Tissue plasminogen activator

Tissue plasminogen activator (abbreviated tPA or PLAT) is a is_associated_with::protein involved in the breakdown of blood is_associated_with::clots. It is a is_associated_with::serine protease found on is_associated_with::endothelial cells, the cells that line the is_associated_with::blood vessels. As an is_associated_with::enzyme, it catalyzes the conversion of is_associated_with::plasminogen to is_associated_with::plasmin, the major enzyme responsible for clot breakdown. Because it works on the is_associated_with::clotting system, tPA is used in is_associated_with::clinical medicine to treat is_associated_with::embolic or is_associated_with::thrombotic is_associated_with::stroke. Use is contraindicated in is_associated_with::hemorrhagic stroke and head trauma. The antidote for tPA in case of toxicity is is_associated_with::aminocaproic acid.

tPA may be manufactured using recombinant biotechnology techniques. tPA created this way may be referred to as recombinant tissue plasminogen activator (rtPA).

Medical uses
tPA is used in some cases of diseases that feature is_associated_with::blood clots, such as is_associated_with::pulmonary embolism, is_associated_with::myocardial infarction, and is_associated_with::stroke, in a medical treatment called is_associated_with::thrombolysis. The most common use is for ischemic stroke. It can either be administered systemically, in the case of acute is_associated_with::myocardial infarction, acute ischemic stroke, and most cases of acute massive is_associated_with::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.

Ischemic stroke
There have been twelve 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, there was an excess of mortality in treated patients in the first week after the event, mostly from intracranial haemorrhage.

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. Indeed, tPA has become widely considered standard of care in acute ischemic stroke, so long as the patient presents soon after the onset of stroke symptoms. 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. Because of this, only about 3% of people qualify for this treatment, since most patients do not seek medical assistance quickly enough. 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. tPA appears to show benefit not only for large artery occlusions but also for is_associated_with::lacunar strokes. Since tPA dissolves is_associated_with::blood clots, there is risk of is_associated_with::hemorrhage with its use.

Use of tPA in the United States in treatment of patients who are eligible for its use, no contra-indications 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.

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. Nonagenarians may do as well as octogenarians following treatment with IV-tPA for acute ischemic stroke. In addition, people with is_associated_with::frostbite treated with tPA had fewer is_associated_with::amputations than those not treated with tPA.

There is significant debate regarding recombinant tPA's effectiveness in is_associated_with::ischemic stroke. The NNT Group on is_associated_with::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). 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. 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." Indeed, even the original publication of the IST-3 trial found that time-window effects were not significant predictors of outcome (p=0.61). In the UK, concerns by stroke specialists have led to a review by the is_associated_with::Medicines and Healthcare products Regulatory Agency.

Pulmonary embolism
Pulmonary embolism (blood clots that have moved to the lung arteries) is usually treated with is_associated_with::heparin generally followed by is_associated_with::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.

Recombinant tissue plasminogen activators
Recombinant tissue plasminogen activators (r-tPAs) include alteplase, is_associated_with::reteplase, and is_associated_with::tenecteplase (TNKase).

Activase (Alteplase) is FDA-approved for treatment of is_associated_with::myocardial infarction with ST-elevation (STEMI), acute is_associated_with::ischemic stroke (AIS), acute massive is_associated_with::pulmonary embolism, and is_associated_with::central venous access devices (CVAD).

is_associated_with::Reteplase is FDA-approved for is_associated_with::acute myocardial infarction, where it has more convenient administration and faster thrombolysis than alteplase.

is_associated_with::Tenecteplase is also indicated in is_associated_with::acute myocardial infarction, showing fewer bleeding complications but otherwise similar mortality rates after one year compared to alteplase.

Additional r-tPAs, such as is_associated_with::desmoteplase, are under clinical development.

Interactions
Tissue plasminogen activator has been shown to interact with:


 * is_associated_with::Fibrinogen alpha chain,
 * is_associated_with::LRP1  and
 * is_associated_with::SERPINI1.

Function


tPA and plasmin are the key enzymes of the fibrinolytic pathway in which tPA mediated plasmin generation occurs. To be specific, tPA cleaves the zymogen plasminogen at its Arg561 - Val562 peptide bond, into the serine protease plasmin.

Increased enzymatic activity causes is_associated_with::hyperfibrinolysis, which manifests as excessive bleeding. Decreased activity leads to is_associated_with::hypofibrinolysis which can result in is_associated_with::thrombosis or is_associated_with::embolism. In ischemic stroke patients, decreased tPA activity was reported to be associated with an increase in plasma P-selectin concentration.

Tissue plasminogen activator also plays a role in is_associated_with::cell migration and is_associated_with::tissue remodeling.

Genetics
Tissue plasminogen activator is a is_associated_with::protein encoded by the PLAT is_associated_with::gene, which is located on is_associated_with::chromosome 8. The is_associated_with::primary transcript produced by this gene undergoes is_associated_with::alternative splicing, producing three distinct is_associated_with::messenger RNAs.

Development
tPA was first produced by recombinant DNA techniques at Genentech in 1982.