fibrin and Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma

Serpinopathies, a group of diseases caused by mutations that disrupt the structurally sensitive serpins, have no known acquired cause. Interestingly, l-asparaginase treatment of acute lymphoblastic leukemia patients causes severe deficiency in the serpin antithrombin. We studied the consequences of this drug on antithrombin levels, activity, conformation, and immunohistological and ultrastructural features in plasma from acute lymphoblastic leukemia patients, HepG2 cells, and plasma and livers from mice treated with this drug. Additionally, we evaluated intracellular deposition of alpha1-antitrypsin. l-Asparaginase did not affect functional or conformational parameters of mature antithrombin; however, patients and mice displayed severe type I deficiency with no abnormal conformations of circulating antithrombin. Moreover, l-asparaginase impaired secretion of antithrombin by HepG2 cells. These effects were explained by the intracellular retention of antithrombin, forming aggregates within dilated endoplasmic reticulum cisterns. Similar effects were observed for alpha1-antitrypsin in plasma, cells, and livers, and intracellular aggregates of additional proteins were observed in frontal cortex and pancreas. This is the first report of a conformational drug-associated effect on serpins without genetic factors involved. l-Asparaginase treatment induces severe, acquired, and transient type I deficiency of antithrombin (and alpha1-antitrypsin) with intracellular accumulation of the nascent molecule, increasing the risk of thrombosis.

Topics: alpha 1-Antitrypsin; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Cell Line, Tumor; Electrophoresis, Polyacrylamide Gel; Factor Xa; Fibrin; Humans; Liver; Male; Mice; Microscopy, Electron, Transmission; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Conformation

We report two cases of atypical defibrination syndromes in patients with respectively acute monoblastic leukemia (chronic myeloid leukemia initially) and acute lymphoblastic leukemia. Hemostasis studies show low fibrinogen level, elevated D-dimers, decreased alpha 2 antiplasmin and factor V, normal antithrombin III values. Plasminogen is below the normal range in one patient. Soluble complexes, which are an important argument for diagnosis of intravascular coagulation disease, are not detected in both patients. Primary or secondary hyperfibrinolysis seems also excluded since euglobulin clot lysis time was normal. Enzymatic proteolysis of fibrinogen (or fibrin) by the blast cells has been reported by some authors; this mechanism could account for the hemostasis abnormalities observed in these two patients.

Topics: Adult; alpha-2-Antiplasmin; Antithrombin III; Diagnosis, Differential; Disseminated Intravascular Coagulation; Factor V Deficiency; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinolysis; Humans; Leukemia, Monocytic, Acute; Male; Neoplastic Stem Cells; Plasminogen; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Syndrome

Two girls with acute lymphocytic leukemia (ALL) are reported. There were difficulties in removing their central venous catheters inserted from a peripheral vein. One girl required surgery under general anesthesia for the removal. The other patient received continuous infusion of low dose urokinase from a distal peripheral vein. The residual catheter was then removed successfully.

Topics: Adolescent; Catheterization, Central Venous; Catheterization, Peripheral; Catheters, Indwelling; Child; Equipment Failure; Female; Fibrin; Humans; Infusions, Intravenous; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Urokinase-Type Plasminogen Activator