Prostate-Specific Antigen, Prostate Cancer, and Disorders of Hemostasis

 

 Buy Article Permissions and Reprints

ABSTRACT

Prostate cancer is the most prevalent malignancy in men and the third leading cause of cancer deaths worldwide. Disorders of hemostasis are commonplace in patients with prostate cancer and include disseminated intravascular coagulation, venous thromboembolism, acute coronary syndrome, and postsurgical bleeding. These hemostatic disorders contribute to the mortality and morbidity of prostate cancer. The leading mechanisms proposed to underlie prostate cancer-related coagulopathies are thought to be a hyperexpression of tissue factor, cancer procoagulant, and platelet-activating factor, which is then accompanied by release of large amounts of both prothrombotic and profibrinolytic substances into the bloodstream. Given the generally accepted notion that prostate-specific antigen (PSA) represents an important biomarker in prostate cancer diagnostics, large population screenings were initiated for early detection of cancer. However, recent clinical and economic drawbacks have been recently raised, including evidence that screening exposes patients to a significant risk of both overdiagnosis and overtreatment. Nevertheless, several lines of evidence suggest that PSA may have tumor-suppressing activities. Despite being a member of the vast kallikrein family, which actively interplays with the coagulation cascade, the role of PSA in the pathogenesis of hemostatic disorders observed in prostate cancer patients remains circumstantial and speculative. However, observations that the levels of this cancer marker tend to correlate positively with those of several markers of thrombin generation, and with postsurgical bleeding as well as with coronary atherosclerosis and negative outcomes of myocardial infarction, raise a new and intriguing scenario regarding the pathophysiological role of this serine protease.

REFERENCES

• 1 Kraut H, Frey Ek, Werle E. Der Nachweis eines Kreislaufhormon in de Pankreasdruse.  Hoppe Seylers Z Physiol Chem. 1930;  189 97-106
  PubMedGoogle Scholar
• 2 Werle E. Zur Kenntnis des haushalts des Kallikreins.  Biochem Z. 1934;  269 415-434
  PubMedGoogle Scholar
• 3 Beaubien G, Rosinski-Chupin I, Mattei M G, Mbikay M, Chrétien M, Seidah N G. Gene structure and chromosomal localization of plasma kallikrein.  Biochemistry. 1991;  30(6) 1628-1635
  CrossrefPubMedGoogle Scholar
• 4 Goold R D, diSibio G L, Xu H et al.. The development of sequence-tagged sites for human chromosome 4.  Hum Mol Genet. 1993;  2(8) 1271-1288
  CrossrefPubMedGoogle Scholar
• 5 Schmaier A H, McCrae K R. The plasma kallikrein-kinin system: its evolution from contact activation.  J Thromb Haemost. 2007;  5(12) 2323-2329
  CrossrefPubMedGoogle Scholar
• 6 Riegman P HJ, Vlietstra R J, Suurmeijer L, Cleutjens C BJM, Trapman J. Characterization of the human kallikrein locus.  Genomics. 1992;  14(1) 6-11
  CrossrefPubMedGoogle Scholar
• 7 Clements J A. The molecular biology of the kallikreins and their roles in inflammation. In: Farmer SG The Kinin System. Vol. 5. New York, NY; Academic Press 1997: 71-97
  PubMedGoogle Scholar
• 8 Rittenhouse H G, Finlay J A, Mikolajczyk S D, Partin A W. Human Kallikrein 2 (hK2) and prostate-specific antigen (PSA): two closely related, but distinct, kallikreins in the prostate.  Crit Rev Clin Lab Sci. 1998;  35(4) 275-368
  CrossrefPubMedGoogle Scholar
• 9 Yousef G M, Diamandis E P. The new human tissue kallikrein gene family: structure, function, and association to disease.  Endocr Rev. 2001;  22(2) 184-204
  CrossrefPubMedGoogle Scholar
• 10 Diamandis E P, Yousef G M, Clements J et al.. New nomenclature for the human tissue kallikrein gene family.  Clin Chem. 2000;  46(11) 1855-1858
  PubMedGoogle Scholar
• 11 Diamandis E P, Yousef G M, Luo L Y, Magklara A, Obiezu C V. The new human kallikrein gene family: implications in carcinogenesis.  Trends Endocrinol Metab. 2000;  11(2) 54-60
  PubMedGoogle Scholar
• 12 Wang M C, Valenzuela L A, Murphy G P, Chu T M. Purification of a human prostate specific antigen.  Invest Urol. 1979;  17(2) 159-163
  PubMedGoogle Scholar
• 13 Papsidero L D, Wang M C, Valenzuela L A, Murphy G P, Chu T M. A prostate antigen in sera of prostatic cancer patients.  Cancer Res. 1980;  40(7) 2428-2432
  PubMedGoogle Scholar
• 14 Lundwall A, Lilja H. Molecular cloning of human prostate specific antigen cDNA.  FEBS Lett. 1987;  214(2) 317-322
  CrossrefPubMedGoogle Scholar
• 15 Schulz P, Stucka R, Feldmann H, Combriato G, Klobeck H G, Fittler F. Sequence of a cDNA clone encompassing the complete mature human prostate specific antigen (PSA) and an unspliced leader sequence.  Nucleic Acids Res. 1988;  16(13) 6226
  CrossrefPubMedGoogle Scholar
• 16 Riegman P HJ, Vlietstra R J, van der Korput J AGM, Romijn J C, Trapman J. Characterization of the prostate-specific antigen gene: a novel human kallikrein-like gene.  Biochem Biophys Res Commun. 1989;  159(1) 95-102
  CrossrefPubMedGoogle Scholar
• 17 Riegman P H, Vlietstra R J, van der Korput J A, Brinkmann A O, Trapman J. The promoter of the prostate-specific antigen gene contains a functional androgen responsive element.  Mol Endocrinol. 1991;  5(12) 1921-1930
  CrossrefPubMedGoogle Scholar
• 18 Cleutjens K B, van Eekelen C C, van der Korput H A, Brinkmann A O, Trapman J. Two androgen response regions cooperate in steroid hormone regulated activity of the prostate-specific antigen promoter.  J Biol Chem. 1996;  271(11) 6379-6388
  CrossrefPubMedGoogle Scholar
• 19 Cleutjens K B, van der Korput H A, van Eekelen C C, van Rooij H C, Faber P W, Trapman J. An androgen response element in a far upstream enhancer region is essential for high, androgen-regulated activity of the prostate-specific antigen promoter.  Mol Endocrinol. 1997;  11(2) 148-161
  CrossrefPubMedGoogle Scholar
• 20 Bansal A, Murray D K, Wu J T, Stephenson R A, Middleton R G, Meikle A W. Heritability of prostate-specific antigen and relationship with zonal prostate volumes in aging twins.  J Clin Endocrinol Metab. 2000;  85(3) 1272-1276
  CrossrefPubMedGoogle Scholar
• 21 Gan L, Lee I, Smith R et al.. Sequencing and expression analysis of the serine protease gene cluster located in chromosome 19q13 region.  Gene. 2000;  257(1) 119-130
  CrossrefPubMedGoogle Scholar
• 22 Bélanger A, van Halbeek H, Graves H C et al.. Molecular mass and carbohydrate structure of prostate specific antigen: studies for establishment of an international PSA standard.  Prostate. 1995;  27(4) 187-197
  CrossrefPubMedGoogle Scholar
• 23 Stephan C, Jung K, Lein M, Diamandis E P. PSA and other tissue kallikreins for prostate cancer detection.  Eur J Cancer. 2007;  43(13) 1918-1926
  CrossrefPubMedGoogle Scholar
• 24 Lilja H, Christensson A, Dahlén U et al.. Prostate-specific antigen in serum occurs predominantly in complex with alpha 1-antichymotrypsin.  Clin Chem. 1991;  37(9) 1618-1625
  PubMedGoogle Scholar
• 25 Mikolajczyk S D, Marks L S, Partin A W, Rittenhouse H G. Free prostate-specific antigen in serum is becoming more complex.  Urology. 2002;  59(6) 797-802
  CrossrefPubMedGoogle Scholar
• 26 Liang S L. Application of prostate-specific antigen in prostate cancer.  MLO Med Lab Obs. 2008;  40(10) 54 56-57
  PubMedGoogle Scholar
• 27 Schieferstein G. Prostate-specific antigen (PSA) in human seminal plasma.  Arch Androl. 1999;  42(3) 193-197
  CrossrefPubMedGoogle Scholar
• 28 Diamandis E P. Prostate-specific antigen: a cancer fighter and a valuable messenger?.  Clin Chem. 2000;  46(7) 896-900
  PubMedGoogle Scholar
• 29 Basso D, Fogar P, Piva M G et al.. Total PSA, free PSA/total PSA ratio, and molecular PSA detection in prostate cancer: which is clinically effective and when?.  Urology. 2000;  55(5) 710-715
  CrossrefPubMedGoogle Scholar
• 30 Clements J A, Willemsen N M, Myers S A, Dong Y. The tissue kallikrein family of serine proteases: functional roles in human disease and potential as clinical biomarkers.  Crit Rev Clin Lab Sci. 2004;  41(3) 265-312
  PubMedGoogle Scholar
• 31 Diamandis E P, Yousef G M. Human tissue kallikreins: a family of new cancer biomarkers.  Clin Chem. 2002;  48(8) 1198-1205
  PubMedGoogle Scholar
• 32 Suzuki K, Kise H, Nishioka J, Hayashi T. The interaction among protein C inhibitor, prostate-specific antigen, and the semenogelin system.  Semin Thromb Hemost. 2007;  33(1) 46-52
  Article in Thieme ConnectPubMedGoogle Scholar
• 33 Lilja H. A kallikrein-like serine protease in prostatic fluid cleaves the predominant seminal vesicle protein.  J Clin Invest. 1985;  76(5) 1899-1903
  CrossrefPubMedGoogle Scholar
• 34 de Lamirande E. Semenogelin, the main protein of the human semen coagulum, regulates sperm function.  Semin Thromb Hemost. 2007;  33(1) 60-68
  Article in Thieme ConnectPubMedGoogle Scholar
• 35 Veveris-Lowe T L, Kruger S J, Walsh T, Gardiner R A, Clements J A. Seminal fluid characterization for male fertility and prostate cancer: kallikrein-related serine proteases and whole proteome approaches.  Semin Thromb Hemost. 2007;  33(1) 87-99
  Article in Thieme ConnectPubMedGoogle Scholar
• 36 Boyle P. Screening for prostate cancer: have you had your cholesterol measured?.  BJU Int. 2003;  92(3) 191-199
  CrossrefPubMedGoogle Scholar
• 37 Gion M, Mione R, Barioli P et al.. Clinical evaluation of percent free prostate-specific antigen using the AxSYM system in the best analytical scenario.  Eur Urol. 2000;  37(4) 460-469
  CrossrefPubMedGoogle Scholar
• 38 Draisma G, Etzioni R, Tsodikov A et al.. Lead time and overdiagnosis in prostate-specific antigen screening: importance of methods and context.  J Natl Cancer Inst. 2009;  101(6) 374-383
  PubMedGoogle Scholar
• 39 Stege R, Grande M, Carlström K, Tribukait B, Pousette A. Prognostic significance of tissue prostate-specific antigen in endocrine-treated prostate carcinomas.  Clin Cancer Res. 2000;  6(1) 160-165
  PubMedGoogle Scholar
• 40 Veneziano S, Pavlica P, Querzé R, Nanni G, Lalanne M G, Vecchi F. Correlation between prostate-specific antigen and prostate volume, evaluated by transrectal ultrasonography: usefulness in diagnosis of prostate cancer.  Eur Urol. 1990;  18(2) 112-116
  PubMedGoogle Scholar
• 41 Carter H B, Pearson J D, Metter E J et al.. Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease.  JAMA. 1992;  267(16) 2215-2220
  CrossrefPubMedGoogle Scholar
• 42 Fichtner J, Graves H C, Thatcher K, Yemoto C, Shortliffe L M. Prostate specific antigen releases a kinin-like substance on proteolysis of seminal vesicle fluid that stimulates smooth muscle contraction.  J Urol. 1996;  155(2) 738-742
  CrossrefPubMedGoogle Scholar
• 43 Cohen P, Graves H C, Peehl D M, Kamarei M, Giudice L C, Rosenfeld R G. Prostate-specific antigen (PSA) is an insulin-like growth factor binding protein-3 protease found in seminal plasma.  J Clin Endocrinol Metab. 1992;  75(4) 1046-1053
  CrossrefPubMedGoogle Scholar
• 44 Cramer S D, Chen Z, Peehl D M. Prostate specific antigen cleaves parathyroid hormone-related protein in the PTH-like domain: inactivation of PTHrP-stimulated cAMP accumulation in mouse osteoblasts.  J Urol. 1996;  156(2 Pt 1) 526-531
  CrossrefPubMedGoogle Scholar
• 45 Bindukumar B, Schwartz S A, Nair M P, Aalinkeel R, Kawinski E, Chadha K C. Prostate-specific antigen modulates the expression of genes involved in prostate tumor growth.  Neoplasia. 2005;  7(3) 241-252
  CrossrefPubMedGoogle Scholar
• 46 Balbay M D, Juang P, Ilansa N et al.. Stable transfection of human prostate cancer cell line PC-3 with prostate-specific antigen induced apoptosis both in vivo and in vitro.  Proc Am Assoc Cancer Res. 1999;  49 225-228
  PubMedGoogle Scholar
• 47 Takayama T K, Fujikawa K, Davie E W. Characterization of the precursor of prostate-specific antigen. Activation by trypsin and by human glandular kallikrein.  J Biol Chem. 1997;  272(34) 21582-21588
  CrossrefPubMedGoogle Scholar
• 48 Wiwanitkit V. Effect of thrombin tube on PSA determination, a clue for false negative in screening for prostate cancer.  J Thromb Thrombolysis. 2009;  27(2) 223-226
  CrossrefPubMedGoogle Scholar
• 49 Yoshida E, Ohmura S, Sugiki M, Maruyama M, Mihara H. Prostate-specific antigen activates single-chain urokinase-type plasminogen activator.  Int J Cancer. 1995;  63(6) 863-865
  CrossrefPubMedGoogle Scholar
• 50 Nielsen J D, Gram J, Holm-Nielsen A, Jespersen J. Bleeding and activation of coagulation during and after transurethral prostatectomy: importance of the acute-phase response and prostate specific antigen?.  BJU Int. 1999;  83(9) 990-995
  CrossrefPubMedGoogle Scholar
• 51 Braun K P, May M, Helke C, Hoschke B, Ernst H. Endoscopic therapy of a massive rectal bleeding after prostate biopsy.  Int Urol Nephrol. 2007;  39(4) 1125-1129
  CrossrefPubMedGoogle Scholar
• 52 Harris M A, Chadwick D, Ward D C. A novel way of controlling rectal bleeding after transrectal ultrasonography-guided prostate biopsies.  BJU Int. 2004;  93(9) 1358
  PubMedGoogle Scholar
• 53 Lind S E, Caprini J A, Goldshteyn S, Dohnal J C, Vesely S K, Shevrin D H. Correlates of thrombin generation in patients with advanced prostate cancer.  Thromb Haemost. 2003;  89(1) 185-189
  PubMedGoogle Scholar
• 54 Weisman K M, Larijani G E, Goldstein M R, Goldberg M E. Relationship between benign prostatic hyperplasia and history of coronary artery disease in elderly men.  Pharmacotherapy. 2000;  20(4) 383-386
  CrossrefPubMedGoogle Scholar
• 55 Patanè S, Marte F, Sturiale M, Grassi R, Patanè F. Significant coronary artery disease associated with coronary artery aneurysm and elevation of prostate-specific antigen during acute myocardial infarction.  Int J Cardiol. 2009 January 10 (Epub ahead of print); 
  PubMedGoogle Scholar
• 56 Patanè S, Marte F. Prostate-specific antigen kallikrein and acute myocardial infarction: Where we are. Where are we going?.  Int J Cardiol. 2009 January 29 (Epub ahead of print); 
  PubMedGoogle Scholar
• 57 Hamilton R J, Goldberg K C, Platz E A, Freedland S J. The influence of statin medications on prostate-specific antigen levels.  J Natl Cancer Inst. 2008;  100(21) 1511-1518
  PubMedGoogle Scholar
• 58 Lippi G, Montagnana M, Guidi G C. Epidemiological association between C-reactive protein and prostate-specific antigen.  Cancer. 2009;  115(5) 1132
  CrossrefPubMedGoogle Scholar
• 59 de la Fouchardière C, Flechon A, Droz J P. Coagulopathy in prostate cancer.  Neth J Med. 2003;  61(11) 347-354
  PubMedGoogle Scholar
• 60 Grignon D, Turnbull D I, Lohmann R C. Carcinoma of the prostate presenting as acute disseminated intravascular coagulation.  CMAJ. 1986;  135(7) 775-776
  PubMedGoogle Scholar
• 61 Al-Mondhiry H, Drago J, Bartholomew M J. The fibrinolytic system in experimental prostate tumor.  Thromb Haemost. 1986;  56(2) 133-136
  PubMedGoogle Scholar
• 62 Spector J I, Zimbler H. Carcinoma of the prostate presenting as acute disseminated intravascular coagulation.  CMAJ. 1987;  136(6) 570
  PubMedGoogle Scholar
• 63 McKechnie J. Prostatic carcinoma presenting as a haemorrhagic diathesis after dental extraction.  Br Dent J. 1989;  166(8) 295-296
  CrossrefPubMedGoogle Scholar
• 64 Jensen J B, Langkilde N C. Subcutaneous bleeding: first sign of prostate cancer.  Scand J Urol Nephrol. 2000;  34(3) 215-216
  PubMedGoogle Scholar
• 65 Cabane J, Etarian C, Louvet C et al.. Disseminated intravascular coagulation associated with prostatic cancer [in French].  Rev Med Interne. 1995;  16(3) 219-224
  PubMedGoogle Scholar
• 66 Martínez J F, Tabernero Redondo M D, Alberca Silva I, Lopez-Borrasca A. Disseminated intravascular coagulation in prostatic carcinoma reversed by antiandrogenic therapy.  JAMA. 1988;  260(17) 2507
  CrossrefPubMedGoogle Scholar
• 67 Smith Jr J A, Soloway M S, Young M J. Complications of advanced prostate cancer.  Urology. 1999;  54(6A, Suppl) 8-14
  CrossrefPubMedGoogle Scholar
• 68 Duran I, Tannock I F. Disseminated intravascular coagulation as the presenting sign of metastatic prostate cancer.  J Gen Intern Med. 2006;  21(11) C6-C8
  CrossrefPubMedGoogle Scholar
• 69 Albiges L, Cottu P H, Cojean-Zelek I et al.. Haematological complications of prostatic cancer: 2 cases, one revealing the neoplasia [in French].  Rev Med Interne. 2007;  28(3) 176-178
  PubMedGoogle Scholar
• 70 Hicks J. Case report: Disseminated intravascular coagulation as the presenting sign of metastatic prostate cancer.  J Gen Intern Med. 2007;  22(7) 1062
  CrossrefPubMedGoogle Scholar
• 71 Bern M M. Coagulopathy, following medical therapy, for carcinoma of the prostate.  Hematology. 2005;  10(1) 65-68
  CrossrefPubMedGoogle Scholar
• 72 Lwaleed B A, Greenfield R, Stewart A, Birch B, Cooper A J. Seminal clotting and fibrinolytic balance: a possible physiological role in the male reproductive system.  Thromb Haemost. 2004;  92(4) 752-766
  PubMedGoogle Scholar
• 73 Nieva J. The clinical significance of circulating tissue factor in prostate cancer.  Thromb Haemost. 2007;  97(3) 329-330
  PubMedGoogle Scholar
• 74 Langer F, Spath B, Haubold K et al.. Tissue factor procoagulant activity of plasma microparticles in patients with cancer-associated disseminated intravascular coagulation.  Ann Hematol. 2008;  87(6) 451-457
  CrossrefPubMedGoogle Scholar
• 75 Delves G H, Stewart A B, Cooper A J, Lwaleed B A. Prostasomes, angiogenesis, and tissue factor.  Semin Thromb Hemost. 2007;  33(1) 75-79
  Article in Thieme ConnectPubMedGoogle Scholar
• 76 Babiker A A, Ekdahl K N, Nilsson B, Ronquist G. Prothrombotic effects of prostasomes isolated from prostatic cancer cell lines and seminal plasma.  Semin Thromb Hemost. 2007;  33(1) 80-86
  Article in Thieme ConnectPubMedGoogle Scholar
• 77 Adamson A S, Luckert P, Pollard M, Snell M E, Amirkhosravi M, Francis J L. Procoagulant activity may be a marker of the malignant phenotype in experimental prostate cancer.  Br J Cancer. 1994;  69(2) 286-290
  PubMedGoogle Scholar
• 78 Kamocka M, Pollard M, Suckow M, Mielicki W P, Rosen E D. Rat prostate tumors express cancer procoagulant, an activator of coagulation factor X.  Comp Med. 2008;  58(3) 282-286
  PubMedGoogle Scholar
• 79 Szajda S D, Darewicz B, Kudelski J et al.. Assessment of the efficacy of cancer procoagulant (CP) activity evaluation in the oncological diagnosis of the urinary system.  Pol Merkuriusz Lek. 2005;  19 596-599
  PubMedGoogle Scholar
• 80 Minhas B S, Kumar R, Ricker D D, Robertson J L, Dodson M G. The presence of platelet-activating factor-like activity in human spermatozoa.  Fertil Steril. 1991;  55(2) 372-376
  PubMedGoogle Scholar
• 81 Sugatani J, Miwa M, Komiyama Y, Murakami T. Quantitative analysis of platelet-activating factor in human plasma. Application to patients with liver cirrhosis and disseminated intravascular coagulation.  J Immunol Methods. 1993;  166(2) 251-261
  CrossrefPubMedGoogle Scholar
• 82 Caramello V, Dovio A, Caraci P, Berruti A, Angeli A. Thrombotic thrombocytopenic purpura in advanced prostate cancer: case report and published work review.  Int J Urol. 2007;  14(2) 150-152
  CrossrefPubMedGoogle Scholar
• 83 Franchini M, Montagnana M, Targher G, Manzato F, Lippi G. Pathogenesis, clinical and laboratory aspects of thrombosis in cancer.  J Thromb Thrombolysis. 2007;  24(1) 29-38
  CrossrefPubMedGoogle Scholar
• 84 Lippi G, Franchini M, Biasiutti C, Dellagiacoma G, Salvagno G L, Guidi G C. Increased D-dimer value and occult cancer in the absence of detectable thrombosis.  Haematologica. 2007;  92(4) e53-e55
  CrossrefPubMedGoogle Scholar
• 85 The Veterans Administration Co-operative Urological Research Group . Treatment and survival of patients with cancer of the prostate.  Surg Gynecol Obstet. 1967;  124(5) 1011-1017
  PubMedGoogle Scholar
• 86 Levitan N, Dowlati A, Remick S C et al.. Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy. Risk analysis using Medicare claims data.  Medicine (Baltimore). 1999;  78(5) 285-291
  CrossrefPubMedGoogle Scholar
• 87 Heit J A. Cancer and venous thromboembolism: scope of the problem.  Cancer Control. 2005;  12(Suppl 1) 5-10
  PubMedGoogle Scholar
• 88 Clement J, Bubley G. Prostasol and venous thromboembolism.  Urology. 2008;  72(3) 664-666
  CrossrefPubMedGoogle Scholar
• 89 Lin A M, Rini B I, Derynck M K et al.. A phase I trial of docetaxel/estramustine/imatinib in patients with hormone-refractory prostate cancer.  Clin Genitourin Cancer. 2007;  5(5) 323-328
  PubMedGoogle Scholar
• 90 Seaman H E, Langley S E, Farmer R D, de Vries C S. Venous thromboembolism and cyproterone acetate in men with prostate cancer: a study using the General Practice Research Database.  BJU Int. 2007;  99(6) 1398-1403
  CrossrefPubMedGoogle Scholar
• 91 Chiappino I, Destefanis P, Addeo A et al.. Activity of weekly paclitaxel in advanced hormone-refractory prostate cancer.  Am J Clin Oncol. 2007;  30(3) 234-238
  CrossrefPubMedGoogle Scholar
• 92 Secin F P, Jiborn T, Bjartell A S et al.. Multi-institutional study of symptomatic deep venous thrombosis and pulmonary embolism in prostate cancer patients undergoing laparoscopic or robot-assisted laparoscopic radical prostatectomy.  Eur Urol. 2008;  53(1) 134-145
  CrossrefPubMedGoogle Scholar
• 93 Beyer J, Wessela S, Hakenberg O W et al.. Incidence, risk profile and morphological pattern of venous thromboembolism after prostate cancer surgery.  J Thromb Haemost. 2009 January 7 (Epub ahead of print); 
  PubMedGoogle Scholar
• 94 Cestari D M, Weine D M, Panageas K S, Segal A Z, DeAngelis L M. Stroke in patients with cancer: incidence and etiology.  Neurology. 2004;  62(11) 2025-2030
  PubMedGoogle Scholar
• 95 Takeda T, Saitoh M, Takeda S. Superior vena cava syndrome caused by an intravascular thrombosis due to underlying prostate carcinoma.  Intern Med. 2008;  47(22) 2007-2009
  CrossrefPubMedGoogle Scholar
• 96 Sahdev P, Wolff M, Widmann W D. Mesenteric venous thrombosis associated with estrogen therapy for treatment of prostatic carcinoma.  J Urol. 1985;  134(3) 563-564
  PubMedGoogle Scholar
• 97 Federici T J. Leuprolide acetate and central retinal vein occlusion.  Ophthalmic Surg Lasers Imaging. 2007;  38(6) 497-499
  PubMedGoogle Scholar
• 98 Kim A W, Trobe J D. Syndrome simulating pseudotumor cerebri caused by partial transverse venous sinus obstruction in metastatic prostate cancer.  Am J Ophthalmol. 2000;  129(2) 254-256
  CrossrefPubMedGoogle Scholar
• 99 Thurairaja R, Pocock R, Crundwell M et al.. Brachytherapy for advanced prostate cancer bleeding.  Prostate Cancer Prostatic Dis. 2008;  11(4) 367-370
  CrossrefPubMedGoogle Scholar
• 100 Kohli M, Kaushal V, Mehta P. Role of coagulation and fibrinolytic system in prostate cancer.  Semin Thromb Hemost. 2003;  29(3) 301-308
  Article in Thieme ConnectPubMedGoogle Scholar
• 101 Orth T, Schnütgen M, Herr W et al.. [Prostate carcinoma associated spontaneous factor VIII:C inhibitor hemophilia. Successful therapy of severe hemorrhagic complication with porcine factor VIII in a 75-year-old patient].  Med Klin (Munich). 1997;  92(4) 241-245
  CrossrefPubMedGoogle Scholar
• 102 Sati H I, Watson H G. Recurrent adenocarcinoma of prostate presenting as acquired haemophilia A.  Thromb Haemost. 1998;  80(6) 1034
  PubMedGoogle Scholar
• 103 Kleinman M B. Anti-inhibitor coagulant complex for the rescue therapy of acquired inhibitors to factor VIII: case report and review of the literature.  Haemophilia. 2002;  8(5) 694-697
  CrossrefPubMedGoogle Scholar
• 104 Barrier F, de La Guerenne A, Semjen E et al.. Spontaneously acquired haemophilia: report of a patient with prostatic adenoma [in French].  Ann Biol Clin (Paris). 2006;  64(4) 347-352
  PubMedGoogle Scholar
• 105 Langer F, Chun F K, Amirkhosravi A et al.. Plasma tissue factor antigen in localized prostate cancer: distribution, clinical significance and correlation with haemostatic activation markers.  Thromb Haemost. 2007;  97(3) 464-470
  Google Scholar
• 106 Caine G J, Lip G Y, Stonelake P S, Ryan P, Blann A D. Platelet activation, coagulation and angiogenesis in breast and prostate carcinoma.  Thromb Haemost. 2004;  92(1) 185-190
  PubMedGoogle Scholar
• 107 Kohli M, Fink L M, Spencer H J, Zent C S. Advanced prostate cancer activates coagulation: a controlled study of activation markers of coagulation in ambulatory patients with localized and advanced prostate cancer.  Blood Coagul Fibrinolysis. 2002;  13(1) 1-5
  CrossrefPubMedGoogle Scholar
• 108 Kaushal V, Kohli M, Dennis R A, Siegel E R, Chiles W W, Mukunyadzi P. Thrombin receptor expression is upregulated in prostate cancer.  Prostate. 2006;  66(3) 273-282
  CrossrefPubMedGoogle Scholar
• 109 Snyder K M, Kessler C M. The pivotal role of thrombin in cancer biology and tumorigenesis.  Semin Thromb Hemost. 2008;  34(8) 734-741
  Article in Thieme ConnectPubMedGoogle Scholar
• 110 Tsopanoglou N E, Maragoudakis M E. Role of thrombin in angiogenesis and tumor progression.  Semin Thromb Hemost. 2004;  30(1) 63-69
  Article in Thieme ConnectPubMedGoogle Scholar
• 111 Stief T W. Kallikrein activates prothrombin.  Clin Appl Thromb Hemost. 2008;  14(1) 97-98
  CrossrefPubMedGoogle Scholar

Giuseppe LippiM.D. 

U.O. Diagnostica Ematochimica, Dipartimento di Patologia e Medicina di Laboratorio, Azienda Ospadaliero-Universitaria di Parma

Strada Abbeveratoia, 2, 43100 Parma, Italy

Email: glippi@ao.pr.it