Elevated tissue factor pathway inhibitor is associated with intracerebral haemorrhage of unknown cause in young adults.

Clinical rationale for study: We have reported that intracerebral haemorrhage (ICH) of unknown cause at a young age is associated with lower prothrombin and factor VII and higher antithrombin activity, along with the formation of looser fibrin networks displaying enhanced lysability. Patients with mild-to-moderate bleeding of unknown cause have elevated levels of free plasma tissue factor pathway inhibitor alpha (fTFPIα), inhibiting the tissue factor-factor VII complex and prothrombinase.

Aim of study: We hypothesised that patients with an intracerebral haemorrhage (ICH) of unknown cause may also exhibit higher fTFPIα.

Material and methods: We studied 44 adults aged ≤ 50 years following ICH of unknown cause at least three months after the incident, and 47 controls matched for age, sex, BMI, and hypertension. We assessed fTFPIα levels along with plasma fibrin clot permeability, turbidity and fibrinolytic capacity, thrombin generation, coagulation factors, antithrombin, and fibrinolysis proteins.

Results: Patients following ICH had 10.8% higher median fTFPIα levels than controls (8.3 [7.6-9.5] vs. 7.4 [6.9-8.5] ng/mL; p = 0.006). fTFPIα was higher in males than in females both in the ICH group (p = 0.0004) and in controls (p = 0.007), and correlated with age (r = 0.38; p = 0.01), fibrinogen (r = -0.39, p = 0.009), PAI-1 antigen (r = -0.32, p = 0.035), and clot maximum absorbance (r = -0.30, p = 0.049), but not with other laboratory variables. Nine patients had fTFPIα levels lower the upper limit of the reference range (i.e. 11.5 ng/mL) and they had a longer lag phase of the turbidity curve (p = 0.023) and clot absorbance (p = 0.042). In univariate analysis, a 1 ng/mL increase in fTFPIα was associated with a 61% greater chance of having an ICH (OR 1.61, 95% CI 1.19-2.18) even after adjusting for potential confounders.

Conclusions: Patients with ICH of unknown cause under the age of 50 are characterised by elevated fTFPIα associated with changes in fibrin clot formation and faster PAI-1-dependent lysis.

Clinical implications: Our study might suggest a novel potential mechanism underlying ICH.