Fibrinogen Replacement to Prevent Intracranial Haemorrhage in Ischemic Stroke Patients After Thrombolysis: a Pilot Probe Randomized Controlled Trial (FibER)

Intravenous recombinant tissue plasminogen activator (rtPA) is the first recommended reperfusion therapy for acute ischemic stroke, as well as endovascular treatment in case of large vessel occlusion, but it increases the risk of ICH.

The pathophysiological mechanisms of ICH after i.v. thrombolysis in ischemic stroke is complex: hyperglycemia, early ischemic changes on neuroimaging, clinical stroke severity assessed by the National Institutes of Health Stroke Scale score (NIHSS) on admission, advanced age and high blood pressure are known risk factors for hemorrhagic cerebral transformations. The risk of bleeding is likely mediated by coagulopathy, reperfusion injury, and breakdown of blood-brain barrier.

The rtPA binds the plasminogen within the clot, converting it to plasmin, a proteolytic enzyme capable to dissolve the clot. However plasmin activity is not specific for clot-associated fibrin, but also breaks down other circulating proteins, including fibrinogen. An early fibrinogen degradation coagulopathy can occur after i.v. thrombolysis, that could be implicated in bleeding complications.

In 2002, it was shown how high levels of fibrin and fibrinogen degradation factors at 2 hours after rtPA could be a risk factor for early ICH.

Few years ago, the investigators published a work demonstrating that an early decrease in fibrinogen levels is a risk factor for ICH within the first 24 hours and 7 days after rtPA therapy in ischemic stroke patients. In this experience, the investigators collected data about ischemic stroke patients that experienced a severe hypofibrinogenemia after 2 hours from iv rtPA. All patient were treated with fibrinogen replacement, fibrinogen infusion was well tolerated, without any thrombotic complication, and the infusion of fibrinogen did not reduce the rate of recanalization and, therefore, did not negatively affect the chances of reopening the occluded vessel. These data agree with another study showing that prominent fibrinogen turnover after thrombolysis is a relevant cause of major bleeding complications, and specifically that a decrease >200 mg/dL in the fibrinogen level 6 hours after thrombolysis emerges as a significant and independent predictor for bleeding risk. Morover, other authors confirmed that the decrease of fibrinogen level less than 2 g/L in the first 2 hours after thrombolysis multiplies the odds of early parenchymal hematoma (PH) by a factor of 12.82 . Similarly, a large study about symptomatic intracerebral haemorrhage (sICH) showed that severe hypofibrinogenemia (<150 mg/dL) was associated with ICH expansion.