Pragmatic choices dominate as guidelines take shape.
by Crystal Phend, Senior Editor, MedPageT
Systemic coagulation problems arising in severely and critically ill COVID-19 patients are putting pressure on centers to make difficult decisions about anticoagulation with a lack of information.
Chinese doctors have noted disseminated intravascular coagulation in the early stages of the pandemic. Autopsies showing clots in "not only the lungs but also the heart, liver, and kidneys" were described in a webinar co-sponsored by the Chinese Cardiovascular Association and the American College of Cardiology in March.
Elevated D-dimer, a fibrin degradation product that indicates thrombosis, on admission has also been linked to substantially higher odds of in-hospital death among COVID-19 patients in Wuhan, China.
"What has really become clear in discussions over the past 2 weeks is that COVID-19 disease is very much associated with thrombosis: large vessel clots, DVT/PE [deep vein thrombosis/pulmonary embolism], perhaps arterial events, and potentially small vessel disease, microvascular thrombosis," said Dr. Stephan Moll, of the University of North Carolina at the Chapel Hill Hemophilia and Thrombosis Center.
As cases in the U.S. have skyrocketed, it has also become clear that hospitalized patients often develop blood clots despite being on prophylactic anticoagulation, he told MedPage Today .
"The question is whether everyone with COVID-19 in the hospital should be taking blood thinners, and the answer is probably yes," he said. "Should they be on higher-than-usual prophylactic doses? And the answer is possibly yes."
Now, the full dose of anticoagulation is being considered even if patients have no documented blood clots, he said, "because it can be microvascular thrombosis in the lung, in the kidneys leading to lung failure and kidney failure and, ultimately, death."
Clinical challenges
"Even diagnosing thrombotic events is difficult in this population due to the risk of exposure during testing, as well as the difficulty in detecting microthrombotic events," commented Ajay Kirtane, MD, SM, director of the cardiac catheterization laboratories at Columbia University Irving Medical Center/NewYork-Presbyterian Hospital in New York City.
Without knowing the true incidence of the events, he told MedPage Today , "empirical anticoagulation with full or partial dose antithrombotics is such an interesting question."
However, doctors need to get involved, and many centers and some professional societies are publishing pragmatic guidelines, according to Moll.
La Sociedad Internacional de Trombosis y Hemostasia recomendó recientemente que todos los pacientes hospitalizados con COVID-19, incluso aquellos que no están en la UCI, reciban heparina de bajo peso molecular (HBPM) con dosis profilácticas, a menos que tengan contraindicaciones (sangrado activo y recuento de plaquetas <25 × 10 9 / L).
The UK guidelines also mandate VTE prophylaxis for all high-risk patients, as well as considering PE for patients with sudden deterioration in oxygenation, respiratory distress, and reduced blood pressure. They suggested LMWH instead of oral anticoagulants, including switching patients who normally take a direct oral anticoagulant (DOAC) or a vitamin K antagonist.
Many institutions are choosing threshold values to start systemic anticoagulation around a D-dimer > 1,500 ng/ml and fibrinogen > 800 mg/ml, noted Jason Katz, MD, director of cardiovascular critical care at Duke University Health System in Durham, North Carolina. "For now, we [at Duke] are taking things on a case-by-case basis, which I think is reasonable in light of the small (although growing) evidence base."
Long-chain (unfractionated) heparin would theoretically be preferable among anticoagulants due to its anti-inflammatory effects, Moll noted, while LMWH has less anti-inflammatory effect and DOACs have little. "And inflammation plays a significant role in COVID-19."
Unfractionated intravenous heparin also has the advantage that it can be stopped quickly if bleeding occurs, Katz noted. While it has been suggested that heparin may influence SARS-CoV-2 binding, "this construct needs to be validated, of course."
However, practical matters may prevail. In New York City, Montefiore and many other hospitals have chosen DOACs, Moll noted. “They don’t want nurses going into patients’ rooms to administer unfractionated heparin two or three times a day or to adjust IV unfractionated heparin. It’s much easier to administer an oral anticoagulant with a large number of patients.”
Mechanism
It is not clear exactly why the virus causes such extensive clotting.
Three ICU patients with COVID-19 in China showed autoimmune antiphospholipid responses, Yongzhe Li, MD, of Peking Union Medical College Hospital in Beijing, and colleagues reported in a letter to the New England Journal of Medicine published Wednesday.
All three tested positive for anticardiolipin IgA and anti-β2-glycoprotein I IgA and IgG.
"The presence of these antibodies can rarely lead to thrombotic events that are difficult to differentiate from other causes of multifocal thrombosis in critically ill patients, such as disseminated intravascular coagulation, heparin-induced thrombocytopenia, and thrombotic microangiopathy," they wrote.
The D-dimer level was greater than 21 mg/L in the first patient, who "had evidence of ischemia in the lower extremities bilaterally, as well as in the second and third fingers of the left hand. Computed tomography of the brain showed bilateral cerebral infarcts in multiple vascular territories." Laboratory results also showed leukocytosis, thrombocytopenia, an elevated prothrombin time and partial thromboplastin time, and elevated fibrinogen levels.
The D-dimer was around 3 mg/L in the other two patients; both had multiple cerebral infarcts in the right frontal lobe and other locations in the brain on imaging, and other findings were also similar.
The lupus anticoagulant was not detected in any of them.
However, Moll cautioned against drawing causal conclusions, as antiphospholipid antibodies are known to be transiently positive during acute infectious disease. Furthermore, the antiphospholipid antibody titers and the laboratory assay used were not reported.
Endothelial damage leading to subsequent coagulation has been promoted as a mechanism by Dr. Bin Cao, of the National Clinical Research Center for Respiratory Diseases in Beijing, who helped develop treatment strategies there since the beginning of the epidemic.
The SARS-CoV-2 virus that causes COVID-19 enters cells through angiotensin-converting enzyme 2 (ACE2) receptors, which are most commonly found on alveolar epithelial cells, followed by endothelial cells, Cao noted in the CCA/ACC webinar last month. When the virus binds to these cells, it can damage the blood vessel, especially the microcirculation of small blood vessels, and thus stimulate platelet aggregation, he said.
Autopsies have also shown inflammatory changes in the heart with fine interstitial mononuclear inflammatory infiltrates, but no viral inclusions in the heart, added Yundai Chen, MD, of the Chinese PLA General Hospital in Beijing, during the webinar. Other potential mechanisms for cardiac damage include hypoxia-induced myocardial injury, cardiac microvascular damage, and systemic inflammatory response syndrome.
Moll pointed out that which of these mechanisms is dominant is very important in the treatment approach. “If thrombosis is the primary cause of multiple organ failure, then anticoagulation is really important. Anticoagulation obviously leads to a higher risk of bleeding, so you don’t want to administer it if that’s not the primary mechanism.”
Further autopsy studies will be important to resolve this, along with studies that correlate those findings with the clinical course, he said.
Main source
New England Journal of Medicine
Reference source: Zhang Y, et al “Coagulopathy and antiphospholipid antibodies in patients with Covid-19” N Engl J Med 2020; DOI: 10.1056/NEJMc2007575.