
Hemorrhagic transformation is a complication of ischemic stroke. It is a feared consequence of thrombolytic therapy, but it can also occur naturally. Hemorrhagic transformation can be divided into two categories: hemorrhagic infarction (petechial hemorrhages) and parenchymal hematoma. The former is usually benign, but the latter can be life-threatening. Hemorrhagic transformation occurs in 10-40% of ischemic strokes, depending on individual factors. The risk of hemorrhagic transformation is increased by the use of thrombolytic therapy, especially if it is administered outside of the recommended time window.
Characteristics | Values |
---|---|
--- | --- |
Incidence | 10-40% |
Time of occurrence | 1-2 weeks after stroke |
Risk factors | Age, cardioembolic stroke etiology, low serum cholesterol, elevated systolic blood pressure, thrombolytic therapy, high blood pressure, high blood sugar, low platelet count, anticoagulant/international normalized ratio/partial thromboplastin time, atrial fibrillation, congestive heart failure, renal impairment, previous stroke, antiplatelet treatment, body weight, ferritin level, history of high serum glucose or hypertension, hypertension or hyperglycemia at the onset of the stroke, INR, antiplatelet usage or the platelet count |
Treatment | IV transfusion of cryoprecipitate, medication to lower blood pressure, surgery to relieve pressure on the brain |
Prognosis | Poor, can lead to death |
What You'll Learn
Risk factors for hemorrhagic transformation
Hemorrhagic transformation is a complication of cerebral ischemic stroke and can significantly worsen prognosis. Here are some risk factors for hemorrhagic transformation:
- Cardioembolic stroke etiology - This is a common predictor for any intracerebral hemorrhage after reperfusion therapies.
- Low serum cholesterol - Lower cholesterol levels are associated with a higher risk of hemorrhagic transformation.
- Elevated systolic blood pressure in the acute setting - This is a common risk factor for hemorrhagic transformation, and it can lead to worse outcomes.
- Thrombolytic therapy or other recanalization - Thrombolytic therapy, such as tissue plasminogen activator (tPA), is a common treatment for ischemic stroke, but it can also increase the risk of hemorrhagic transformation.
- Age - Older age is a risk factor for hemorrhagic transformation, especially in those over 80.
- High blood pressure - High blood pressure is a risk factor for hemorrhagic transformation, and it can lead to worse outcomes.
- High blood sugar - High blood sugar levels are associated with a higher risk of hemorrhagic transformation and worse outcomes.
- Atrial fibrillation - Atrial fibrillation is a common predictor for any intracerebral hemorrhage after reperfusion therapies.
- Stroke severity - A higher score on the National Institutes of Health Stroke Scale (NIHSS) is associated with a higher risk of hemorrhagic transformation.
- Size of infarct - Larger infarcts, particularly in the middle cerebral artery territory, are associated with a higher risk of hemorrhagic transformation.
- Previous stroke - A history of previous stroke is a risk factor for hemorrhagic transformation.
- Antiplatelet treatment - Previous use of antiplatelet medications is a risk factor for hemorrhagic transformation.
- Neutrophil-to-lymphocyte ratio - A higher neutrophil-to-lymphocyte ratio is associated with an increased risk of hemorrhagic transformation.
- Renal impairment - Renal dysfunction is a risk factor for hemorrhagic transformation, especially in those with severe renal impairment.
- Hyperdense artery sign - This is a radiographic finding that indicates a higher clot burden and is associated with a higher risk of hemorrhagic transformation.
- Early ischemic changes - Early ischemic changes on CT scans, such as hypodensity and swelling, are associated with a higher risk of hemorrhagic transformation.
- Number of thrombectomy passes - A higher number of thrombectomy passes during endovascular thrombectomy is associated with an increased risk of hemorrhagic transformation.
- Use of the Merci Device - The use of the Merci Device during endovascular thrombectomy is associated with an increased risk of hemorrhagic transformation.
- Statin use - Statin use is associated with an increased risk of hemorrhagic transformation, particularly in the first few days after a stroke.
- Onset-to-treatment time - A longer time from stroke onset to treatment is associated with an increased risk of hemorrhagic transformation.
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The impact of rtPA on hemorrhagic transformation
The exact mechanisms by which rtPA causes hemorrhagic transformation are not fully understood, but several factors are thought to be involved. These include:
- Coagulopathy: rtPA can cause a breakdown of the blood-brain barrier, which can lead to bleeding in the brain.
- Reperfusion injury: rtPA can trigger harmful cascades, such as oxidative stress and inflammation, which can damage blood vessels and lead to bleeding.
- Matrix metalloproteinases (MMPs): rtPA can increase the levels of MMPs, which are enzymes that break down the extracellular matrix and can contribute to bleeding.
- Blood pressure: High blood pressure is a risk factor for hemorrhagic transformation, and it may be elevated after rtPA administration.
- Other factors: Other factors such as age, stroke severity, and underlying medical conditions can also increase the risk of hemorrhagic transformation.
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The clinical outcome of hemorrhagic transformation
- Hemorrhagic infarction (HI) - This is a heterogeneous hyperdensity occupying a portion of an ischemic infarct zone on computed tomography (CT) images. HI is further divided into HI type 1 (HI1) and HI type 2 (HI2). HI1 is characterised by small hyperdense petechiae, whereas HI2 refers to more confluent hyperdensity throughout the infarct zone. Both of the two types are without mass effect.
- Parenchymal hematoma (PH) - This refers to a more homogeneous, dense hematoma with mass effect. PH is further divided into PH type 1 (PH1) and PH type 2 (PH2). PH1 refers to the homogeneous hyperdensity occupying less than 30% of the infarct zone, with some mass effect, and PH2 refers to the homogeneous hyperdensity occupying over 30% of the infarct zone, with significant mass effect.
The prognosis of HT is dependent on its type. Only PH2 is found to be a significant predictor of neurological deterioration and higher mortality.
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The pathophysiology and molecular mechanisms of hemorrhagic transformation
Hemorrhagic transformation is a complication of cerebral ischemic stroke and can significantly worsen prognosis. It occurs when peripheral blood extravasates across a disrupted blood brain barrier (BBB) into the brain following ischemic stroke. Preventing HT is important as it worsens stroke outcome and increases mortality. Factors associated with increased risk of HT include stroke severity, reperfusion therapy (thrombolysis and thrombectomy), hypertension, hyperglycemia, and age.
The pathophysiology of HT involves the disruption of the BBB, which is composed of endothelial cells, basement membrane, pericytes, and astrocytes, collectively referred to as the neurovascular unit (NVU). The integrity of the BBB is crucial in maintaining the homeostasis of the brain parenchyma. Early ischemia, via ruining these structures and processes, disrupts the BBB. Components of neuroinflammatory mechanisms are activated involving microglia and astrocyte activation and the secretion of proinflammatory cytokines and growth factors like TNF-α, IL-1β, IL-17, INFγ, VEGF, and matrix metalloproteinases (MMPs).
The disruption of the BBB and NVUs can be caused by both reperfusion and ischemic stroke. Reperfusion can trigger harmful cascades, such as oxidative stress, suppression of protein synthesis, platelet activation, activation of the complement system, leukocyte infiltration, basal lamina disruption, and eventual cerebral cell death in the central nervous system. Reperfusion injury alone seems to be enough to cause fatal hematoma, but all ischemic strokes with tissue reperfusion do not cause hematoma.
Inflammation and the immune system are important contributors to BBB disruption and HT and are associated with many of the risk factors for HT. In the following sections, we present the relationship of inflammation and immune activation to HT in the context of reperfusion therapy, hypertension, hyperglycemia, and age.
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Future therapeutic possibilities and protecting factors
Future Therapeutic Possibilities
The only approved drug for acute ischemic stroke is intravenous thrombolytic alteplase, which is usually recommended to be administered within 4.5 hours of symptom onset. However, there are other fibrinolytic agents being evaluated in clinical trials for the treatment of AIS, including desmoteplase, recombinant staphylokinase, and modified urokinase.
Tenecteplase is a next-generation genetically modified rtPA and is currently the most promising alternative agent. It has a better safety profile than alteplase due to its lower risk of hemorrhagic transformation, greater fibrin specificity, faster onset of action, and longer half-life. It is administered via a single IV bolus, as opposed to the 1-hour infusion for alteplase.
The risk of potential bleeding complications, especially symptomatic intracerebral hemorrhage, is one of the reasons for the reluctance to administer IVT. The approval of safer and more effective thrombolytic agents would greatly increase the treatment access and improve upon outcome.
The development of safer anticoagulant drugs would improve the management of patients with atrial fibrillation. The inhibitors of FXIa are expected to have better safety profiles; in fact, data on animal and human carriers of FXI deficiency have suggested that they have a nonsignificant incidence of bleeding but a lower risk of ischemic events. Several ongoing trials are evaluating the safety and efficacy of anti-FXIa in secondary prevention of ischemic stroke.
Regarding secondary prevention in the absence of AF, aspirin is the most widely used agent, with a relative risk reduction of 15% for any type of stroke. Clopidogrel is another antiplatelet agent that has shown lower risks of recurrent stroke and bleeding events compared to aspirin.
Protecting Factors
The risk of intracerebral hemorrhage after intravenous thrombolysis can be predicted by several factors, including severe strokes (NIHSS >14), proximal middle cerebral artery occlusion, hypodensity (CT) affecting >1/3 of the middle cerebral artery territory, and delayed recanalization (>6 hours after stroke onset).
The development of safer, faster, and more manageable thrombolytic agents might result in increased rates of patients being treated with EVT, with reduced door-to-needle and door-to-groin times and a positive impact on the functional outcome of treated patients.
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Frequently asked questions
Hemorrhagic transformation is a complication of ischemic stroke. It occurs when blood vessels in the brain rupture after blood flow is restored to the brain after a stroke.
Risk factors for hemorrhagic transformation include:
- Cardioembolic stroke etiology
- Low serum cholesterol
- Elevated systolic blood pressure in the acute setting
- Thrombolytic therapy or other recanalization
- Age
- Chronic hypertension
- Acute high blood pressure
- Hyperglycemia
- History of high glucose level
- Congestive heart failure
- Renal impairment
- Antiplatelet or dual antiplatelet usage before or after rtPA treatment
- Anticoagulant/international normalized ratio/partial thromboplastin time
Hemorrhagic transformation is treated like any other brain hemorrhage, with the primary focuses being:
- Stopping the bleeding
- Controlling blood pressure
- Addressing neurological changes
- Reducing pressure around the brain
- Treating any complications that arise, such as seizures