Fibrinogen replacement could prevent haemorrhagic complications in ischemic stroke patients with secondary post-rtPA hypofibrinogenemia

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.

The correction of the coagulopathy after rtPA remained the mainstay of treatment for sICH after

thrombolysis, but no specific agent has been shown to be most effective. Data from other disease states, however, raise the possibility that certain agents not routinely used, may be effective. As regard, in the consensus statement of 2017, American Heart Association Stroke (AHA) Council investigated possible treatments for sICH after rtPA in ischemic stroke patients, evaluating the role of cryoprecipitate, prothrombin complex concentrate, fresh frozen plasma, antifibrinolytic agents, platelets, Factor VI and vit. K. In particular, infusion of cryoprecipitate was suggested because it contains fibrinogen, that corrects dysfibrinogenemia. In particular, if sICH is diagnosed, physicians were recommended to consider immediately sending a blood sample for fibrinogen level and empirically transfusing with 10 U cryoprecipitate and anticipate giving more cryoprecipitate as needed to achieve a fibrinogen level of >150 mg/dL.

Indeed, several studies in other different medical fields, suggested fibrinogen supplementation with anti- haemorrhagic purposes in patients with severe haemorrhages and related fibrinogen deficiency, following trauma and surgery.

The investigators had previously analysed the trend of fibrinogen decrease after i.v. rtPA in 56 ischemic patients taking fibrinogen dosage at 2, 6, 12 and 24 hours from rtPA infusion: fibrinogen level drops within the first 2 hours and then slowly increases in the following 24 hours, still being lower than basal fibrinogen value. Dividing patients in two subgroups according to pre-rtPA fibrinogen level, a higher baseline fibrinogen resulted in higher risk of deep decrease in fibrinogen value. Medical literature about the rate of thrombotic complication after fibrinogen concentrate administration in stroke patients is relatively lacking. However, experiences in cardiac surgery showed that administration of fibrinogen concentrate was not associated with an increased risk of mortality and thromboembolic events, and a recent Cochrane review on fibrinogen concentrate in bleeding patients, did not show any adverse events such as thrombotic episodes following the use of fibrinogen concentrate.

In a pilot experience, the investigators administrated i.v. fibrinogen in 39 patients with severe hypofibrinogenemia after 2 hours from i.v. rtPA. Fibrinogen infusion was well tolerated: no thrombotic complications occurred in 37 out of 39 patients (94.77%). Two patients developed pulmonary embolism, of which 1 was only segmental and 1 in an active cancer patient. Moreover fibrinogen replacement did not reduce the rate of recanalization, so it did not negatively affect the chances of reopening the occluded vessel.

Inclusion criteria:

• patients with acute ischemic stroke treated with i.v. thrombolysis (rtPA 0,9 mg/Kg, 10% in bolus and 90% in infusion in 60 minutes)
• age >18 years
• critical hypofibrinogenemia post-tPA, defined as a decrease of serum fibrinogen level <200 mg/dl and/or a rate decrease >50% than baseline level
• written informed consent

Exclusion criteria:

• contraindication to rtPA treatment;
• patients who present symptomatic ICH during infusion of rt-PA,
• absence of written informed consent

blinded-endpoint (PROBE)