Blood Thinners Not a Firm Contraindication for tPA, Study Finds

I'd suggest you call up the hospital president and ask if they have a research analyst whose only job is to monitor and implement stroke research. If they don't have one, YOU DON'T HAVE A FUNCTIONING STROKE HOSPITAL! RUN AWAY!

 Otherwise you may not get tPA when you need it.

Blood Thinners Not a Firm Contraindication for tPA, Study Finds

Intracranial hemorrhage rate did not differ regardless of use of antiplatelet or anticoagulants

by Joyce Frieden, Washington Editor, MedPage Today October 13, 2023

PHILADELPHIA -- Current anticoagulant or antiplatelet use is not necessarily a contraindication for administering tissue plasminogen activator (tPA) to a stroke patient in the emergency department, a researcher said here at the annual meeting of the American College of Emergency Physiciansopens in a new tab or window.

Traditionally, a patient being on blood thinners has been somewhat of a contraindication for tPA administration, said Salil Phadnis, MD, a third-year emergency medicine resident at Florida Atlantic University. "But at a lot of sites, especially ones without the most up-to-date academic stroke team, it ends up being more an absolute 'shut down' contraindication: 'Oh, they're on blood thinners; they can't have tPA.' So what we wanted to do was look at the rates of hemorrhage and disability that happens in patients who are on both medications."

The researchers performed a retrospective chart review of patients evaluated in the emergency department for stroke who received either tPA or a procedural intervention, or both, between March 2018 and May 2020. They collected data on pre-stroke antiplatelet use, anticoagulant use, the patient's initial NIH stroke score (NIHSS), postintervention modified Rankin score (mRS), and incidence of intracranial hemorrhage (ICH) at 3 months. They then compared ICH and mRS outcomes among patients based on their antithrombotic use for each of the intervention groups.

Out of 663 stroke activations, 251 patients received neurointervention, Phadnis said; that included 140 patients (55.8%) who received tPA only, 77 (30.7%) who received thrombectomy only, and 34 (13.5%) who received both. "The overall hemorrhage rate for intervention was 16.7%, with a mRS of 3," he said. "That basically means [they had] some disability, but they are able to ambulate without having someone supporting them at all times."

Overall, "the main result that we found was that there were no significant differences in incidence of intracranial hemorrhage between patients," he said. This was true "regardless of what kind of antiplatelets they're using, regardless of what kind of anticoagulant they're using, or a combination of the two, whether they got tPA, whether they got thrombectomy, or whether they got both."

There were a few other differences in mRS scores, however, he said: "Patients who were taking antiplatelets and got multiple interventions had a significantly higher mRS score," at an average of 5. "Five means you're bed-bound, essentially." Similarly, patients who were taking multiple antithrombotics also had a higher mRS score, he added.

"I think the main takeaway from this is just that in those precious few moments when a stroke first comes in, there is that mad scramble to get information -- their medication lists ... and other factors that could be contributing to what we see in front of us, and there is such limited information and time," said Phadnis. "Sometimes it seems like the medication list, and especially anticoagulant status, plays a bit of an outsize role."

"I think maybe we'd be better off looking more at the individual patient and whether they stand to benefit from getting tPA and thrombectomy without letting anticoagulant status be a deal-breaker for us," he added. "Or at the very least, we could do a little bit more as far as learning methods to rapidly reverse these medications, or determining a threshold below which you can get a consensus that tPA is safe -- kind of like what we've done with warfarin and an INR [international normalized ratio] of 1.7."

Limitations of the study included difficulties in consistently documenting the NIHSS score at every step of the evaluation, Phadnis noted. "And last known medication ingestion is something that we weren't able to accurately track for every single patient. As you can probably tell, it makes a difference whether you took the [medication] the night before or the week before."

Hopefully these results will be practice-changing, especially at smaller community hospitals, Phadnis told MedPage Today. "When you have a single ED [emergency department] provider making the decisions, hopefully having data like this would be a little bit more reassuring rather than to say, 'Oh, they're on [anticoagulants]; OK, we're done.'"

• 

  Joyce Frieden oversees MedPage Today’s Washington coverage, including stories about Congress, the White House, the Supreme Court, healthcare trade associations, and federal agencies. She has 35 years of experience covering health policy. Follow

Disclosures

The authors reported no disclosures.

Primary Source

American College of Emergency Physicians

Source Reference: opens in a new tab or windowPhadnis S et al "Effect of prior antithrombotic medication use on patients receiving emergent comprehensive stroke treatment" ACEP 2023.

Study finds which blood thinner is least likely to cause internal bleeding

But what we really need to know is what persons are at risk of gastrointestinal bleeding from using aspirin.

Study finds which blood thinner is least likely to cause internal bleeding

Researchers have identified which blood thinner is least likely to cause gastrointestinal bleeding. Image credit: mailsonpignata/500px/Getty Images.

• For people with atrial fibrillation, doctors can prescribe direct oral anticoagulant drugs to lower the risk of stroke, a typical result of the condition.
• A new observational study finds that one of these drugs, apixaban, is associated with a reduced risk of a common anticoagulant side effect: gastrointestinal bleeding.
• The study looked at four different DOACs and found they were equally effective at averting stroke, making them critically important for people with atrial fibrillation.

Atrial fibrillationTrusted Source (AFib) is a heart arrhythmia in which the beating of the upper and lower chambers of the heart become uncoordinated. When this occurs, the heartbeat may speed up, slow down or become irregular.

The condition is associated with an increased risk of stroke. The Centers for Disease Control and Prevention (CDC) suggestTrusted Source that it may be the cause of one in seven strokes.

The agency also reports that in 2019 AFib was responsible for 26,535 deaths in the United States and that by 2030, 12.1 million Americans will have the condition.

The front-line recommended treatment for AFib is a blood thinner, one of four direct oral anticoagulantsTrusted Source, or DOACs: apixaban, dabigatran, edoxaban, and rivaroxaban. While all four DOACs are similarly effective, a new observational study finds that one may be safer than the others.

The study, in Annals of Internal Medicine, found that apixaban is less often associated with gastrointestinal (GI) bleeding, a frequent side effect of DOACs.

Dr. Gregory Marcus, professor of medicine at the University of California, San Francisco, was not involved in the study. He expressed to Medical News Today enthusiasm for its findings.

“The compelling evidence favoring apixaban in this observational study fits nicely with what had already been intuitively extrapolated from randomized trials of each individual DOAC versus warfarin,” Dr. Marcus told us.

“I already favored apixaban in my practice based on previous data, but it’s nice to know that these comparisons support that practice,” he said.

“Big picture, it’s most important that atrial fibrillation patients at risk for stroke are on, really, any anticoagulant, preferably a DOAC.”

– Dr. Gregory Marcus

Putting the study in perspective

Cardiologist Dr. Gregg C. Fonarow of UCLA Health in California noted to MNT that he had concerns about the study: “This new study is an observational analysis using electronic health care databases from five different countries. The treatment assignment was not randomized, and thus potentially subject to selection biases and the outcome analyses to residual measured and unmeasured confounding.”

“Prior studies have shown limitations in [the] use of electronic health for reliably determining bleeding rates,” pointed out Dr. Fonarow, who was not involved in the study.

“Due to the limitations,” he said, “these findings are unlikely to influence guidelines or prescription patterns.”

“There have not been large-scale randomized trials comparing the four approved DOACs. To reliably evaluate the comparative efficacy and safety among these four agents, randomized clinical trials would be needed.”

Dr. Fonarow underscored that, “[w]hile the authors focus on differences in gastrointestinal bleeding rates, the most reliably ascertained outcomes of ischemic stroke or systemic embolization, intracranial hemorrhage, and all-cause mortality showed no differences among the four agents.”

“Sometimes,” Dr. Marcus pointed out, “neither we as prescribers nor patients have the luxury to select one agent over another, often due to insurance coverage.”

“I therefore view [the] selection of one particular DOAC over another as icing on the cake, given the tremendous benefit of really any of these drugs in preventing stroke, death, and other complications in appropriately selected patients,” he added.

Why apixaban may be easier on the GI tract

Dr. Marcus hypothesized that dosing may be a reason for apixaban’s apparently reduced risk of GI bleeding: “As a once-a-day drug, Xarelto [rivaroxaban] exhibits a pretty steep peak level in order to avoid too low a concentration at the trough, whereas apixaban may deliver more of a steady level with its twice a day dosing.”

“Dabigatran requires acid for absorption and the heightened risk of bleeding with that drug is often attributed to the acid that is inherent to the drug to help facilitate that absorption,” he explained.

The authors of the study also looked at outcomes for people over 80, or with chronic kidney disease, and found no significant difference between the four DOACs in efficacy.

“Those over 80 tend to be at both a higher risk for stroke and for bleeding and therefore can be both challenging to treat, but also those most in need,” explained Dr. Marcus. “Chronic kidney disease is relevant because there is substantial variability in drug metabolism related to kidney function between the various anticoagulants.”

“Another potential advantage of apixaban over the other factor Xa inhibitors,” Dr. Marcus speculated, “is that it is much less reliant on kidney excretion and therefore, perhaps less prone to cause problems in those with chronic kidney diseases or fluctuating kidney function.”

Warfarin and DOACs

Before the embrace of DOACs for stroke prevention, the treatment of choice was the drug warfarin.

Dr. Fonarow explained why clinicians today prefer the DOACs, saying that “[r]andomized clinical trials have compared each of the individual DOACs to warfarin in patients with atrial fibrillation.”

“These trials have established advantages to DOAC compared to warfarin anticoagulation in patients with atrial fibrillation who are eligible for oral anticoagulation,” he noted.

“Meta-analyses of these randomized clinical trials show lower rates of ischemic stroke or systemic embolization, lower rates of intracranial hemorrhage, and lower rates of all-cause mortality,” Dr. Fonarow further added.

Now, said Dr. Fonarow, “[n]ational and international guidelines recommend use of DOACs preferentially to the use of warfarin in patients with atrial fibrillation.”

“DOACs,” added Dr. Marcus, “are much more convenient to take than warfarin, not requiring blood draws, dose adjustments, or changes in diet.”

“In addition, all the DOACs have a significantly lower risk of intracranial bleeding compared to warfarin. DOACs are generally now considered first line for prevention of stroke and thromboembolism in the setting of atrial fibrillation, and warfarin is second line,” he pointed out.

“Of note, there are some special circumstances where warfarin, and not DOACs, remains indicated, such as among patients with mitral stenosisTrusted Source or m

echanical heart valves,” Dr. Marcus cautioned.

• Stroke
• Cardiovascular / Cardiology
• Drugs

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By Robby Berman on November 4, 2022 — Fact checked by Anna Guildford, Ph.D.

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Blood Thinners Again Linked to COVID-19 Survival in Hospital

Something I've been suggesting for months, but I'm specifically going to ask for heparin. 

I'm going to be asking for heparin as a blood thinner because of this:

Common FDA-approved drug may effectively neutralize virus that causes COVID-19

But your doctor needs to resolve this conundrum:

Preemptive Blood Thinners Tied to More Deaths in Hospitalized COVID-19 Patients

But Hypoxemia suggests something different.  The transit of the bubbles suggested vasodilation of the lung capillaries, Poor said. That could mean that blood may be flowing too fast through those capillaries to absorb enough oxygen.

COVID Hypoxemia: Finally, an Explanation

The latest here:

Blood Thinners Again Linked to COVID-19 Survival in Hospital

— This time with better methodology

by Crystal Phend, Senior Editor, MedPage Today August 26, 2020

Anticoagulation for patients hospitalized with COVID-19 was associated with lower risk of death or intubation in an observational study from New York City's pandemic peak.

In-hospital mortality risk was a relative 50% lower with standard prophylactic dosing and 47% lower with higher therapeutic-level dosing after adjustment for other factors, both statistically significant when compared with COVID-19 patients in Mount Sinai hospitals not given an anticoagulant (mortality rates of 21.6%, 28.6%, and 25.6%, respectively).

Intubation was less likely for anticoagulant-treated COVID-19 patients as well (adjusted HR 0.69 with prophylactic dosing, 95% CI 0.51-0.94, and aHR 0.72 with therapeutic dosing, 95% CI 0.58-0.89), reported Anuradha Lala, MD, of the Icahn School of Medicine at Mount Sinai in New York City, and colleagues in the Journal of the American College of Cardiology.

Major bleeding events adjudicated by clinician chart review turned up a "low" rate of 1.7% (33 of 1,959) on prophylactic anticoagulation and 3% (27 of 900) on therapeutic anticoagulation compared with 1.9% (29 of 1,530) on no anticoagulant during hospitalization.

"The study has severe limitations due to its retrospective nature," cautioned Stephan Moll, MD, of the University of North Carolina at Chapel Hill Hemophilia and Thrombosis Center.

"However, NIH prospective studies on inpatient and outpatient [prophylaxis] comparing different anticoagulation management strategies are planned and hopefully starting soon so that we can get beyond all these retrospective studies and data of the last few months, which all have ascertainment bias," he told MedPage Today.

Lala's group had previously reported on their experience with anticoagulation among 2,773 patients treated early in the pandemic, finding an in-hospital survival advantage with therapeutic-dose anticoagulation among mechanically ventilated patients and with longer duration anticoagulation.

A subsequent study had suggested elevated mortality risk with preemptive therapeutic-dose anticoagulation in COVID-19 patients.

The new data included 4,389 adults with laboratory-confirmed SARS-CoV-2 infection admitted from March 1 to April 30, 2020, at the five New York City hospitals in the Mount Sinai system.

The researchers conservatively classified anyone treated for less than 48 hours with an anticoagulant as fitting the control group, unless the drug was stopped due to major bleeding. Patients discharged within 24 hours, as well as those treated with both therapeutic and prophylactic regimens, were excluded.

The study also evaluated the first 26 autopsies on COVID-19 patients in the health system, which turned up thromboembolism in 11 (42%), while it had been suspected pre-mortem in only one. "Our findings are in line with what other studies have shown," Lala said. "We're seeing more clots than we would have ever suspected previously."

 

Persistent Symptoms in Patients After Acute COVID-19

Get treated, staying home does nothing.  

I'm still going to be requesting heparin or Lovenox shots immediately because I don't want all the microthrombi circulating  in my blood causing all kinds of havoc. But don't listen to me, I'm not medically trained. 

I'm going to be asking for heparin as a blood thinner because of this:

Common FDA-approved drug may effectively neutralize virus that causes COVID-19

The latest here:

Persistent Symptoms in Patients After Acute COVID-19

Angelo Carfì, MD¹; Roberto Bernabei, MD¹; Francesco Landi, MD, PhD¹; et al for the Gemelli Against COVID-19 Post-Acute Care Study Group

Author Affiliations Article Information

JAMA. 2020;324(6):603-605. doi:10.1001/jama.2020.12603

COVID-19 Resource Center

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In Italy, a large proportion of patients with coronavirus disease 2019 (COVID-19) presented with symptoms (71.4% of 31 845 confirmed cases as of June 3, 2020).¹ Common symptoms include cough, fever, dyspnea, musculoskeletal symptoms (myalgia, joint pain, fatigue), gastrointestinal symptoms, and anosmia/dysgeusia.^2-4 However, information is lacking on symptoms that persist after recovery. We assessed persistent symptoms in patients who were discharged from the hospital after recovery from COVID-19.

Methods

In the waning phase of the pandemic, beginning on April 21, 2020, the Fondazione Policlinico Universitario Agostino Gemelli IRCCS in Rome, Italy, established a postacute outpatient service for individuals discharged from the hospital after recovery from COVID-19. All patients who met World Health Organization criteria for discontinuation of quarantine (no fever for 3 consecutive days, improvement in other symptoms, and 2 negative test results for severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] 24 hours apart) were followed up. At enrollment in the study, real-time reverse transcriptase–polymerase chain reaction for SARS-CoV-2 was performed and patients with a negative test result were included.

Patients were offered a comprehensive medical assessment with detailed history and physical examination. Data on all clinical characteristics, including clinical and pharmacological history, lifestyle factors, vaccination status, and body measurements, were collected in a structured electronic data collection system. The COVID-19 postacute outpatient service is currently active, and further details about the patient evaluation protocol are described elsewhere.⁵

In particular, data on specific symptoms potentially correlated with COVID-19 were obtained using a standardized questionnaire administered at enrollment. Patients were asked to retrospectively recount the presence or absence of symptoms during the acute phase of COVID-19 and whether each symptom persisted at the time of the visit. More than 1 symptom could be reported. The EuroQol visual analog scale was used to ask patients to score their quality of life from 0 (worst imaginable health) to 100 (best imaginable health) before COVID-19 and at the time of the visit. A difference of 10 points defined worsened quality of life. All analyses were performed using R version 3.6.3 (R Foundation).

This study was approved by the Università Cattolica and Fondazione Policlinico Gemelli IRCCS Institutional Ethics Committee. Written informed consent was obtained from all participants.

Results

From April 21 to May 29, 2020, 179 patients were potentially eligible for the follow-up post–acute care assessment; 14 individuals (8%) refused to participate and 22 had a positive test result. Thus, 143 patients were included. The mean age was 56.5 (SD, 14.6) years (range, 19-84 years), and 53 (37%) were women. During hospitalization, 72.7% of participants had evidence of interstitial pneumonia. The mean length of hospital stay was 13.5 (SD, 9.7) days; 21 patients (15%) received noninvasive ventilation and 7 patients (5%) received invasive ventilation. The characteristics of the study population are summarized in the Table.

Patients were assessed a mean of 60.3 (SD, 13.6) days after onset of the first COVID-19 symptom; at the time of the evaluation, only 18 (12.6%) were completely free of any COVID-19–related symptom, while 32% had 1 or 2 symptoms and 55% had 3 or more. None of the patients had fever or any signs or symptoms of acute illness. Worsened quality of life was observed among 44.1% of patients. The Figure shows that a high proportion of individuals still reported fatigue (53.1%), dyspnea (43.4%), joint pain, (27.3%) and chest pain (21.7%).

Discussion

This study found that in patients who had recovered from COVID-19, 87.4% reported persistence of at least 1 symptom, particularly fatigue and dyspnea. Limitations of the study include the lack of information on symptom history before acute COVID-19 illness and the lack of details on symptom severity. Furthermore, this is a single-center study with a relatively small number of patients and without a control group of patients discharged for other reasons. Patients with community-acquired pneumonia can also have persistent symptoms, suggesting that these findings may not be exclusive to COVID-19.⁶

Clinicians and researchers have focused on the acute phase of COVID-19, but continued monitoring after discharge for long-lasting effects is needed

 

USC scientists identify the order of COVID-19’s symptoms

 I can see zero reason for self-isolating, you are just hoping against hope that you will not get a severe case. 

I'm still going to be requesting heparin or Lovenox shots immediately because I don't want all the microthrombi circulating  in my blood causing all kinds of havoc. But don't listen to me, I'm not medically trained. 

I'm going to be asking for heparin as a blood thinner because of this:

Common FDA-approved drug may effectively neutralize virus that causes COVID-19

The latest here:

USC scientists identify the order of COVID-19’s symptoms

 

University of Southern California Health News|August 14, 2020

USC researchers have found what appears to be the likely order in which COVID-19 symptoms first appear: fever, cough and muscle pain, then nausea and/or vomiting, then diarrhea.

Knowing the order of COVID-19’s symptoms may help patients seek care promptly or decide promptly to self-isolate, the scientists say. It also could help doctors rule out other illnesses or plan how to treat patients, according to the study led by doctoral candidate Joseph Larsen and his colleagues with faculty advisers Peter Kuhn and James Hicks at the USC Michelson Center for Convergent Bioscience’s Convergent Science Institute in Cancer.

The scientific findings were published in the journal Frontiers in Public Health.

“This order is especially important to know when we have overlapping cycles of illnesses like the flu that coincide with infections of COVID-19,” said Kuhn, professor of medicine, biomedical engineering, and aerospace and mechanical engineering at the USC Dornsife College of Letters, Arts and Sciences. “Doctors can determine what steps to take to care for the patient, and they may prevent the patient’s condition from worsening.”

“Given that there are now better approaches to treatments for COVID-19, identifying patients earlier could reduce hospitalization time,” said Larsen, the study’s lead author and a USC Dornsife professor.

Determining COVID-19 symptoms can help doctors plan treatments accordingly

Fever and cough are frequently associated with a variety of respiratory illnesses, including Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS). But the timing and symptoms in the upper and lower gastrointestinal tract set COVID-19 apart.

“The upper GI tract (i.e., nausea/vomiting) seems to be affected before the lower GI tract (i.e., diarrhea) in COVID-19, which is the opposite from MERS and SARS,” the scientists wrote.

The authors predicted the order of symptoms this spring from the rates of symptom incidence of more than 55,000 confirmed coronavirus cases in China, all of which were collected from Feb. 16-24 by the World Health Organization. They also studied a dataset of nearly 1,100 cases collected from Dec. 11-Jan. 29 by the China Medical Treatment Expert Group via the National Health Commission of China.

To compare the order of COVID-19 symptoms to influenza, the researchers examined data from 2,470 cases in North America, Europe and the Southern Hemisphere that were reported to health authorities from 1994 to 1998.

“The order of the symptoms matter. Knowing that each illness progresses differently means that doctors can identify sooner whether someone likely has COVID-19, or another illness, which can help them make better treatment decisions,” Larsen said.

To read more, click here

Blood-thinner with no bleeding side-effects is here

What is your doctor and hospital doing to follow this news? NOTHING?  Then go to the top and get the board of directors fired.

Blood-thinner with no bleeding side-effects is here

Date:

August 4, 2020

Source:

Ecole Polytechnique Fédérale de Lausanne

Summary:

Scientists have developed a synthetic blood-thinner that, unlike all others, doesn't cause bleeding side-effects. The highly potent, highly selective, and highly stable molecule can suppress thrombosis while letting blood clot normally following injury.

Share:

FULL STORY

---

Patients who suffer from thrombosis, pulmonary embolism or stroke are usually put on drugs that help their blood flow more smoothly through their body. Occupying a large section of the drug market, anticoagulants, or "blood thinners" as they are popularly known, can keep blood clots from forming or getting bigger, and can therefore help with recover from heart defects or prevent further complications.

But there is a catch: blood thinners work by blocking enzymes that help to stop bleeding after an injury. Because of this, virtually every blood thinner available today can lead to serious, and even life-threatening bleeding following an injury.

The problem remained unsolved until a few years ago, when a study was carried out on mice that had been genetically modified to be deficient in an enzyme that normally helps blood clot. The enzyme is called "coagulation factor XII" (FXII), and the mice without the enzyme had a very reduced risk of thrombosis without having bleeding side-effects. The discovery triggered a race for FXII inhibitors.

Finally, a synthetic inhibitor

Participating in the race, the Laboratory of Therapeutic Proteins and Peptides of Professor Christian Heinis at EPFL has developed the first synthetic inhibitor of FXII. The inhibitor has high potency, high selectivity, and is highly stable, with a plasma half-life of over 120 hours. Published in Nature Communications, the study is the result of an extensive collaboration with three other labs in Switzerland and the US.

"The FXII inhibitor is a variation of a cyclic peptide that we identified in a pool of more than a billion different peptides, using a technique named phage display," says Heinis. The researchers then improved the inhibitor by painstakingly replacing several of its natural amino acids with synthetic ones. "This wasn't a quick task; it took over six year and two generations of PhD students and post-docs to complete."

With a potent FXII inhibitor in hand, Heinis's group wanted to evaluate it in actual disease models. To do this, they teamed up with experts in blood and disease-modeling at the University Hospital of Bern (Inselspital) and the University of Bern.

Working with the group of Professor Anne Angellillo-Scherrer (Inselspital), they showed that the inhibitor efficiently blocks coagulation in a thrombosis model without increasing the bleeding risk. Then they assessed the inhibitor's pharmacokinetic properties with the group of Professor Robert Rieben (University of Bern). "Our collaboration found that it is possible to achieve bleeding-free anti-coagulation with a synthetic inhibitor," says Heinis.

Artificial lungs

"The new FXII inhibitor is a promising candidate for safe thromboprotection in artificial lungs, which are used to bridge the time between lung failure and lung transplantation," says Heinis. "In these devices, contact of blood proteins with artificial surfaces such as the membrane of the oxygenator or tubing can cause blood clotting." Known as 'contact activation', this can lead to severe complications or even death and limits the use of artificial lungs for longer than a few days or weeks.

To test the effectiveness of the FXII inhibitor in artificial lungs, Heinis's group turned to Professor Keith Cook at Carnegie Mellon University (US), an expert for artificial lung system engineering. Cook's group tested the inhibitor in an artificial lung model, and found that it efficiently reduced blood clotting, all without any bleeding side-effects.

The only problem is that the inhibitor has a relatively short retention time in the body: it's too small and the kidneys would filter it out. In the context of artificial lungs, this would mean constant infusion, since suppressing blood clotting for several days, weeks or months requires a long circulation time.

But Heinis is optimistic: "We're fixing this; we're currently engineering variants of the FXII inhibitor with a longer retention time."

---

Story Source:

Materials provided by Ecole Polytechnique Fédérale de Lausanne. Original written by Nik Papageorgiou. Note: Content may be edited for style and length.

---

Journal Reference:

1. Jonas Wilbs, Xu-Dong Kong, Simon J. Middendorp, Raja Prince, Alida Cooke, Caitlin T. Demarest, Mai M. Abdelhafez, Kalliope Roberts, Nao Umei, Patrick Gonschorek, Christina Lamers, Kaycie Deyle, Robert Rieben, Keith E. Cook, Anne Angelillo-Scherrer, Christian Heinis. Cyclic peptide FXII inhibitor provides safe anticoagulation in a thrombosis model and in artificial lungs. Nature Communications, 2020; 11 (1) DOI: 10.1038/s41467-020-17648-w

CBD may help avert lung destruction in COVID-19

You should ask your hospital RIGHT NOW what their treatment protocols are for COVID-19.  I'm not waiting for full clinical studies, I would be dead before they are completed. Remember you can't listen to me, I'm not medically trained.

I'm going to be asking for heparin as a blood thinner because of this:

Common FDA-approved drug may effectively neutralize virus that causes COVID-19

And this:

The autopsy findings caused a stir at many hospitals and influenced some doctors to start giving blood thinners to all covid-19 patients. It is now common practice. 

Another takeaway is that the findings underscore the importance of getting people on supplementary oxygen quickly to prevent irreversible brain damage.

 

CBD may help avert lung destruction in COVID-19

Newswise: Respiratory Diseases and Disorders|July 16, 2020

Cannabidiol, or CBD, may help reduce the cytokine storm and excessive lung inflammation that is killing many patients with COVID-19, researchers say.

While more work, including clinical trials to determine optimal dosage and timing, is needed before CBD becomes part of the treatment for COVID-19, researchers at the Dental College of Georgia and Medical College of Georgia have early evidence it could help patients showing signs of respiratory distress avoid extreme interventions like mechanical ventilation as well as death from acute respiratory distress syndrome.

"ARDS is a major killer in severe cases of some respiratory viral infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and we have an urgent need for better intervention and treatment strategies," says Dr. Babak Baban, immunologist and interim associate dean for research at DCG and corresponding author of the study in the journal Cannabis and Cannabinoid Research.

Our laboratory studies indicate pure CBD can help the lungs recover from the overwhelming inflammation, or cytokine storm, caused by the COVID-19 virus, and restore healthier oxygen levels in the body, says co-author Dr. Jack Yu, physician-scientist and chief of pediatric plastic surgery at MCG.

Their CBD findings were enabled by their additional finding of a safe and relatively inexpensive model to duplicate the lung damage caused by ARDS. Work on the virus itself is limited to a handful of labs in the nation that can safely manage the highly contagious virus, and their newly reported approach opens more doors for studying SARS-CoV-2, COVID-19 and similar virus-induced conditions, they say.

Their model, which takes advantage of the large, unique genetic structure of the novel coronavirus, produced classic symptoms of ARDS like the overwhelming, destructive immune response, then CBD significantly downregulated classic indicators of the excess, like inflammation-promoting cytokines as it improved oxygen levels in the blood and enabled the lungs to recover from the structural damage.

A major problem with SARS-CoV-2 is instead of just killing the virus, the over-the-top immune response can quickly disable the lungs, transforming them to a place where virus is replicated, rather than a place that makes oxygen available for our bodies and eliminates potentially harmful gases like carbon dioxide.

Mechanical ventilators can take over these vital functions for a while, and enable critically ill people to use less energy to just breathe and have more energy to fight infection, while ideally the lungs recover from the assault. However evidence suggests 30-50% of patients who get to the point of mechanical ventilation, don't survive.

The cytokines in these now famous "storms" are a class of molecules like interferon and interleukin, secreted by immune cells and other cells like endothelial cells that line blood vessels, which impact cell communication and can both promote and deter inflammation. In the case of COVID-19, there is excessive production of inflammation-promoting molecules like the interleukins IL-6 and IL-1β, as well as immune cells like neutrophils and monocytes, the researchers say.

They looked at objective measures of lung function in mice like levels of proinflammatory cytokines, oxygen levels in the blood before and after treatment, as well as temperature, an indicator of inflammation. Oxygen levels went up, while temperatures and cytokine levels went down with CBD therapy. Days later, a more detailed analysis of the lungs, reinforced reduction of key indicators of destructive inflammation, which their model, like the virus, drove way up including reduced levels of IL-6 and infiltrating neutrophils.

In fact, both clinical symptoms and physical lung changes resulting from ARDS were reversed with CBD treatment, they say.

Their model was created with the help of a synthetic analog of double-stranded RNA called POLY (I:C). In humans, our double-stranded DNA contains our genetic information and our single-stranded RNA carries out the instruction of our DNA to make certain proteins. In the family of coronaviruses, the double-stranded RNA carries the genetic material needed to reproduce the viruses and hijacks the cell machinery of our body to do that, Baban says.

"The natural instinct of the virus is to make more of itself," Baban says. "It weaves with our DNA to make the cell produce food and everything it needs." Viruses also tend to have a tissue or tissues they prefer — some can and do go anywhere — and for SARS-CoV-2, the lungs are high on the list, he says.

Our bodies aren't used to this double-stranded RNA so, like the virus, POLY (I:C) gets the immediate and extreme attention of toll-like receptor 3, a family of receptors that help our body recognize invaders like a virus and activate our frontline, innate immune response.

"The toll-like receptors 3 see this and just go nuts," Yu says. The fact that the coronaviruses are literally big and have the largest known viral RNA genome make such a vigorous cytokine and immune response both plausible and probable, adds Baban.

Mice received three, once-a-day doses of POLY (I:C) in the nasal passageway. CBD was given by a shot in the abdomen, the first dose two hours after the second POLY (I:C) treatment, then every other day for a total of three days in a process that sought to mimic mice getting treatment about the time a human would begin to experience trouble breathing and likely seek medical care. Given too early, CBD might actually interfere with a proper immune response against the virus, Yu says.

CBD quickly improved the clinical symptoms, then later detailed studies of the lungs showed damage to their structure, like tissue overgrowth, scarring and swelling, also had totally or partially resolved. Their next steps include doing similar studies on other organs impacted by COVID-19 including the gut, heart and brain, Baban says.

At least one way CBD is thought to calm the immune response is because it looks similar to endocannabinoids, a natural cell signaling system in our bodies believed to be involved in a wide variety of functions from sleep to reproduction to inflammation and immune response. CB1 and CB2, the main receptors for this system, are found extensively throughout the body including the brain and respiratory system, where we breathe in manmade and natural irritants in the air — as well as viruses and bacteria — that might inflame. While understanding the workings of the natural endocannabinoid system is still very much a work in progress, it's thought that one way CBD works to reduce seizures, for example, is indirectly through the large number of CB1 receptors in the brain, says Yu.

CBD is available without a prescription, and is used to treat problems like seizures as well as Parkinson's, Crohn's and other conditions where pain and/or inflammation are a major factor. It's derived from the hemp and cannabis plant, which are essentially the same although hemp has a much lower concentration of the "high" producing THC. Other investigators have shown the calming effect of CBD, for example, can block IL-6 in other models of inflammatory disease.

ARDS is a rapid, severe infection of the lungs that results in widespread inflammation, shortness of breath, rapid breathing and the inability to sustain adequate oxygen levels to the body and brain. Shortness of breath or difficulty breathing are some of the early signs of COVID-19. ARDS is a major cause of death in patients who are critically ill for a variety of reasons, including common sepsis.

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Common FDA-approved drug may effectively neutralize virus that causes COVID-19

So maybe when you are asking for immediate blood thinners you ask for heparin. But I'm not medically trained so I know nothing. 

So YOU WILL NEED TO ENSURE YOUR DOCTOR DOES THE FOLLOWING:

The autopsy findings caused a stir at many hospitals and influenced some doctors to start giving blood thinners to all covid-19 patients. It is now common practice. 

Another takeaway is that the findings underscore the importance of getting people on supplementary oxygen quickly to prevent irreversible brain damage.

 

Common FDA-approved drug may effectively neutralize virus that causes COVID-19

Newswise: Infectious Diseases|July 15, 2020

A common drug, already approved by the Food and Drug Administration (FDA), may also be a powerful tool in fighting COVID-19, according to research published this week in Antiviral Research.

SARS-CoV-2, the virus that causes COVID-19, uses a surface spike protein to latch onto human cells and initiate infection. But heparin, a blood thinner also available in non-anticoagulant varieties, binds tightly with the surface spike protein, potentially blocking the infection from happening. This makes it a decoy, which might be introduced into the body using a nasal spray or nebulizer and run interference to lower the odds of infection. Similar decoy strategies have already shown promise in curbing other viruses, including influenza A, Zika, and dengue.

“This approach could be used as an early intervention to reduce the infection among people who have tested positive, but aren’t yet suffering symptoms. But we also see this as part of a larger antiviral strategy,” said Robert Linhardt, lead author and a professor of chemistry and chemical biology at Rensselaer Polytechnic Institute. “Ultimately, we want a vaccine, but there are many ways to combat a virus, and as we’ve seen with HIV, with the right combination of therapies, we can control the disease until a vaccine is found.”

To infect a cell, a virus must first latch onto a specific target on the cell surface, slice through the cell membrane, and insert its own genetic instructions, hijacking the cellular machinery within to produce replicas of the virus. But the virus could just as easily be persuaded to lock onto a decoy molecule, provided that molecule offers the same fit as the cellular target. Once bound to a decoy, the virus would be neutralized, unable to infect a cell or free itself, and would eventually degrade.

In humans, SARS-CoV-2 binds to an ACE2 receptor, and the researchers hypothesized that heparin would offer an equally attractive target. In a binding assay, the researchers found that heparin bound to the trimeric SARS-CoV-2 spike protein at 73 picomoles, a measure of the interaction between the two molecules.

“That’s exceptional, extremely tight binding,” said Jonathan Dordick, a chemical and biological engineering professor at Rensselaer who is collaborating with Linhardt to develop the decoy strategy. “It’s hundreds of thousands of times tighter than a typical antibody antigen. Once it binds, it’s not going to come off.”

Internationally recognized for his creation of synthetic heparin, Linhardt said that, in reviewing sequencing data for SARS-CoV-2, the team recognized certain motifs on the spike protein and strongly suspected it would bind to heparin. In addition to the direct binding assay, the team tested how strongly three heparin variants — including a non-anticoagulant low molecular weight heparin — bind to SARS-CoV-2, and used computational modeling to determine the specific sites where the compounds bind to the virus. All the results confirm heparin as a promising candidate for the decoy strategy. The researchers have subsequently initiated work on assessments of antiviral activity and cytotoxicity in mammalian cells.

“This isn’t the only virus that we’re going to confront in a pandemic,” Dordick said. “We don’t really have great antivirals, but this is a pathway forward. We need to be in a position where we understand how things like heparin and related compounds can block virus entry.”

In previous work, a team led by Linhardt and Dordick demonstrated the decoy strategy on viruses with a mechanism similar to SARS-CoV-2. In 2019, the team created a trap for dengue virus, attaching specific aptamers — molecules the viral latches will bind to — precisely to the tips and vertices of a five-pointed star made of folded DNA. Floating in the bloodstream, the trap lights up when sprung, creating the world’s most sensitive test for mosquito-borne diseases. In work prior to that, they created a synthetic polymer configured to match the sialic acid latch points on influenza virus, reducing influenza A mortality in mice from 100% to 25% over 14 days.

“This innovative approach to effectively trapping virusus is a prime example of how biotechnology approaches developed at Rensselaer are being brought forward to address challenging global health problems,” said Deepak Vashishth, the director of the Center for Biotechnology and Interdisciplinary Studies at Rensselaer, of which both Dordick and Linhardt are a part. “Professors Dordick and Linhardt have worked collaboratively across disciplines, and their research shows promise even beyond this current pandemic.”

“Characterization of glycosaminoglycan and novel coronavirus (SARS-CoV-2) spike glycoprotein binding interactions” was published in Antiviral Research. At Rensselaer, Linhardt and Dordick were joined on the research by Fuming Zhang, and also by researchers at the University of California San Diego, Duke University, and the University of George, Athens with support from the National Institutes of Health.

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COVID-19 Is an Independent Stroke Risk Factor

This is absolutely appalling. Suggesting monitoring rather than action. Just maybe you want what other ER docs are already doing.

The autopsy findings caused a stir at many hospitals and influenced some doctors to start giving blood thinners to all covid-19 patients. It is now common practice. 

Another takeaway is that the findings underscore the importance of getting people on supplementary oxygen quickly to prevent irreversible brain damage.

The latest here:

COVID-19 Is an Independent Stroke Risk Factor

After adjusting for traditional vascular risk factors, radiologists encourage aggressive monitoring of COVID-19 patients for blood flow changes to the brain.

There is a significant link between the virus that causes COVID-19 and strokes, newly published research reveals, indicating providers should adjust their treatment of these patients accordingly.
In the American Journal of Neuroradiology, investigators from Ichan School of Medicine at Mount Sinai published the results of an evaluation of more than 120 patients admitted for possible stroke during the pandemic to six New York City hospitals. Their findings indicate that clinicians should more actively monitor these patients to identify any problems as soon as possible.
“This is the first major peer-reviewed study to show that COVID-19 infection is a risk factor for acute strokes,” said lead study author Puneet Belani, M.D., assistant professor of radiology and neurosurgery. “Patients with COVID-19 should be evaluated early for acute neurological changes and timely workup should be performed in patients suspected to have stroke to reduce morbidity and mortality.”
Belani’s team conducted a retrospective, case-control study with 41 patients. Each patient had a stroke confirmed with non-contrast head CT followed by vascular imaging, and the researchers compared that analysis to 82 control participants who, with the same image confirmation, had no evidence of stroke.
Based on their evaluation, they determined that more than 46 percent of patients with acute ischemic stroke also had COVID-19 infection. The same was true for only 18 percent of the control group. After they adjusted for sex, age, and other risk factors, the association between the virus and stroke was clear.
“We found that COVID-19 is an independent risk factor for imaging-confirmed acute ischemic stroke during stroke alert evaluation, after controlling for traditional vascular risk factors,” the team said. “This finding suggests that COVID-19 infection is associated with increased morbidity and mortality that transcends the primary cardiopulmonary sequelae from the infection.”

Coronavirus autopsies: A story of 38 brains, 87 lungs and 42 hearts

I got two takeaways from this; 

1. Blood thinners/anti-coagulation immediately.

2. Oxygen uptake, maybe these?

Sesquiterpenes, a natural compound found in essential oils of Vetiver, Patchouli, Cedarwood, Sandalwood and Frankincense, can increase levels of oxygen in the brain by up to 28 percent 

Or this?

University of Glasgow Study Demonstrates the Ability of Oxycyte® to Supply Oxygen to Critical Penumbral Tissue in Acute Ischemic Stroke  

Or this? having red blood cells release more oxygen.

Methylene blue shows promise for improving short-term memory

 

Coronavirus autopsies: A story of 38 brains, 87 lungs and 42 hearts

The findings caused a stir at many hospitals and influenced some doctors to start giving blood thinners to all covid-19 patients. It is now common practice. 

Another takeaway is that the findings underscore the importance of getting people on supplementary oxygen quickly to prevent irreversible brain damage.

Defining causality in COVID-19 and neurological disorders

While these people wait for more clinical evidence to come in, I am using the results from autopsies on lungs showing lots of micro-thrombi to conclude it is a clotting problem. The solution is clot busting tPA and blood thinners like Lovenox and warfarin. I'm not going to die just because my doctor is waiting for clear clinical studies, I will take charge and direct my doctor on what to do. Doing this fast enough should prevent the need for mechanical ventilation.  A friend was on blood thinner eliquis, got COVID-19 and survived, age 70+. But I'm not medically trained so don't listen to me. 

Defining causality in COVID-19 and neurological disorders

1. Mark Ellul1,2,3,
2. Aravinthan Varatharaj4,5,
3. Timothy R Nicholson6,
4. Thomas Arthur Pollak6,
5. Naomi Thomas7,8,
6. Ava Easton9,
7. Michael S Zandi10,
8. Hadi Manji10,
9. Tom Solomon1,2,3,
10. Alan Carson11,
11. http://orcid.org/0000-0003-0267-3180Martin R Turner12,
12. Rachel Kneen1,3,13,
13. http://orcid.org/0000-0002-1268-5102Ian Galea4,5,
14. Sarah Pett14,15,
15. Rhys Huw Thomas7,16,
16. http://orcid.org/0000-0002-8693-8926Benedict Daniel Michael1,2,3
17. CoroNerve Steering Committee

Author affiliations

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http://dx.doi.org/10.1136/jnnp-2020-323667

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When faced with acute neurological presentations in a patient with COVID-19, how confident can one be that SARS-CoV2 is causal?

Introduction

Clinicians are increasingly recognising neurological presentations occur in some patients.1 A case series from Wuhan described associated neurological syndromes (eg, ‘dizziness’ and ‘impaired consciousness’), but with little detail regarding symptomatology, and cerebrospinal fluid (CSF) and neuroimaging findings.2 The extent to which these disorders were caused by the virus per se, rather than being complications of critical illness, unmasking of degenerative disease, or iatrogenic effects of repurposed medications is not clear.

Numerous case reports have since emerged and, at the time of writing, published cases include encephalopathy,3 encephalitis,4 Guillain-Barré syndrome (GBS)5 and stroke.6 In most of these cases, the virus has been identified in respiratory samples, and in a small number in CSF. So far, the reporting of clinical features has been extremely variable, for example, several cases have claimed to report encephalitis without clear evidence of central nervous system (CNS) inflammation, which would not meet established definitions of the disease.7

Whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is associated with neurological manifestations is of critical importance as this may result in substantial morbidity and mortality.

Defining causality

It is crucial that neurologists and neuropsychiatrists apply a systematic strategy to determine whether there is evidence that SARS-CoV2 is causing these manifestations, whether they are a consequence of severe systemic disease alone, or simply coincidence. In 1965, Hill proposed criteria on which to build an argument for disease causation, which can be applied to COVID-19.8

What is the strength of the association? So far, it appears fairly weak. >2.5 million people have been infected with SARS-CoV2 and to date (to the authors’ knowledge) there have been only 93 published cases of neurological manifestations (about 5/100 000). However, reported cases are an underestimate of the real incidence, and this underscores the need for proper epidemiological study.

What is the consistency of the association? So far, there have been published reports of neurological manifestations across the globe, including from China, Japan, Italy, France, the USA and the UK. Although the numbers are low, these are not isolated incidences and have occurred throughout the evolution of the pandemic.

To what extent is the relationship specific? The range of neurological manifestations reported in association with SARS-CoV2 is wide, from the CNS through to peripheral nerves. However, in previous pandemics, similar central and peripheral associations have been well recognised.9

What can temporality tell us about the association? The delay between infection and the neurological presentation may give a clue to mechanisms. Direct CNS infection might be expected to be contemporaneous with, or shortly after, fever and respiratory symptoms. Parainfectious disease, owing to innate immune responses, such as acute necrotising encephalopathy, usually occurs in the days following infection. Post-infectious syndromes, due to adaptive immune responses, such as GBS, are typically in the few weeks following infection. In most reported cases, respiratory disease has occurred a few days prior to the onset of the neurological syndrome although significant delays between a neurological presentation and COVID-19 diagnosis in some raise the possibility of nosocomial infection.

Hill asks us to look for a biological gradient. In general, those with neurological manifestations have had severe COVID-19 respiratory disease suggesting the possibility that higher viral loads and/or more fulminant inflammatory responses may be accountable for both.

Is there biological plausibility? Many human viruses can enter the CNS and some coronaviruses exhibit neurotropism in animal models.10 The syndromes described so far could plausibly be related to primary infection with SARS-CoV2, although improved understanding of host responses is needed.

Hill asks us to consider the coherence of the evidence. Perhaps our best sources of coherent data are the SARS and Middle East respiratory syndrome (MERS) epidemics: coronaviruses with about 80% and 50% homology to SARS-CoV2, respectively. Neurological syndromes were reported in association with both, including acute disseminated encephalomyelitis-like presentations with MERS and encephalopathy/encephalitis with SARS.11

Is there any possibility of experimental evidence? The ideal investigational vehicle would be a case control study, but this presents design challenges as exposure is high and we do not yet have validated widespread antibody testing to ascertain seroprevalence.

Can we learn by analogy with other similar scenarios? Other respiratory viruses, most notably influenza, are well-established triggers of CNS damage. During the H1N1 pandemic, neurological syndromes were well described, including acute necrotising encephalopathy bearing striking resemblance to the case recently described with COVID-19.9 So, the emergence of neurological disorders associated with pandemic viral infections is less the exception, and more the norm.

Conclusions

As always, our evidence must be founded on clear and systematic assessment of the clinical syndromes, supported by well-designed laboratory studies. Cases must be reported in line with clear clinical case definitions, both systematically and transparently, and with honesty about negative or missing results.

These aims are best served by standardisation and centralisation of case reporting, which calls for a truly collaborative approach between neurologists, neuropsychiatrists and allied colleagues.

To address this, we have established the CoroNerve Studies Group as a collaboration between professional bodies in the UK (CoroNerve.com), and similar studies are underway in other countries. However, a joined-up international approach is necessary. To begin this process, a complimentary initiative, the COVID-Neuro Network, through Brain Infections Global, is supporting collaboration among several lower and middle-income countries.

We all must learn the lessons from previous pandemics, and the principles of Bradford Hill if we are to translate these rapidly growing datasets into meaningful advances in our understanding of the neurological complications of COVID-19.

Acknowledgments

CoroNerve Study Management Group: Mark Ellul, Ian Galea, Rachel Kneen, Benedict Michael, Sarah Pett, Naomi Thomas, Rhys Thomas, Ara Varantharaj. CoroNerve Steering Committee: Laura Benjamin, Jonathan Coles, Nicholas WS Davies, Ava Easton, Hadi Manji, David Menon, Craig Smith, Tom Solomon, Michael Zandi.