Systemic clotting problems emerging in severe and critically-ill COVID-19 patients are pushing centers to make tough decisions on anticoagulation with a dearth of information.

Disseminated intravascular coagulation has been noted by Chinese physicians on the initial front of the pandemic. Autopsies showing clots in "not only the lungs but also including the heart, the liver, and the kidney," were described on a webinar co-sponsored by the Chinese Cardiovascular Association and American College of Cardiology in March.

Elevated D-dimer, a fibrin degradation product indicating thrombosis, at admission has also been linked to substantially higher odds of death in hospital among COVID-19 patients in Wuhan, China.

"What really has become clear in the discussions in the last 2 weeks is that the COVID-19 disease is much associated with thrombosis: large vessel clots, DVT/PE [deep vein thrombosis/pulmonary embolism], maybe arterial events, and potentially small vessel disease, microvascular thrombosis," said Stephan Moll, MD, of the University of North Carolina at Chapel Hill Hemophilia and Thrombosis Center.

As U.S. cases 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 everybody with COVID-19 in the hospital should be on 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, full-dose anticoagulation is being considered even if patients don't have documented blood clots, he said, "because it may be microvascular thrombosis in the lung, in the kidneys that lead to pulmonary failure and renal failure and eventually death."

Clinical Challenges

"Even the diagnosis of thrombotic events is difficult in this population because of the risk of exposure when performing testing as well as the difficulty testing for 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 events, he told MedPage Today, "empiric anticoagulation with either full dose or partial dose antithrombotics is such an interesting question."

Physicians are having to dive in, though, with pragmatic guidelines being released by many centers and some professional societies and more on the way, according to Moll.

The International Society on Thrombosis and Haemostasis recently recommended that all hospitalized COVID-19 patients, even those not in the ICU, should get prophylactic-dose low molecular weight heparin (LMWH), unless they have contraindications (active bleeding and platelet count <25×109/L).

Recommendations from Britain also call for VTE prophylaxis for all high-risk patients as well as considering PE for patients with sudden onset of oxygenation deterioration, respiratory distress, and reduced blood pressure. It suggested LMWH rather than oral anticoagulants, including switching patients who normally take a direct oral anticoagulant (DOAC) or vitamin K antagonist.

Many institutions are choosing threshold values upon which 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 (albeit growing) evidence base."

Long chain (unfractionated) heparin would theoretically be preferable among anticoagulants because of their anti-inflammatory effects, Moll noted, while LMWH has less of an anti-inflammatory effect and DOACs have little. "And inflammation plays a big role in COVID-19."

IV unfractionated heparin also has an advantage in that it can be stopped quickly if bleeding occurs, Katz noted. While there has been some suggestion that heparin may influence SARS-CoV-2 binding, "this construct needs to be validated, of course."

However, practical matters may dominate. In New York City, Montefiore and many other hospitals have chosen DOACs, Moll noted. "They don't want the nurses to go into the patients' room to give the unfractionated heparin two or three times a day or to adjust the IV unfractionated heparin. It's much easier to just give an oral anticoagulant with a huge number of patients."

Mechanism

Exactly why the virus causes such extensive coagulation isn't clear.

Three ICU patients with COVID-19 in China showed antiphospholipid autoimmune responses, reported Yongzhe Li, MD, of Peking Union Medical College Hospital in Beijing, and colleagues 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 may rarely lead to thrombotic events that are difficult to differentiate from other causes of multifocal thrombosis in critically patients, such as disseminated intravascular coagulation, heparin-induced thrombocytopenia, and thrombotic microangiopathy," they wrote.

D-dimer was over 21 mg/L in the first patient, who "had evidence of ischemia in the lower limbs bilaterally as well as in digits two and three of the left hand. Computed tomographic imaging of the brain showed bilateral cerebral infarcts in multiple vascular territories." Lab results also showed leukocytosis, thrombocytopenia, an elevated prothrombin time and partial thromboplastin time, and elevated levels of fibrinogen.

D-dimer was around 3 mg/L in the other two patients, both had multiple cerebral infarctions in the right frontal lobe and other locations in the brain on imaging, and other findings were similar as well.

Lupus anticoagulant was not detected in any of them.

However, Moll cautioned against drawing any causal conclusions, as antiphospholipid antibodies are well known to be transiently positive at the time of acute infectious illness. Also, antiphospholipid antibody titers and lab assay used were not reported.

Endothelial damage leading to subsequent clotting has been promoted as the mechanism by Bin Cao, MD, of the National Clinical Research Center for Respiratory Diseases in Beijing, who helped develop treatment strategies there from the beginning of the epidemic.

The SARS-CoV-2 virus that causes COVID-19 disease enters cells via the angiotensin converting enzyme 2 (ACE2) receptors, which are most commonly found in the alveolar epithelial cells, followed by endothelial cells, Cao noted on the CCA/ACC webinar last month. When the virus binds to these cells, it may damage the blood vessel, especially the microcirculation of the small blood vessels, and thus spur 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, Yundai Chen, MD, of the Chinese PLA General Hospital in Beijing, added during the webinar. Other potential mechanisms for the cardiac damage are hypoxia-induced myocardial injury, cardiac microvascular damage, and systemic inflammatory response syndrome.

Which of these mechanisms is dominant matters a lot in treatment approach, Moll noted. "If the thrombosis is the major reason for multiorgan failure, then the anticoagulation is really important. Anticoagulation obviously leads to higher risk of bleeding, so you don't want to give it if that's not the main mechanism."

Further autopsy studies will be important in sorting this out, along with studies correlating those findings to clinical course, he said.