thromboplastin and Hodgkin-Disease

We demonstrated previously that selective thrombosis of the blood vessels of solid tumors in mice can be achieved by targeting the extracellular domain of tissue factor by means of an antibody to an experimentally induced marker on tumor vascular endothelium. In the present study, we extend this finding to a naturally occurring marker of tumor vascular endothelium, vascular cell adhesion molecule-1 (VCAM-1). VCAM-1 is expressed by vascular endothelial cells in Hodgkin's disease and various solid tumors in mice and humans. It is absent from vascular endothelial cells in normal tissues in mice, with the exception of the heart and lungs, where it is present on venules. A monoclonal antibody to murine VCAM-1 was covalently linked to the extracellular domain of human tissue factor to create a "coaguligand." After i.v. administration to severe combined immunodeficient mice bearing human Hodgkin's tumors, the coaguligand localized selectively to VCAM-1-expressing vessels, caused thrombosis of those vessels, and retarded tumor growth. The coaguligand also localized to VCAM-1-expressing vessels in the heart and lungs of the mice but did not induce thrombosis in these sites. An immunohistochemical evaluation of the distribution of a monoclonal anti-phosphatidylserine (PS) antibody in the mice showed that the VCAM-1-expressing vessels in the tumor expressed PS, whereas the VCAM-1-expressing vessels in the heart and lungs lacked PS. The lack of thrombotic effect of the coaguligand on heart and lung vessels may be because PS is needed to provide the procoagulant surface upon which coagulation complexes can assemble. The requirement for coincident expression of the targeted marker and PS on tumor endothelium probably contributes to the selectivity of thrombotic action and the safety of coaguligands.

Topics: Animals; Antibodies, Monoclonal; Factor V; Hodgkin Disease; Humans; Male; Mice; Mice, SCID; Phosphatidylserines; Rats; Thromboplastin; Thrombosis; Vascular Cell Adhesion Molecule-1

Thrombosis is a recognized complication of Hodgkin's disease. The mechanism for thrombosis in this setting is not known. We determined the functional expression of tissue factor on peripheral blood monocytes in 14 consecutive patients with relapsed Hodgkin's disease. Marked elevations in activity were present in slightly more than half of the subjects. Tissue factor activities varied over 75-fold. Patients with higher tissue factor levels tended to be males who had not undergone splenectomy as part of their staging evaluation. Definite thrombotic complications occurred in three of the patients with the highest levels of tissue factor. While monocyte tissue factor may play a contributory role in the development of thrombotic complications in some patients with relapsed Hodgkin's disease, marked elevation of tissue factor is characteristic of only a subpopulation of these patients. This suggests that patient-, therapy- or disease-specific variables, including tissue factor, may determine the development of thrombosis in these patients.

Topics: Adult; Bone Marrow Transplantation; Catheters, Indwelling; Female; Hodgkin Disease; Humans; Male; Middle Aged; Monocytes; Reference Values; Splenectomy; Stem Cell Transplantation; Thromboplastin; Thrombosis

Endothelial cell activation and alterations of intravascular coagulation were investigated in 27 cases of Hodgkin's disease (HD), in five cases of anaplastic large cell lymphoma (ALCL), and in ten reactive lymph nodes. Lymph node sections were immunostained for E-selectin, a molecule present on cytokine-activated endothelial cells; for tissue factor (TF), a cellular initiator of the coagulation cascade; for glycoprotein (gp) II/III, a platelet-specific antigen; and for fibrin. In HD, vascular activation was particularly prominent in the nodular sclerosis subtype, as indicated by a larger number of E-selectin-positive blood vessels (72 +/- 49) compared with mixed cellularity (22 +/- 37). High expression of E-selectin was associated with alterations of intravascular coagulation, as indicated by immunostaining of some vascular endothelial cells for TF, by a higher incidence of intravascular thrombi, and by the extensive presence of areas of fibrin exudation and necrosis. In ALCL, the levels of endothelial cell activation and intravascular coagulation were comparable to those of HD nodular sclerosis. In reactive nodes, some E-selectin-positive blood vessels were observed only in 3/10 cases; immunostaining for TF was not detected on endothelial cells; and alterations of intravascular coagulation were rarely observed.

Topics: Adolescent; Adult; Aged; Cell Adhesion Molecules; E-Selectin; Endothelium, Vascular; Female; Fibrin; Hodgkin Disease; Humans; Lymph Nodes; Male; Middle Aged; Necrosis; Neoplasm Proteins; Regional Blood Flow; Thromboplastin; Thrombosis

Nonmalignant lymphoid tissue and tissue from patients with nodular sclerosis, Hodgkin's disease, and large cell lymphocytic lymphoma was examined by immunohistochemical techniques for the occurrence in situ of components of coagulation and fibrinolysis reaction pathways. Staining for material interpreted as fibrinogen was observed in abundance in both malignant and reactive lymphoid tissue. Fibrin also occurred to a variable extent but focally in all tissues. Components of coagulation pathways, including tissue factor, factor VII, factor X, and factor XIII ("a" subunit), were restricted to tissue macrophages. Double-labeling techniques revealed fibrin in direct apposition to tissue macrophages. We conclude that fibrinogen and fibrin occur in both benign and malignant lymphoid tissue and that the transformation of fibrinogen to fibrin is attributable to macrophage-initiated thrombin formation. We postulate that both systemic and local hypercoagulability associated with these disorders may be attributable to macrophage activation resulting in expression of procoagulant activity.

Topics: Adolescent; Adult; Aged; Factor VII; Factor VIII; Factor X; Female; Fibrin; Fibrinogen; Fibrinolysis; Hodgkin Disease; Humans; Immunohistochemistry; Leukemia, Lymphocytic, Chronic, B-Cell; Lymph Nodes; Lymphoid Tissue; Lymphoma, Large B-Cell, Diffuse; Macromolecular Substances; Macrophages; Male; Middle Aged; Sclerosis; Thromboplastin

Procoagulant activity of peripheral blood mononuclear leucocytes was studied in 24 consecutive patients with Hodgkin's disease. Mononuclear cells, tested immediately after isolation, expressed very low activity which was, however, somewhat higher than that of cells from a matched control group (P = 0.063). Procoagulant activity generated by patients' mononuclear cells following stimulation with bacterial endotoxin was significantly higher than that produced by control cells (P less than 0.01). There was no apparent relation between procoagulant activity and pathological staging. The increased capacity of mononuclear phagocytes to produce procoagulant activity might help explain activation of blood coagulation and subsequent fibrin deposition in patients with Hodgkin's disease.

Topics: Adult; Endotoxins; Female; Hodgkin Disease; Humans; Lymphocyte Activation; Male; Middle Aged; Monocytes; Neoplasm Staging; Phytohemagglutinins; Thromboplastin

Topics: Adult; Autoantibodies; Autoimmune Diseases; Complement Fixation Tests; Cyclophosphamide; Hodgkin Disease; Humans; Isoantibodies; Male; Prednisone; Remission, Spontaneous; Splenectomy; Thrombocytopenia; Thromboplastin