Leukomogenesis as a Toxic Response

Human Leukemias
Leukemias are proliferative disorders of hematopoietic tissue that originate from individual bone marrow cells. It has been classified as myeloid or lymphoid, referring to the major lineages for erythrocytes/granulocytes/thrombocytes or lymphocytes.

Acute Leukemias
Acute lymphoblastic leukemia (ALL) Avute myelogenous leukemia (AML)

Chronic Leukemias
Chronic lymphocytic leukemias (CLL) Chronic myelogenous leukemias (CML) Myelodysplastic syndromes (MDS)

Mechanisms of Toxic Leukomogenesis

Acute myelogenesis leukemia (AML) is the dominant leukemia associated with drug or chemical exposure, followed by myelodysplastic syndromes (MDS). This represents a continuum of one toxic response that has been linked to cytogenetic abnormalities, particularly the loss of all or part of chromosomes 5 and 7. AML patients occupationally exposed to benzene, who also show aneuploidy with a high frequency of involvement of chromosome 7.

Leukemogenic Agents
Most alkylating agents used in cancer chemotherapy can cause MDS and/or AML. Benzene leukemogenic Treatment with the topoisomerase II inhibitors, etoposide and teniposide can induce AML. Exposure to high-dose y- or x-ray radiations has long been associated with ALL, AML and CML. Controversial agents: 1,3-butadiene, nonionizing radiation (electromagnetic, microwave, infrared and the high end of the ultraviolet spectrum), cigarette smoking and form aldehyde.

Toxicology of Platelets and Hemostasis

 Hemostasis is a multicomponent system responsible for preventing the loss of blood from sites of vascular injury and maintaining circulating blood in a fluid state. Loss of blood is prevented by formation of stable hemostatic plugs. The major constituents of the hemostatic system include circulating platelets, a variety of plasma proteins and vascular endothelial cells. Alterations in these components or systemic activation of this system can lead to the clinical manifestations or deranged hemostasis, including excessive bleeding and thrombosis. The hemostatic system is a frequent target of therapeutic intervention as well as inadvertent expression of the toxic effect of a variety of xenobiotics.

Toxic Effects on Platelets

The Thrombocyte Platelets are essential for formation of a stable hemostatic plug in response to vascular injury. It adheres to the damaged wall. Xenobiotics may interfere with the platelet response by causing thrombocytopenia or interfering with platelet function.

Thrombocytopenia May be due to decreased production or increase destruction. It is a common side effect of intensive chemotherapy, due to the predictable effect of antiproliferative agents of hematopoietic precursors. Exposure to xenobiotics may caused increased destruction through any one of the several mechanisms. A second mechanism of immune thrombocytopenia is initiated by change in a platelet membrane glycoprotein caused by the xenobiotic.

 Thrombocytopenia is an uncommon but serious complication of inhibitors of factors involved in the clot-formation cascade. These inhibitors can change the conformation of these factors, causing exposure of certain peptides (called neoepitopes because they are newly exposed to the immune system) on the factors that react with endogenous antibodies. Exposure of epitopes that react with naturally occurring antibodies represents a third mechanism of immune mediated platelet destruction.

 Heparin-induced thrombocytopenia (HIT) represents a fourth mechanism of immune-mediated platelet destruction. Thrombotic thrombocytopenia purpura (TTP) is a syndrome characterized by the sudden onset of thrombocytopenia, a microangiopathic haemolytic anemia and multisystem organ failure.

Toxic Effects on Platelet Function Platelet function is dependent on the coordinated interaction of a number of biochemical response pathways. Major drug groups that affect platelet function include NSAIDS, lactam-containing antibiotics, CVS drugs, particularly beta blockers, psychotrophic drugs, anesthetics, antihistamines and some chemotherapeutic agents.