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

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.

KEYWORDS

Hemostasis - prostate - prostate cancer - prostate-specific antigen - thrombosis

REFERENCES

• 1 Kraut H, Frey Ek, Werle E. Der Nachweis eines Kreislaufhormon in de Pankreasdruse.  Hoppe Seylers Z Physiol Chem. 1930;  189 97-106
• 2 Werle E. Zur Kenntnis des haushalts des Kallikreins.  Biochem Z. 1934;  269 415-434
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 14 Lundwall A, Lilja H. Molecular cloning of human prostate specific antigen cDNA.  FEBS Lett. 1987;  214(2) 317-322
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 26 Liang S L. Application of prostate-specific antigen in prostate cancer.  MLO Med Lab Obs. 2008;  40(10) 54 56-57
• 27 Schieferstein G. Prostate-specific antigen (PSA) in human seminal plasma.  Arch Androl. 1999;  42(3) 193-197
• 28 Diamandis E P. Prostate-specific antigen: a cancer fighter and a valuable messenger?.  Clin Chem. 2000;  46(7) 896-900
• 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
• 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
• 31 Diamandis E P, Yousef G M. Human tissue kallikreins: a family of new cancer biomarkers.  Clin Chem. 2002;  48(8) 1198-1205
• 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
• 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
• 34 de Lamirande E. Semenogelin, the main protein of the human semen coagulum, regulates sperm function.  Semin Thromb Hemost. 2007;  33(1) 60-68
• 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
• 36 Boyle P. Screening for prostate cancer: have you had your cholesterol measured?.  BJU Int. 2003;  92(3) 191-199
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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); 
• 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); 
• 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
• 58 Lippi G, Montagnana M, Guidi G C. Epidemiological association between C-reactive protein and prostate-specific antigen.  Cancer. 2009;  115(5) 1132
• 59 de la Fouchardière C, Flechon A, Droz J P. Coagulopathy in prostate cancer.  Neth J Med. 2003;  61(11) 347-354
• 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
• 61 Al-Mondhiry H, Drago J, Bartholomew M J. The fibrinolytic system in experimental prostate tumor.  Thromb Haemost. 1986;  56(2) 133-136
• 62 Spector J I, Zimbler H. Carcinoma of the prostate presenting as acute disseminated intravascular coagulation.  CMAJ. 1987;  136(6) 570
• 63 McKechnie J. Prostatic carcinoma presenting as a haemorrhagic diathesis after dental extraction.  Br Dent J. 1989;  166(8) 295-296
• 64 Jensen J B, Langkilde N C. Subcutaneous bleeding: first sign of prostate cancer.  Scand J Urol Nephrol. 2000;  34(3) 215-216
• 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
• 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
• 67 Smith Jr J A, Soloway M S, Young M J. Complications of advanced prostate cancer.  Urology. 1999;  54(6A, Suppl) 8-14
• 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
• 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
• 70 Hicks J. Case report: Disseminated intravascular coagulation as the presenting sign of metastatic prostate cancer.  J Gen Intern Med. 2007;  22(7) 1062
• 71 Bern M M. Coagulopathy, following medical therapy, for carcinoma of the prostate.  Hematology. 2005;  10(1) 65-68
• 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
• 73 Nieva J. The clinical significance of circulating tissue factor in prostate cancer.  Thromb Haemost. 2007;  97(3) 329-330
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 87 Heit J A. Cancer and venous thromboembolism: scope of the problem.  Cancer Control. 2005;  12(Suppl 1) 5-10
• 88 Clement J, Bubley G. Prostasol and venous thromboembolism.  Urology. 2008;  72(3) 664-666
• 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
• 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
• 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
• 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
• 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); 
• 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
• 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
• 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
• 97 Federici T J. Leuprolide acetate and central retinal vein occlusion.  Ophthalmic Surg Lasers Imaging. 2007;  38(6) 497-499
• 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
• 99 Thurairaja R, Pocock R, Crundwell M et al.. Brachytherapy for advanced prostate cancer bleeding.  Prostate Cancer Prostatic Dis. 2008;  11(4) 367-370
• 100 Kohli M, Kaushal V, Mehta P. Role of coagulation and fibrinolytic system in prostate cancer.  Semin Thromb Hemost. 2003;  29(3) 301-308
• 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
• 102 Sati H I, Watson H G. Recurrent adenocarcinoma of prostate presenting as acquired haemophilia A.  Thromb Haemost. 1998;  80(6) 1034
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 110 Tsopanoglou N E, Maragoudakis M E. Role of thrombin in angiogenesis and tumor progression.  Semin Thromb Hemost. 2004;  30(1) 63-69
• 111 Stief T W. Kallikrein activates prothrombin.  Clin Appl Thromb Hemost. 2008;  14(1) 97-98