Tissue plasminogen activators (tPA) may help COVID-19 patients in danger of respiratory failure

Researchers at MIT and the University of Colorado at Denver have proposed a stopgap measure that they believe could help Covid-19 patients who are in acute respiratory distress.

By repurposing a drug that is now used to treat blood clots, they believe they could help people in cases where a ventilator is not helping, or if a ventilator is not available.

Three hospitals in Massachusetts and Colorado are developing plans to test this approach in severely ill Covid-19 patients.

The drug, a protein called tissue plasminogen activator (tPA), is commonly given to heart attack and stroke victims. The approach is based on emerging data from China and Italy that Covid-19 patients have a profound disorder of blood clotting that is contributing to their respiratory failure.

“If this were to work, which I hope it will, it could potentially be scaled up very quickly, because every hospital already has it in their pharmacy,” says Michael Yaffe, a David H. Koch Professor of Science at MIT.

“We don’t have to make a new drug, and we don’t have to do the same kind of testing that you would have to do with a new agent. This is a drug that we already use. We’re just trying to repurpose it.”

Yaffe, who is also a member of MIT’s Koch Institute for Integrative Cancer Research and an intensive care physician at Boston’s Beth Israel Deaconess Medical Center/Harvard Medical School, is the senior author of a paper describing the new approach.

The paper, which appears in the Journal of Trauma and Acute Care Surgery, was co-authored by Christopher Barrett, a surgeon at Beth Israel Deaconess and a visiting scientist at MIT; Hunter Moore, Ernest Moore, Peter Moore, and Robert McIntyre of the University of Colorado at Denver; Daniel Talmor of Beth Israel Deaconess; and Frederick Moore of the University of Florida.

Breaking up clots

In one large-scale study of the Covid-19 outbreak in Wuhan, China, it was found that 5 percent of patients required intensive care and 2.3 percent required a ventilator. Many doctors and public health officials in the United States worry that there may not be enough ventilators for all Covid-19 patients who will need them.

In China and Italy, a significant number of the patients who required a ventilator went on to die of respiratory failure, despite maximal support, indicating that there is a need for additional treatment approaches.

The treatment that the MIT and University of Colorado team now proposes is based on many years of research into what happens in the lungs during respiratory failure. In such patients, blood clots often form in the lungs.

Very small clots called microthrombi can also form in the blood vessels of the lungs. These tiny clots prevent blood from reaching the airspaces of the lungs, where blood normally becomes oxygenated.

The researchers believe that tPA, which helps to dissolve blood clots, may help patients in acute respiratory distress. A natural protein found in our bodies, tPA converts plasminogen to an enzyme called plasmin, which breaks down clots.

Larger amounts are often given to heart attack patients or stroke victims to dissolve the clot causing the heart attack or stroke.

Animal experiments, and one human trial, have shown potential benefits of this approach in treating respiratory distress. In the human trial, performed in 2001, 20 patients who were in respiratory failure following trauma or sepsis were given drugs that activate plasminogen (urokinase or streptokinase, but not tPA).

All of the patients in the trial had respiratory distress so severe that they were not expected to survive, but 30 percent of them survived following treatment.

That is the only study using plasminogen activators to treat respiratory failure in humans to date, largely because improved ventilator strategies have been working well. This appears not to be the case for many patients with Covid-19, Yaffe says.

The idea to try this treatment in Covid-19 patients arose, in part, because the Colorado and MIT research team has spent the last several years studying the inflammation and abnormal bleeding that can occur in the lungs following traumatic injuries.

It turns out that Covid-19 patients also suffer from inflammation-linked tissue damage, which has been seen in autopsy results from those patients and may contribute to clot formation.

Researchers from MIT and the University of Colorado at Denver propose using a protein called tissue plasminogen activator, whose structure is shown here, to treat Covid-19 patients in acute respiratory distress. The image is credited to Wikimedia, MedicineFTWq; edited by MIT News.

“What we are hearing from our intensive care colleagues in Europe and in New York is that many of the critically ill patients with Covid-19 are hypercoagulable, meaning that they are clotting off their IVs, and having kidney and heart failure from blood clots, in addition to lung failure.

There’s plenty of basic science to support the idea that this concept should be beneficial,” Yaffe says. “The tricky part, of course, is figuring out the right dose and route of administration. But the target we are going after is well-validated.”

Potential benefits

The researchers will test tPA in patients under the FDA’s “compassionate use” program, which allows experimental drugs to be used in cases where there are no other treatment options. If the drug appears to help in an initial set of patients, its use could be expanded further, Yaffe says.

“We learned that the clinical trial will be funded by BARDA [the Biomedical Advanced Research and Development Authority], and that Francis Collins, the NIH director, was briefed on the approach yesterday afternoon,” he says.

“Genentech, the manufacturer of tPA, has already donated the drug for the initial trial, and indicated that they will rapidly expand access if the initial patient response is encouraging.”

Based on the latest data from their colleagues in Colorado, these groups plan to deliver the drug both intravenously and/or instill it directly into the airways. The intravenous route is currently used for stroke and heart attack patients.

Their idea is to give one dose rapidly, over a two-hour period, followed by an equivalent dose given more slowly over 22 hours.

Applied BioMath, a company spun out by former MIT researchers, is now working on computational models that may help to refine the dosing schedule.

“If it were to work, and we don’t yet know if it will, it has a lot of potential for rapid expansion,” Yaffe says. “The public health benefits are obvious.

We might get people off ventilators quicker, and we could potentially prevent people from needing to go on a ventilator.”

Funding: The hospitals planning to test this approach are Beth Israel Deaconess, the University of Colorado Anschultz Medical Campus, and Denver Health. The research that led to this proposal was funded by the National Institutes of Health and the Department of Defense Peer Reviewed Medical Research Program.

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STROKE IS A LEADING CAUSE of long-term disability and is the fifth leading cause of death in the United States (^{Benjamin et al., 2017}). Approximately 795,000 people in the United States experience a new or recurrent stroke each year, with approximately 133,000 stroke-related deaths (^{Benjamin et al., 2017}).

The estimated annual direct medical cost of stroke in the United States is approximately $18 billion; the estimated annual total cost is approximately $34 billion, including direct costs such as health care services and medications and indirect costs such as lost productivity (^{Benjamin et al., 2017}).

In a population-based study of patients who survived 30 days after a first-ever stroke, approximately one third remained disabled, with one in seven patients requiring permanent institutional care (^{Hankey, Jamrozik, Broadhurst, Forbes, & Anderson, 2002}).

The most common type of stroke is acute ischemic stroke (AIS), which accounts for 87% of all strokes (^{Benjamin et al., 2017}). Ischemic stroke is caused by a blood clot or blockage in a cerebral artery that interrupts blood flow to the brain, resulting in neurological dysfunction (^{Sacco et al., 2013}). 

Alteplase is a recombinant human tissue plasminogen activator approved for management of AIS (^{“Activase (alteplase),” 2017}).

Alteplase causes fibrin degradation and thrombolysis by binding to fibrin in a thrombus and stimulating fibrin-bound plasminogen to active plasmin (^{“Activase (alteplase),” 2017}).

In clinical trials, patients who received alteplase within 3 hr of stroke onset were more likely to have minimal or no disability as well as improved Barthel Index, modified Rankin Scale, Glasgow Outcome Scale, and National Institutes of Health Stroke Scale scores at 3 months compared with those who received placebo (^{Lees et al., 2010; National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group, 1995}).

The American Heart Association (AHA)/American Stroke Association (ASA) guidelines for early management of patients with AIS recommend administration of intravenous alteplase within 0–4.5 hr after onset of ischemic stroke in eligible patients (^{Powers et al., 2018}).

In 2016, the AHA/ASA published an advisory statement on the scientific rationale behind the inclusion and exclusion criteria for intravenous alteplase treatment of AIS and administration of alteplase within 3–4.5 hr after stroke onset (^{Demaerschalk et al., 2016}).

Eligibility criteria are similar to what is advised in the U.S. Food and Drug Administration (FDA) label, with the following additional exclusion criteria: patients older than 80 years, those receiving oral anticoagulants regardless of international normalized ratio, those with a baseline National Institutes of Health Stroke Scale score more than 25, those with imaging evidence of ischemic injury involving more than one third of the middle cerebral artery territory, and those with a history of both stroke and diabetes mellitus (^{Demaerschalk et al., 2016}).

Alteplase is the first FDA-approved recombinant human tissue plasminogen activator that is also indicated for treatment of acute myocardial infarction (AMI) and acute massive pulmonary embolism (PE) (^{“Activase (alteplase),” 2017}).

Other recombinant tissue plasminogen activators have since been approved for AMI, including the modified recombinant human tissue plasminogen activators tenecteplase (^{“TNKase (tenecteplase),” 2017}) and reteplase (^{“Retavase (reteplase),” 2017}).

Recent clinical studies have demonstrated comparable efficacy and safety of tenecteplase and alteplase in patients with mild AIS (^{Huang et al., 2015; Logallo et al., 2017}). Neither tenecteplase nor reteplase is FDA approved for use in AIS; however, the AHA/ASA guidelines recommend that tenecteplase may be considered as an alternative to alteplase in patients with minor neurological impairment and no major intracranial occlusion, even though tenecteplase has not been proven to be superior or noninferior to alteplase (^{Powers et al., 2018}).

Between 2000 and 2014, the FDA received 21 reports of medication errors involving alteplase and tenecteplase (^{Tu, 2015}). Reports of accidental substitution of reteplase for alteplase have also been documented (^{Scott & Davis, 2001}).

In patients with AIS, wrongful administration of tenecteplase or reteplase instead of alteplase results in failure to treat patients using a drug with known effectiveness and the potential for overdose, particularly with respect to tenecteplase (^{Institute for Safe Medication Practices [ISMP], 2015}). 

Tenecteplase overdose may increase the risk of intracranial hemorrhage, retroperitoneal bleeding, extended hospitalization, and death (^{ISMP, 2015; Tu, 2015}). The objective of this review is to compare the clinical features of alteplase, tenecteplase, and reteplase and to provide steps to reduce medication errors in administration of alteplase for AIS.

INDICATION, MODE OF ADMINISTRATION, AND DOSING

Alteplase is the only tissue plasminogen activator approved for AIS after excluding intracranial hemorrhage. Neither tenecteplase nor reteplase is approved for treatment of AIS or PE. Alteplase is administered by intravenous infusion, with dose and infusion time dependent on the indication; dosing for AIS and AMI is also based on patient weight (see Table 1; ^{“Activase (alteplase),” 2017}).

In patients with AMI, alteplase should be administered as soon as possible after symptom onset by one of two administration regimens (see Figure 1; ^{“Activase (alteplase),” 2017}). The clinical outcomes of alteplase administration by accelerated or 3-hr infusion in patients with AMI have not been compared in controlled clinical studies.

For AMI, tenecteplase is given as a single intravenous bolus for 5 s (^{“TNKase (tenecteplase),” 2017}), with the recommended dose based on patient weight (^{“TNKase (tenecteplase),” 2017}). The maximum recommended dose for alteplase (90 mg; ^{“Activase (alteplase),” 2017}) in AIS is higher than the maximum labeled dose for tenecteplase (50 mg; ^{“TNKase (tenecteplase),” 2017}); thus, tenecteplase overdose may occur if a patient inadvertently receives tenecteplase instead of alteplase using the alteplase weight-based dosing regimen (i.e., administering tenecteplase at the alteplase dose would be almost double the highest recommended tenecteplase dose).

Reteplase is administered by intravenous bolus injection as two 10-unit doses 30 min apart, which should be started quickly after onset of AMI symptoms (^{“Retavase (reteplase),” 2017}).

Accidentally administering 100 units of reteplase instead of alteplase would be less likely to occur than accidentally administering 100 mg of tenecteplase, given that the reteplase and alteplase dosing units are different and the reteplase vial size (each vial contains 10 units = 34.8 mg) would require 2.9 vials to be administered for a single-bolus injection.

PACKAGING

Alteplase is provided as a preservative-free, sterile, lyophilized powder in 50-mg vials with a vacuum or 100-mg vials without a vacuum (see Table 1). To make the solution for injection, each vial is packaged with a 50- or 100-ml vial, respectively, of sterile water USP; 100-mg vials are also accompanied by a transfer device for reconstitution and a clear plastic hanger to facilitate infusion from the vial.

After reconstitution, each vial will contain alteplase 1 mg/ml; if necessary, the alteplase solution can be further diluted with an equivalent amount of 0.9% sterile saline injection, USP, or 5% dextrose injection, USP.

Tenecteplase is provided as a preservative-free, sterile, lyophilized powder in 50-mg vials under partial vacuum, with a 10-ml vial of sterile water for making the solution for injection, USP, a 10-ml syringe with Twinpak dual-cannula device (Becton Dickinson, Franklin Lakes, NJ) for reconstitution and administration, and three alcohol preparation pads (see Table 1). Tenecteplase should be administered as a reconstituted 5-mg/ml solution.

Reteplase is supplied in a full- or half-kit configuration with preservative-free, sterile, lyophilized powder in 10-unit vials without a vacuum with components for reconstitution and delivery (see Table 1).

The full kit contains the components for a single dosing regimen (i.e., two 10-unit bolus injections), including two 10-unit vials of reteplase, two 10-ml prefilled syringes of sterile water for injection, USP, two syringe plungers, two 10-ml graduated syringes, and two sterile reconstitution spikes, whereas each half kit contains one of each component.

After reconstitution, each reteplase vial contains 10 ml of reteplase 1 unit/ml (i.e., one 10-unit bolus injection) plus a small amount of extra solution to ensure sufficient drug for administration.

ERROR PREVENTION

A primary contributing factor to tissue plasminogen activator drug errors is use of the abbreviation “TPA” (^{ISMP, 2015; Scott & Davis, 2001; Tu, 2015}). “TPA” (or “tPA”) is the abbreviation commonly used for “tissue plasminogen activator.”

However, health care professionals often use “TPA” to refer specifically to alteplase because it was the first FDA-approved recombinant human tissue plasminogen activator; in addition, alteplase is often referred to as “TPA” in published literature.

Because “TPA” is the abbreviation used for the drug class that encompasses all tissue plasminogen activators, use of “TPA” in written or verbal prescriptions may lead to confusion regarding the intended agent. In addition, health care professionals may refer to tenecteplase as “TNK,” an abbreviation of the tenecteplase brand name TNKase (Genentech, Inc., South San Francisco, CA); however, “TNK” has been frequently confused with “TPA,” further increasing the potential for medication error (^{Tu, 2015}).

“TPA,” “tPA,” and “TNK” are listed in the ISMP list of error-prone abbreviations, symbols, and dose designations and the list of high-alert medications in acute care settings (^{ISMP, 2018a, 2018b}).

Both the FDA and the ISMP recommend using full brand or generic names for the approved tissue plasminogen activators in prescriptions, order sets, treatment protocols, and published literature (see Table 2; ^{ISMP, 2015; Tu, 2015}).

The abbreviation “TPA” should not be used for written prescriptions or verbal orders for alteplase. Similarly, the abbreviation “TNK” should not be used to prescribe tenecteplase; the full brand name TNKase or full generic name tenecteplase should be used in written prescriptions and verbal orders. The ISMP also recommends including the indication on written prescriptions (^{ISMP, 2015}).

Because alteplase is the only tissue plasminogen activator approved for management of AIS and PE, including the indication may help reduce confusion in prescriptions for patients with these conditions.

Separate order sets can be established for each indication (i.e., AIS, AMI, and PE). In addition, hospital pharmacy formularies could be limited to one fibrinolytic agent if possible.

If more than one agent is available, using a pocket in an automated dispensing machine that is sized to fit only one treatment dose of a fibrinolytic could be a possibility. Similarly, for institutions that use smart pumps for dosing, the indication can be used for correct selection.

Both the FDA and the ISMP require participating hospitals to have “look-alike–sound-alike” medication lists to raise awareness of confusing medication names. They recommend using bolded tall man letters to draw attention to dissimilarities with look-alike names (e.g., predniSONE vs. prednisoLONE; ^{ISMP, 2018c}).

Additional warning labels could be included to alert staff to look-alike or sound-alike drugs, particularly in hospitals that have limited technology. For hospitals with computerized physician order entry systems, written orders could be discouraged in general to prevent confusion.

If door-to-needle times will not be compromised, entering an order and bar code scanning the medication before administration can be considered. If the medication is stored in an automated dispensing machine, an alert can be activated to ensure that the correct medication is being acquired.

Other factors contributing to drug errors among tissue plasminogen activators may include similar settings of use, such as emergency departments and critical care areas; approval of alteplase, tenecteplase, and reteplase for treatment of AMI; inadequate knowledge of or experience with multiple tissue plasminogen activators; lack of understanding of the differences among tissue plasminogen activators; stocking of a single tissue plasminogen activator for cardiac use in emergency departments; and/or use of automated drug-dispensing systems that may or may not recognize “TPA” or “tPA” (^{Cohen & Smetzer, 2015; ISMP, 2015; Scott & Davis, 2001}).

Additional steps to reduce errors may include revision of stroke treatment protocols to reduce the chance of drug substitutions, increased physician and staff education on the differences among tissue plasminogen activators, and addition of alerts in electronic prescriber order entry systems or automated medication-dispensing systems to ensure selection of the correct agent (^{Cohen & Smetzer, 2015; ISMP, 2015; Scott & Davis, 2001}). Several strategies to prevent medication errors are summarized in Table 2.

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Source:
MIT