In 1878, Billroth discovered that tumor cells invest themselves in a fibrin thrombus, and he hypothesized that fibrin promotes tumor growth and invasion. Since then, many observations have supported this concept, showing that many hemostatic factors including fibrinogen, fibrin, and components of the fibrinolytic system have indeed a complex interaction with cancer growth and metastasis. Fibrin promotes cell migration by providing a matrix for tumor cell migration and by interactions with adhesive molecules and integrins. Fibrin-containing vascular endothelial growth factor promotes angiogenesis. Fibrin interacts with platelets and leukocytes, and promotes their respective carcinogenic properties. Fibrinolytic components exert different effects on tumors. Plasmin activates latent growth factors, and breaks down extracellular matrix (ECM), while urokinase plasminogen activator (uPA) and the uPA receptor (uPAR) form complexes with vitronectin and integrins to promote tumor cells to adhere to the ECM. This complex also binds the epidermal growth factor receptor on the tumor cell membrane, and signals the RAF-MEK-ERK pathway. The complex also binds to the G protein-coupled receptors leading to cell proliferation. Plasminogen activator inhibitor 1 (PAI-1) inhibits apoptosis, and increases tumor cell survival. PAI-1 also enhances cell senescence, leading to production of tumorigenic cytokines by the senescence secretome. The presence of uPA/uPAR and PAI-1 represents a strong biomarker for tumor aggressiveness and poor prognosis. Multiple attempts by blocking various carcinogenic steps have shown tumor-suppressing effects in experimental animals, but human responses are uncertain without clinical trials.

Viscoelastic hemostatic assay (VHAs) are whole blood point-of-care tests that have become an essential method for assaying hemostatic competence in liver transplantation, cardiac surgery, and most recently, trauma surgery involving hemorrhagic shock. It has taken more than three-quarters of a century of research and clinical application for this technology to become mainstream in these three clinical areas. Within the last decade, the cup and pin legacy devices, such as thromboelastography (TEG^® 5000) and rotational thromboelastometry (ROTEM^® delta), have been supplanted not only by cartridge systems (TEG^® 6S and ROTEM^® sigma), but also by more portable point-of-care bedside testing iterations of these legacy devices (e.g., Sonoclot^®, Quantra^®, and ClotPro^®). Here, the legacy and new generation VHAs are compared on the basis of their unique hemostatic parameters that define contributions of coagulation factors, fibrinogen/fibrin, platelets, and clot lysis as related to the lifespan of a clot. In conclusion, we offer a brief discussion on the meteoric adoption of VHAs across the medical and surgical specialties to address COVID-19-associated coagulopathy.

Thrombosis is a major cause of mortality and morbidity in polycythemia vera (PV). The wide range of thrombotic events reflects the complex picture in PV. There are multiple factors involved in thrombogenesis in this disease, including increased hematocrit, thrombocytosis, impaired fibrinolytic activity, platelet activation, leukocyte activation, endothelial damage, interactions between platelets and endothelium, various modalities of therapy, and increased in whole-blood viscosity. Among them, the increase in blood viscosity, and hence the impairment of blood flow, is the major factor. In this article, the role of hyperviscosity in PV is reviewed. A high hematocrit occurs under PV and many other conditions with abnormal red blood cell aggregation. The impaired capillary blood flow results in neurological manifestations and increased bleeding risk in PV. Thrombotic complications can also occur in both arteries and veins and manifest as stroke, myocardial infarction, deep vein thrombosis, or pulmonary embolism. The hemodynamic principle is aptly applied in the management of PV. The most important objective is the reduction of the patient's hematocrit.

Whole blood viscosity is affected by a number of factors, among which plasma proteins are a major component. They exert their effects either directly or through their influence on red cell aggregation. Changes in fibrinogen and in immunoglobulins, under both physiologic and pathologic conditions can increase whole blood viscosity. Blood flow through the microvasculature is impaired when viscosity increases, leading to tissue ischemia and a syndrome complex usually referred to as the hyperviscosity syndrome. Abnormalities of fibrinogen greatly increase its ability to cause red cell aggregation, and is a contributory pathogenic factor in ischemic heart disease and stroke. Immunoglobulins may affect blood viscosity directly, or by increasing the red cell aggregation. Changes are seen in many clinical disorders, ranging from inflammatory diseases to plasma cell dyscrasias. The clinical manifestations may be mild and often unnoticed, or they may be life threatening requiring emergency plasmapheresis. Proper management requires a clear understanding of the underlying pathology. When the symptom complex indicates a high probability of the hyperviscosity syndrome, it should lead to early diagnosis and treatment. Therapeutic approaches should include both removing the abnormal plasma protein and treating the primary cause.

The expression of several components of the plasminogen–plasmin (P–P) system in tumor tissues has been shown to have prognostic significance in many human cancers, including those of the breast, prostate, lung, brain, ovary, stomach, colon, rectum, oral cavity, kidney, and bone. Mechanisms of action of the individual components have been extensively studied in tumor cells in vitro and in animal models. By interrupting various putative pathways involved in tumor progression in several experimental tumor models in animals, varying degrees of tumor control have been achieved. However, these efforts have thus far not been able to exert any impact in oncologic clinical practice. A possible explanation is our incomplete understanding of the complex involvement of the P–P system and its interactions with other tumorigenic factors. In this article, the role of various members of the P–P system in cancer is reviewed. Proteolysis via the urokinase-type plasminogen activator–plasminogen activation pathway tends to enhance tumor growth and invasion, and its natural inhibitor plasminogen activator inhibitor type 1 may also enhance tumor growth through the inhibition of apoptosis, enhancing cell proliferation and the promotion of angiogenesis. Meaningful drug designs for therapeutic intervention require a thorough understanding of the role of all of the components involved in this complex mechanism of tumor progression.