Direct Oral Anticoagulants in Cancer Patients. Time for a Change in Paradigm.

Thrombosis is a more common occurrence in cancer patients compared to the general population and is one of the main causes of death in these patients. Low molecular weight heparin (LMWH) has been the recognized standard treatment for more than a decade, both in cancer-related thrombosis and in its prevention. Direct oral anticoagulants (DOACs) are a new option for anticoagulation therapy. Recently published results of large randomized clinical trials have confirmed that DOAC may be a reasonable alternative to LMWH in cancer patients. The following review summarizes the current evidence on the safety and efficacy of DOAC in the treatment and prevention of cancer-related thrombosis. It also draws attention to the limitations of this group of drugs, knowledge of which will facilitate the selection of optimal therapy.

It is not just the drugs that matter: the nocebo effect.

The role of psychological mechanisms in the treatment process cannot be underestimated, the well-known placebo effect unquestionably being a factor in treatment. However, there is also a dark side to the impact of mental processes on health/illness as exemplified by the nocebo effect. This phenomenon includes the emergence or exacerbation of negative symptoms associated with the therapy, but arising as a result of the patient's expectations, rather than being an actual complication of treatment. The exact biological mechanisms of this process are not known, but cholecystokinergic and dopaminergic systems, changes in the HPA axis, and the endogenous secretion of opioids are thought to be involved. The nocebo effect can affect a significant proportion of people undergoing treatment, including cancer patients, leading in some cases to the cessation of potentially effective therapy, because of adverse effects that are not actually part of the biological effect of treatment. In extreme cases, as a result of suggestions and expectations, a paradoxical effect, biologically opposite to the mechanism of the action of the drug, may occur. In addition, the nocebo effect may significantly interfere with the results of clinical trials, being the cause of a significant proportion of complications reported. Knowledge of the phenomenon is thus necessary in order to facilitate its minimalization and thus improve the quality of life of patients and the effectiveness of treatment.

Co-localization of Coagulation Factor X and its Inhibitory System, PZ/ZPI, in Human Endometrial Cancer Tissue.

BACKGROUND/AIM: Hemostatic system components contribute to cancer progression independently from their roles in hemostasis. It has been shown that protein Z (PZ)/protein Z-dependent protease inhibitor (ZPI) inhibit coagulation factor X (FX). The aim of the study was to analyze the expression of PZ/ZPI in relation to the main coagulation factor - FX in human endometrial cancer tissue. MATERIALS AND METHODS: Immunohistochemical analysis was performed on 21 endometrial cancer specimens employing antibodies against ZPI, PZ and FX. RESULTS: Endometrial cancer cells showed a strong expression of ZPI and PZ and medium expression of FX. Normal endometrial tissue showed no expression of ZPI, PZ or FX. CONCLUSION: Strong expression of PZ and ZPI in endometrial cancer cells suggests a role of these proteins in endometrial cancer.

Protein Z/protein Z-dependent protease inhibitor system in loco in human gastric cancer.

In gastric cancer, hemostatic system components contribute to cancer progression, as activation of factor X (FX) was observed. The protein Z (PZ)/protein Z-dependent protease inhibitor (ZPI) complex inhibits factor Xa proteolytic activity. The purpose of this study was to determine the distribution of ZPI and PZ in relation to FX, and prothrombin fragment (F1 + 2), a standard marker for blood coagulation activation, in human gastric cancer tissue. ABC procedures and a double staining method employed polyclonal antibodies against PZ, FX, and F1 + 2 and a monoclonal antibody against ZPI. In situ hybridization (ISH) methods employed biotin-labeled 25-nucleotide single-stranded DNA probes directed to either PZ or ZPI mRNAs. FX and components of PZ/ZPI coagulation inhibitory system were observed in cancer cells. F1 + 2 was observed in gastric cancer cells as well. Double staining studies revealed FX/PZ, FX/ZPI, and PZ/ZPI co-localization on gastric cancer cells. ISH studies demonstrated the presence of PZ mRNA and ZPI mRNA in gastric cancer cells indicating induced synthesis of these proteins. The co-localization of PZ/ZPI and FX in gastric cancer cells indicates in loco that these proteins may play a role in anticoagulant events at the tumor tissue.

Co-localization of Protein Z, Protein Z-Dependent protease inhibitor and coagulation factor X in human colon cancer tissue: implications for coagulation regulation on tumor cells.

INTRODUCTION: Several hemostatic system components, including factor X (FX), contribute to cancer progression. The Protein Z (PZ)/protein Z-dependent protease inhibitor (ZPI) complex directly inhibits factor Xa proteolytic activity. The aim of this study was to determine the antigenic distribution of ZPI and PZ, in relation to FX, as well as indicators of blood coagulation activation (F1+2 and fibrin) in human colon cancer tissue. MATERIALS & METHODS: Studies were performed on human colon cancer fragments. Immunohistochemical (IHC) ABC procedures and double staining method employed polyclonal antibodies against PZ, FX, F1+2 and monoclonal antibodies against ZPI and fibrin. In-situ hybridization (ISH) methods employed biotin-labeled 25-nucleotide single-stranded DNA probes directed to either FX, PZ or ZPI mRNAs. RESULTS: Expression of FX, PZ and ZPI in association with colon cancer cells was observed by IHC. Moreover, the presence of both F1+2 and fibrin in association with colon cancer cells was found, which indicates that blood coagulation activation proceeds extravascularly at the tumor site. Furthermore, expression of FX and PZ was visualized in association with endothelial cells. In turn, colon cancer-associated macrophages were characterized by FX , PZ and ZPI presence. The double staining studies revealed strong FX/PZ, FX/ZPI, as well as PZ/ZPI co-localization on colon cancer cells. ISH studies revealed the presence of FX mRNA, PZ mRNA and ZPI mRNA in colon cancer cells indicating induced synthesis of these proteins. CONCLUSIONS: The localization of PZ/ZPI and FX in colon cancer cells indicates that PZ/ZPI may contribute to anticoagulant events at the tumor site. Strong co-localization of PZ/ZPI and FX in cancer cells, and the presence of the mRNAs encoding the proteins, suggests their role in the tumor's biology. However, the presence of F1+2 and fibrin at the colon cancer site also suggests that the regulation of FXa by the PZ/ZPI complex at this site is incomplete.

Protein Z/protein Z-dependent protease inhibitor system in human non-small-cell lung cancer tissue.

INTRODUCTION: NSCLC progression is often associated with VTE. Activation of factor X is an important step in blood coagulation activation in cancer patients. PZ)/ZPI contribute to direct factor Xa inhibition, and ZPI - attenuates factors IXa and XIa activity. The role of the PZ/ZPI in NSCLC is obscure. The aim of the study was to localize ZPI and PZ in NSCLC tissue in relation to factors X, IX and XI, as well as indicators of blood coagulation activation: prothrombin fragment F1+2 (F1+2) and fibrin. MATERIAL & METHODS: Immunohistochemical studies were performed on surgical NSCLC specimens employing antibodies against ZPI, PZ, coagulation factors X, IX, XI, as well as fibrinogen, F1+2 and fibrin. A semiquantitative analysis (acc. to immunoreactive score-IRS) was conducted. RESULTS: Medium expression of ZPI(IRS=6.5), together with weak expression of PZ(IRS=4), was observed in cancer cells. Strong or medium staining for factors IX, X, and XI(IRS=8-9) was revealed in cancer cells. Fibrinogen(IRS=10) and fibrin(IRS=8) were demonstrated in tumor stroma and cancer cells. F1+2(IRS=10) was localized in NSCLC cells. Endothelial cells (ECs) and tumor infiltrating macrophages (TAMs) were characterized by a positive staining for ZPI and PZ. CONCLUSIONS: ZPI and PZ expression in NSCLC cells, ECs and TAMs may suggest a role for PZ/ZPI in the anticoagulant mechanisms at the tumor site. The presence of F1+2 and fibrin, along with a disproportional expression of ZPI and PZ, might point to impaired function of the coagulation inhibitory system in NSCLC tissue.

[Expression evaluation of in loco coagulation system in colorectal cancer]. / Ocena ekspresji in loco czynników ukladu krzepniecia krwi w raku jelita grubego.

Colorectal cancer is the third most often cause of morbidity and mortality due to cancer in Poland. Thromboembolic complications are common events during the course of the disease. It is well known that hemostatic proteins play an important role in cancer progression. The purpose of the study was to evaluate the in loco interactions among colorecatal cancer and coagulation factors. 21 cases of G2 colorectal adenocarcinoma obtained during surgical resection were examined. Immunohistochemical procedures according to ABC method were employed. Tissue factor (TF) and coagulation factors II, VII, X, IX were observed in cancer cells and except factors II and IX--in tumor associated macrophages. TF was also demonstrated in endothelial cells of small blood vessels. Strong expression of fibrinogen was observed among connective tissue at some distance around malignant tumor while weaker expression was found in tumor stroma. Expression of F(1+2), the by-product of thrombin generation, was revealed in cancer cells, macrophages and in the tumor stroma. The results indicate extravascular activation of blood coagulation in loco in colorectal cancer that is TF-dependent.

[The location of components of fibrinolytic system in laryngeal cancer]. / Lokalizacja skladowych ukladu fibrynolizy w raku krtani.

Laryngeal cancer is the most common neoplasm of the head and neck region. Laryngeal cancer patients experience thromboembolic complications more often than the general population. Our previous studies revealed in loco activation of blood coagulation in laryngeal cancer. The purpose of the present study was to examine the interactions among the laryngeal cancer cells and fibrinolytic system components in loco. Twenty-two cases of squamous carcinoma of the larynx were examined. AMeX method-preserved cancer tissues were examined using immunohistochemical ABC method. Fibrin and D-D fibrin dimers were demonstrated in the matrix, predominantly on the tumor-host front. Plasminogen, tissue-type plasminogen activator (t-PA) and plasmin were detected in cancer cells, but the intensity of their expression revealed a negative correlation with the degree of malignancy. A weak expression of high molecular weight urokinase (HMW-UK) was observed in cancer cells in the centers of the cancer foci, and a product of its degradation--low molecular weight urokinase (LMW-UK) was observed in cancer cells on the invasion front. The presence of plasminogen activator inhibitors (PAI-1, PAI-2, PAI-3) was also documented in the cancer cells. The expression of urokinase receptor (u-PAR) was very weak. Based on the results of the study, we suggest that in laryngeal cancer a suboptimal activation of fibrinolysis occurs that contributes to fibrin deposition in the tumour.

[Protein Z]. / Bialko Z.

Protein Z (PZ) is a 6.2 kDa vitamin K-dependent protein, synthesized in the liver. The gene for human PZ is localized to chromosome 13 at band 34 q. The structure of PZ is very similar to that of factors VII, IX, X and protein C. Very low plasma levels of protein Z were observed under oral anticoagulant treatment. The cause of this phenomenon might be increased protein Z binding on the surface of endothelial cells. Protein Z is consumed during coagulopathy. About 60% of humans suffering from a bleeding tendency of unknown origin presented with decreased plasma levels of protein Z. PZ forms a Ca(2+)-dependent complex with activated factor X (Xa) on phospholipid surfaces, that leads to the inhibition of factor Xa and decrease in thrombin generation. Inhibition of factor Xa may be caused directly by protein Z or indirectly by the activity of protein Z-dependent protease inhibitor (ZPI). ZPI is a 72 kDa member of the serpin family of proteinase inhibitors, synthesized in the liver. ZPI circulates in plasma in complex with protein Z. ZPI in the presence of Ca2+ and phospholipids inhibits factor Xa. The presence of protein Z enhances this process by more than 1000 times. ZPI also inhibits activated factor XI in the absence of protein Z, Ca2+ or phospholipids. Protein Z deficiency may induce bleeding as well as prothrombotic tendencies and might occur as an inherited disorder. Protein Z deficiency may aggravate mild bleeding tendency in subjects with diagnosed borderline decrease in von Willebrand factor and factor VII activity. Patients presenting with factor V Leiden mutation and low protein Z levels show earlier onset and higher frequency of thromboembolic events comparing to patients with normal protein Z levels.