tPA is used in some cases of diseases that feature
blood clots, such as
pulmonary embolism,
myocardial infarction, and
stroke, in a medical treatment called
thrombolysis. The most common use is for ischemic stroke. It can either be administered systemically, in the case of acute
myocardial infarction,
acute ischemic stroke, and most cases of acute massive
pulmonary embolism, or administered through an arterial catheter directly to the site of occlusion in the case of peripheral arterial
thrombi and thrombi in the proximal deep veins of the leg.[6]
Ischemic stroke
Statistics
There have been 12 large scale, high-quality trials of rtPA in acute ischemic stroke. A meta-analysis of these trials concluded that rtPA given within 6 hours of a stroke significantly increased the odds of being alive and independent at final follow-up, particularly in patients treated within 3 hours. However a significant mortality rate was noted, mostly from intracranial haemorrhage at 7 days, but later mortality was not significant amongst treated and non-treated patients.[7]
It has been suggested that if tPA is effective in ischemic stroke, it must be administered as early as possible after the onset of
stroke symptoms, given that patients present to an ED in a timely manner.[7][8] Many national guidelines including the AHA have interpreted this cohort of studies as suggesting that there are specific subgroups who may benefit from tPA and thus recommend its use within a limited time window after the event. Protocol guidelines require its use intravenously within the first three hours of the event, after which its detriments may outweigh its benefits.
For example, the Canadian Stroke Network guideline states "All patients with disabling acute ischemic stroke who can be treated within 4.5 hours of symptom onset should be evaluated without delay to determine their eligibility for treatment" with tPA.[9] Delayed presentation to the ED leads to decreased eligibility; as few as 3% of people qualify for this treatment.[10] Similarly in the United States, the window of administration used to be 3 hours from onset of symptoms, but the newer guidelines also recommend use up to 4.5 hours after symptom onset, depending on the patient's presentation, past medical history, current
comorbidities and medication usage.[11] tPA appears to show benefit not only for large artery occlusions but also for
lacunar strokes. Since tPA dissolves
blood clots, there is risk of
hemorrhage with its use.[12][13]
Administration criteria
Use of tPA in the United States in treatment of patients who are eligible for its use, have no contraindications, and arrival at the treating facility less than 3 hours after onset of symptoms, is reported to have doubled from 2003 to 2011. Use on patients with mild deficits, of nonwhite race/ethnicity, and oldest old age increased. However, many patients who were eligible for treatment were not treated.[14][15]
tPA has also been given to patients with acute ischemic stroke above age 90 years old. Although a small fraction of patients 90 years and above treated with tPA for acute ischemic stroke recover, most patients have a poor 30-day functional outcome or die.[16] Nonagenarians may do as well as octogenarians following treatment with IV-tPA for acute ischemic stroke.[17] In addition, people with
frostbite treated with tPA had fewer
amputations than those not treated with tPA.[18]
General consensus on use
There is consensus amongst stroke specialists that tPA is the standard of care for eligible stroke patients, and benefits outweigh the risks. There is significant debate mainly in the emergency medicine community regarding recombinant tPA's effectiveness in
ischemic stroke. The NNT Group on
evidence-based medicine concluded that it was inappropriate to combine these twelve trials into a single analysis, because of substantial clinical heterogeneity (i.e., variations in study design, setting, and population characteristics).[19] Examining each study individually, the NNT group noted that two of these studies showed benefit to patients given tPA (and that, using analytical methods that they think flawed); four studies showed harm and had to be stopped before completion; and the remaining studies showed neither benefit nor harm. On the basis of this evidence, the NNT Group recommended against the use of tPA in acute ischaemic stroke.[19] The NNT Group notes that the case for the 3-hour time window arises largely from analysis of two trials: NINDS-2 and subgroup results from IST-3. "However, presuming that early (0-3h) administration is better than later administration (3-4.5h or 4.5-6h) the subgroup results of IST-3 suggest an implausible biological effect in which early administration is beneficial, 3-4.5h administration is harmful, and 4.5-6h administration is again beneficial."[19] Indeed, even the original publication of the IST-3 trial found that time-window effects were not significant predictors of outcome (p=0.61).[20] In the UK, concerns by stroke specialists have led to a review by the
Medicines and Healthcare products Regulatory Agency.[21]
Pulmonary embolism
Pulmonary embolism (blood clots that have moved to the lung arteries) is usually treated with
heparin generally followed by
warfarin. If pulmonary embolism causes severe instability due to high pressure on the heart ("massive PE") and leads to low blood pressure, recombinant tPA is recommended.[22][23][24]
Recombinant tissue plasminogen activators (r-tPA)
tPA was first produced by recombinant DNA techniques at Genentech in 1982.[25]
Tissue-type plasminogen activators were initially identified and isolated from mammalian tissues after which a
cDNA library was established with the use of
reverse transcriptase and
mRNA from human melanoma cells. The aforementioned
mRNA was isolated using antibody based
immunoprecipitation. The resulting cDNA library was subsequently screened via
sequence analysis and compared to a whole
genome library for confirmation of specific protein isolation and accuracy. cDNA was cloned into a synthetic
plasmid and initially expressed in E. coli cells, followed by yeast cells with successful results confirmed via sequencing before attempting in mammalian cells. The transformants were selected with the use of
methotrexate. Methotrexate strengthens selection by inhibiting
DHFR activity which then compels the cells to express more DHFR (exogenous) and consequently more recombinant protein to survive. The highly active transformants were subsequently placed in an
industrial fermenter. The tPA which was then secreted into the culture medium was isolated and collected for therapeutic use. For pharmaceutical purposes, tPA was the first pharmaceutical drug produced synthetically with the use of mammalian cells, specifically Chinese hamster ovarian cells (
CHO). Recombinant tPA is commonly referred to as r-tPA and sold under multiple brand names.[26][27]
FDA-approved for
acute myocardial infarction, where it has more convenient administration and faster thrombolysis than alteplase. This is because it is a second generation engineered TPA, hence its half life is up to 20 minutes which allows it to be administered as a bolus injection rather than an infusion like Alteplase.[28]
Indicated in
acute myocardial infarction, showing fewer bleeding complications but otherwise similar mortality rates after one year compared to Alteplase.[28]
Interactions
Tissue plasminogen activator has been shown to
interact with:
A simplified illustration demonstrates clot breakdown (
fibrinolysis), with blue arrows denoting stimulation, and red arrows inhibition.
tPA and plasmin are the key enzymes of the fibrinolytic pathway in which tPA-mediated plasmin generation occurs.
tPA cleaves the zymogen plasminogen at its Arg561 - Val562 peptide bond, into the serine protease plasmin.[34]
Increased enzymatic activity causes
hyperfibrinolysis, which manifests as excessive bleeding and/or an increase of the vascular permeability.[35] Decreased activity leads to
hypofibrinolysis, which can result in
thrombosis or
embolism.
In patients with ischemic strokes, decreased tPA activity was reported to be associated with an increase in plasma P-selectin concentration.[36]
In vivo mechanism of action of tPA within the fibrinolytic system. tPA can go one of three ways in the body; (1) uptaken by the liver and cleared through receptors therein, (2) inhibited by a plasminogen activator inhibitor (PAI) and subsequently cleared from the liver, or (3) through the activation of plasminogen to plasmin for degradation to result in fibrin degradation product.[37][38]
Once in the body, tPA has can cause the desired
thrombolytic activity (see figure), or be inactivated and removed. In the bloodstream tPA has a
half-life of 4 to 6 minutes.[39] tPA can be bound by a plasminogen activator inhibitor, resulting in inactivation of its activity. The protein is then removed from the bloodstream by the liver. One of the specific receptors responsible for this processes is a protein known as the
LDL Receptor-Related Protein (LRP1), which clears tPA which is bound to the
Plasminogen Activator Inhibitor 1 (PAI-1).[38] However, when present in a high enough concentration to counteract the effects of plasminogen activator inhibitor, tPA can bind plasminogen, cleaving off the bound
plasmin from it. Plasmin, another type of
protease, can either be bound by a plasmin inhibitor, or work to degrade
fibrin clots, which is the main therapeutic pathway.[37]
A theoretical full-length model of t-PA. The finger domain is in red, the EGF-like domain in green, the kringle 1 and 2 domains in blue and yellow respectively, and the serine protease domain in magenta.A 360 view of t-PA showing its structure.
^DeMers G, Meurer WJ, Shih R, Rosenbaum S, Vilke GM (December 2012). "Tissue plasminogen activator and stroke: review of the literature for the clinician". The Journal of Emergency Medicine. 43 (6): 1149–54.
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^Lindsay, Gubitz G, Bayley M, Hill MD, Davies-Schinkel C, Singh S, Phillips S (8 December 2010).
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^Liu C, Xie J, Sun S, Li H, Li T, Jiang C, Chen X, Wang J, Le A, Wang J, Li Z, Wang J, Wang W (April 2022). "Hemorrhagic Transformation After Tissue Plasminogen Activator Treatment in Acute Ischemic Stroke". Cell Mol Neurobiol. 42 (3): 621–46.
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