Inhibitor of the thrombin time in systemic amyloidosis: a common coagulation abnormality

Abstract

Patients with primary systemic amyloidosis (AL) often experience bleeding, and we report a newly recognized coagulation abnormality in AL. Of 103 patients with primary systemic AL studied over 2 years, 41 had prolongation of the thrombin time (range, 25 to 46 seconds; normal, less than 22 seconds) and reptilase time (range, 17 to 39 seconds; normal, 14 to 16 seconds). The fibrinogen from the plasma of 36 patients was precipitated by beta-alanine and diluted to a concentration of approximately 200 mg/dL. The thrombin times of the precipitated fibrinogens were normal in 34 patients, implying that an inhibitor was responsible for the abnormal tests. The addition of patient fibrinogen-free plasma to normal plasma prolonged the thrombin times, and this result confirmed the presence of an inhibitor. The inhibitor is more likely to be present in patients with nephrotic syndrome (20 of our patients) and congestive heart failure (six). A circulating monoclonal protein (24 patients), the presence of amyloid liver involvement (eight), and the presence of amyloid neuropathy (nine) were not predisposing factors. Only one patient had deficiency of factor X. We conclude that inhibition of fibrinogen conversion to a fibrin clot rather than dysfibrinogenemia is the cause of the prolonged thrombin time in primary systemic AL.

Bleeding symptoms and coagulation abnormalities in 337 patients with AL‐amyloidosis

“…Finally, our finding of a further independent association between prolongation of the TT and amyloid liver disease suggests that, in addition, some of our patients may show defective fibrinogen synthesis as a result of hepatic infiltration. These conclusions differ from those of a previous study in which it was also noted that prolongation of the TT was usually accompanied by prolongation of the RT and that there was an association with nephrotic syndrome (Gastineau et al, 1991). It was concluded from mixing studies that a thrombin inhibitor was present, although the possibility of hypoalbuminaemia was not considered in these experiments.…”

“…Multiple factor deficiencies and hypofibrinogenaemia have been described in amyloidosis in association with disseminated intravascular coagulation and increased fibrinolysis (Perlin et al, 1971;Liebman et al, 1983). Abnormalities of fibrin polymerization are common in the lymphoproliferative disorders, and one study reported that a thrombin inhibitor was the most frequent coagulation abnormality in AL-amyloidosis (Gastineau et al, 1991). Evidence that clotting factors may bind to amyloid (Furie et al, 1977(Furie et al, , 1981 and anecdotal reports of improved haemostasis after the removal of severely amyloidotic spleens (Greipp et al, 1981) have raised the possibility that clotting factors may be sequestered within amyloid in vivo.…”

Pathogenesis and management of bleeding and thrombosis in plasma cell dyscrasias

“…Thrombin conversion of purified fibrinogen to fibrin was normal in 34 of 36 patients with AL amyloidosis and prolonged thrombin times, ruling out acquired dysfibrinogenemia as the aetiology (Gastineau et al, 1991). However, the fibrinogen depleted plasma from the 36 patients retained TT inhibitor activity when added to purified thrombin and control fibrinogen, whether or not an M protein was detected (Gastineau et al, 1991). Additional studies to characterize the inhibitor activity in AL plasma have not been reported.…”

“…Concurrent prolongation of the RT and lack of correction with protamine rules out a circulating heparin-like anticoagulant. Prolonged TT and RT occur in primary amyloid patients with and without detectable serum M-proteins (Gastineau et al, 1991;Mumford et al, 2000) and in patients with AA amyloidosis associated with chronic infection (Yood et al, 1983), suggesting that interference is not due to intact or fragments of M-proteins. Thrombin conversion of purified fibrinogen to fibrin was normal in 34 of 36 patients with AL amyloidosis and prolonged thrombin times, ruling out acquired dysfibrinogenemia as the aetiology (Gastineau et al, 1991).…”

“…Prolonged TT and RT occur in primary amyloid patients with and without detectable serum M-proteins (Gastineau et al, 1991;Mumford et al, 2000) and in patients with AA amyloidosis associated with chronic infection (Yood et al, 1983), suggesting that interference is not due to intact or fragments of M-proteins. Thrombin conversion of purified fibrinogen to fibrin was normal in 34 of 36 patients with AL amyloidosis and prolonged thrombin times, ruling out acquired dysfibrinogenemia as the aetiology (Gastineau et al, 1991). However, the fibrinogen depleted plasma from the 36 patients retained TT inhibitor activity when added to purified thrombin and control fibrinogen, whether or not an M protein was detected (Gastineau et al, 1991).…”