Tissue plasminogen activator

Tissue plasminogen activator (abbreviated tPA or PLAT) is a protein involved in the breakdown of blood clots. It is aserine protease (EC 3.4.21.68) found on endothelial cells, the cells that line the blood vessels. As an enzyme, it catalyzesthe conversion of plasminogen to plasmin, the major enzyme responsible for clot breakdown. Because it works on theclotting system, tPA is used in clinical medicine to treat embolic or thrombotic stroke. Use is contraindicated in hemorrhagic stroke and head trauma. The antidote for tPA in case of toxicity is aminocaproic acid.

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

Medical uses[edit]

tPA is used in some cases of diseases that feature blood clots, such as pulmonary embolism, myocardial infarction, andstroke, 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.

Ischemic stroke[edit]

There is significant debate regarding recombinant tPA's effectiveness in ischemic stroke. There have been twelve relevant, large scale, high-quality trials of rtPA in acute ischemic stroke. A prominent 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.^[2]

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).^[3] 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.^[3]

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.^[2][4] 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.^[4] 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.^[5] Because of this, only about 3% of people qualify for this treatment, since most patients do not seek medical assistance quickly enough.^{[citation needed]} 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.^[6] 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.

However, the NNT Group notes that the case for this 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."^[3] Indeed, even the original publication of the IST-3 trial found that time-window effects were not significant predictors of outcome (p=0.61).^[7]

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.^[8][9]

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.^[10] Nonagenarians may do as well as octogenarians following treatment with IV-tPA for acute ischemic stroke.^[11] In addition, people with frostbite treated with tPA had fewer amputations than those not treated with tPA.^[12]

Recombinant tissue plasminogen activators[edit]

Recombinant tissue plasminogen activators (r-tPAs) include alteplase, reteplase, and tenecteplase (TNKase).^[1]

Activase (Alteplase) is FDA-approved for treatment of myocardial infarction with ST-elevation (STEMI), acute ischemic stroke (AIS), acute massive pulmonary embolism, andcentral venous access devices (CVAD).^[1]

Reteplase is FDA-approved for acute myocardial infarction, where it has more convenient administration and faster thrombolysis than alteplase.^[1]

Tenecteplase is also indicated in acute myocardial infarction, showing fewer bleeding complications but otherwise similar mortality rates after one year compared to alteplase.^[1]

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