Status quo and prospect of intravenous thrombolytic therapy for acute ischemic stroke

1 Theoretical basis and time window selection of thrombolytic therapy

As we all know, the most critical issue that determines the success or failure of thrombolytic therapy is the treatment time window, that is, the interval
between the onset of illness and the start of treatment.

Pathophysiological studies have shown that the ischemic semi-dark band is the area between the focal area of infarction and the normal area
.

However, how to individually assess the presence time of ischemic semi-dark bands has become an important problem
that needs to be solved urgently for prolonging the treatment time window.

Two studies currently underway are also venous thrombolytic studies
based on imaging screening for an expanded time window (NCT00887328, NCT02101606
).

2 Ultra-early thrombolytic drugs

At present, the commonly used intravenous thrombolytic drugs in China are urokinase (UK) and recombinant human tissue plasminogen activator (rt-PA
).

2.

2.

1 UK 

UK is currently a commonly used thrombolytic drug in China, it is a proteolytic enzyme, can lyse the fibrin on the surface of the thrombus, and can lyse the fibrin free in the blood, but it affects the coagulation system, the potential danger of inducing blood in the clinic is higher than that of tissue plasminogen activator (tPA) and rt-PA, but the UK price is cheap and easy to be accepted
by most people.

China's "Ninth Five-Year Plan" research project confirms that the UK is effective and safe
as an intravenous thrombolytic treatment for acute cerebral infarction
.

2.

SK has similar thrombolytic ability to tPA, but intravenous use of SK for stroke is dangerous, and the European Streptokinase Study (MASTE) showed a significant increase in early mortality and hemorrhagic changes in the intravenous SK group in 310 patients
, and was prone to allergic reactions.

2.

The UK can specifically bind to fibrin at the site of the thrombus, causing local fibrinolysis of the thrombus, while the systemic effect on the systemic fibrinolysis of the whole body is small, and its special thrombospecific can reduce the risk
of systemic hemorrhage and cerebral hemorrhage.

PROACT II.

2.

rt-PA is a plasminogen activator extracted from mammalian cells and Escherichia coli using recombinant techniques
.

Based on the ECASS-III study, the time window for intravenous thrombolytic treatment of rt-PA has been extended to 4.
5 h
.
At present, rt-PA is the most commonly used intravenous thrombolytic drug for cerebral infarction in the world, and the evidence-based medical evidence is sufficient to be recommended
by national guidelines.

2.
2 Novel thrombolytic drug 2.
2.
1 tenectase

Tenectase differs from wild-type tPA in that amino acids at positions 103 and 117 are different
.
The advantage of tenectase is that it has a longer half-life, about 11 220 min, and the specificity of binding to fibrin is higher than that of tPA, which has less
effect on systemic fibrinolytic activity.
Early studies have shown that the controlled trials of tenectase and tPA in patients with acute ischemic stroke within 3 h of onset concluded that there was no significant difference between the improved Rankin scale score and the tPA group at 3 months, and the safety of tenectase was higher
.

0.
1 mg/kg, 0.
25 mg/kg tenectase compared with 0.
9 mg/kg rt-PA intravenous thrombolysis, the former has a higher rate of vascular relay, and has a good safety profile
.
In addition, tenectase requires only 1 group
injection of the drug, which is clinically more convenient to use
.
However, phase II clinical studies have not confirmed that 0.
25 mg/kg tenectase is superior to 0.
9 mg/kgrt-PA intravenous thrombolysis
.
Considering the disadvantage of the above research, the sample
cost is small
.
The recently published expanded NOR-TEST study showed that teneplase has similar efficacy and safety to alteplase intravenous thrombolysis and did not find an advantage in
teneplase.

However, based on the advantages of tenectase, this drug deserves further exploration
.

2.
2.
2 Ralteplase

Mutants of the reteplase line of single-stranded tPA have less systemic fibrinolytic activity than streptokinase, but greater than tPA, and lower affinity for fibrin than tPA
.
Like tPA and teneplase, reteplase can specifically bind to fibrin, at which time the catalytic effect of fibrin on plasminogen activation is rapidly enhanced, while streptokinase and UK act directly on plasminogen and lack specificity
.
Ratiprase theoretically works better than urokinase and streptokinase and is safer
.
However, there is currently a lack of research
on acute stroke.

2.
2.
3 Deamiplase

Deamiprase is a thrombolytic drug isolated from the saliva of vampire bats
.
At present, it can be prepared by genetic recombination
.
Animal experiments confirm that tPA may mediate cell death; Conversely, the activity of deamipsin depends on fibrin and does not occur similar to tPA
.
Deamprazase has been shown to be effective
up to 9 hours after the onset
of acute ischemic stroke.
And some basic studies have found that intravenous injection of tPA promotes NMDA-mediated cell damage and increases NMDA-induced cell death, while de-amprease does not have these adverse effects
.

However, neither deamipsine II nor III studies have confirmed its effectiveness
in the treatment of acute cerebral infarction.

3 Complications of thrombolytic therapy

3.
1 Bleeding complications

Intracranial hemorrhage is a common complication
of thrombolytic therapy.
Bleeding complications should be considered if there is a sudden impaired consciousness, headache, nausea and vomiting, or exacerbation of limb disturbances during thrombolytic processes
.
It is generally believed that one of the mechanisms that cause bleeding is damage to the walls of blood vessels after ischemia, which can cause blood extravasation when the blood vessels are reopened to restore blood flow ; Another mechanism is thought to be related
to increased perfusion pressure after recirculation and secondary hyperfibrinolysis and hemostasis and coagulation dysfunction.

There are no standardized guidelines for the management of bleeding complications after thrombolysis, and the management measures recommended by the NINDS (national institute of neurological disorders and stroke) study include :(1) discontinuation of thrombolytic drugs
.
(2) Review CT
immediately.
(3) Check platelets and coagulation indicators
.
(4) Can be transfused frozen plasma or new plasma
.
(5) L-platelets
can be transfused.

3.
2 Reperfusion injury

Ischemic reperfusion injury can occur after venous thrombolysis, and free radicals are considered an important cause of
reperfusion injury.
Therefore, the clinical application of free radical scavengers and neuroprotective agents can help treat ischemia and reperfusion injury, but it is not yet certainly effective
.
In addition, active control of blood pressure may be reasonable, but the specific scope of control is not clear and needs to be further studied and explored
.

3.
3 Vascular reocclusion

It is currently considered that the criteria for further deterioration of the NIHSS score is that neurologic symptoms initially improve by 2 points, then worsen again by 2 points, or worsen by 4 points compared to the baseline score
.
Consider postthrombolytic vascular re-occlusion
.
The reocclusion rate is 10% to 20%, and the mechanism is unknown
.
And how to deal with re-occlusion is not yet clear, clinical cases of use of anticoagulants can prevent reinfarction is not clear, some studies believe that anticoagulants may be effective in preventing postthrombolytic re-occlusion of blood vessels and improving nerve function
.

4 Other treatments

4.
1 Selective arterial thrombolytic therapy

Arterial thrombolysis is by intubation through the femoral or carotid arteries, systemic heparinization, traceability by DSA image, identification of the site of occlusion, and injection of drugs close to the local embolus or contact emboli through microcatheterization for ultraselective intra-arterial thrombolysis therapy
.
The Chinese Guidelines for the Endovascular Treatment of Acute Ischemic Stroke point out that for patients with
cerebral infarction within 6 h of onset, intra-arterial thrombolysis therapy can be considered in experienced and conditional situations
.
For the basilar arteries, the treatment window can also be appropriately extended, and in patients with basilar artery obstruction, intra-artery administration of the UK and rt-PA may be effective
even if the onset exceeds 12 hours.
Arterial contact thrombolysis has been shown to be less effective than intravascular mechanical thromboplasty and can therefore be used in clinical practice as an alternative or adjunctive treatment for
intravascular mechanical thromboplasty.

4.
2 Endovascular embolectomy

Intravascular thrombectomy is the same as thrombolysis, and the most critical factor affecting its efficacy and safety is still the time
window
.
The earlier the blood vessel is opened within the time window, the better the efficacy and the fewer
complications.
In 2015, five randomized clinical trials (MR CLEAN, ESCAPE, REVASCAT, SWIFT PRIME and EXTEND I.
A) showed efficacy
of endovascular thrombectomy for acute ischemic stroke due to anterior circulation proximal artery occlusion.

4.
3 Ultrasound-assisted thrombolytic therapy

First described in the 1970s, it was believed that the microflow of mechanical pressure waves from ultrasound could
increase the contact between the drug and the emboli, thus facilitating the re-opening
of blood vessels.
Later, the improvement used microbubbles to assist ultrasonic thrombolysis
.
Microbubbles are shells formed by lipids, albumin, or galactose in sizes ranging from 0.
5 to 5.
0 μm
.
Under the action of ultrasound, the surface of the embolus is eroded and the
thrombolysis threshold is
reduced.
A 2010 meta-analysis concluded that ultrasound-assisted thrombolysis increased vascular opening without increasing the risk of intracranial hemorrhage
.
The NOR-SASS study, currently the largest sample size published in 2017, has not confirmed the benefits of ultrasound-assisted thrombolysis, so further clinical studies are needed, such as screening for what patients are more likely to benefit
from ultrasound-assisted thrombolysis.

4.
4 Thrombolytic drugs combined with antithrombotic drugs

To increase the vascular retransmission rate of thrombolytic drugs, another possible therapeutic strategy is to combine antithrombotic drugs
.
The ARTIS study explored the efficacy and safety of alteplase plus intravenous aspirin for acute cerebral infarction, and showed that the combination did not improve outcomes at 3 months and increased the risk
of symptomatic intracranial hemorrhage.
Based on the same concept, the study of agatraban in conjunction with alteplase has achieved gratifying results
.
ARTSS2 studies have shown that agatureban combined with alteplase can improve the opening rate in patients with cerebral infarction with macrovascular disease and does not increase the risk of symptomatic intracranial hemorrhage
.
However, the sample size of
this study is relatively small, and it is worth expanding the sample size for further study
.

5 Outlook

There is no doubt that intravenous thrombolysis is an effective measure for the treatment of acute ischemic stroke, but its efficacy is limited by the time window, the limitations of the drug itself and the duration of ischemic semi-dark bands in thrombolytic individuals, but with the advancement of science and technology, more specific, more efficient and safer new thrombolytic drugs are developed and gradually applied to clinical practice, as well as more accurate evaluation of ischemic semi-dark band imaging methods The exploration and application, it is believed that acute ultra-early thrombolytic individuals will get safer and more effective treatment measures
.

And in the future, acute stroke treatment will be a combination of multiple drugs and multiple treatments, and no single drug or treatment can cure all patients
.
Therefore, the future challenges of stroke treatment lie in the development of new thrombolytic drugs, as well as the determination of the dosage of new drugs, as well as the search for studies that can screen patients who may benefit from thrombolytic therapy with the help of imaging
.
Future treatment of stroke still has a long way to go and faces many challenges
.