Portal de Periódicos da CAPES

What protects Asians from venous thromboembolism?

2004; Elsevier BV; Volume: 116; Issue: 7 Linguagem: Inglês

10.1016/j.amjmed.2004.01.005

1555-7162

Arthur L. Klatsky, David Baer,

Atrial Fibrillation Management and Outcomes

The study of ethnic disparities in the incidence and prevalence of disease is a productive area of observational epidemiology. Explanations, often complex, can include both genetic and environmental influences. The well-established higher prevalence of systemic hypertension and its complications in African Americans compared with whites is an excellent example. Explanatory factors include genetic predisposition plus differences in lifestyle traits, the prevalence of obesity, psychosocial stress, and accessibility to medical care associated with socioeconomic status (1Friedman G.D. Primer of Epidemiology.5th ed. McGraw-Hill, New York, New York2004Google Scholar). Increased risk of a condition in an ethnic group often leads to fruitful searches for new predisposing traits. Even without established explanations, known high prevalence properly leads to public health measures to control known risk factors and to ascertain and manage patients with the disease.Reduced risk in a specific population can result from lower prevalence of acquired or genetic risk traits, but such a finding raises the intriguing possibility of protective factors. One example is that persons with pigmented skin have lower risk of basal cell skin cancer, a condition that is 100 times more common in whites than in blacks (1Friedman G.D. Primer of Epidemiology.5th ed. McGraw-Hill, New York, New York2004Google Scholar). Use of sun-screening agents for skin protection can be viewed as an attempt to simulate the genetic protection afforded by pigmented skin.The rapidly growing Asian American and Pacific Islander population in the United States (12.1 million in the 2000 census) is a potential gold mine for the study of environmental and genetic traits that influence the incidence and expression of disease. Included among Asian American and Pacific Islanders are ethnic groups with diverse cultures, languages, countries of origin, and immigration histories. Some, such as Vietnamese, Filipinos, and South Asians (Indians, Pakistanis, Sri Lankans, and Bangladeshi) are largely foreign born. The Chinese population in the United States includes a substantial proportion of recent immigrants as well as people born here, and the Japanese have the highest proportion of U.S.–born people, with many third and fourth generation family members in the United States. Although considered at high risk for certain cancers, tuberculosis, and hepatitis B, Asian American and Pacific Islanders have been relatively understudied epidemiologically until recently. Observational data suggest interethnic disparities in the risk of coronary disease (high in South Asians, low in Chinese [2Klatsky A.L. Tekawa I. Armstrong M.A. Sidney S. The risk of hospitalization for ischemic heart disease among Asian Americans in Northern California.Am J Public Health. 1994; 84: 1672-1675Crossref PubMed Scopus (46) Google Scholar]), hypertension (high in Filipinos [3Angel A. Armstrong M.A. Klatsky A.L. Blood pressure among Asian-Americans living in Northern California.Am J Cardiol. 1989; 64: 237-240Abstract Full Text PDF PubMed Scopus (16) Google Scholar]), and hemorrhagic stroke (high in Filipinos and Japanese) (A. L. Klatsky, MD, unpublished data, 2003). Behavioral traits presumably play an important role in these inter-Asian ethnic disparities, but the relative roles of genetic and environmental traits remain unclear.In this issue of The American Journal of Medicine, Stein et al (4Stein PD, Kayali F, Olson RE, Milford CE. Pulmonary thromboembolism in Asian-Pacific islanders in the United States: analysis of data from the National Hospital Discharge Survey and the United States Bureau of the Census. Am J Med. 2004;116:435–442Google Scholar) use National Hospital Discharge Survey data to provide robust confirmation of previous reports (5White R.H. Zhou H. Romano P.S. Incidence of idiopathic deep venous thrombosis and secondary thromboembolism among ethnic groups in California.Ann Intern Med. 1998; 128: 737-740Crossref PubMed Scopus (294) Google Scholar, 6Klatsky A.L. Armstrong M.A. Poggi J. Risk of pulmonary embolism and/or deep venous thrombosis in Asian Americans.Am J Cardiol. 2000; 85: 1334-1337Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar, 7White R.H. The epidemiology of venous thromboembolism.Circulation. 2003; 107: I4-I8Crossref PubMed Scopus (1750) Google Scholar) suggesting lower prevalence of venous thromboembolism among all Asian American and Pacific Islanders compared with whites or African Americans. These investigators point out that comparison of differences in the prevalence of venous thromboembolism in clinical reports may be confounded by disparate exclusion and inclusion criteria for case ascertainment. Reported studies involving Asian American and Pacific Islanders variably use autopsy, primary (or all) hospitalization diagnoses, several clinical endpoints, and diagnostic tests of differing sensitivity and specificity. We agree that adjusted rates or relative risks in similarly defined populations are the preferred measures (see Stein et al's Figure 1 for a clear pictorial representation of the disparity in rates). The reported odds ratios of 0.20 (vs. whites) and 0.15 (vs. African Americans) are remarkable for ethnic risk differences in U.S. populations and are even more convincing by their similarity in sex- and age-specific subgroups. The odds ratios were virtually identical in a prospective analysis of hospitalizations for venous thromboembolism (6Klatsky A.L. Armstrong M.A. Poggi J. Risk of pulmonary embolism and/or deep venous thrombosis in Asian Americans.Am J Cardiol. 2000; 85: 1334-1337Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar), which showed similarly low risk in each Asian American and Pacific Islander subset (e.g., Chinese, Filipinos, Japanese). For an indirect explanation to be responsible, the confounder would need to be strongly (≥5/1 odds ratio) associated with all Asian ethnicities and with venous thromboembolism.As explanations, we should consider possible lower prevalence of acquired venous thromboembolism risk traits in Asians. These traits consist of two groups (7White R.H. The epidemiology of venous thromboembolism.Circulation. 2003; 107: I4-I8Crossref PubMed Scopus (1750) Google Scholar, 8Anderson FA Jr, Spencer FA. Risk factors for venous thromboembolism. Circulation. 2003;17;107(Suppl 1):I9-I16Google Scholar): factors associated with increased venous stasis, such as obesity, immobility, trauma, surgery, travel, age, heart failure, or any proximal venous obstruction or compression, and factors associated with thrombophilia, such as oral contraceptive or hormone replacement use, pregnancy, obesity, cancer, antiphospholipid antibodies, various arteriopathies, and endothelial damage. In the report by White et al (5White R.H. Zhou H. Romano P.S. Incidence of idiopathic deep venous thrombosis and secondary thromboembolism among ethnic groups in California.Ann Intern Med. 1998; 128: 737-740Crossref PubMed Scopus (294) Google Scholar) of ethnic differences, only subjects with idiopathic venous thromboembolism were included, presumably minimizing the role of specific risk factors for venous thromboembolism. In the Kaiser Permanente prospective analysis (6Klatsky A.L. Armstrong M.A. Poggi J. Risk of pulmonary embolism and/or deep venous thrombosis in Asian Americans.Am J Cardiol. 2000; 85: 1334-1337Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar), the odds ratios were virtually identical in analyses adjusted for age alone and in those analyses also adjusted for sex, race, body mass index, marital status, education, smoking, alcohol, and a coronary disease risk/symptoms composite, thereby indicating a minor role for these potential confounders. The odds ratios in that study were also similar for U.S.– and foreign-born Asian Americans, which is evidence against a role of acculturation. In the National Hospitalization Discharge Survey data (4Stein PD, Kayali F, Olson RE, Milford CE. Pulmonary thromboembolism in Asian-Pacific islanders in the United States: analysis of data from the National Hospital Discharge Survey and the United States Bureau of the Census. Am J Med. 2004;116:435–442Google Scholar), the Asian/white disparity was independent of total hospitalization rates for the races. Thus, available data do not support lower prevalence of acquired venous thromboembolism traits in Asians as the explanation for lower risk.Could Asians have a higher prevalence of antithrombotic factors? An antiplatelet agent in Chinese foods called “mo-er” (black tree fungus) has been reported to cause bleeding, a condition known as Szechwan purpura (9Hammerschmidt D.E. Szechwan purpura.N Engl J Med. 1980; 302: 1191-1193Crossref PubMed Scopus (39) Google Scholar). Components in certain Chinese herbal drugs may also have antiplatelet effects (10Okuyama T. Shibata S. Hoson M. Effect of oriental plant drugs on human platelet aggregation III. Effect of Chinese drug “Xiebai” on human platelet aggregation.Planta Medica. 1986; 3: 171-175Crossref PubMed Scopus (52) Google Scholar). However, it is unclear whether these are differences likely to be major factors in more acculturated Asian American persons (e.g., Japanese) and antiplatelet agents are not highly effective for preventing venous thromboembolism. Further indirect evidence of an antithrombotic tendency could be inferred from the lower warfarin dose needed by Asians (4Stein PD, Kayali F, Olson RE, Milford CE. Pulmonary thromboembolism in Asian-Pacific islanders in the United States: analysis of data from the National Hospital Discharge Survey and the United States Bureau of the Census. Am J Med. 2004;116:435–442Google Scholar, 6Klatsky A.L. Armstrong M.A. Poggi J. Risk of pulmonary embolism and/or deep venous thrombosis in Asian Americans.Am J Cardiol. 2000; 85: 1334-1337Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar), a difference that could have a genetic or dietary basis.Genetic factors probably play a role in the low risk of venous thromboembolism among Asians. As Stein et al discuss, Asians have low prevalence of the thrombophilic trait known as factor V Leiden mutation and may have lower mean levels of fibrinogen, factor VIIc, and factor VIIIc. Another thrombophilic genetic variant, thrombin gene G20210A, is associated with increased plasma prothrombin and also may be less prevalent in Asians. Homocystinemia, a partially genetically determined promoter of venous thromboembolism, is not less prevalent in Asians.Pure coincidence is an unlikely explanation of the coexistence in Asians of low prevalence of venous thromboembolism and a virtual absence of factor V Leiden (factor V Arg506gln). This mutation is the most common cause of resistance to activated protein C, a key component of the natural anticoagulant system. Present in approximately 5% of whites and rare in Asians, factor V Leiden homozygosity carries a 50- to 100-fold more risk of venous thromboembolism (7White R.H. The epidemiology of venous thromboembolism.Circulation. 2003; 107: I4-I8Crossref PubMed Scopus (1750) Google Scholar, 8Anderson FA Jr, Spencer FA. Risk factors for venous thromboembolism. Circulation. 2003;17;107(Suppl 1):I9-I16Google Scholar). Although heterozygosity has much less predictive power, there may be synergistic risk in concert with other risk traits for venous thromboembolism, as evidenced by reports of 35-fold increased venous thromboembolism with the use of oral contraceptive agents, and a 13-fold increase with hormone replacement therapy. At present, only a minority of all venous thromboembolism can be attributed to known genetic procoagulant traits (7White R.H. The epidemiology of venous thromboembolism.Circulation. 2003; 107: I4-I8Crossref PubMed Scopus (1750) Google Scholar), although this proportion is more substantial in juvenile, idiopathic, and recurrent episodes (7White R.H. The epidemiology of venous thromboembolism.Circulation. 2003; 107: I4-I8Crossref PubMed Scopus (1750) Google Scholar, 8Anderson FA Jr, Spencer FA. Risk factors for venous thromboembolism. Circulation. 2003;17;107(Suppl 1):I9-I16Google Scholar). It is unlikely that all relevant genetic traits have been uncovered or that knowledge is complete about interactions with other modifiers of the risk of venous thromboembolism. A rapid expansion of knowledge in these areas is likely.Pulmonary embolism and deep venous thrombosis are generally considered two parts of the same pathologic process, and the term venous thromboembolism is used to denote both. Yet we are intrigued by Stein et al's suggestion that symptomatic events may be relatively more rare in Asians than asymptomatic deep venous thrombosis (4Stein PD, Kayali F, Olson RE, Milford CE. Pulmonary thromboembolism in Asian-Pacific islanders in the United States: analysis of data from the National Hospital Discharge Survey and the United States Bureau of the Census. Am J Med. 2004;116:435–442Google Scholar). It has been speculated (7White R.H. The epidemiology of venous thromboembolism.Circulation. 2003; 107: I4-I8Crossref PubMed Scopus (1750) Google Scholar) that Asians may have more efficient inactivation of activated protein C or greater fibrinolytic activity than whites. In the Kaiser Permanente data, with 188,937 person-years of follow-up among 13,593 Asians, there was not a single hospitalization with a primary discharge diagnosis of pulmonary embolism (6Klatsky A.L. Armstrong M.A. Poggi J. Risk of pulmonary embolism and/or deep venous thrombosis in Asian Americans.Am J Cardiol. 2000; 85: 1334-1337Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar). This is another area in need of investigation.Is this lower risk of venous thromboembolism likely to be associated with analogous protection against atherothrombotic events and with increased tendency to bleed? Except for homocystinemia, intrinsic thrombophilic factors are different for the arterial and venous systems. In Kaiser Permanente data, only Chinese had a lower risk of myocardial infarction than whites (1Friedman G.D. Primer of Epidemiology.5th ed. McGraw-Hill, New York, New York2004Google Scholar), but Asian American and Pacific Islander groups in general had lower risk of ischemic stroke (11Klatsky A.L. Armstrong M.A. Sidney S. Friedman G.D. Alcohol drinking and risk of ischemic stroke.Am J Cardiol. 2001; 88: 703-706Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar) and an almost two-fold higher risk of hemorrhagic stroke (12Klatsky A.L. Armstrong M.A. Sidney S. Friedman G.D. Alcohol drinking and risk of hemorrhagic stroke.Neuroepidemiology. 2002; 21: 115-122Crossref PubMed Scopus (71) Google Scholar). Asian American and Pacific Islanders have increased risk of hospitalization for upper gastrointestinal bleeding (relative risk = 1.6; confidence interval: 1.2 to 2.2), although there are little more than hints of the presence of an increased bleeding tendency among Asians (A. L. Klatsky, MD, unpublished data, 2003).Definitive answers about initiation and duration of anticoagulant therapy in Asians must await evidence from studies specifically in Asian populations. We agree with Stein et al (4Stein PD, Kayali F, Olson RE, Milford CE. Pulmonary thromboembolism in Asian-Pacific islanders in the United States: analysis of data from the National Hospital Discharge Survey and the United States Bureau of the Census. Am J Med. 2004;116:435–442Google Scholar) that, for clinicians who treat Asians, it would be prudent to require high diagnostic certainty of venous thromboembolism before starting anticoagulation therapy and to be wary of using anticoagulants for prophylaxis against venous thromboembolism in borderline situations. Perhaps, for Asians, a point or two might be deducted from venous thromboembolism probability scores (13Fedullo P.F. Tapson V.F. Clinical practice. The evaluation of suspected pulmonary embolism.N Engl J Med. 2003; 349: 1247-1256Crossref PubMed Scopus (321) Google Scholar). Although explanations remain largely speculative, the low risk of venous thromboembolism in Asians has important research and clinical implications and is not an esoteric curiosity. The study of ethnic disparities in the incidence and prevalence of disease is a productive area of observational epidemiology. Explanations, often complex, can include both genetic and environmental influences. The well-established higher prevalence of systemic hypertension and its complications in African Americans compared with whites is an excellent example. Explanatory factors include genetic predisposition plus differences in lifestyle traits, the prevalence of obesity, psychosocial stress, and accessibility to medical care associated with socioeconomic status (1Friedman G.D. Primer of Epidemiology.5th ed. McGraw-Hill, New York, New York2004Google Scholar). Increased risk of a condition in an ethnic group often leads to fruitful searches for new predisposing traits. Even without established explanations, known high prevalence properly leads to public health measures to control known risk factors and to ascertain and manage patients with the disease. Reduced risk in a specific population can result from lower prevalence of acquired or genetic risk traits, but such a finding raises the intriguing possibility of protective factors. One example is that persons with pigmented skin have lower risk of basal cell skin cancer, a condition that is 100 times more common in whites than in blacks (1Friedman G.D. Primer of Epidemiology.5th ed. McGraw-Hill, New York, New York2004Google Scholar). Use of sun-screening agents for skin protection can be viewed as an attempt to simulate the genetic protection afforded by pigmented skin. The rapidly growing Asian American and Pacific Islander population in the United States (12.1 million in the 2000 census) is a potential gold mine for the study of environmental and genetic traits that influence the incidence and expression of disease. Included among Asian American and Pacific Islanders are ethnic groups with diverse cultures, languages, countries of origin, and immigration histories. Some, such as Vietnamese, Filipinos, and South Asians (Indians, Pakistanis, Sri Lankans, and Bangladeshi) are largely foreign born. The Chinese population in the United States includes a substantial proportion of recent immigrants as well as people born here, and the Japanese have the highest proportion of U.S.–born people, with many third and fourth generation family members in the United States. Although considered at high risk for certain cancers, tuberculosis, and hepatitis B, Asian American and Pacific Islanders have been relatively understudied epidemiologically until recently. Observational data suggest interethnic disparities in the risk of coronary disease (high in South Asians, low in Chinese [2Klatsky A.L. Tekawa I. Armstrong M.A. Sidney S. The risk of hospitalization for ischemic heart disease among Asian Americans in Northern California.Am J Public Health. 1994; 84: 1672-1675Crossref PubMed Scopus (46) Google Scholar]), hypertension (high in Filipinos [3Angel A. Armstrong M.A. Klatsky A.L. Blood pressure among Asian-Americans living in Northern California.Am J Cardiol. 1989; 64: 237-240Abstract Full Text PDF PubMed Scopus (16) Google Scholar]), and hemorrhagic stroke (high in Filipinos and Japanese) (A. L. Klatsky, MD, unpublished data, 2003). Behavioral traits presumably play an important role in these inter-Asian ethnic disparities, but the relative roles of genetic and environmental traits remain unclear. In this issue of The American Journal of Medicine, Stein et al (4Stein PD, Kayali F, Olson RE, Milford CE. Pulmonary thromboembolism in Asian-Pacific islanders in the United States: analysis of data from the National Hospital Discharge Survey and the United States Bureau of the Census. Am J Med. 2004;116:435–442Google Scholar) use National Hospital Discharge Survey data to provide robust confirmation of previous reports (5White R.H. Zhou H. Romano P.S. Incidence of idiopathic deep venous thrombosis and secondary thromboembolism among ethnic groups in California.Ann Intern Med. 1998; 128: 737-740Crossref PubMed Scopus (294) Google Scholar, 6Klatsky A.L. Armstrong M.A. Poggi J. Risk of pulmonary embolism and/or deep venous thrombosis in Asian Americans.Am J Cardiol. 2000; 85: 1334-1337Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar, 7White R.H. The epidemiology of venous thromboembolism.Circulation. 2003; 107: I4-I8Crossref PubMed Scopus (1750) Google Scholar) suggesting lower prevalence of venous thromboembolism among all Asian American and Pacific Islanders compared with whites or African Americans. These investigators point out that comparison of differences in the prevalence of venous thromboembolism in clinical reports may be confounded by disparate exclusion and inclusion criteria for case ascertainment. Reported studies involving Asian American and Pacific Islanders variably use autopsy, primary (or all) hospitalization diagnoses, several clinical endpoints, and diagnostic tests of differing sensitivity and specificity. We agree that adjusted rates or relative risks in similarly defined populations are the preferred measures (see Stein et al's Figure 1 for a clear pictorial representation of the disparity in rates). The reported odds ratios of 0.20 (vs. whites) and 0.15 (vs. African Americans) are remarkable for ethnic risk differences in U.S. populations and are even more convincing by their similarity in sex- and age-specific subgroups. The odds ratios were virtually identical in a prospective analysis of hospitalizations for venous thromboembolism (6Klatsky A.L. Armstrong M.A. Poggi J. Risk of pulmonary embolism and/or deep venous thrombosis in Asian Americans.Am J Cardiol. 2000; 85: 1334-1337Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar), which showed similarly low risk in each Asian American and Pacific Islander subset (e.g., Chinese, Filipinos, Japanese). For an indirect explanation to be responsible, the confounder would need to be strongly (≥5/1 odds ratio) associated with all Asian ethnicities and with venous thromboembolism. As explanations, we should consider possible lower prevalence of acquired venous thromboembolism risk traits in Asians. These traits consist of two groups (7White R.H. The epidemiology of venous thromboembolism.Circulation. 2003; 107: I4-I8Crossref PubMed Scopus (1750) Google Scholar, 8Anderson FA Jr, Spencer FA. Risk factors for venous thromboembolism. Circulation. 2003;17;107(Suppl 1):I9-I16Google Scholar): factors associated with increased venous stasis, such as obesity, immobility, trauma, surgery, travel, age, heart failure, or any proximal venous obstruction or compression, and factors associated with thrombophilia, such as oral contraceptive or hormone replacement use, pregnancy, obesity, cancer, antiphospholipid antibodies, various arteriopathies, and endothelial damage. In the report by White et al (5White R.H. Zhou H. Romano P.S. Incidence of idiopathic deep venous thrombosis and secondary thromboembolism among ethnic groups in California.Ann Intern Med. 1998; 128: 737-740Crossref PubMed Scopus (294) Google Scholar) of ethnic differences, only subjects with idiopathic venous thromboembolism were included, presumably minimizing the role of specific risk factors for venous thromboembolism. In the Kaiser Permanente prospective analysis (6Klatsky A.L. Armstrong M.A. Poggi J. Risk of pulmonary embolism and/or deep venous thrombosis in Asian Americans.Am J Cardiol. 2000; 85: 1334-1337Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar), the odds ratios were virtually identical in analyses adjusted for age alone and in those analyses also adjusted for sex, race, body mass index, marital status, education, smoking, alcohol, and a coronary disease risk/symptoms composite, thereby indicating a minor role for these potential confounders. The odds ratios in that study were also similar for U.S.– and foreign-born Asian Americans, which is evidence against a role of acculturation. In the National Hospitalization Discharge Survey data (4Stein PD, Kayali F, Olson RE, Milford CE. Pulmonary thromboembolism in Asian-Pacific islanders in the United States: analysis of data from the National Hospital Discharge Survey and the United States Bureau of the Census. Am J Med. 2004;116:435–442Google Scholar), the Asian/white disparity was independent of total hospitalization rates for the races. Thus, available data do not support lower prevalence of acquired venous thromboembolism traits in Asians as the explanation for lower risk. Could Asians have a higher prevalence of antithrombotic factors? An antiplatelet agent in Chinese foods called “mo-er” (black tree fungus) has been reported to cause bleeding, a condition known as Szechwan purpura (9Hammerschmidt D.E. Szechwan purpura.N Engl J Med. 1980; 302: 1191-1193Crossref PubMed Scopus (39) Google Scholar). Components in certain Chinese herbal drugs may also have antiplatelet effects (10Okuyama T. Shibata S. Hoson M. Effect of oriental plant drugs on human platelet aggregation III. Effect of Chinese drug “Xiebai” on human platelet aggregation.Planta Medica. 1986; 3: 171-175Crossref PubMed Scopus (52) Google Scholar). However, it is unclear whether these are differences likely to be major factors in more acculturated Asian American persons (e.g., Japanese) and antiplatelet agents are not highly effective for preventing venous thromboembolism. Further indirect evidence of an antithrombotic tendency could be inferred from the lower warfarin dose needed by Asians (4Stein PD, Kayali F, Olson RE, Milford CE. Pulmonary thromboembolism in Asian-Pacific islanders in the United States: analysis of data from the National Hospital Discharge Survey and the United States Bureau of the Census. Am J Med. 2004;116:435–442Google Scholar, 6Klatsky A.L. Armstrong M.A. Poggi J. Risk of pulmonary embolism and/or deep venous thrombosis in Asian Americans.Am J Cardiol. 2000; 85: 1334-1337Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar), a difference that could have a genetic or dietary basis. Genetic factors probably play a role in the low risk of venous thromboembolism among Asians. As Stein et al discuss, Asians have low prevalence of the thrombophilic trait known as factor V Leiden mutation and may have lower mean levels of fibrinogen, factor VIIc, and factor VIIIc. Another thrombophilic genetic variant, thrombin gene G20210A, is associated with increased plasma prothrombin and also may be less prevalent in Asians. Homocystinemia, a partially genetically determined promoter of venous thromboembolism, is not less prevalent in Asians. Pure coincidence is an unlikely explanation of the coexistence in Asians of low prevalence of venous thromboembolism and a virtual absence of factor V Leiden (factor V Arg506gln). This mutation is the most common cause of resistance to activated protein C, a key component of the natural anticoagulant system. Present in approximately 5% of whites and rare in Asians, factor V Leiden homozygosity carries a 50- to 100-fold more risk of venous thromboembolism (7White R.H. The epidemiology of venous thromboembolism.Circulation. 2003; 107: I4-I8Crossref PubMed Scopus (1750) Google Scholar, 8Anderson FA Jr, Spencer FA. Risk factors for venous thromboembolism. Circulation. 2003;17;107(Suppl 1):I9-I16Google Scholar). Although heterozygosity has much less predictive power, there may be synergistic risk in concert with other risk traits for venous thromboembolism, as evidenced by reports of 35-fold increased venous thromboembolism with the use of oral contraceptive agents, and a 13-fold increase with hormone replacement therapy. At present, only a minority of all venous thromboembolism can be attributed to known genetic procoagulant traits (7White R.H. The epidemiology of venous thromboembolism.Circulation. 2003; 107: I4-I8Crossref PubMed Scopus (1750) Google Scholar), although this proportion is more substantial in juvenile, idiopathic, and recurrent episodes (7White R.H. The epidemiology of venous thromboembolism.Circulation. 2003; 107: I4-I8Crossref PubMed Scopus (1750) Google Scholar, 8Anderson FA Jr, Spencer FA. Risk factors for venous thromboembolism. Circulation. 2003;17;107(Suppl 1):I9-I16Google Scholar). It is unlikely that all relevant genetic traits have been uncovered or that knowledge is complete about interactions with other modifiers of the risk of venous thromboembolism. A rapid expansion of knowledge in these areas is likely. Pulmonary embolism and deep venous thrombosis are generally considered two parts of the same pathologic process, and the term venous thromboembolism is used to denote both. Yet we are intrigued by Stein et al's suggestion that symptomatic events may be relatively more rare in Asians than asymptomatic deep venous thrombosis (4Stein PD, Kayali F, Olson RE, Milford CE. Pulmonary thromboembolism in Asian-Pacific islanders in the United States: analysis of data from the National Hospital Discharge Survey and the United States Bureau of the Census. Am J Med. 2004;116:435–442Google Scholar). It has been speculated (7White R.H. The epidemiology of venous thromboembolism.Circulation. 2003; 107: I4-I8Crossref PubMed Scopus (1750) Google Scholar) that Asians may have more efficient inactivation of activated protein C or greater fibrinolytic activity than whites. In the Kaiser Permanente data, with 188,937 person-years of follow-up among 13,593 Asians, there was not a single hospitalization with a primary discharge diagnosis of pulmonary embolism (6Klatsky A.L. Armstrong M.A. Poggi J. Risk of pulmonary embolism and/or deep venous thrombosis in Asian Americans.Am J Cardiol. 2000; 85: 1334-1337Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar). This is another area in need of investigation. Is this lower risk of venous thromboembolism likely to be associated with analogous protection against atherothrombotic events and with increased tendency to bleed? Except for homocystinemia, intrinsic thrombophilic factors are different for the arterial and venous systems. In Kaiser Permanente data, only Chinese had a lower risk of myocardial infarction than whites (1Friedman G.D. Primer of Epidemiology.5th ed. McGraw-Hill, New York, New York2004Google Scholar), but Asian American and Pacific Islander groups in general had lower risk of ischemic stroke (11Klatsky A.L. Armstrong M.A. Sidney S. Friedman G.D. Alcohol drinking and risk of ischemic stroke.Am J Cardiol. 2001; 88: 703-706Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar) and an almost two-fold higher risk of hemorrhagic stroke (12Klatsky A.L. Armstrong M.A. Sidney S. Friedman G.D. Alcohol drinking and risk of hemorrhagic stroke.Neuroepidemiology. 2002; 21: 115-122Crossref PubMed Scopus (71) Google Scholar). Asian American and Pacific Islanders have increased risk of hospitalization for upper gastrointestinal bleeding (relative risk = 1.6; confidence interval: 1.2 to 2.2), although there are little more than hints of the presence of an increased bleeding tendency among Asians (A. L. Klatsky, MD, unpublished data, 2003). Definitive answers about initiation and duration of anticoagulant therapy in Asians must await evidence from studies specifically in Asian populations. We agree with Stein et al (4Stein PD, Kayali F, Olson RE, Milford CE. Pulmonary thromboembolism in Asian-Pacific islanders in the United States: analysis of data from the National Hospital Discharge Survey and the United States Bureau of the Census. Am J Med. 2004;116:435–442Google Scholar) that, for clinicians who treat Asians, it would be prudent to require high diagnostic certainty of venous thromboembolism before starting anticoagulation therapy and to be wary of using anticoagulants for prophylaxis against venous thromboembolism in borderline situations. Perhaps, for Asians, a point or two might be deducted from venous thromboembolism probability scores (13Fedullo P.F. Tapson V.F. Clinical practice. The evaluation of suspected pulmonary embolism.N Engl J Med. 2003; 349: 1247-1256Crossref PubMed Scopus (321) Google Scholar). Although explanations remain largely speculative, the low risk of venous thromboembolism in Asians has important research and clinical implications and is not an esoteric curiosity.