristic Odds ratio 95% Confi dence interval Hospitalization For acute medical illness 7.98 4.49-14.18 For major surgery 21.72 9.44-49.93 Trauma 12.69 4.06-39.66 Malignancy Without chemotherapy 4.05 1.93-8.52 With chemotherapy 6.53 2.11-20.23 Prior central venous catheter or transvenous pacemaker 5.55 1.57-19.58 Prior superfi cial vein thrombosis 4.32 1.76-10.61 Neurologic disease with extremity paresis 3.04 1.25-7.38 Serious liver disease 0.10 0.01-0.71 From Heit JA, Silverstein MD, Mohr DN, et al. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med. 2000;160:809-15. Used with permission. CHAPTER 5 Thrombophilia 63 cancer of the liver, leukemia, and colorectal and other di- gestive cancers, and for patients with distant metastases. Those receiving immunosuppressive or cytotoxic chemo- therapy, such as L-asparaginase, thalidomide, angiogen- esis inhibitors, tamoxifen, and erythropoietin, are at even higher risk for VTE. Patients with a central venous catheter or transvenous pacemaker now account for about 9% of those with inci- dent VTE in the community. However, warfarin and low- molecular-weight heparin (LMWH) prophylaxis are not effective in preventing catheter-induced venous throm- bosis and are not recommended. Prior superfi cial vein thrombosis is an independent risk factor for subsequent deep vein thrombosis (DVT) or pulmonary embolism (PE) remote from the episode of superfi cial thrombophlebitis. The risk of DVT imparted by varicose veins is uncertain and appears to be higher among persons younger than 40 years. Long-haul air travel (>6 hours) is associated with a slightly increased risk for VTE, which is preventable with elastic stockings. Studies regarding the protective effect of coenzyme A reductase inhibitor (statin) therapy against VTE have provided confl icting results. In addition, the risk associated with atherosclerosis, or other risk factors for atherosclerosis such as diabetes mellitus, remains un- certain. Body mass index, current or past tobacco smok- ing, chronic obstructive pulmonary disease, and renal failure are not independent risk factors for VTE. The risk associated with congestive heart failure, independent of hospitalization, is low. Among women, additional risk factors for VTE include oral contraceptive use and hormone therapy, pregnancy, and the postpartum period. The greatest risk may occur during early use of oral contraceptives and hormone therapy. This risk may be lower for second-generation oral contraceptives or progesterone alone compared with fi rst- or third-generation oral contraceptives. For women with disabling perimenopausal symptoms that cannot be controlled with non-estrogen therapy, esterifi ed oral estro- gen or transdermal estrogen therapy may confer less risk than oral conjugated equine estrogen therapy. Although VTE can occur anytime during pregnancy, the highest in- cidence is during the fi rst 2 postpartum weeks, especially for older mothers. Independent risk factors for pregnancy- associated VTE include tobacco smoking and prior super- fi cial vein thrombosis. Women receiving therapy with the selective estrogen receptor modulators tamoxifen and raloxifene also are at increased risk for VTE. Recent family-based studies indicate that VTE is highly heritable and follows a complex mode of inheritance in- volving environmental interaction. Inherited decreases in natural plasma anticoagulants (antithrombin III, protein C, or protein S) have long been recognized as uncommon but potent risk factors for VTE. More recent fi ndings of other decreased natural anticoagulants or anticoagulant cofactors, impaired downregulation of the procoagulant system (e.g., activated protein C resistance, factor V Lei- den), increased plasma concentrations of procoagulant factors (e.g., factors I [fi brinogen], II [prothrombin], VIII, IX, and XI), increased basal procoagulant activity, im- paired fi brinolysis, and increased basal innate immunity activity and reactivity have added to the list of inherited or acquired disorders predisposing persons to thrombosis. These plasma hemostasis-related factors or markers of co- agulation activation correlate with increased thrombotic risk and are highly heritable. Inherited thrombophilias interact with such clinical risk factors as oral contracep- tives, pregnancy, hormone therapy, surgery, and cancer to compound the risk of incident VTE. Similarly, genetic interaction increases the risk of incident VTE. Thus, it may be reasonable to consider thrombophilia testing of asymp- tomatic family members with a known history of familial thrombophilia. Secondary Prevention of Recurrent VTE VTE recurs frequently; about 30% of patients have recur- rence within ten years (Table 5.5). A recent modeling study suggested that more than 900,000 incident or recurrent VTE events occurred in the United States in 2002. The hazard of recurrence varies with the time since the incident event and is highest within the fi rst 6 to 12 months. Additional independent predictors of recurrence include male sex, increasing patient age and body mass index, neurologic disease with extremity paresis, and active malignancy (Table 5.6). Other predictors of recurrence include: “idio- pathic” VTE; a persistent lupus anticoagulant or high-titer antiphospholipid antibody; antithrombin, protein C, or protein S defi ciency; compound heterozygous carriers for Table 5.5 Cumulative Incidence and Hazard of Venous Thromboembolism Recurrence Venous thromboembolism recurrence Time to recurrence Cumulative recurrence, % Hazard of recurrence, per 1,000 person-days (SD) 0 days 0.0 0 7 days 1.6 170 (30) 30 days 5.2 130 (20) 90 days 8.3 30 (5) 180 days 10.1 20 (4) 1 year 12.9 20 (2) 2 years 16.6 10 (1) 5 years 22.8 6 (1) 10 years 30.4 5 (1) Modifi ed from Heit JA, Mohr DN, Silverstein MD, et al. Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-based cohort study. Arch Intern Med. 2000;160:761-8. Used with permission. Vascular Medicine and Endovascular Interventions 64 more than one familial thrombophilia (e.g., heterozygous for the factor V Leiden and prothrombin G20210A muta- tions) or homozygous carriers; decreased tissue-factor pathway inhibitor levels; persistent residual DVT; and possibly increased procoagulant factor VIII and factor IX levels. • VTE recurs frequently; about 30% of patients have re- currence within 10 years Data regarding the risk of recurrent VTE among isolated heterozygous carriers of either the factor V Leiden or the prothrombin G20210A mutation are confl icting. In a recent meta-analysis that pooled results from ten studies involv- ing 3,104 patients with incident VTE, the factor V Leiden mutation was present in 21.4% of patients and was asso- ciated with an increased risk of recurrent VTE. Similarly, pooled results from nine studies involving 2,903 patients showed that the prothrombin G20210A mutation was present in 9.7% and was associated with an increased risk of recurrence. The estimated population-attributable risk of recurrence was 9.0% and 6.7% for the factor V Leiden and the prothrombin G20210A mutations, respectively. An increased D-dimer level measured at least 1 month after discontinuing warfarin therapy may be a predictor of DVT recurrence independent of residual venous obstruc- tion. Secondary prophylaxis with anticoagulation therapy should be considered for patients with these characteris- tics. Although the incident event type (DVT alone vs PE) is not a predictor of recurrence, any recurrence is signifi cant- ly more likely to be the same as the incident event type. Because the 7-day case fatality rate is signifi cantly higher for recurrent PE (34%) than for recurrent DVT alone (4%), secondary prophylaxis should be considered for incident PE, especially for patients with chronically reduced cardio- pulmonary functional reserve. Diagnostic Thrombophilia Testing: Who Should Be Tested? Current Recommendations Currently recommended indications for thrombophilia testing include idiopathic or recurrent VTE; a fi rst episode of VTE at a “young” age (≤40 years); a family history of VTE (in particular, a fi rst-degree relative with throm- bosis at a young age); venous thrombosis in an unusual vascular territory (e.g., cerebral, hepatic, mesenteric, or renal vein thrombosis); and neonatal purpura fulminans or warfarin-induced skin necrosis. If two or more of these thrombosis characteristics are present, the prevalence of antithrombin, protein C, or protein S defi ciency, and the factor V Leiden and prothrombin G20210A mutations are increased. Consequently, a “complete” laboratory inves- tigation (described below) is recommended for patients who meet these criteria, whereas more selective testing (e.g., for activated protein C resistance and factor V Leiden and prothrombin G20210A mutations) is recommended for other patients. The prevalence of hereditary thrombophilia is substantial among patients with a fi rst VTE (Table 5.7). Because knowl- edge of a hereditary thrombophilia may be important for estimating the risk of VTE recurrence, testing for a heredi- tary thrombophilia should be considered for patients with a fi rst thrombosis, not limited to patients with recurrent VTE. Moreover, although patients with idiopathic or recur- rent VTE may have a higher prevalence of a recognized thrombophilia, these patients should be considered for secondary prophylaxis regardless of the results of throm- bophilia testing. In addition, the prevalence of hereditary thrombophilia, such as activated protein C resistance, is substantial among patients with a fi rst episode of VTE at an older age (Table 5.8). Therefore, testing for a hereditary thrombophilia should not be limited to patients with a fi rst episode of VTE before age 40 to 50 years. Although persons with defi ciency of antithrombin III, protein C, or protein S are more likely to have thrombosis at a younger age, genetic interaction (e.g., factor V Leiden or prothrombin G20210A mutation combined with either antithrombin, protein C, or protein S defi ciency) compounds the risk of thrombosis such that testing among older patients should not be lim- ited to activated protein C resistance (factor V Leiden) or the prothrombin G20210A mutation. • Currently recommended indications for thrombophilia testing include idiopathic or recurrent VTE; a fi rst epi- sode of VTE at a “young” age (≤40 years); a family his- tory of VTE (in particular, a fi rst-degree relative with thrombosis at a young age); venous thrombosis in an unusual vascular territory (e.g., cerebral, hepatic, me- Table 5.6 Independent Predictors of Venous Thromboembolism Recurrence Characteristic Hazard ratio 95% Confi dence interval Age * 1.17 1.11-1.24 Body mass index † 1.24 1.04-1.47 Neurologic disease with extremity paresis 1.87 1.28-2.73 Active malignancy With chemotherapy 4.24 2.58-6.95 Without chemotherapy 2.21 1.60-3.06 * Per decade increase in age. † Per 10 kg/m 2 increase in body mass index. From Heit JA, Mohr DN, Silverstein MD, et al. Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-based cohort study. Arch Intern Med. 2000;160:761-8. Used with permission. CHAPTER 5 Thrombophilia 65 senteric, or renal vein thrombosis); and neonatal pur- pura fulminans or warfarin-induced skin necrosis • The prevalence of hereditary thrombophilia is substan- tial among patients with a fi rst VTE Recent evidence suggests that a family history of VTE does not increase the likelihood of a recognized familial throm- bophilia. The cumulative lifetime incidence (penetrance) of thrombosis among carriers of the most common familial thrombophilia (factor V Leiden) is only about 10%. There- fore, most patients with an inherited thrombophilia do not have a family history of thrombosis. Consequently, throm- bophilia testing should not be limited to symptomatic pa- tients with a family history of VTE. The most common presentations of familial throm- bophilia are DVT of the leg veins and PE. Except for cath- eter-induced thrombosis, all VTE is most likely associated with an underlying thrombophilia. Therefore, limiting testing of patients with thrombosis in unusual vascular territories will miss most patients with an identifi able fa- milial (or acquired) thrombophilia. Several additional issues should be considered regard- ing testing for a possible thrombophilia. For example, the prevalence of hereditary thrombophilia among patients with VTE differs substantially by ethnic ancestry, but variable testing based on ethnic ancestry has not been directly addressed. The factor V Leiden and prothrombin 20210 mutation carrier frequencies among asymptomatic African, Asian, and Native Americans, as well as African Americans with VTE, are extremely low, such that test se- lection for hereditary thrombophilia most likely should be tailored to patient ethnic ancestry. The risk of VTE during pregnancy or the postpartum period, and the risk of recur- rent fetal loss, is increased among patients with acquired or hereditary thrombophilia. Women with VTE during pregnancy or post partum or recurrent fetal loss should be tested. Recent evidence suggests that patients with acute VTE in the presence of active malignancy are also more likely to have an underlying thrombophilia (e.g., factor V Leiden). Nevertheless, thrombophilia testing for patients with thrombosis associated with active cancer or another Table 5.7 Familial or Acquired Thrombophilia: Estimated Prevalence, and Incidence and Relative Risk of Incident or Recurrent VTE by Type of Thrombophilia Prevalence, %* Incident VTE Recurrent VTE Thrombophilia Normal Incident VTE Recurrent VTE Incidence † (95% CI) Relative risk (95% CI) Incidence † (95% CI) Relative risk (95% CI) Antithrombin III defi ciency 0.02-0.04 1-2 2-5 500 (320-730) 17.5 (9.1-33.8) 10,500 (3,800-23,000) 2.5 Protein C defi ciency 0.02-0.05 2-5 5-10 310 (530-930) 11.3 (5.7-22.3) 5,100 (2,500-9,400) 2.5 Protein S defi ciency 0.01-1 1-3 5-10 710 (530-930) 32.4 (16.7-62.9) 6,500 (2,800-11,800) 2.5 Factor V Leiden ‡ 3-7 12-20 30-50 150 (80-260) 4.3 § (1.9-9.7) 3,500 (1,900-6,100) 1.3 (1.0-3.3) Prothrombin G20210A ‡ 1-3 3-8 15-20 350 1.9 (0.9-4.1) … 1.4 (0.9-2.0) Combined thrombophilias … … … 840 (560-1,220) 32.4 (16.7-62.9) 5,000 (2,000-10,300) … Hyperhomocysteinemia … … … … … … 2.5 Antiphospholipid Ab … … … … … … 2.5 Factor VIII (>200 IU/dL) … … … … … … 1.8 (1.0-3.3) Ab, antibody; CI, confi dence interval; VTE, venous thromboembolism. *In whites. † Per 100,000 person-years. ‡ Heterozygous carriers. § Homozygous carriers, relative risk=80. Table 5.8 Age-Specifi c Annual Incidence and Relative Risk of First Lifetime VTE Among Factor V Leiden Carriers VTE Study Age, y Incidence* (95% CI) Relative risk † (95% CI) Ridker et al 1997 40-49 50-59 60-69 ≥70 0 197 (72-428) 258 (95-561) 783 (358-1,486) … 2.7 2.7 4.2 Middeldorp et al 1998 15-30 31-45 46-60 >60 250 (120-490) 470 (230-860) 820 (350-1,610) 1,100 (240-3,330) ≈15 4.3 2.4 2.8 Simioni et al 1999 <15 16-30 31-45 46-60 >60 0 182 (59-424) 264 (86-616) 380 (104-973) 730 (150-2,128) … 3.6 3.7 1.4 ≈700 Heit et al 2005 15-29 30-44 45-59 ≥60 0 (0-112) 61 (7-219) 244 (98-502) 764 (428-1,260) 0 (0-1.22) 1.96 (0.24-7.04) 1.73 (0.70-3.56) 3.61 (2.02-5.95) CI, confi dence interval; VTE, venous thromboembolism. *VTE incidence per 100,000 person-years. † Compared with factor V Leiden non-carriers. Vascular Medicine and Endovascular Interventions 66 risk exposure (e.g., surgery, hospitalization for acute medical illness, trauma, neurologic disease with extrem- ity paresis, or upper extremity thrombosis in the presence of a central venous catheter or transvenous pacemaker) is controversial. Suggested Revised Recommendations All patients with VTE—regardless of age, sex, race, loca- tion of venous thrombosis, initial or recurrent event, or family history of VTE—should be tested for an acquired or hereditary thrombophilia. Women with recurrent fetal loss or complications of pregnancy and patients with un- explained arterial thrombosis also should be tested. These recommendations are controversial and not universally accepted. • Most patients with an inherited thrombophilia do not have a family history of thrombosis • Women with VTE during pregnancy or post partum or recurrent fetal loss should be tested Diagnostic Thrombophilia Testing: For What Should I Test? General Testing A complete history and physical examination is manda- tory in evaluating persons with a recent or remote history of thrombosis, with special attention given to age of onset, location of prior thromboses, and results of objective di- agnostic studies documenting thrombotic episodes. An inquiry regarding interval imaging to establish a new baseline image is particularly important when diagnosing recurrent thrombosis in the same vascular territory as a previous thrombosis. For patients with an uncorroborated history of DVT, non-invasive venous vascular laboratory or venous duplex ultrasonographic evidence of venous outfl ow obstruction (e.g., residual vein thrombosis) or possibly venous valvular incompetence may be helpful in corroborating the clinical history. Patients should be questioned carefully about diseases, exposures, conditions, or drugs that are associated with thrombosis (Tables 5.1 and 5.4). A family history of throm- bosis may provide insight for a potential familial throm- bophilia, especially in fi rst-degree relatives. Thrombosis can be the initial manifestation of a malignancy, so a com- plete review of systems directed at symptoms of occult malignancy is important, including whether indicated screening tests for normal health maintenance (e.g., mam- mography, colon imaging) are current. Ethnic background should be considered given the extremely low prevalence of the factor V Leiden and prothrombin G20210A muta- tions in those of African, Asian, or Native American an- cestry. The physical examination should include a careful pe- ripheral pulse examination as well as examination of the extremities for signs of superfi cial or deep vein thrombosis and vascular anomalies. The skin should be examined for venous stasis syndrome (e.g., leg swelling, stasis pigmen- tation or dermatitis, or stasis ulcer), varicose veins, and livedo reticularis, skin infarction, or other evidence of microcirculatory occlusive disease. Given the strong asso- ciation of thrombosis with active cancer, a careful exami- nation for lymphadenopathy, hepatosplenomegaly, and abdominal or rectal mass should be performed, as well as breast and pelvic examinations for women, and testicular and prostate examinations for men. The laboratory evaluation for patients with thrombosis should be selective and based on the history and physical examination (Table 5.9). Specifi c tests may include a com- plete blood count with peripheral smear, serum protein electrophoresis, serum chemistries for electrolytes and liver and renal function, prostate specifi c antigen, carci- noembryonic antigen, α-fetoprotein, β-human chorionic gonadotropin, cancer antigen 125, antinuclear antibodies (double-stranded DNA, rheumatoid factor, extractable nuclear antigen), and urinalysis. Elevations in hematocrit or platelet count may indicate the presence of a myelo- proliferative disorder, which can be associated with either venous or arterial thrombosis. Secondary polycythemia can also provide evidence of an underlying occult malig- nancy. Leukopenia and thrombocytopenia can be found in paroxysmal nocturnal hemoglobinuria, which is charac- terized by intravascular hemolysis along with thrombotic sequelae. The development of thrombosis and thrombo- cytopenia concurrent with heparin administration should always prompt consideration of heparin-induced throm- bocytopenia. The peripheral smear should be reviewed for evidence of red cell fragmentation that would indicate microangiopathic hemolytic anemia such as occurs with intravascular coagulation and fi brinolysis. In patients with malignancy, chronic intravascular coagulation and fi brinolysis can result in either venous or arterial thrombo- sis. A leukoerythroblastic picture with nucleated red cells or immature white cells suggests the possibility of marrow infi ltration by tumor. Chest radiography should be performed along with ap- propriate imaging studies according to standard health maintenance guidelines (e.g., Papanicolaou test, mam- mography, colon imaging). More detailed imaging, such as angiography or chest, abdominal, or pelvic computed tomography or magnetic resonance imaging should be performed only if other independent reasons exist to sus- pect an occult malignancy or other arterial disease (in the case of arterial thrombosis). Routine screening for occult cancer in patients presenting with idiopathic VTE has not CHAPTER 5 Thrombophilia 67 been shown to improve cancer-related survival and is not warranted in the absence of clinical features and abnormal basic laboratory fi ndings suggestive of underlying malig- nancy. Sputum cytology, an otolaryngologic examination, and upper gastrointestinal tract endoscopy should be con- sidered for tobacco smokers or others at risk for esopha- geal or gastric cancer. In addition to a Papanicolaou test, endometrial sampling should be considered for women at risk of endometrial cancer. Recommended assays for initial and refl ex special co- agulation testing for a familial or acquired thrombophilia are provided in Table 5.9. Detailed discussions regarding the interpretation and nuances of specifi c assays are pro- vided with the description of the biochemistry, molecular biology, and epidemiology of each thrombophilia at the end of this chapter. • Routine screening for occult cancer in patients present- ing with idiopathic VTE has not been shown to improve cancer-related survival and is not warranted in the ab- sence of clinical features and abnormal basic laboratory fi ndings Arterial Thrombosis Familial or acquired thrombophilia appears to be an un- usual cause of stroke, myocardial infarction, or other organ or skin infarction, except in the presence of antiphospholi- pid antibodies (e.g., lupus anticoagulant, anticardiolipin antibody, anti–β2-glycoprotein-1 antibodies), heparin-in- duced thrombocytopenia, myeloproliferative disorders, homocystinuria, and possibly hyperhomocysteinemia. A young patient with organ or skin infarction in the absence of one of the above disorders or risk factors for athero- sclerosis (e.g., diabetes mellitus, hypertension, hyperlipi- demia, tobacco exposure) or cardioembolism (e.g., cardiac arrhythmia), should be carefully evaluated for occult arte- rial disease (Table 5.10). Organ infarction should not be deemed to be caused by a “hypercoagulable disorder” simply because the patient is young or lacks common risk factors for atherosclerosis or arterial thromboembolism. A detailed inquiry into con- stitutional or specifi c symptoms of vasculitis (primary or secondary), infection (systemic [e.g., endocarditis] or local [e.g., infected aneurysm with artery-to-artery embolism]), atheroembolism, trauma (accidental, thermal, or occu- pational), dissection, vasospasm, or vascular anomaly is required. Pulse should also be carefully examined, includ- ing an examination for aneurysmal disease. Evidence of microcirculatory occlusive disease of the hand, such as livedo, skin or nailbed infarction, or ulcer, should prompt Table 5.9 Laboratory Evaluation for Suspected Familial or Acquired Thrombophilia* General Blood: CBC, peripheral smear, ESR, chemistries, PSA, β-HCG, CA 125, ANA (dsDNA, rheumatoid factor, ENA) PA/lateral chest radiography, urinalysis, mammography Colon imaging, especially if no prior screening (proctosigmoidoscopy, colonoscopy) Chest imaging for smokers (CT, MRI) Otolaryngology consultation, especially for smokers UGI/upper endoscopy Abdominal imaging (CT, MRI, ultrasonography) Angiography Special coagulation laboratory testing Platelets HITTS testing: plasma anti-PF4/glycosaminoglycan (heparin) antibodies ELISA; platelet 14 C-serotonin release assay; heparin-dependent platelet aggregation Plasma coagulation Prothrombin time, aPTT (with phospholipid “mixing” procedure if inhibited) Thrombin time/reptilase time Dilute Russell viper venom time (with confi rm procedures) Mixing studies (inhibitors) Specifi c factor assays (as indicated) Fibrinolytic system Fibrinogen Plasma fi brin D-dimer Soluble fi brin monomer complex Natural anticoagulation system Antithrombin (activity, antigen) Protein C (activity, antigen) Protein S (activity, total and free antigen) APC-resistance ratio (second generation; factor V–defi cient plasma mixing study) Direct genomic DNA mutation testing Factor V Leiden gene (depending on the result of the APC-resistance ratio) Prothrombin G20210A Additional general testing Anticardiolipin (antiphospholipid) antibodies (IgG and IgM isotypes); anti–β2-glycoprotein-1 antibodies Plasma homocysteine (basal, postmethionine load) Additional selective testing Flow cytometry for PNH Plasma ADAMTS-13 activity Plasminogen (activity) ANA, antinuclear antibody; APC, activated protein C; aPTT, activated partial thromboplastin time; β-HCG, β-human chorionic gonadotropin; CA 125, cancer antigen 125; CBC, complete blood count; CT, computed tomography; dsDNA, double-stranded DNA; ELISA, enzyme-linked immunosorbent assay; ENA, extractable nuclear antigen; ESR, erythrocyte sedimentation rate; HITTS, heparin-induced thrombotic thrombocytopenia syndrome; MRI, magnetic resonance imaging; PA, posteroanterior; PF4, platelet factor 4; PNH, paroxysmal nocturnal hemoglobinuria; PSA, prostate-specifi c antigen; UGI, upper gastrointestinal tract series. * Suggested tests that should be performed selectively based on clinical judgment. Vascular Medicine and Endovascular Interventions 68 evaluations for endocarditis (infectious and non-infec- tious), thoracic outlet syndrome or other causes of repeti- tive arterial trauma (e.g., hypothenar hammer syndrome), atheroembolism, and thermal injury. Such physical fi nd- ings in the foot should include a similar search plus an evaluation for abdominal aortic or popliteal artery aneu- rysmal disease with athero- or thromboembolism. • Familial or acquired thrombophilia appears to be an unusual cause of stroke, myocardial infarction, or other organ or skin infarction, except in the presence of an- tiphospholipid antibodies, heparin-induced thrombo- cytopenia, myeloproliferative disorders, homocystinu- ria, and possibly hyperhomocysteinemia Fibromuscular disease typically affects the carotid and renal arteries and may present as stroke or renal infarcts due to carotid and renal artery dissection or embolism, respectively. Because the vascular supply to organs can- not be directly palpated or observed, arteriography is required to evaluate organ infarction. In general, duplex ultrasonography and computed tomography or magnetic resonance imaging angiography do not provide suffi cient resolution to exclude these arteriopathies, with the ex- ception of carotid artery disease. Contrast arteriography should be performed by a vascular physician (vascular radiologist, vascular surgeon, or vascular medicine/car- diologist) who is experienced in diagnosing occult vascu- lar disease, including careful and detailed selective arteri- ography of the involved and upstream vascular territory with selective vasodilator injection and magnifi ed views, if appropriate. Timing of Diagnostic Thrombophilia Testing: When Should I Test? Many of the natural anticoagulant and procoagulant plasma proteins are acute-phase reactants. Acute throm- bosis can transiently decrease the levels of antithrombin III and occasionally proteins C and S. Consequently, testing should not be performed during the acute phase of throm- bosis or during pregnancy. A delay of at least 6 weeks after the acute thrombosis, or after delivery, usually allows suf- fi cient time for acute-phase reactant proteins to return to baseline. Heparin therapy can lower antithrombin III activity and antigen levels and can impair interpretation of clot- based assays for a lupus anticoagulant. A delay of at least 5 days after heparin is withdrawn before testing is usually feasible. Warfarin therapy decreases the activity and anti- gen levels of the vitamin K–dependent factors, including proteins C and S. Rarely, warfarin has also been shown to elevate antithrombin III levels into the normal range in those with a hereditary defi ciency. Many authorities recommend delaying testing until the effects of warfarin therapy also have resolved. For those in whom tempo- rary discontinuation of anticoagulation is not practical, heparin can be substituted for warfarin. However, the ef- fect of warfarin on protein S levels may not resolve for up to 6 weeks. The clinical decision regarding secondary prophylaxis may depend on the results of special coagulation testing. Testing for protein C or S defi ciency may be done during stable warfarin anticoagulation therapy, with adjustment of the protein C and S levels for the warfarin effect by comparison with the levels of other vitamin K–depend- ent proteins with similar plasma half-lives (e.g., factors VII and II [prothrombin], respectively). If the levels of protein C or S are within the normal range, the diagnosis of defi - ciency can be reliably excluded. However, any abnormal result should be confi rmed after the patient is off warfarin for a suffi cient amount of time to allow the warfarin effect to resolve (if possible), or by testing a fi rst-degree family member. Direct leukocyte genomic DNA testing for the factor V Leiden and prothrombin G20210A mutations is unaffected by anticoagulation therapy; such testing can be performed at any time. Thrombophilia Diagnostic Testing • In general, testing should be delayed at least 6-12 weeks after an acute thrombosis Table 5.10 Occult Causes of Arterial Thrombosis Cardioembolism (atrial fi brillation, left ventricular or atrial septal aneurysm, endocarditis [infectious or non-infectious], ASD or PFO with “paradoxic” embolism, cardiac tumors) Artery-to-artery embolism (thromboembolism, cholesterol, tumor, infection) Arterial dissection (large and small vessel) Fibromuscular dysplasia (cervical and renal arteries) Cystic adventitial disease Arterial aneurysmal disease with thrombosis in situ Trauma Arterial entrapment (thoracic outlet syndrome, popliteal entrapment, common femoral entrapment at the inguinal ligament) Vasculitis (primary or secondary) Thromboangiitis obliterans Arterial wall infection Vasospasm Vascular tumors Vascular anomalies Thermal injury (erythromelalgia, chilblain, frostbite) Occupational trauma (hypothenar hammer syndrome, etc) Hyperviscosity syndromes Cold agglutinins Cryoglobulinemia ASD, atrial septal defect; PFO, patent foramen ovale. [...]... 11.4 (1.1) 66 24 >150 22 701 109 100 299 296 23 (2 .3) 36 55 19 21 455 23 17 121 15 0-4 50 1 0-1 2 2 4 -3 7 2 4 -3 5 1 8-2 5 1 7-2 3 2 0-4 40 7 2-1 40 6 5-1 60 5 5-1 45 4,00 0-8 ,000 . 1 -3 5-1 0 710 ( 53 0-9 30 ) 32 .4 (16. 7-6 2.9) 6,500 (2,80 0-1 1,800) 2.5 Factor V Leiden ‡ 3- 7 1 2-2 0 3 0-5 0 150 (8 0-2 60) 4 .3 § (1. 9-9 .7) 3, 500 (1,90 0-6 ,100) 1 .3 (1. 0 -3 .3) Prothrombin G20210A ‡ 1 -3 3- 8 . 0.0 2-0 .04 1-2 2-5 500 (32 0-7 30 ) 17.5 (9. 1 -3 3.8) 10,500 (3, 80 0-2 3, 000) 2.5 Protein C defi ciency 0.0 2-0 .05 2-5 5-1 0 31 0 ( 53 0-9 30 ) 11 .3 (5. 7-2 2 .3) 5,100 (2,50 0-9 ,400) 2.5 Protein S defi ciency 0.0 1-1 . 4 0-4 9 5 0-5 9 6 0-6 9 ≥70 0 197 (7 2-4 28) 258 (9 5-5 61) 7 83 (35 8-1 ,486) … 2.7 2.7 4.2 Middeldorp et al 1998 1 5 -3 0 3 1-4 5 4 6-6 0 >60 250 (12 0-4 90) 470 ( 23 0-8 60) 820 (35 0-1 ,610) 1,100 (24 0 -3 ,33 0) ≈15 4 .3 2.4 2.8 Simioni