Excessive fibrinolysis in AL-amyloidosis is induced by urokinae-type plasminogen activator from bone marrow plasma cells

Abstract

Activation of fibrinolysis system and excessive fibrinolysis are observed in monoclonal antibody light chain (AL)-amyloidosis. However, the mechanisms by which activation of fibrinolysis occurs in AL-amyloidosis have not been fully elucidated. To determine whether urokinase type-plasminogen activator (uPA), an important activator of fibrinolytic system, contributes to the activation of fibrinolytic system in AL-amyloidosis, we immunohistologically examined uPA in bone marrow plasma cells. More than 90% of bone marrow plasma cells from five different AL-amyloidosis patients were uPA-positive as examined with immunohistochemical staining. All the bone marrow plasma cells from seven different patients with multiple myeloma were uPA-negative. A patient with AL-amyloidosis, who had bleeding diathesis and excessive fibrinolysis with hypofibrinogenemia, was treated with nafamostat mesilate, a potential inhibitor of uPA. After the administration of nafamostat mesilate, the bleeding diathesis disappeared, and excessive fibrinolysis and hypofibrinogenemia were improved. The present data suggested that uPA expressed in plasma cells may have contributed to the pathogenesis of excessive fibrinolysis.

Prevalence and prognostic value of D‐dimer elevation in patients with AL amyloidosis

“…In this study, a clinically significant VTE was seen in only 71 patients, although it is possible that additional patients had undetected venous or arterial thrombi, as asymptomatic patients were not screened for the presence of a thrombus. Activation of fibrinolysis may also lead to D‐dimer elevation, as the fibrinolytic pathway is known to be active in AL amyloidosis and could be the mechanism by which many patients have an increased bleeding risk . Additionally, the elevation in D‐dimer may be related to the underlying endothelial dysfunction and abnormal vascular morphology found in AL amyloidosis .…”

“…The organs most commonly affected in this disease are the kidneys, heart, liver, and nerves. In addition, dysregulated coagulation, with bleeding and clotting complications, has also been reported . Bleeding diatheses in AL amyloidosis are often related to factor deficiencies, with Factor X deficiency being the most widely studied .…”

“…Bleeding diatheses in AL amyloidosis are often related to factor deficiencies, with Factor X deficiency being the most widely studied . In addition, increased fibrinolysis has also been reported as a mechanism of heightened bleeding risk in AL amyloidosis …”

Elevation of Plasmin-α2-plasmin Inhibitor Complex Predicts the Diagnosis of Systemic AL Amyloidosis in Patients with Monoclonal Protein

“…Fibrinolysis is known to be exacerbated in patients with systemic AL amyloidosis ( 3 , 6 - 10 ). A few studies have reported elevated levels of plasmin-α2-plasmin inhibitor complex (PIC) in patients with systemic amyloidosis ( 3 , 6 , 8 , 10 ). However, whether or not the elevation of PIC is specific to patients with systemic AL amyloidosis or common in patients with serum monoclonal protein is unclear.…”

Coagulation and fibrinolysis abnormalities in familial amyloid polyneuropathy

“…Amyloidogenic mutated transthyretin (TTR) is the most common FAP-related protein worldwide [1]. Several studies reported coagulation factor X (FX) deficiency and excessive fibrinolysis in immunoglobulin light chain amyloidosis (AL amyloidosis) patients [2][3][4]. However, few have investigated coagulation and fibrinolysis in FAP.…”