There is significant debate regarding recombinant tPA's effectiveness in ischemic stroke. There have been twelve relevant, large scale, high-quality trials or rtPA in acute ischemic stroke. One common complaint about these studies is that they all have authors with significant conflicts of interest such as financial ties to Genentech, which manufactures tPA. 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, and no reduction in mortality by the trials' final follow-up.
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). 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.
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 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." Indeed, even the original publication of the IST-3 trial found that time-window effects were not significant predictors of outcome (p=0.61).
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 frostbite treated with tPA had fewer amputations than those not treated with tPA.
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. To be specific, tPA cleaves the zymogen plasminogen at its Arg561 - Val562 peptide bond, into the serine protease plasmin.
Increased enzymatic activity causes hyperfibrinolysis, which manifests as excessive bleeding. Decreased activity leads to hypofibrinolysis which can result in thrombosis or embolism.
Tissue plasminogen activator also plays a role in cell migration and tissue remodeling.
^ abDeMers G, Meurer WJ, Shih R, Rosenbaum S, Vilke GM (December 2012). "Tissue plasminogen activator and stroke: review of the literature for the clinician". J Emerg Med43 (6): 1149–54. doi:10.1016/j.jemermed.2012.05.005. PMID22818644.Cite uses deprecated parameters (help)
^Lindsay, Gubitz G, Bayley M, Hill MD, Davies-Schinkel C, Singh S, Phillips S, Canadian Stroke Strategy Best Practices and Standards Writing Group (Dec 8, 2010). "Hyperacute stroke management". Canadian best practice recommendations for stroke care. Ottawa, ON: Canadian Stroke Network. pp. 55–84. Retrieved 30 November 2013.
^Schwamm LH, Ali SF, Reeves MJ, Smith EE, Saver JL, Messe S, Bhatt DL, Grau-Sepulveda MV, Peterson ED, Fonarow GC (August 2013). "Temporal Trends in Patient Characteristics and Treatment With Intravenous Thrombolysis Among Acute Ischemic Stroke Patients at Get With the Guidelines-Stroke Hospitals". Circ Cardiovasc Qual Outcomes. doi:10.1161/CIRCOUTCOMES.111.000095. PMID23963655. "The frequency of IV tPA use among all AIS patients, regardless of contraindications, nearly doubled from 2003 to 2011. Treatment with tPA has expanded to include more patients with mild deficits, nonwhite race/ethnicity, and oldest old age"Cite uses deprecated parameters (help)
^Twomey JA, Peltier GL, Zera RT (2005). "An open-label study to evaluate the safety and efficacy of tissue plasminogen activator in treatment of severe frostbite". J Trauma59: 1350–1354.; and repeated by Bruen KJ, Ballard JR, Morris SE, Cochran A, Edelman LS, Saffle JR (June 2007). "Reduction of the incidence of amputation in frostbite injury with thrombolytic therapy". Arch Surg142 (6): 546–51; discussion 551–3. doi:10.1001/archsurg.142.6.546. PMID17576891.Cite uses deprecated parameters (help)
^Tsurupa G, Medved L (2001). "Identification and characterization of novel tPA- and plasminogen-binding sites within fibrin(ogen) alpha C-domains". Biochemistry40 (3): 801–8. PMID11170397.
^Zhuo M, Holtzman DM, Li Y, Osaka H, DeMaro J, Jacquin M, Bu G (2000). "Role of tissue plasminogen activator receptor LRP in hippocampal long-term potentiation". J. Neurosci.20 (2): 542–9. PMID10632583.
^Parmar PK, Coates LC, Pearson JF, Hill RM, Birch NP (2002). "Neuroserpin regulates neurite outgrowth in nerve growth factor-treated PC12 cells". J. Neurochem.82 (6): 1406–15. PMID12354288.
Rijken DC (1988). "Relationships between structure and function of tissue-type plasminogen activator". Klin. Wochenschr. 66 Suppl 12: 33–9. PMID3126346.
Bode W, Renatus M (1998). "Tissue-type plasminogen activator: variants and crystal/solution structures demarcate structural determinants of function". Curr. Opin. Struct. Biol.7 (6): 865–72. doi:10.1016/S0959-440X(97)80159-5. PMID9434908.
Collen D, Billiau A, Edy J, De Somer P., Identification of the human plasma protein which inhibits fibrinolysis associated with malignant cells, Biochim Biophys Acta. 1977 Sep 29;499(2):194-201
Anglés-Cano E, Rojas G (2003). "Apolipoprotein(a): structure-function relationship at the lysine-binding site and plasminogen activator cleavage site". Biol. Chem.383 (1): 93–9. doi:10.1515/BC.2002.009. PMID11928826.
Ny T, Wahlberg P, Brändström IJ (2003). "Matrix remodeling in the ovary: regulation and functional role of the plasminogen activator and matrix metalloproteinase systems". Mol. Cell. Endocrinol.187 (1–2): 29–38. doi:10.1016/S0303-7207(01)00711-0. PMID11988309.
Teesalu T, Kulla A, Asser T et al. (2002). "Tissue plasminogen activator as a key effector in neurobiology and neuropathology". Biochem. Soc. Trans.30 (2): 183–9. doi:10.1042/BST0300183. PMID12023848.
Pang PT, Lu B (2005). "Regulation of late-phase LTP and long-term memory in normal and aging hippocampus: role of secreted proteins tPA and BDNF". Ageing Res. Rev.3 (4): 407–30. doi:10.1016/j.arr.2004.07.002. PMID15541709.
Sheehan JJ, Tsirka SE (2005). "Fibrin-modifying serine proteases thrombin, tPA, and plasmin in ischemic stroke: a review". Glia50 (4): 340–50. doi:10.1002/glia.20150. PMID15846799.