Alterations of coagulation and fibrinolysis in patients with angioedema due to C1-inhibitor deficiency

Abstract

Patients with functional deficiency of C1-inhibitor (C1-INH) suffer from recurrent acute attacks (AA) of localized oedema associated with activation of the contact system, complement and fibrinolysis. To unravel further the role of coagulation and fibrinolysis in the pathophysiology of C1-INH deficiency, we performed simultaneous thrombin and plasmin generation measurements in plasma from patients with hereditary angioedema (HAE) due to C1-INH deficiency during AA (n = 23), in remission (R) (n = 20) and in controls (n = 20). During AA thrombin generation after in-vitro activation of plasma was higher than in controls, as demonstrated by shorter thrombin peak-time (P < 0·05), higher thrombin peak-height (P < 0·001) and increased area under the curve (AUC) (P < 0·05). Additionally, elevated levels of prothrombin fragment 1+2 (P < 0·0001) were observed in non-activated plasma from the same patients. In contrast, in activated plasma from patients during AA plasmin generation estimated as plasmin peak-height (P < 0·05) and plasmin potential (P < 0·05) was reduced, but non-activated plasma of the same patients showed elevated plasmin-anti-plasmin (PAP) complexes (P < 0·001). This apparent discrepancy can be reconciled by elevated soluble thrombomodulin (sTM) (P < 0·01) and thrombin activatable fibrinolysis inhibitor (TAFI) in patients during AA providing possible evidence for a regulatory effect on fibrinolysis. Plasminogen activator inhibitor-1 (PAI-1) was reduced in patients during AA indicating, together with the observed reduction of plasmin generation, the consumption of fibrinolytic factors. In conclusion, our results support the involvement of coagulation and fibrinolysis in the pathophysiology of HAE and show the possible application of simultaneous measurement of thrombin and plasmin generation to evaluate different clinical conditions in HAE patients.

Fig. 1

Thrombin generation in patients with C1-inhibitor (C1-INH) deficiency. Thrombin peak-time (min) (a), thrombin peak-height (nM) (b), and area under the curve (AUC, nM/min) (c), in healthy controls, patients during acute attacks (AA) and in remission (R). The horizontal lines indicate median values.

Fig. 2

Correlation between coagulation parameters in patients with C1-inhibitor (C1-INH) deficiency. (a) Correlation between C1-INH activity (%) and area under the curve (AUC) (nM/min) (b) correlation between F1+2 (pmol/l) and AUC (nM/min). Solid line represents the correlation for the patient under acute attacks (AA). Filled circles refer to patients with AA and open circles refer to patients in remission (R). r, Pearson's correlation coefficient.

Fig. 3

Evaluation of fibrinolysis in patients with C1-inhibitor (C1-INH) deficiency. Plasmin peak-height (nM) (a), and plasmin potential (nM/min) (b) in healthy controls, patients with C1-INH deficiency during acute attacks (AA) and during remission (R). The horizontal lines indicate median values.

Fig. 4

Soluble thrombomodulin (sTM) antigen, thrombin activatable fibrinolysis (TAFI) activity and plasminogen activator inhibitor-1 (PAI-1) activity levels in patients with C1-inhibitor (C1-INH) deficiency. sTM antigen, levels were measured in plasma of healthy controls and patients with C1-INH deficiency during acute attacks (AA) and during remission (R). Due to limited sample supply we could measure TAFI and PAI-1 only in a subgroup of patients. The dashed lines indicate upper and lower limit of the normal reference range. The horizontal solid lines indicate median values.