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Increased levels of plasma tissue factor pathway inhibitor in patients with glioblastoma and intracerebral metastases
From Neurological Research, 6/1/03 by Gerlach, Rudiger

Tissue Factor Pathway Inhibitor (TFPI) prevents further participation of Tissue Factor (TF) in the coagulation process by forming a stable quaternary complex of TF-FVIIa-FXa-TFPI. Recently, plasma TFPI level were found to be elevated in patients with malignant disease outside the brain. Therefore the aim of this study was to investigate the TFPI plasma level in patients with primary brain tumors and intracerebral metastases. From May 2000 to December 2001 the total tissue factor pathway inhibitor antigen (TFPI) was preoperatively determined in blood samples of 225 patients with primary or metastatic brain tumors. Tumor histology classified as benign (WHO grade I and II) and malignant (WHO grade III and IV, intracerebral metastases) was correlated to plasma TFPI-levels. Plasma TFPI was significantly higher in patients with malignant tumors including intracerebral metastasis compared to benign tumors (80.1 + or - 34.31 versus 64.3 + or - 25.8 ng ml^sup -1^ [p

[Neurol Res 2003; 25: 335-338]

Keywords: TFPI; serine proteinase inhibitors; neoplasm; craniotomy; neurosurgical procedure


Coagulation is initiated by the binding of plasma factor VIIa (VIIa) to the cell surface receptor tissue factor (TF), which serves as the cofactor for the ligand protease VIIa in the activation of macromolecular substrate factors X and IX. The catalytic function of the TF-VIIa complex is regulated by a specific serine protease inhibitor, which is the tissue factor pathway inhibitor (TFPI). TFPI prevents further participation of TF in the coagulation process by forming a stable quaternary complex of TF-FVIIa-FXa-TFPI, resulting in greatly accelerated inhibition of the initiation complex as compared to free inhibitor alone. Human TFPI is a modular protein comprised of three Kunitz type domains, the first domain inhibits VIIa complexed to TF while the second domain inhibits Xa. No direct protease inhibiting functions have been demonstrated for the third domain1. A primary site of TFPI synthesis is the endothelium and the endothelium-bound TFPI contributes to the antithrombotic potential of the vascular endothelium.

Increased plasma TFPI levels were found in patients with septicemia, disseminated intravascular coagulation and solid tumors outside the brain, whereas patients with leukemia and related blood malignancies have levels within normal range2. The median plasma levels of the Xa-TFPI complex were also significantly higher in patients with solid tumors, compared to patients with hematological malignancy and healthy controls3. However, there are no data about TFPI levels in patients with brain tumors so far. Therefore the aim of this study was to correlate the plasma TFPI levels in patients with primary and metastatic brain tumors to the histopathological type and the grade of malignancy according to the WHO tumor grading system.


Patients (n = 225) with intracranial lesions were included in this study. All patients underwent treatment at the Neurosurgical Department, Johann Wolfgang Goethe-University between June 2000 and December 2001. Ninety-two (40.9%) of the 225 patients were male and 133 (59.1%) were female with a mean age of 53.1+ or -14.5 and 55.7+ or -13.4 years, respectively. Informed consent was obtained from each patient prior to blood sampling.

Each patient underwent pre-operative contrast enhanced computerized tomography (CT) or magnetic resonance imaging (MRI) to diagnose the lesion. According to the location, size and number of the intracranial lesion the surgical treatment strategy was defined. If possible complete tumor removal was achieved. If the tumor infiltrated eloquent brain regions a partial tumor removal or stereotactic biopsy was performed to establish histological diagnosis. Table 1 summarizes patients' characteristics and the histological diagnosis of the intracranial lesions. After histopathological investigation tumors were classified according to the WHO grading system (grade I and II benign and grade III and IV malignant).

Laboratory investigations

Blood was taken at the day of admission for routine pre-operative analysis using the Sarstedt Monovette system for all blood sampling procedures (Sarstedt, Numbrecht, Germany). Citrate blood samples were centrifugated for 40 min at 4000 rpm at room temperature and stored at 70[degrees]C until TFPI assay was performed. Determination of plasma TFPI antigen was done using the lmubind total TFPI ELISA kit (American Diagnostica Inc. Greenwich, CT, USA) according to the manufacturer's instruction.

Statistical analysis

Statistical analysis was performed using commercially available software (SPSS Inc., Chicago, IL, USA, Version 10.0). Data of TFPI are given as mean + or - standard deviation (SD). To compare pre-operative plasma TFPI levels between different patient groups, the unpaired Student t-test was used. Probability values


In this study 225 patients were included (Table 1). There was a slight predominance of female (59.1%) compared to male (40.9%) but no statistically significant difference for total plasma TFPI was found between female and male patients (69.9+ or -33.7 versus 72.9+ or - 25.9 ng ml^sup -1^).

Plasma TFPI was significantly higher in patients with malignant tumors including intracerebral metastasis compared to benign tumors (80.1+ or -34.3 versus 64.3+ or - 25.8 ng ml^sup -1^ [p

Patients with glioblastoma multiforme and with intracerebral metastasis had a significant higher plasma TFPI level compared to patients with astrocytomas, neurinomas, pituitary tumors and hemangiopericytomas (p


Tissue factor pathway inhibitor and malignancy

Tissue factor (TF) is a cell surface glycoprotein of factor VII/VIIa that initiates the coagulation protease cascade and it is expressed in some tumor cells. TF belongs to the interferon receptor family, and it is one of the early immediate genes, suggesting that TF has a biological function other than hemostasis. lmmunohistochemical analysis of 44 surgical specimens revealed that 19 (95%) of 20 glioblastomas, 12 (86%) of 14 anaplastic astrocytomas and 1 (10%) of 10 benign giiomas were moderately or strongly positive for TF. Therefore TF expression was correlated to the grade of malignancy in giiomas, suggesting that TF may participate in cell growth4-6. Beside its procoagulant activity TF may influence tumor metastasis, since in melanoma cells the expression of TF appears to correlate with hematogenous metastasis7, which is thought to be independent of the role of TF in coagulation8. Tumor cell adhesion and subsequent migration was found to be enhanced by binding of TFPI to the extracellular domain of TF9. An alternative mechanism by which TFPI may promote invasion and metastasis of cancer cells could involve inhibition of other serine proteases known to help cellular migration on the extracellular matrix10. In addition to promoting metastasis, TF has been implicated in the organization and integrity of the vessel wall during angiogenesis in a hemostasis independent manner11, especially in tumor associated angiogenesis12. Tissue factor levels have not been determined in this series and therefore no correlation of TF to plasma TFPI and the grade of malignancy can be done. Although TFPI levels were significantly higher in patients with malignant brain tumors, a considerable variation of plasma TFPI was seen within the groups of patients with the same histopathological diagnosis. The range of TFPI varies in each group and high plasma level occurred in patients with benign tumors and also low TFPI levels were detected in patients with malignant tumors. However, the significant increased plasma TFPI in patients with malignant brain tumors supports the hypothesis that TF and TFPI may be involved in such processes as metastatic spreading, tumor growth and angiogenesis. The increased level of TFPI in patients with meningiomas, which is significantly lower compared to glioblastoma, but not to metastasis may also reflect the role of TFPI in angiogenesis, since other tumors as neurinomas or pituitary tumors are less vascularized and have also a lower plasma TFPI.

Tissue factor pathway inhibitor and thrombosis

Venous thromboembolism is a well known complication of cancer and is a common problem in neurosurgical patients13-15. This appears to be partly due to shedding of the procoagulant TF into the circulation16,17 from malignant tumors of various organs18,19 with subsequent activation of coagulation20. This leads to a hypercoagulable state which could be shown to be associated with elevated TFPI in patients with solid systemic tumors2,3.

None of the patients presented in this study developed a thrombosis during the post-operative course in the hospital. Therefore no correlation of plasma TFPI level and DVT could be established in this series. It was recently shown that total TFPI antigen levels were significantly lower in patients with deep venous thrombosis compared to controls21. The increased levels of TFPI in patients with glioblastoma and metastases may reflect a compensatory mechanism in controlling coagulation activation and may therefore lead to a reduction of hypercoagulability especially in patients with malignancy.

In immunohistochemical studies of normal human tissues, TFPI was found to be restricted to the microvascular endothelium and megakaryocytes18. TFPI is distributed in three pools in vivo. About 80%-85% is associated with the endothelial cell surface, ~10% circulates in plasma primarily in association with lipoproteins and a small amount in free form and about 3% is found in platelets22,23. Therefore high levels of the inhibitory FXa-TFPI complex in cancer patients may protect against microthrombosis and the endothelium bound TFPI is thought to contribute, in part, towards maintaining the lumen in an antithrombotic state.


This is the first study showing the relation of plasma TFPI levels to the histological type of brain tumor in neurosurgical patients. Patients with malignant tumors especially patients with glioblastoma and brain metastases have a significantly higher plasma TFPI level compared to benign brain tumors. Further studies are needed to determine the clinical relevance of these findings with regard to clinical events like DVT or intratumoral hemorrhage.


1 Bajaj MS, Birktoft JJ, Steer SA, Bajaj SP. Structure and biology of tissue factor pathway inhibitor. Thromb Haemost 2001; 86: 959-972

2 Iversen N, Lindahl AK, Abildgaard U. Elevated TFPI in malignant disease: Relation to cancer type and hypercoagulation. Br J Haematol 1998; 102: 889-895

3 Iversen N, Lindahl AK, Abildgaard U. Elevated plasma levels of the factor Xa-TFPI complex in cancer patients. Thromb Res 2002; 105: 33-36

4 Hamada K, Kuratsu J, Saitoh Y, Takeshima H, Nishi T, Ushio Y. Expression of tissue factor in glioma. Noshuyo Byori 1996; 13: 115-118

5 Hamada K, Kuratsu J, Saitoh Y, Takeshima H, Nishi T, Ushio Y. Expression of tissue factor correlates with grade of malignancy in human glioma. Cancer 1996; 77: 1877-1883

6 Guan M, Su B, Lu Y. Quantitative reverse transcription-PCR measurement of tissue factor mRNA in glioma. Mol Biotechnol 2002; 20: 123-129

7 Osterud B, Bajaj MS, Bajaj SP. Sites of tissue factor pathway inhibitor (TFPI) and tissue factor expression under physiologic and pathologic conditions. On behalf of the Subcommittee on Tissue factor Pathway Inhibitor (TFPI) of the Scientific and Standardization Committee of the ISTH. Thromb Haemost 1995; 73: 873-875

8 Bromberg ME, Konigsberg WH, Madison JF, Pawashe A, Garen A. Tissue factor promotes melanoma metastasis by a pathway independent of blood coagulation. Proc Natl Acad Sci USA 1995; 92: 8205-8209

9 Fischer EG, Riewald M, Huang HY, Miyagi Y, Kubota Y, Mueller BM, Ruf W. Tumor cell adhesion and migration supported by interaction of a receptor-protease complex with its inhibitor. J CHn Invest 1999; 104: 1213-1221

10 Rao CN, Gomez DE, Woodley DT, Thorgeirsson UP. Partial characterization of novel serine proteinase inhibitors from human umbilical vein endothelial cells. Arch Biochem Biophys 1 995; 319: 55-62

11 Carmeliet P, Mackman N, Moons L, Luther T, Gressens P, Van Vl, Demunck H, Kasper M, Breier G, Evrard P, Muller M, Risau W, Edgington T, Collen D. Role of tissue factor in embryonic blood vessel development. Nature 1996; 383: 73-75

12 Zhang Y, Deng Y, Luther T, Muller M, Ziegler R, Waldherr R, Stern DM, Nawroth PP. Tissue factor controls the balance of angiogenic and antiangiogenic properties of tumor cells in mice. J Clin Invest 1994; 94: 1320-1327

13 Sawaya R, Zuccarello M, Elkalliny M, Nishiyama H. Postoperative venous thromboembolism and brain tumors: Part I. Clinical profile. J NeuroOncol 1992; 14: 119-125

14 Thoron L, Arbit E. Hemostatic changes in patients with brain tumors. J NeroOncol 1994; 22: 87-100

15 Hamilton MG, Hull RD, Pineo GF. Venous thromboembolism in neurosurgery and neurology patients: A review. Neurosurgery 1994; 34: 280-296

16 Lindahl AK, Sandset PM, Abildgaard U. Indices of hypercoagulation in cancer as compared with those in acute inflammation and acute infarction. Haemostasis 1990; 20: 253-262

17 Rao LV. Tissue factor as a tumor procoagulant. Cancer Metastasis Rev 1992; 11:249-266

18 Werling RW, Zacharski LR, Kisiel W, Bajaj SP, Memoli VA, Rousseau SM. Distribution of tissue factor pathway inhibitor in normal and malignant human tissues. Thromb Haemost 1993; 69: 366-369

19 Callander NS, Varki N, Rao LV. lmmunohistochemical identification of tissue factor in solid tumors. Cancer 1992; 70: 1194-1201

20 Kakkar AK, DeRuvo N, Chinswangwatanakul V, Tebbutt S, Williamson RC. Extrinsic-pathway activation in cancer with high factor VIIa and tissue factor. Lancet 1995; 346: 1004-1005

21 Amini-Nekoo A, Futers TS, Moia M, Mannucci PM, Grant PJ, Ariens RA. Analysis of the tissue factor pathway inhibitor gene and antigen levels in relation to venous thrombosis. Br J Haematol 2001; 113: 537-543

22 Broze GJ Jr, Lange GW, Duffin KL, MacPhail L. Heterogeneity of plasma tissue factor pathway inhibitor. Blood Coag Fibrinolysis 1994; 5: 551-559

23 Bajaj, MS, Ameri A, Bajaj SP. Tissue factor pathway inhibitor - A regulator of tissue factor-induced coagulation. In: Green D, ed. Anticoagulants: Physiologic, Pathologic and Pharmacologic, Florida: CRC Press, 1994: pp. 41-65

Rudiger Gerlach, Timm Scheuer, Martina Bohm*, Jurgen Beck, Alina Woszczyk, Andreas Raabe, Inge Scharrer* and Volker Seifert

Department of Neurosurgery, Johann Wolfgang Goethe-University, Frankfurt/Main

*Department of Medicine, Johann Wolfgang Goethe-University, Frankfurt/Main, Germany

Correspondence and reprint requests to: Rudiger Gerlach, MD, Department of Neurosurgery, Johann Wolfgang Goethe-University, Schleusenweg 2-16, 60528 Frankfurt/Main, Germany.

[] Accepted for publication February 2003.

Copyright Forefront Publishing Group Jun 2003
Provided by ProQuest Information and Learning Company. All rights Reserved

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