Role of Seminal Hemostatic Factors and Semenogelins in the Reproductive Tract

Hemostasis is an important initiator in healing processes, involving recruitment and activation of cells as well as platelets and soluble mediators. Fibrinolysis plays a complementary role. The key mediators in the hemostatic system do not need explanation in a journal of thrombosis and hemostasis.

Initiating pregnancy similarly requires recruitment of sperm competing to fertilize the ovum and of cells for maternal tissue remodeling after fertilization. Sperm maturation and function is strongly influenced by the milieu. Seminal plasma, like blood, is subject to fluctuations between coagulation and liquefaction, the control of which is critical to fertility. The coagulum is based on the high molecular weight seminal vesicle (HMW-SV) proteins and the key protein in its dissolution is prostate-specific antigen (PSA).

There are obvious roles for hemostatic processes in reproductive physiology, such as controlling minor bleeding provoked during sexual intercourse or the major bleeding caused when the placenta is shed.

Molecules easily become typecast according to the first role discovered for them. Many predate phylogenetically the physiology with which they are mostly associated, and have alternate roles in unfamiliar fields. It would be surprising if the two coagulation/liquefaction processes outlined above did not interact or share some common elements. Certainly it appears that components of the two systems coexist in the reproductive tract. The extent of functional interaction, although as yet incompletely resolved, forms the basis of this issue of Seminars in Thrombosis and Hemostasis.

In the opening article, Dr. Lwaleed and coworkers give a historical perspective describing how elements of the hemostatic system have been found to occur in semen. Initially, these were mostly isolated studies on single components. More recently, the picture of a relatively comprehensive catalog has emerged, and points of interaction have been identified between the established seminal coagulum-forming and -dissolving system and the hemostatic cascades. Some correlations with conventional fertility parameters have also been established, despite difficulties in defining infertility numerically. Novel functions for classical hemostatic molecules when located in the genitourinary tract are alluded to in this article.

Drs. Fernández and Heeb highlight the importance of semen coagulation in fertilization and compare its biochemistry with that of hemostasis and fibrinolysis: both require proteases to convert a soluble substrate to an insoluble gel, and then dissolve the gel in a controlled fashion over a protracted time course. The particularly high levels of protein C inhibitor and tissue factor (TF) in semen are highlighted. Progress toward understanding their unique functions in seminal coagulum formation and dissolution, as well as other aspects of fertilization, is detailed.

Dr. Van Dreden and associates make a practical connection between fibrinolysis, semen liquefaction, and sperm function. This group has studied plasminogen activators and their inhibitors in whole and split ejaculates from men attending an infertility clinic with no genitourinary pathology. Abnormal liquefaction was associated with low levels of tissue plasminogen activator, whereas high levels of the inhibitor were found where sperm were absent or abnormal.

This theme is carried forward by Professor Liu, who reviews evidence that the plasminogen activator system is involved in sperm production as well as function in several species including man. Particular emphasis is placed on the participation of plasminogen activator receptors and plasminogen activator inhibitor type 1 in the acrosomal reaction, sperm-egg recognition, and fertilization.

Dr. España and coworkers also provide evidence for a key molecule in the control of blood coagulation and fibrinolysis having a direct influence on fertility-indeed on fertilization itself. Protein C inhibitor (PCI) interacts with other regulatory molecules in semen, including PSA, mediating the liquefaction of the seminal coagulum. In doing so, it is inactivated. At the point of fertilization, however, residual PCI reduces the ability of even fully capacitated sperm to fertilize an ovum.

The biochemistry of the interactions of PCI and the proteins of the semenogelin system with PSA are examined by Professor Suzuki and coworkers. PSA (a product of the prostate) and both PCI and the HMW-SV proteins (which are secreted by the seminal vesicles) begin to interact only when the two secretions mix in the seminal plasma. Ionic conditions in the plasma influence these reactions, resulting in a finely controlled dissolution of the seminal coagulum, orchestrated to optimize the release of capacitated sperm in the cervix.

Seminal vesicle proteins may also have other functions. Dr. Metafora and associates describe a chemopreventive role for one such protein (rat seminal vesicle protein 4 [SV-IV]). Apart from its function related to coagulum formation, it also modulates hemostasis and inflammation. An additional action is to protect sperm from damage in the female tract, either from oxidative damage or immunological attack, both arguably having similar end-effector mechanisms. The switching of roles for SV-IV seems to depend on its state of oligomerization. SV-IV and its products have been the subject of exhaustive structural studies by this group; the main features are documented elegantly and illustrated here.

In human semen, seminal vesicle proteins have diverse functions, albeit all related to optimizing the chances of successful fertilization. While the coagulum is set, semenogelin inhibits sperm motility and retards capacitation. Dr. de Lamirande describes the action of PSA in degrading semenogelin as regulatory in sperm capacitation and promoting motility. Although the range of targets and effects of semenogelin and its degradation peptides are incompletely understood, they participate in antibacterial activity as well as enzyme activation and ion shuttling. These events are time dependent and imbalances or irregularities may adversely impinge on fertility.

Dr. Roudebush continues the theme of multipotent mediators by describing platelet-activating factor as a potent signaling phospholipids with pleiotropic biological activities. With respect to reproductive physiology, its influence is discernible not only at fertilization but for implantation and embryo development. In semen it is synthesized and used by sperm; concentrations correlate directly with an array of fertility parameters. Despite clear evidence of its importance, exact mechanisms of action are not well understood.

The role of lipids in hemostatic mechanisms is well established. In semen, a rich source of lipid lies in prostasomes, microparticles (or exosomes) secreted by prostatic epithelial cells. Prostasomes also bear many membrane-associated proteins, including TF. Their importance may extend to neoplastic disease in the prostate. Dr. Delves and coworkers illustrate that they may influence angiogenesis, a key event in tumor progression, although the direction of that influence may depend on conditions surrounding the production of the microparticles and the milieu in which they are located-naturally in the ejaculate or extopically in tissue spaces of the disrupted architecture in cancer.

Dr. Babiker and associates pursue the relationships among prostasomes, TF, and cancer further. Differences between normal prostasomes and those from cancerous tissue are highlighted, and it is postulated that their high TF content combined with abnormal release into the circulation may contribute to thromboembolic complications in prostate cancer.

Dr. Veveris-Lowe and coworkers also touch on cancer in discussing the products of the kallikrein-related protease (KLK) gene family. These products have a role in normal reproductive physiology, but also include the well-known product, PSA, which is currently the biomarker of choice for monitoring progression in prostate cancer, albeit with several reservations about the interpretation of results. Other candidate prognostic markers emerging from proteomic analyses of seminal plasma are discussed.

Cancer is sometimes described as “a wound that won't heal.” Professor Preissner and Dr. Bronson describe hemostatic processes as prominent in the early stages of healing and relying substantially on cell adhesion molecules and receptors. The same molecules appear to orchestrate the movement of spermatids in the testis during spermatogenesis, and facilitate mature and capacitated sperm in fusing with oocytes. The thesis is illustrated by experiments describing how vitronectin and other hemostatic factors act as a multifunctional adhesion molecule throughout the independent existence of spermatozoa.

Finally, Professor Lockwood and coworkers follow the influence of hemostatic factors, postfertilization, in placental development and on to their obviously critical and classically hemostatic role after birth when the placenta is shed. Throughout gestation these factors are important in maintaining homeostasis in maternal-fetal relations and abnormalities or imbalances result in malformed or malfunctioning placentas or preeclampsia. Thrombin also plays a part in the normal estrus cycle by promoting cytokines and the enzymes involved in tissue remodelling.

If serious malfunction of blood coagulation is life-threatening to the individual, as crucial to our species' survival is reproductive function, in which coagulation and liquefaction are also critical. Components of the hematological system certainly are present and active in processes impinging on fertility, from spermatogenesis to fertilization and fetal development, either in their classical roles, or by interactions with the semenogelins and PSA or revealing other activities. Abnormalities, qualitative or quantitative, predispose to life-threatening conditions such as eclampsia or cancer progression, as well as the socially debilitating condition of infertility. There is ample scope for the hematologist in the study of reproductive biology and medicine.