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Elevation of Plasma Von Willebrand Factor and Tumor Necrosis Factor- [Alpha] in Obese Subjects and Their Reduction By the Low Molecular Weight Heparin Tinzaparin

Posted on: Tuesday, 22 November 2005, 03:02 CST

By Mousa, S A

Aim. Increased plasma-soluble von Willebrand factor (vWF) level, a marker of vascular endothelial cell dysfunction, is a predictor of atherosclerotic cardiovascular disease. We compared associations between vWF level and markers of inflammation as well as the effects of LMWH in obese as compared to healthy human subjects.

Methods. Plasma samples were obtained from healthy volunteers (n=32) and obese subjects (n=12) before and after administration of a single subcutaneous dose of tinzaparin, given at 75 IU/kg once a day, a deep vein thrombosis prophylaxis dose. Plasma samples were analyzed for vWF and tumor necrosis factor-α (TNF-α) using specific and sensitive ELISA.

Results. Obese subjects showed relatively higher plasma levels of TNF-α compared with normal-weight subjects. Regression analysis showed that plasma vWF levels to be directly associated with the presence of higher plasma levels of TNF-α in these obese subjects. Tinzaparin significantly reduced elevated plasma levels of both vWF and TNFα levels (P<0.01).

Conclusion. Plasma values of vWF and TNF-α are higher in obese than in normal-weight individuals. Treatment with tinzaparin lowers plasma levels of TNF-α in both obese and normal-weight subjects. The levels of vWF were higher in obese subjects than in normal-weight ones, which might be due to the higher levels of circulating TNF-α. Tinzaparin reduced vWF levels in these obese subjects.

[Int Angiol 2005;24:278-81]

Key words: von Willebrand factor - Tumor necrosis factor-α Heparin - Low molecular weight heparin - Obesity - Inflammation - Vascular, endothelium.

Obesity is associated with an increased risk of atherosclerotic cardiovascular disease. Changes in the coagulation system, such as platelet hyperaggregability, hypercoagulability, and hypofibrinolysis, may contribute to atherosclerotic processes in obese persons.1

The association between increased body mass index and waist-to- hip ratio and prothrombotic factors and impaired fibrinolysis suggests that obesity is a risk factor whose effect is mediated in part by a prothrombotic state and driven by proinflammatory stimuli.2

A marker of cellular injury is von Willebrand factor (vWF), which is produced in megakaryocyte and endothelial cells, stored in the ( granule of platelets and the Weibl-Palade body of endothelial cells, and is present in plasma and vascular sub-endothelium.3 This multimeric protein plays a pivotal role in both hemostasis and pathological intravascular thrombosis. Epidemiological studies have demonstrated that levels of vWF to be associated with the onset of atherosclerosis, the incidence of vascular diseases, and its acute thrombotic complications. Increased plasma levels of vWF have been documented in patients suffering from systemic inflammatory response syndrome.4 The increased plasma level of vWF is due to endothelial cell insult, activation and degranulation.

Clinical investigations for the low molecular weight heparin (LMWH) enoxaparin or dalteparin versus unfractionated heparin (UFH) in patients with unstable angina or non-ST segment elevation acute myocardial infarction (ARMADA study and other studies) demonstrated superior clinical outcome with the LMWH over UFH.5

Plasma levels of vWF, a marker of vascular endothelial cell dysfunction, are predictive of atherosclerotic cardiovascular disease and have been reported to be elevated in obese individuals.1,6 Tumor necrosis factor-α (TNF-oc), a marker of inflammation, has also been postulated to play a role in endothelial dysfunction in obesity.7,8

TABLE I.-Effect of tinzapariu (75 IU/kg, SC, q.d.) on plasma vWF in obese and normal-weight subjects.

TABLE II.-Effect of tinzaparin (75 IU/kg, SC) on plasma TNF- in obese and normal-weight subjects.

Figure 1.-Effect of tinzaparin on plasma von Willebrand factor in obese and normal-weight subjects.

Figure 2.-Effect of tinzaparin on plasma tumor necrosis factor- α in obese and normal-weight subjects.

TABLE III.-Effect of tinzaparin (175 IU/kg, SC) on day 1 and 2 on plasma TNF- in obese subjects.

We determined the levels of plasma-soluble vWF and TNF-α in obese subjects and in healthy subjects of normal body weight before and after treatment with the LMWH tinzaparin.9 The effects of the LMWHs tinzaparin and enoxaparin on release of vWF from human umbilical vein endothelial cells in response to oxidized low density lipoprotein (LDL) or endotoxin were also evaluated.

Materials and methods

Subjects

A total of 32 healthy volunteers of normal body weight and 12 obese subjects were studied. Obesity was defined a body mass index >30 kg/m^sup 2^. Male and female obese subjects aged 18 to 70 years weighing between 100 and 160 kg were eligible for the study.10

Dosing

Tinzaparin was administered as single subcutaneous (SC) doses:

* 75 IU/kg body weight (deep vein thrombosis(DVT(prophylaxis dose) in obese subjects;

* 175 IU/kg body weight (DVT treatment dose) in normal healthy subjects.

In one comparison, obese subjects received 75 IU/kg body weight and normal-weight subjects received 175 IU/kg body weight (Tables I and II; Figures 1 and 2). In another comparison, both groups of subjects received 175 IU/kg body weight (Table III). Samples were evaluated 12 and 24 h after two exposures to the 175-IU/kg dose.

Evaluation of plasma samples

Plasma samples were obtained before and after the administration of tinzaparin and analyzed for vWF activity (IU/mL) and levels of TNF-α (pg/mL) with the use of ELISAs.

Results

Effects of tinzaparin on plasma levels ofvWF

At baseline, mean plasma levels of vWF were higher in obese subjects compared with normalweight subjects (Table I). SC administration of 75 IU/kg tinzaparin significantly reduced plasma levels of vWF in obese subjects (Table I; Figure 1).

Effects of tinzaparin on plasma levels of TNF-α

At baseline, obese subjects had higher plasma levels of TNF- α when compared with normalweight subjects (Table II). Administration of 75 IU/kg tinzaparin reduced the level of TNF- α in obese subjects at 2 h postadministration (Figure 2). There was no significant change in normalweight subjects.

The 175-IU/kg dose of tinzaparin also reduced levels of TNF- α at 12 and 24 h postadministration for both first and second exposures to tinzaparin (Table III).

Association between levels of vWFand TNF-α

Regression analysis showed that plasma vWF levels were directly associated with the presence of higher plasma levels of TNF-α in these obese subjects.

Discussion

Pharmacodynamic study with tinzaparin examined weight-based dosing in heavyweight/obese subjects. Single doses (175 and 75 IU/ kg) were administered SC to 37 healthy heavy-weight subjects (101- 165 kg; 26-61 kg/m^sup 2^). Anti-Xa and antiIIa activities were consistent over these body weight and body mass index (BMI) ranges, indicating that tinzaparin pharmacodynamics are not influenced by body weight or BMI. Tinzaparin was well tolerated, although injection site bruising was commonly reported. SC tinzaparin dosing in heavy or obese patients is appropriate based on body weight alone; the dose need not be capped at a maximal absolute dose.10

Recent data showed that monocytes in obese subjects are in a proinflammatory state with an increase in intranuclear NF-κ binding, a decrease in I&946;, and an increase in the transcription of proinflammatory genes regulated by NF-κB.11

Conclusions

Plasma values of vWF and TNF-α are greater in obese subjects compared with those of normal body weight. Treatment with tinzaparin results in reduced plasma levels of vWF and TNF-α in obese subjects.

The higher levels of vWF in obese subjects compared with normal- weight subjects may be attributed to higher levels of circulating TNF-α. The reduction of levels of vWF and TNF-α in obese subjects after treatment with tinzaparin warrants further clinical study.

Received May 11, 2005.

Accepted for publication June 14, 2005.

References

1. Mertens I, Van Gaal LF. Obesity, haemostasis, and the fibrinolytic system. Obes Rev 2002;3:85-101.

2. Rosito GA, D'Agostino RB, Massaro J, Lipinska I, Mittleman MA, Sutherland P et al. Association between obesity and a prothrombotic state: the Framingham Offspring Study. Thromb Haemost 2004;91:683- 9.

3. Sugimoto M, Miyata S. Functional property of von Willebrand factor under flowing blood. Int J Hematol 2002:75:19-24.

4. McGill SN, Ahmed NA, Christou NV. Increased plasma von Willebrand factor in the systemic inflammatory response syndrome is derived from generalized endothelial cell activation. Crit Care Med 1998;26:296300.

5. Montalescot G, Bal-dit-Sollier C, Chibedi D, Collet JP, Soulat T, Dalby M et al; ARMADA Investigators. Comparison of effects on markers of blood cell activation of enoxaparin, dalteparin, and unfractionated heparin in patients with unstable angina pectoris or non-ST-segment elevation acute myocardial infarction (the ARMADA study). Am J Cardiol 2003;91:925-30.

6. Blann AD, Bushell D, Davies A, Faragher EB, Miller JP, McCollum CN. von Willebrand factor, the endothelium, and obesity. Int J Obes Relat Metab Disord 1993;17: 723-5.

7. Winkler G, Lakatos P, Salamon F, Nagy Z, Speer G, Kovacs M et al.. Elevated serum TNF-_ level as a link between endothelial dysfunction and insulin resi\stance in normotensive obese patients. Diabet Med 1999; 16: 207-11.

8. Xu H, Uysal KT, Becherer JD, Arner P, hotamisligil GS. Altered tumor necrosis factor-alpha (TNF-_) processing in adipocytes and increased expression of transmembane TNF-_ in'obesity. Diabetes 2002;51:1876-83.

9. Mousa SA. The low molecular weight heparin, tinzaparin, in thrombosis and beyond. Cardiovasc Drug Rev 2002;20:199-216.

10. Hainer JW, Barren JS, Assaid CA, Fossler MJ, Cox DS, Leathers T et al. Dosing in heavy-weight/obese patients with the LMWH, tinzaparin: a pharmacodynamic study. Thromb Haemost 2002:87:817-23.

11. Ghanim H, Aljada A, Hofmeyer D, Syed T, Mohanty P, Dandona P. Circulating mononuclear cells in the obese are in a proinflammatory state. Circulation 2004; 110:156471.

S. A. MOUSA

Albany College of Pharmacy, Albany, NY, USA

Address reprint requests to: S. A. Mousa, PhD, MBA, FACC, FACB, Pharmaceutical Research Institute at Albany College of Pharmacy, 106 New Scotland Avenue, Albany, NY 12208, USA. E-mail: mousas@acp.edu

Copyright Edizioni Minerva Medica Sep 2005

Source: International Angiology

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