Thrombin and plasmin generation in patients with plasminogen or plasminogen activator inhibitor type 1 deficiency

Abstract

Introduction Deficiencies of plasminogen and plasminogen activator inhibitor type 1 (PAI‐1) are rare disorders of fibrinolysis. Current laboratory assays for analysis of activity of plasminogen and PAI‐1 do not provide an accurate correlation with clinical phenotype. Methods The Nijmegen Hemostasis Assay (NHA) was used to simultaneously measure thrombin and plasmin generation in 5 patients with plasminogen deficiency (PLGD) and 10 patients with complete PAI‐1 deficiency. Parameters analysed included: lag time ratio, thrombin peak time ratio, thrombin peak height, thrombin potential (AUC), fibrin lysis time, plasmin peak height and plasmin potential. Parameters were expressed as a percentage compared to a reference value of 53 healthy normal controls. Results Patients with PLGD demonstrated a short lag time and thrombin peak time, with normal thrombin peak height but an increased AUC. Plasmin generation was able to be detected in only one (23% plasminogen activity) of the five PLGD patients. All ten PAI‐1 deficient patients demonstrated a short lag and thrombin peak time, low thrombin peak height with normal AUC. Plasmin generation revealed an increased plasmin peak and plasmin potential; interestingly, there was a large variation between individual patients despite all patients having the same homozygous defect. Conclusion Patients with either PLGD or PAI‐1 deficiency show distinct abnormalities in plasmin and thrombin generation in the NHA. The differences observed in the propagation phase of thrombin generation may be explained by plasmin generation. These results suggest that disorders of fibrinolysis also influence coagulation and a global assay measuring both activities may better correlate with clinical outcome.

Functional Fibrinolysis Assays Reveal Different Mechanisms underlying Plasminogen Dysfunction in Ligneous Conjunctivitis

“…by urokinase. In agreement with the results of the cell-based ECLT assay, the K19E/other group had a significantly decreased urokinase-induced plasmin formation rate compared with controls (26 [22][23][24][25][26][27][28] vs. 41 [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51] mDO/min À1 , p < 0.05; ►Fig. 4C).…”

“…Similar results have been recently found in LC patients with inherited PLG deficiency using a turbidimetric t-PA resistance assay and a t-PA plasmin generation assay. 25,26 These results suggest that t-PA-based functional assays could provide a reliable tool to predict clinical expression in PLG deficiency. In contrast, the fact that some LC patients had normal urokinase-induced PLG activity indicate that urokinase-dependent assays might not be adapted for such purposes.…”

Thrombin generation abnormalities in Quebec platelet disorder

“…Furthermore, some QPD PRP TG abnormalities (eg, reduced peak thrombin concentration) resemble those of PAI-1-deficient PPP tested with added tPA. 24 It remains possible that other pathological changes to QPD platelets contribute to their TG abnormalities, including the deficiency of MMRN1. We studied TG without thrombomodulin, as recommended for bleeding disorder investigations.…”

“…22,23 The greater effects of TXA (a lysine analogue that inhibits fibrinolysis) on PRP compared to PPP TG are interesting and could reflect that platelets express uPAR 37 and release polyphosphate that also enhances plasmin generation. 38 It would be interesting to determine if TXA improves or corrects the TG abnormalities of severe PAI-1-deficient samples, 24 in TG assays of PPP and PRP, with or without added uPA and tPA. Both plasma and platelets contain plasminogen, 7 and we could not obtain plasminogen-deficient PRP to further verify that TXA improves TG by inhibiting plasmin generation.…”

“…Some fibrinolytic disorders do not alter TG, and adding tissue plasminogen activator (tPA) to normal PPP has minimal effects on TG 22,23 . In TG assays with added tPA, severe PAI‐1‐deficient PPP shows a shortened lag time, shortened time to peak TG, and reduced peak thrombin concentration that have been attributed to increased activation, and inactivation, of multiple coagulation factors by plasmin 24 . As QPD increases platelet uPA and depletes platelets of active PAI‐1, 10 it might similarly alter TG.…”