Elevated urokinase‐type plasminogen activator level and bleeding in amyloidosis: Case report and literature review

Abstract

Hyperfibrinolytic states are reported to be a cause of bleeding in patients with amyloidosis. We reviewed the literature on excessive fibrinolysis in association with amyloidosis and report our findings from a patient with idiopathic amyloidosis who developed a bleeding diathesis. Coagulation laboratory studies indicated elevated plasminogen activator levels associated with a reduction of plasminogen and alpha 2-plasmin inhibitor (alpha 2-PI) levels. The level of tissue-type plasminogen activator (t-PA) inhibitor and t-PA antigen were normal. However, the patient did have a five- to sevenfold increase in amidolytic activity for the urokinase substrate pyro-Glu-Gly-Arg-pNA (S-2444). This case therefore represents a novel example of a hyperfibrinolytic state associated with amyloidosis caused by elevated urokinase-type plasminogen activator (u-PA). Epsilon-amino caproic acid (EACA) therapy resulted in an increase in alpha 2-PI and plasminogen levels and effectively reduced the blood loss. Hyperfibrinolytic states in amyloidosis have now been reported to be due to elevated t-PA and u-PA and depleted t-PA inhibitor.

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

“…In addition, nafamostat mesilate, an inhibitor of uPA [6], improved excessive fibrinolysis and hypofibrinogenemia. These results were consistent with previous observation in which uPA levels increased in ALamyloidosis [4,5] and indicate that uPA produced from bone marrow plasma cells initiates activation of fibrinolytic system. Bleeding diathesis is observed in patients of congenital, especially homozygous, deficiency of a 2 -antiplasmin [8].…”

“…Activation of fibrinolysis system is initiated by plasminogen activators (PA), either tissue plasminogen activator (tPA) or urokinase-type plasminogen activator (uPA). tPA plays a predominant role in the physiological clot lysis; the level of tPA is normal in AL-amyloidosis [4]. In contrast, levels of uPA were increased in patients with AL-amyloidosis [4,5].…”

“…tPA plays a predominant role in the physiological clot lysis; the level of tPA is normal in AL-amyloidosis [4]. In contrast, levels of uPA were increased in patients with AL-amyloidosis [4,5]. However, precise mechanisms by which uPA increases in AL-amyloidosis are not clarified.…”

Serum, salivary, and tissue levels of plasminogen in familial Mediterranean fever, amyloidosis, and chronic periodontitis

“…However, patients with FMF‐associated amyloidosis had severe chronic inflammation and activation (assessed histopathologically), increased severity of the clinical periodontal parameters, and higher salivary PLG levels (clinically) when compared with patients with FMF without amyloidosis and the systemically healthy controls. Patients with amyloidosis are in a hyperfibrinolytic state due to elevated t‐PA and urokinase‐type PA and a depleted t‐PA inhibitor . Increased amidolytic activity for the urokinase substrate pyro‐Glu‐Gly‐Arg‐pNA is observed in patients with amyloidosis, although t‐PA inhibitor and t‐PA antigen levels are normal .…”

Bleeding and Thrombosis Risks in Plasma Cell Dyscrasias

“…7,23 In rare cases of multiple myeloma complicated by severe bleeding, paraproteins with specificity for thrombin 24 and factor VIII 7 have been identified. Both solid tumors and multiple myeloma have been associated with rare cases of acquired hyperfibrinolysis due to excess release of tissue plasminogen activator or urokinase-type plasminogen activator, 25 and circulating heparin-like anticoagulants. 26,27 Although the pathophysiology of both of these hemostasis disorders remains obscure, treatment with protamine infusions and antifibrinolytics respectively has been effective.…”