Venous Thromboembolism with Chronic Liver Disease

CLINICAL RESEARCH STUDY

Venous Thromboembolism with Chronic Liver Disease Tarek Saleh, MD,a Fadi Matta, MD,b Fadi Alali, MD,a Paul D. Stein, MDb,c a

Department of Internal Medicine, St. Joseph Mercy Oakland Hospital, Pontiac, Mich; bDepartment of Internal Medicine and Research and Advanced Studies Program, College of Osteopathic Medicine, Michigan State University, East Lansing; cDepartment of Research, St. Mary Mercy Hospital, Livonia, Mich.

ABSTRACT BACKGROUND: Patients with chronic liver disease have both antithrombotic and prothrombotic coagulation abnormalities. Published data conflict on whether patients with chronic liver disease have a high or low prevalence of venous thromboembolism. METHODS: The number of patients discharged from hospitals throughout the US with a diagnostic code for chronic alcoholic and chronic nonalcoholic liver disease from 1979 through 2006 was obtained from the National Hospital Discharge Survey. We compared prevalences of venous thromboembolism among patients with chronic alcoholic liver disease and chronic nonalcoholic liver disease. RESULTS: Among 4,927,000 hospitalized patients with chronic alcoholic liver disease from 1979-2006, the prevalence of venous thromboembolism was 0.6%, compared with 0.9% among 4,565,000 hospitalized patients with chronic nonalcoholic liver disease. CONCLUSION: The prevalence of venous thromboembolism in hospitalized patients with chronic liver disease, both alcoholic and nonalcoholic, was low. The prevalence of venous thromboembolism was higher in those with chronic non-alcoholic liver disease, but the difference was small and of no clinical consequence. Based on the literature, both showed a lower prevalence of venous thromboembolism than in hospitalized patients with most other medical diseases. It may be that both chronic alcoholic liver disease and chronic nonalcoholic liver disease have protective antithrombotic mechanisms, although the mechanisms differ. © 2011 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2011) 124, 64-68 KEYWORDS: Chronic hepatitis; Cirrhosis; Deep venous thrombosis; Liver disease; Pulmonary embolism; Venous thromboembolism

Patients with liver disease have both antithrombotic and prothrombotic coagulation abnormalities.1-4 Antithrombotic abnormalities include impaired production of vitamin K-dependent procoagulant factors, including factors II, V, VII, IX, X, and XI.1 Patients with serious liver disease often have prolonged clotting times, reduced clearance of fibrin degradation products, and thrombocytopenia.2 However, numerous prothrombotic factors may counteract the hypocoagulable state. Patients with liver disease may have decreased production of

Funding: None. Conflict of Interest: None of the authors have any financial or other potential conflicts of interest relative to the data in this manuscript. Authorship: All authors had access to the data and played a role in writing this manuscript. Requests for reprints should be addressed to Paul D. Stein, MD, Michigan State University, College of Osteopathic Medicine, Venous Thromboembolism Research Unit, St. Joseph Mercy Oakland Hospital, 44405 Woodward Avenue, Pontiac, MI 48341-5023. E-mail address: [email protected]

0002-9343/$ -see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2010.08.014

protein C, protein S, thrombomodulin, and tissue plasminogen activator.1 Other prothrombotic factors include lupus anticoagulant, activated protein C resistance, PT20210A mutation, Factor V Leiden, MTHFR mutation,3 increased levels of factor VIII,4 and antiphospholipid antibodies.5-9 The latter may result from ethanol-induced free radical formation, oxidative liver injury, and the development of antibodies targeting complexes between oxidized cardiolipin and beta 2 glycoprotein.5 Patients with alcoholic liver disease have higher levels of anticardiolipin antibodies than patients with nonalcoholic liver disease associated with hepatitis C,10 and these also appear to have thrombogenic properties.11 Patients with nonalcoholic liver disease, on the other hand, have endothelial dysfunction3,12 and a prothrombotic state that appears to be through the systemic release of proinflammatory and procoagulant factors from the liver such as C-reactive protein, plasminogen activator inhibitor-1, interleukin-6, fibrinogen, and other proinflammatory cytokines.13 The reported prevalence of venous thromboembolism in patients with chronic liver disease has varied. Some showed

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that “serious” liver disease was associated with a 90% identified.18 In using the National Hospital Discharge Sur2 decrease in risk for venous thromboembolism. The prevavey database, first-listed diagnoses are retrievable, and we lence of venous thromboembolism in hospitalized patients presumed the first-listed diagnosis was the principal with cirrhosis was approximately 0.5%-0.8%.14,15 Some diagnosis. found no reduced risk of venous thromboembolism in paThe International Classification of Diseases, 9th Revitients with chronic liver disease.16 sion, Clinical Modification codes Others showed that patients with used to identify patients with chronic cirrhosis of the liver had an apalcoholic liver disease, chronic nonalCLINICAL SIGNIFICANCE proximately doubled risk of vecoholic liver disease, pulmonary emnous thromboembolism compared bolism, and deep venous thrombosis ● Hospitalized patients with chronic liver diswith the general population.17 are shown in Table 1. ease (alcoholic and nonalcoholic) had a low Some observed venous thromboprevalence of venous thromboembolism. embolism in 6.3% of hospitalized Statistical Analysis and ● Patients with chronic alcoholic liver disease patients with chronic liver Methodological had a lower prevalence of venous thrombodisease.15 Considerations In view of uncertainty about embolism than those with nonalcoholic Differences of prevalence were the risk of venous thromboemboliver disease, but the difference was small based on chi-squared. InStat verlism in patients with chronic liver and clinically unimportant. sion 3.0 (GraphPad Software, San disease, we assessed the prevaDiego, Calif) was used to calcu● Hospitalized patients with chronic liver lence-based data from the Nalate P value. disease (alcoholic and nonalcoholic) had tional Hospital Discharge Sur18 a lower prevalence of venous thromboemvey. We stratified patients bolism than medical patients hospitalized according to whether they had RESULTS chronic alcoholic liver disease or with most other diseases. Demographics chronic nonalcoholic liver disease. Patients with chronic alcoholic liver disease were younger than those with chronic nonalcoholic liver disease (52 ⫹ 13 years METHODS vs 60 ⫹ 15 years [mean ⫹ standard deviation], respectively) The number of patients aged ⱖ18 years discharged from (P ⬍.0001). Alcoholic liver disease patients had a higher short-stay hospitals with a diagnostic code of chronic alcoproportion of men (72%) than patients with nonalcoholic holic liver disease and chronic nonalcoholic liver disease from 1979 through 2006 was obtained from the National liver disease (47%) (P ⬍.0001). Among those with alcoHospital Discharge Survey.18 Among these patients, the holic liver disease, 62% were white, compared with 70% number with pulmonary embolism, deep venous thromboamong those with nonalcoholic liver disease (P ⬍.0001). sis, or venous thromboembolism, defined as pulmonary embolism or deep venous thrombosis or both, was determined. Chronic Alcoholic Liver Disease The National Hospital Discharge Survey consists of data Among 4,927,000 hospitalized patients with chronic alcoobtained annually from approximately 270,000 sampled inholic liver disease from 1979-2006, the prevalence of pulpatient records from about 500 nonfederal short-stay hosmonary embolism was 0.1%, the prevalence of deep venous pitals (average length of stay ⬍30 days) in 50 states and the 18 thrombosis was 0.5%, and the prevalence of venous thromDistrict of Columbia. The National Hospital Discharge boembolism was 0.6% (Figure, Table 2). Survey samples about 8% of short-stay nonfederal hospitals and about 1% of discharges. We identified all hospitalized patients with chronic alcoholic liver disease and chronic nonalcoholic liver disease Table 1 ICD-9-CM Codes Used who had associated pulmonary embolism, deep venous Disease of Procedure ICD-9 Codes thrombosis, or venous thromboembolism. We also identified those with a principal diagnosis of chronic alcoholic Chronic alcoholic liver disease 571.0, 571.2 Chronic nonalcoholic liver 571.4, 571.5, 571.6, 571.8, liver disease and chronic nonalcoholic liver disease who had disease 571.9 associated pulmonary embolism, deep venous thrombosis, Pulmonary embolism 415.1, 634.6, 635.6, 636.6, or venous thromboembolism. In the National Hospital Dis637.6, 638.6, 673.2 charge Survey, discharge diagnoses listed on the face sheet Deep venous thrombosis 451.1, 451.2, 451.8, 451.9, of the medical record are transcribed in the order listed. The 453.2, 453.4, 453.8, 453.9, principal diagnosis is the condition chiefly responsible for 671.3, 671.4, 671.9 occasioning the admission. The coded diagnosis identified ICD-9-CM ⫽ International Classification of Diseases, 9th Revision, as the first listed diagnosis on the face sheet is considered Clinical Modification. the principal diagnosis if the principal diagnosis cannot be

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Figure Prevalence from 1979-2006 of pulmonary embolism (PE), deep venous thrombosis (DVT), and venous thromboembolism (VTE) in hospitalized adult patients with alcoholic liver disease and nonalcoholic liver disease (all differences P ⬍.0001).

Among patients hospitalized with a principal diagnosis of chronic alcoholic liver disease from 1979-2006, the prevalence of secondary venous thromboembolism was 0.6% (5000 of 885,000).

Chronic Nonalcoholic Liver Disease Among 4,565,000 hospitalized patients with chronic nonalcoholic liver disease from 1979-2006, the prevalence of pulmonary embolism was 0.3%, the prevalence of deep

Table 2 Prevalence of Venous Thromboembolism (VTE) in Patients with Chronic Alcoholic and Nonalcoholic Liver Disease According to Age

Age (Years) 18-39 40-59 ⱖ60 All ages Sex Men Women Race Whites African Americans

Chronic Alcoholic Liver Disease and VTE n/N (%)

Chronic Non-Alcoholic Liver Disease and VTE n/N (%)

* 15,000/2667,000 (0.6) 12,000/1,407,000 (0.9) 30,000/4,927,000 (0.6)

5000/485,000 (1.0) 15,000/1,652,000 (0.9) 22,000/2,429,000 (0.9) 42,000/4,565,000 (0.9)

24,000/3,553,000 (0.7) 7000/1,374,000 (0.5)

18,000/2,125,000 (0.8) 24,000/2,440,000 (1.0)

21,000/3,054,000 (0.7) 5000/698,000 (0.7)

28,000/3,208,000 (0.9) 6000/398,000 (1.5)

*Insufficient data.

venous thrombosis was 0.6%, and the prevalence of venous thromboembolism was 0.9% (Figure, Table 2). Prevalences of pulmonary embolism, deep venous thrombosis, and venous thromboembolism were lower than in patients with chronic alcoholic liver disease (all P ⬍.0001) (Figure, Table 2). Among patients hospitalized with a principal diagnosis of chronic nonalcoholic liver disease from 1979-2006, the prevalence of secondary venous thromboembolism was 0.4% (5000 of 1,130,000).

DISCUSSION Hospitalized patients with chronic liver disease had a prevalence of venous thromboembolism that ranged from 0.6% to 0.9%, depending on whether the patients had chronic alcoholic liver disease or chronic nonalcoholic liver disease. Patients with chronic alcoholic liver disease had a lower prevalence of venous thromboembolism than patients with chronic nonalcoholic liver disease, but the difference, although statistically significant, was not clinically important. The prevalences of venous thromboembolism in patients with chronic alcoholic liver disease and with chronic nonalcoholic liver disease were similar to the prevalences shown by others with cirrhosis, 0.5%-0.8%.14,15 The prevalences of venous thromboembolism in patients with alcoholic liver disease compared with patients with nonalcoholic liver disease were lower in both men and women. Age-adjusted rates of deep venous thrombosis and unadjusted rates of deep venous thrombosis are higher in women than men.19

Saleh et al Table 3

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Prevalence of Deep Venous Thrombosis and Venous Thromboembolism in Selected Medical Illnesses

Medical Illness

Prevalence of DVT (%)

Prevalence of VTE (%)

Age Group

Reference (First Author)

Non-alcoholic liver disease Alcoholic liver disease Cancer of pancreas Cancer of brain Myeloproliferative, lymphatic/ hematopoietic Cancer of stomach Obesity Cancer of prostate Rheumatoid arthritis Cancer of colon Ulcerative colitis Nephrotic syndrome Hemorrhagic stroke Hypothyroidism Human immunodeficiency virus Heart failure Crohn disease COPD Diabetes mellitus Ischemic stroke Sickle cell disease

0.6 0.5 3.9 3.7 3.0

0.9 0.6 5.1 4.9 3.4

ⱖ18 years ⱖ18 years All ages All ages All ages

Present study Present study Stein20 Stein20 Stein20

2.2 2.0 1.7 1.6 1.5 1.5 1.5 1.4 1.4 1.4 1.0 1.1 1.1 1.0 0.7 0.6

2.6 ⫺ 2.2 2.3 2.1 1.9 ⫺ 1.9 1.8 1.7 1.6 1.2 1.6 1.4 1.2 ⫺

All ages All ages All ages All ages All ages All ages ⬎1 month All ages All ages ⱖ18 years All ages All ages ⬎20 years All ages All ages All ages

Stein20 Stein21 Stein20 Matta22 Stein20 Saleh23 Kayali24 Skaf25 Danescu26 Matta27 Beemath28 Saleh23 Stein29 Stein30 Skaf25 Stein31

COPD ⫽ chronic obstructive pulmonary disease; DVT ⫽ deep venous thrombosis; VTE⫽ venous thromboembolism.

Patients with chronic liver disease, irrespective of whether alcoholic or nonalcoholic, had lower prevalence of deep venous thrombosis and venous thromboembolism than patients hospitalized with most other medical illnesses, based on previously reported data obtained with the National Hospital Discharge Survey20-31 (Table 3). Differences in the prevalence shown in patients with chronic liver disease and those with other diseases would be underestimated when comparing the present investigation with investigations that were based on hospitalized patients of all ages. The inclusion of infants and children in the population of hospitalized patients would lower the calculated prevalences among hospitalized patients of deep venous thrombosis and venous thromboembolism. Strengths of our investigation are the large number of patients identified with alcoholic liver disease and venous thromboembolism (30,000 patients) and nonalcoholic liver disease with venous thromboembolism (42,000 patients). Additional strengths are the diversity of the population in terms of age, race, sex, and geographic regions (all 50 states and the District of Columbia), the extensive duration of observation (28 years), and the meticulous and statistically robust methods of sampling.18 Limitations include lack of data on the severity of the liver disease, the proportion with ascites, hepatic decompensation, reason for hospitalization, proportion of patients hospitalized more than once, and the basis for the diagnosis of liver disease. There were not enough patients to stratify on the basis of cirrhosis. In conclusion, the prevalence of venous thromboembolism in hospitalized patients with chronic liver disease, both

alcoholic and nonalcoholic, was low. Both showed a lower prevalence of venous thromboembolism than in hospitalized patients with most other medical diseases. It may be that both chronic alcoholic liver disease and chronic nonalcoholic liver disease have protective antithrombotic mechanisms, although the mechanisms differ.

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20. Stein PD, Beemath A, Meyers FA, et al. Incidence of venous thromboembolism in patients hospitalized with cancer. Am J Med. 2006; 119:60-68. 21. Stein PD, Beemath A, Olson RE. Obesity as a risk factor in venous thromboembolism. Am J Med. 2005;118: 978-980. 22. Matta F, Singala R, Yaekoub AY, et al. Risk of venous thromboembolism with rheumatoid arthritis. Thromb Haemost. 2009;101:134-138. 23. Saleh T, Matta F, Yaekoub AY, Danescu SC, Stein PD. Risk of venous thromboembolism with inflammatory bowel disease. Clin Appl Thromb Hemost. 2010 March 8 [Epub ahead of print]. 24. Kayali F, Najjar R, Aswad F, et al. Venous thromboembolism in patients hospitalized with nephrotic syndrome. Am J Med. 2008;121: 226-230. 25. Skaf E, Stein PD, Beemath A, et al. Venous thromboembolism in patients with ischemic and hemorrhagic stroke. Am J Cardiol. 2005; 96:1731-1733. 26. Danescu L, Badshah A, Danescu SC, et al. Venous thromboembolism in patients hospitalized with thyroid dysfunction. Clin Appl Thromb Hemost. 2009;15:676-680. 27. Matta F, Yaekoub AY, Stein PD. Human immunodeficiency virus infection and risk of venous thromboembolism. Am J Med Sci. 2008; 336:402-406. 28. Beemath A, Stein PD, Skaf E, et al. Risk of venous thromboembolism in patients hospitalized with heart failure. Am J Cardiol. 2006;98:793-795. 29. Stein PD, Beemath A, Meyers FA, et al. Pulmonary embolism and deep venous thrombosis in patients hospitalized with chronic obstructive pulmonary disease. J Cardiovasc Med. 2007;8:253-257. 30. Stein PD, Goldman J, Matta F, et al. Diabetes mellitus and risk of venous thromboembolism. Am J Med Sci. 2009;337:259-264. 31. Stein PD, Beemath A, Meyers FA, et al. Deep venous thrombosis and pulmonary embolism in patients hospitalized with sickle cell disease. Am J Med. 2006;119:897-901.