Fibrinolytic assays in bleeding of unknown cause: Improvement in diagnostic yield

Abstract

Introduction: Analysis of fibrinolytic disorders is challenging and may potentially lead to underdiagnosis of patients with an increased bleeding tendency.

Aim: To compare clinical characteristics, laboratory measurements, and treatment modalities in a monocenter cohort of patients in whom fibrinolytic studies were performed.

Methods: Retrospective study of patients in whom fibrinolytic studies were performed between January 2016 and February 2020 in the Hemophilia Treatment Center, Nijmegen-Eindhoven-Maastricht, the Netherlands. Plasminogen activator inhibitor type 1 (PAI-1) antigen and activity level, α2-antiplasmin activity, tissue plasminogen activator, and euglobulin clot lysis time (ECLT) before and after venous compression were determined in all patients. Data of bleeding assessment tool (BAT) score, clinical characteristics, results of primary and secondary hemostasis assays, and general treatment plans were collected.

Results: In total, 160 patients were included: 97 (61%) without and 63 (39%) with a laboratory-based fibrinolytic disorder. Mean BAT score did not differ between the groups (9.3 vs 9.8, respectively). The presumptive fibrinolytic disorders were distributed as follows: 34 patients had an increased ECLT ratio or low baseline ECLT, 25 patients had low PAI-1 antigen and activity level, and four patients had both. The majority of these patients were treated with tranexamic acid monotherapy (60%) with only 40% additional treatment options, whereas 80% of patients without a presumptive fibrinolytic disorder had multiple treatment modalities.

Discussion: Analysis of fibrinolytic disorders in selected patients has a high diagnostic yield. General incorporation of fibrinolytic analysis in the diagnostic workup of patients with bleeding of unknown cause can improve diagnosis and management of their bleeding episodes.

Keywords: bleeding of unknown cause; fibrin clot lysis time; fibrinolysis; plasminogen activator inhibitor 1; tissue plasminogen activator; tranexamic acid.

FIGURE 1

Flow diagram of patients included. Increased euglobulin clot lysis time (ECLT) ratio was defined as a ratio >5.7 or patients with a short ECLT at baseline (<116 min). Low PAI‐1 is defined as a PAI‐1 activity level ≤1.0 ng/ml in combination with a PAI‐1 antigen level <3.4 ng/ml. PAI‐1, plasminogen activator inhibitor type 1

FIGURE 2

BAT score of patients included in the study, divided according to the results of fibrinolysis studies. Total BAT score of the patients without (gray) and with a presumptive fibrinolytic disorder (purple). Right, the patients with a fibrinolytic disorder are subdivided in patients with an increased euglobulin clot lysis time (ECLT) ratio or short baseline ECLT (red), patients with a low PAI‐1 antigen and activity level (ag and act; blue), and patients with both a high ECLT ratio and low PAI‐1 antigen and activity level (green). Box represents median with interquartile range, whiskers indicate range. BAT, bleeding assessment tool; PAI‐1, plasminogen activator inhibitor type 1

FIGURE 3

Results of euglobulin clot lysis time ratio and tissue plasminogen activity (tPA) after compression. (a) Result of the euglobulin clot lysis time (ECLT) ratio in the group without (gray) and with a presumptive fibrinolytic disorder (purple). To the right of the line, ECLT ratio in patients with an increased ECLT ratio or short baseline ECLT (red), patients with a low PAI‐1 antigen and activity level (blue), and patients with both an increased ECLT ratio and low PAI‐1 antigen and activity level (green). (b) tPA after venous compression in patients without (gray) and with a presumptive fibrinolytic disorder (purple). To the right of the dotted line, tPA in patients with only an increased ECLT ratio or short baseline ECLT (red), patients with a low PAI‐1 antigen and activity level (blue), and patients with both an increased ECLT ratio and low PAI‐1 antigen and activity level (green). In panels a and b, box represents median with interquartile range, whiskers indicate range. PAI‐1, plasminogen activator inhibitor type 1

FIGURE 4

Results of PAI‐1 antigen and activity level. (a) PAI‐1 antigen level (on left y‐axis) and PAI‐1 activity level (on right y‐axis) in patients without (gray) and with a presumptive fibrinolytic disorder (purple). (b) PAI‐1 antigen level (left y‐axis) and PAI‐1 activity level (right y‐axis) in patients with only a high ECLT ratio (red), patients with a low PAI‐1 antigen and activity level (blue), and patients with both a high ECLT ratio and low PAI‐1 antigen and activity level (green). Box represents median with interquartile range, whiskers indicate range. *Low PAI‐1 was defined as a PAI‐1 activity level ≤1.0 ng/ml; therefore, almost no values are shown. Three patients had a PAI‐1 activity level of 0.5 ng/ml. ECLT, euglobulin clot lysis time; PAI‐1, plasminogen activator inhibitor type 1