CMAAO CORONA FACTS and MYTH BUSTER 108 Thrombo-inflammation

CMAAO CORONA FACTS and MYTH BUSTER 108 Thrombo-inflammation

Dr K K Aggarwal

President CMAAO

With inputs from Dr Monica Vasudev

930: Complete Fibrinolysis Shutdown in Severe COVID-19

COVID-19 causes not only hypercoagulability, but also "fibrinolysis shutdown," which is associated with venous thromboembolism (VTE), stroke, and renal failure.

Complete lack of clot lysis at 30 minutes on a thromboelastogram (TEG) assay, coupled with a D-dimer value above 2600 ng/mL, identifies high-risk individuals who will potentially require more aggressive anticoagulation.

Patients with COVID-19 are at high risk of blood clots, both in small and large blood vessels.

The study was published online May 7 in the Journal of the American College of Surgeons.

Wright and colleagues did a retrospective study of 44 COVID-19 patients (28 male; median age, 54 years).

The primary study outcomes were VTE events and new-onset renal failure requiring dialysis. Forty-one (93%) patients required mechanical ventilation, 16 (36%) had acute renal failure requiring dialysis, 11 (25%) had a VTE, and six (14%) had a thrombotic stroke.

Derangements in coagulation laboratory values included an elevated D-dimer level and elevated fibrinogen, with normal platelet counts in the majority of patients and mildly elevated prothrombin time (PT) and partial thromboplastin time (PTT), with median values at or slightly above the upper limits of normal.

The median International Society on Thrombosis and Haemostasis (ISTH) disseminated intravascular coagulation (DIC) score was 0, with no patient having a score higher than 4. TEG variables were consistent with a hypercoagulable state with an elevated maximum amplitude and low lysis at 30 minutes.

On TEG testing, more than half of patients (57%) had a complete lack of clot lysis at 30 minutes (LY30), and this was a significant predictor of VTE, with an area under the receiver operating characteristic curve (AUROC) of 0.742 (P = .021).

A D-dimer cutoff of 2600 ng/mL was a significant predictor of need for dialysis, with an AUROC of 0.779 (P = .005).

Overall, patients with no clot lysis at 30 minutes on TEG assay and a D-dimer value above 2600 ng/mL had a rate of VTE of 50%, compared with 0% for patients with neither risk factor (P = .008). The time to VTE was also significantly shorter in patients with fibrinolysis shutdown.

The hemodialysis rate was 80% with these two coagulation risk factors, compared with 14% without (P = .004).

This cohort of critically ill COVID-19 patients was clearly hypercoagulable, despite high normal or frankly elevated PT and PTT levels, demonstrating the importance of using whole blood coagulation assays (which more closely approximate in vivo conditions including the presence of cells and platelets) such as the TEG for improved risk stratification."

1.     Coronavirus disease 2019 (COVID-19) is associated with a hypercoagulable state associated with acute inflammatory changes and laboratory findings that are distinct from acute disseminated intravascular coagulation (DIC), save for those with very severe disease.

2.     Fibrinogen and D-dimer are increased, with typically only modest prolongation of the prothrombin time (PT) and activated partial thromboplastin time (aPTT) and mild thrombocytosis or thrombocytopenia.

3.     The presence of a lupus anticoagulant (LA) is common in individuals with a prolonged aPTT.

4.     The risk for venous thromboembolism (VTE) is markedly increased, especially in patients in the intensive care unit (ICU), with case series reporting prevalences of 25 to 43 percent in ICU patients, often despite prophylactic-dose anticoagulation.

5.      The risk for other thrombotic events (stroke, microvascular thrombosis) is less clear.

6.     All patients admitted to the hospital for COVID-19 should have a baseline complete blood count (CBC) with platelet count, PT, aPTT, fibrinogen, and D-dimer. Repeat testing is done according to the patient's clinical status.

7.      Outpatients do not require coagulation testing.

8.     All inpatients should receive thromboprophylaxis unless contraindicated. Low molecular weight (LMW) heparin is preferred, but unfractionated heparin can be used if LMW heparin is unavailable or if kidney function is severely impaired. Some institutional protocols include more aggressive anticoagulation with intermediate-dose or even therapeutic-dose anticoagulation for thromboprophylaxis.

9.     Therapeutic-dose (full-dose) anticoagulation is appropriate to treat deep vein thrombosis (DVT) or pulmonary embolism (PE), unless contraindicated.

10.  Bleeding is unusual but can occur. If it occurs, treatment is similar to non-COVID-19 patients and may include transfusions, anticoagulant reversal or discontinuation, or specific products for underlying bleeding disorders.

What’s new

COVID-19 hypercoagulable state (May 2020): Many reports have described a hypercoagulable state associated with COVID-19. The prevalence of venous thromboembolism (VTE) is increased, especially in critically ill individuals, often despite prophylactic anticoagulation. Arterial thrombosis has also been reported but the prevalence is not known. Some individuals have markedly elevated D-dimer, which correlates with worse prognosis. Unlike disseminated intravascular coagulation (DIC), the fibrinogen is often elevated, and clotting times and platelet counts are typically normal.

Causes of death from COVID-19 (May 2020)

Two new autopsy studies, together including a total of 33 individuals who died of COVID-19, have revealed common causes of death to be pneumonia and pulmonary embolism.

Lung histology also showed diffuse alveolar damage consistent with early acute respiratory distress syndrome, and inflammatory infiltrates consistent with viral or bacterial pneumonitis. In both studies, the average age was in the mid-70s, most were men, and most had preexisting conditions, especially heart disease, hypertension, diabetes, and obesity. While both studies were small, they emphasize the contributions of lung inflammation and hypercoagulability to fatal illness in this disease.  [uptodate]

RV dilatation

Respiratory distress and myocarditis common in patients hospitalized with COVID-19 have an impact on the right ventricle (RV), but the acute effects and whether they create longer-lasting damage is less well understood as per a pair of recent reports in JACC: Cardiovascular Imaging.

In the retrospective study, 31% of more than 100 such patients with a clinical indication for echocardiography were found to have RV dilation, a feature that didn't track with myocardial inflammation or injury or with pulmonary embolism (PE). But it did independently predict more than a fourfold increase in in-hospital mortality.

The RV dilation wasn't continuous, typically. These changes were  dynamic. We saw patients moving in either direction, going from normal ventricle to enlarged and going from enlarged to normalized.

All of the people who had RV enlargement underwent CT angiography to look for pulmonary embolisms, and only 50% of them had PE

The echocardiography study, was published May 15.

The other report included findings on postdischarge MRI in 26 consecutive patients from one center in Wuhan, China, who had recovered from COVID-19 but later experienced cardiac symptoms, such as chest pain or palpitations; none had a pre-COVID-19 history of myocarditis or other heart disease.

Fifteen of the cohort, or 58%, showed MRI signatures for diffuse myocardial edema and for fibrosis by late-gadolinium enhancement (LGE), or for both along with impaired RV cardiac index and ejection fraction, despite preserved LV function.

That was compared with 20 recent historical control subjects without documented cardiovascular or inflammatory disease who underwent the same MRI examinations.

The presence of myocardial tissue abnormalities in otherwise healthy subjects suggests cardiac involvement as a lasting consequence of SARS-CoV-2 infection

Lu Huang, MD, PhD, Tongji Medical College and Huazhong University of Science and Technology, Wuhan, in their report published May 11.