**Venous Thromboembolism Prophylaxis for the Medical Patient**

John A. Heit, M.D.

From the Divisions of Cardiovascular Diseases (Section of Vascular
Diseases) and Hematology (Section of Hematology Research), Department of
Internal Medicine; and the Divisions of Hematopathology and Laboratory
Genetics, Department of Laboratory Medicine and Pathology; Mayo Clinic
and College of Medicine, Rochester, MN.

Short title: VTE-Medical Patient Prophylaxis

Funded, in part, by grants from the National Institutes of Health
(HL-66216, HL-83141, HL-83797, U-195457, and AR-30582), and the Centers
for Disease Control and Prevention (TS-1255), U.S. Public Health
Service; and by Mayo Foundation.

Correspondence to: Dr. John A. Heit, Hematology Research, Stabile 660,
Mayo Clinic, 200 First Street SW, Rochester, MN 55905; Telephone:
(507)284-4634; Facsimile: (507)266-9302; e-mail: .

Word Count: 1,015

© 2006 Mayo Foundation

**Introduction**

In order to reduce the occurrence ("incidence") of venous
thromboembolism, persons at risk must first be identified and the risk
exposure either avoided or modified. If the risk exposure cannot be
modified, then appropriate primary prophylaxis must be provided to
reduce the venous thromboembolism risk.

As has already been discussed, patient age and gender significantly
influences the risk of venous thromboembolism; the incidence increases
dramatically with advancing age, and the incidence is higher among women
during childbearing years, and higher among men after age 50 years.^1^
Additional independent risk factors for venous thromboembolism include
surgery, trauma, hospitalization for acute medical illness, nursing home
confinement, active cancer, neurological disease with leg weakness or
paralysis, prior blood clots within the superficial veins just under the
skin, and among women, oral contraceptives, pregnancy and the postpartum
period, and hormone therapy.^2-5^

Hospitalization, either for surgery or for an acute medical illness, is
increasingly recognized as a major risk factor for venous
thromboembolism. Compared to a non-hospitalized community resident, the
incidence of venous thromboembolism is increased over 150-fold when such
a person requires hospitalization.^6^ Of the more than 900,000 venous
thromboembolism events that occur each year in the US, over two-thirds
are related to recent hospitalization.^7^ This section will review risk
factors for venous thromboembolism among patients hospitalized for acute
medical illness, and the available pharmacologic and mechanical methods
for preventing venous thromboembolism in this high-risk subgroup.

**Venous Thromboembolism and Hospitalization for Acute Medical Illness**

Patients who are hospitalized for acute medical illness have over a
10-fold increased risk for venous thromboembolism (**Table 1**) .^2^
Hospitalization for acute medical illness accounts for over one-fifth of
the burden of venous thromboembolism disease occurring in the
community.^8^ Emerging information from recent research suggests that we
may be able to identify subsets of acute medical inpatients who are at
especially high risk for venous thromboembolism. In addition to older
age (e.g., \>75 years), a prior history of venous thromboembolism,
active cancer and an acute infection appear to increase the risk of
venous thromboembolism about 1.5- to 2-fold (**Table 2**).^9^ Additional
risk factors for a first-lifetime venous thromboembolism in the acute
medical inpatient included obesity (increasing body mass index
\[**BMI**\]), neurological disease with lower extremity weakness,
long-bone fracture, chronic renal disease, a prior superficial vein
thrombosis and prolonged immobilization such as while bedridden (**Table
3**).^10,11^ These characteristics can be used by physicians to stratify
acute medical inpatients into high- and low-risk for venous
thromboembolism.^12^

Venous thromboembolism risk among active cancer patients can be further
stratified by tumor site, presence of distant metastases and active
chemotherapy. Although all active cancer patients are at risk, the risk
appears to be higher for pancreatic cancer, lymphoma, malignant brain
tumors, cancer of the liver, leukemia, and colorectal and other
digestive cancers^13-15^ (**Table 4**), and for patients with distant
metastases.^16^ Cancer patients receiving immunosuppressive or cytotoxic
chemotherapy are at even higher risk for venous thromboembolism^2,16^,
including therapy with L-asparaginase^17^, thalidomide^18^ and other
angiogenesis inhibitors^19^, tamoxifen^11,20^ and erythropoietin.^21^

Nursing home residents also are at increased risk for venous
thromboembolism; the risk is increased over 2-fold.^2^ Confinement to a
nursing home accounts for over 13% of all venous thromboembolism
occurring in the community.^8^ However, in contrast to patients
hospitalized for acute medical illness, additional venous
thromboembolism risk factors do not seem to convey the same risk for
nursing home residents.^22^ For example, such common risk factors as
obesity, active cancer, neurological disease, fracture and infection do
not seem to increase the risk of venous thromboembolism among nursing
home residents. Additional studies will be required to identify
independent venous thromboembolism risk factors among nursing home
residents.

**Venous Thromboembolism Prophylaxis for Patients Hospitalized for Acute
Medical Illness**

*Pharmacologic Prophylaxis*

Parenteral pharmacologic prophylaxis agents that are available in the US
include unfractionated (standard) heparin \[**UFH**\],
low-molecular-weight heparin \[**LMWH**\], an indirect Factor Xa
inhibitor and direct Factor IIa (thrombin) inhibitors. Available LMWHs
include enoxaparin sodium (Lovenox) and dalteparin sodium (Fragmin) in
the US, and tinzaparin sodium (Innohep) in Canada, while the indirect
Factor Xa inhibitor fondaparinux (Arixtra) and the direct Factor IIa
(thrombin) inhibitors lepirudin (Refludan), argatroban and bivalirudin
(hirulog). The only effective oral pharmacologic prophylaxis agent
available in the US is warfarin sodium.

Low-dose UFH (e.g., 5000 units subcutaneously three times daily), LMWH
and fondaparinux are effective and safe as venous thromboembolism
prophylaxis for acutely ill medical inpatients.^23-27^ Both enoxaparin
and dalteparin are FDA-approved for prophylaxis in this population, and
while fondaparinux is not yet FDA-approved, one randomized clinical
trial has demonstrated it's efficacy and safety in this population.^27^
Recombinant hirudin (desirudin) and bivalirudin have been tested as
venous thromboembolism prophylaxis after major orthopedic surgery and
both appeared to be effective and safe.^28,29\ ^Although not
FDA-approved as prophylaxis for acutely-ill medical patients, lepirudin
and argatroban are effective as prophylaxis or therapy for
heparin-induced thrombocytopenia.^30^ In general, warfarin sodium is not
recommended as prophylaxis for acutely-ill medical patients. However,
such patients who are chronically anticoagulated with warfarin for other
indications (e.g., mechanical prosthetic heart valve, atrial
fibrillation) are protected against venous thromboembolism.

For acutely ill medical patients admitted to hospital with congestive
heart failure, severe respiratory disease, or who are confined to bed
and one additional risk factor, (active cancer, acute neurological
disease, inflammatory bowel disease), prophylaxis with UFH 5000 units
subcutaneously [three]{.underline} times daily or LMWH (enoxaparin or
dalteparin) according to recommended dose and schedule is
recommended.^23^

*Mechanical Prophylaxis Methods*

Mechanical prophylaxis methods prevent venous thromboembolism by
increasing venous outflow and preventing blood stasis within veins. This
is accomplished by delivering external pressure circumferentially around
the leg, with a gradation in pressure from relatively high around the
foot and lower leg to progressively less pressure up the leg. This
gradation in pressure may be relatively static (e.g., graduated
compression stocking) or intermittent (e.g., external pneumatic
compression). The venous foot pump delivers intermittent compression
just to the foot.

Mechanical prophylaxis methods have been demonstrated to be effective
and safe prophylaxis after several surgical procedures, and by
extrapolation, are recommended for prophylaxis of acutely-ill medical
patients for whom anticoagulant-based prophylaxis is
contraindicated.^23^ For these methods to be effective, the devices must
be properly fitted and applied to the legs, and they must remain on the
legs except during ambulation.

**References**

1.  Silverstein MD, Heit JA, Mohr DN, Petterson TM, O'Fallon WM, Melton,
    III LJ. Trends in the incidence of deep vein thrombosis and
    pulmonary embolism: A 25-year population-based, cohort study. Arch
    Intern Med 1998;158:585-593.

2.  Heit JA, Silverstein MD, Mohr DN, Petterson TM, O'Fallon WM, Melton
    LJ III: Risk factors for deep vein thrombosis and pulmonary
    embolism: a population-based case-control study. Arch Intern Med
    2000;160:809-815.

3.  Samama M-M for the Sirius Study Group. An epidemiologic study of
    risk factors for deep vein thrombosis in medical outpatients. Arch
    Intern Med 2000;160:3415-20.

4.  Gomes MPV, Deitcher SR. Risk of venous thromboembolic disease
    associated with hormonal contraceptives and hormone replacement
    therapy. Arch Intern Med 2004;164:1965-76.

5.  Heit JA, Kobbervig CE, James AH, Petterson TM, Bailey KR, Melton
    LJ III. Trends in the incidence of deep vein thrombosis and
    pulmonary embolism during pregnancy or the puerperium: A 30-year
    population-based study. Ann Intern Med 2005;143:697-706.

6.  Heit JA, Melton LJ III, Lohse CM, Petterson TM, Silverstein MD, Mohr
    DN, O'Fallon WM. Incidence of venous thromboembolism in hospitalized
    patients versus community residents. Mayo Clin Proc 2001;76:1102-10.

7.  Heit JA, Cohen AT, Anderson FA Jr. Estimated annual number of
    incident and recurrent, non-fatal and fatal venous thromboembolism
    (VTE) events in the US. Blood 2005;106(11):abstract #910, p. 267a.

8.  Heit JA, O\'Fallon WM, Petterson TM, et al. Relative impact of risk
    factors for deep vein thrombosis and pulmonary embolism: a
    population-based study. Arch Intern Med 2002;162:1245-8.

9.  Alikhan R, Cohen AT, Combe S, Samama MM, Desjardins L, Eldor A,
    Janbon C, Leizorovicz A, Olsson C-G, Turpie AGG. Risk factors for
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    illness. Arch Intern Med 2004;164:963-8.

10. Heit JA, Petterson TM, Bailey KR, Melton LJ III. Risk Factors For
    Venous Thromboembolism (VTE) Among Patients Hospitalized For Acute
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    Australia, August 2005. J Thromb Haemost 2005;3(suppl 1):abstract
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11. Heit JA, Farmer SA, Petterson TM, Bailey KR, Melton LJ III. Novel
    Risk Factors for Venous Thromboembolism: A Population-Based,
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12. Zakai NA, Wright J, Cushman M. Risk factors for venous thrombosis in
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    Haemost 2004; 2: 2156--61.

13. Heit JA, Petterson TM, Bailey KR, Melton LJ III. The influence of
    tumor site on venous thromboembolism risk among cancer patients: a
    population-based study (abstract 2596). Congress of the American
    Society of Hematology. Blood 2004;104 (11):711a.

14. Chew HK, Wun T, Harvey D, Zhou H, White RH. Incidence of venous
    thromboembolism and its effect on survival among patients with
    common cancers. Arch Intern Med 2006;166:458-464.

15. Stein PD, Beemath A, Meyers FA, Skaf E, Sanchez J, Olson RE.
    Incidence of venous thromboembolism in patients hospitalized with
    cancer. Amer J Med 2006;119:60-68.

16. Blom JW, Vanderschoot JPM, Oostindier MJ, Osanto S, van der Meer
    FJM, Rosendaal FR. Incidence of venous thrombosis in a large cohort
    of 66 329 cancer patients: results of a record linkage study. J
    Thromb Haemost 2006;4(3):529.

17. Kucek, O., H. Kwaan, et al. (1985). \"Thromboembolic complications
    associated with L-asparaginase therapy.\" [Cancer]{.underline} 55:
    702.

18. Zangari, M., E. Anaissie, et al. (2001). \"Increased risk of
    deep-vein thrombosis in patients with multiple myeloma receiving
    thalidomide and chemotherapy.\" [Blood]{.underline} 98(5):
    1614-1615.

19. Kuenen, B., L. Rosen, et al. (2002). \"Dose-finding and
    pharmacokinetic study of cisplatin, gemcitabine, and SU5416 in
    patients with solid tumors.\" [Journal of Clinical
    Oncology]{.underline} 20(6): 1657-1667.

20. Pritchard, K., A. Paterson, et al. (1996). \"Increased
    thromboembolic complications with concurrent tamoxifen and
    chemotherapy in a randomized trial of adjuvant therapy for women
    with breast cancer. National Cancer Institute of Canada Clinical
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21. Wun, T., L. Law, et al. (2003). \"Increased incidence of symptomatic
    venous thrombosis in patients with cervical carcinoma treated with
    concurrent chemotherapy, radiation, and erythropoietin.\"
    [Cancer]{.underline} 98: 1514-1520.

22. Petterson TM, Leibson CL, Heit JA, Bailey DR, Melton LJ III. Venous
    thromboembolism risk factors among nursing home residents: a
    population-based case-control study (abstract 2608). Congress of the
    American Society of Hematology. Blood 2004;104 (11):714a.

23. Geerts WH, Pineo GF, Heit JA, Bergqvist D, Lassen MR, Colwell CW,
    Ray JG. Prevention of Venous Thromboembolism: The Seventh ACCP
    Conference on Antithrombotic and Thrombolytic Therapy Chest 2004;126
    338S-400S.

24. Samama MM, Cohen AT, Darmon JY, et al. A comparison of enoxaparin
    with placebo for the prevention of venous thromboembolism in acutely
    ill medical patients. N Engl J Med 1999;341:793-800.

25. Leizorovicz A, Cohen AT, Turpie AG, Olsson CG, Vaitkus PT, Goldhaber
    SZ. PREVENT Medical Thromboprophylaxis Study Group. Randomized,
    placebo-controlled trial of dalteparin for the prevention of venous
    thromboembolism in acutely ill medical patients. Circulation
    2004;110(7):874-9.

26. Kucher N, Leizorovicz A, Vaitkus PT, Cohen AT, Turpie AG, Olsson CG,
    Goldhaber SZ, Efficacy and safety of fixed low-dose dalteparin in
    preventing venous thromboembolism among obese or elderly
    hospitalized patients: a subgroup analysis of the PREVENT trial.
    Arch Intern Med 2005;165(3):341-5.

27. Cohen AT, Davidson BL, Gallus AS, Lassen MR, Prins MH, Tomkowski W,
    Turpie AG, Egberts JF, Lensing AW. ARTEMIS Investigators. Efficacy
    and safety of fondaparinux for the prevention of venous
    thromboembolism in older acute medical patients: randomised placebo
    controlled trial. BMJ 2006;332(7537):325-9.

28. Eriksson BI, Wille-Jørgensen P, Kälebo P, et al. A comparison of
    recombinant hirudin with a low-molecular-weight heparin to prevent
    thromboembolic complications after total hip replacement. N Engl J
    Med. 1997;337:1329-35.

29. Ginsberg JS, Nurmohamed MT, Gent M, et al. Use of Hirulog in the
    prevention of venous thrombosis after major hip or knee surgery.
    Circulation. 1994;90:2385-9.

30. Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia:
    recognition, treatment, and prevention. The 7^th^ ACCP Conference on
    Antithrombotic and Thrombolytic Therapy. Chest
    2004;126(3):311S-337S.

**Table 1. Independent General Risk Factors for Venous Thromboembolism,
and the Population-Attributable Risk Associated with Each**

+-----------------------------------------------+----------+---------------+
| **Characteristic**                            | **OR\*** | **AR^†^ (%)** |
+-----------------------------------------------+----------+---------------+
|                                               |          |               |
+-----------------------------------------------+----------+---------------+
| Hospitalization for Acute Medical Illness     | 10.5     | 21.5          |
+-----------------------------------------------+----------+---------------+
|                                               |          |               |
+-----------------------------------------------+----------+---------------+
| Nursing Home Confinement                      | 2.3      | 13.3          |
+-----------------------------------------------+----------+---------------+
| Active Malignant Neoplasm                     | 5.2      | 6.4           |
|                                               |          |               |
| Without chemotherapy                          | 9.7      | 11.6          |
|                                               |          |               |
| With chemotherapy                             |          |               |
+-----------------------------------------------+----------+---------------+
| Central Venous Catheter/Transvenous Pacemaker | 5.9      | 9.1           |
+-----------------------------------------------+----------+---------------+
| Neurological Disease with Extremity Paresis   | 6.1      | 6.9           |
+-----------------------------------------------+----------+---------------+
|                                               |          |               |
+-----------------------------------------------+----------+---------------+
| Prior Superficial Vein Thrombosis             | 3.8      | 5.4           |
+-----------------------------------------------+----------+---------------+
|                                               |          |               |
+-----------------------------------------------+----------+---------------+

\*Odds Ratio

**^†^**Population-Attributable Risk

Heit, et al. Arch Intern Med 2000

Heit, et al. Arch Intern Med 2002

**Table 2. Independent Risk Factors for Venous Thromboembolism Among
Patients Hospitalization for Acute Medical Illness (MEDENOX)**

  ----------------------------- -------- ------------- -------------
  **Characteristic**            **OR**   **95% CI**    **P-value**
                                                       
  Age \> 75 years               1.03     1.00, 1.06    0.0001
                                                       
  Cancer                        1.62     0.93, 2.75    0.08
  Previous VTE                  2.06     1.10, 2.75    0.02
  Acute Infectious Disease      1.74     1.12, 10.14   0.02
                                                       
  Chronic Respiratory Disease   0.60     0.38, 0.92    0.02
                                                       
  ----------------------------- -------- ------------- -------------

Samama, et al. Arch Intern Med 2004

**Table 3. Independent Risk Factors for Venous Thromboembolism Among
Patients Hospitalized for Acute Medical Illness\*(Olmsted County, MN)**

  ------------------------------------------------ -------- ------------- -------------
  **Characteristic**                               **OR**   **95% CI**    **P-value**
                                                                          
  Age (per 10 years increase in age)               1.23     1.08, 1.40    0.001
                                                                          
  Body Mass Index (kg/m^2^; per 2-fold increase)   2.73     1.52, 4.92    \<0.001
  Neurological Disease with Extremity Paresis      5.07     2.13, 12.07   \<0.001
  Fracture                                         4.06     1.62, 10.14   0.003
  Chronic Renal Disease                            3.70     1.08, 12.67   0.037
  Central Venous Catheter                          3.30     1.63, 6.70    \<0.001
  Prior Superficial Vein Thrombosis                2.46     1.19, 5.11    0.016
                                                                          
  Immobility Requiring Physical Therapy            2.30     1.30, 4.05    0.004
                                                                          
  ------------------------------------------------ -------- ------------- -------------

\*After controlling for event year and active cancer.

Heit, et al. J Thromb Haemost 2005

**Table 4. The Relative Risk of Venous Thromboembolism by Tumor Site**

  ---------------------- -------- ------------
  **Tumor Type**         **RR**   **95% CI**
                                  
                                  
                                  
  Pancreatic             37.0     19.7, 63.2
                                  
  Lymphoma               31.8     17.8, 52.4
  Brain                  26.6     5.5, 77.9
  Liver                  24.0     2.9, 86.7
  Leukemia               21.0     9.0, 41.3
  Other digestive        17.0     4.6, 43.5
  Other gynecologic      14.1     5.7, 29.1
  Multiple myeloma       12.3     1.5, 44.4
  Bladder                11.7     4.7, 24.2
  Breast                 11.5     6.8, 18.1
  Colon/rectal           10.9     6.8, 16.6
  Ovary                  10.6     1.3, 38.1
  Lung                   10.4     6.1, 16.4
  Prostate               9.8      6.1, 15.0
                                  
  Remaining Cancers^†^   5.1      2.3, 9.7
                                  
  ---------------------- -------- ------------

Heit, et al. Blood 2004