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Early Data Suggest Caution with Empiric Escalation of Anticoagulation in COVID-19

Key findings

  • A multicenter retrospective study evaluated the thrombotic and bleeding complications of 400 adults with COVID-19
  • The rate of radiographically confirmed venous thromboembolism was 4.8% (7.6% in critically ill patients)
  • The bleeding rate was 4.8% (7.6% in critically ill patients), with a major bleeding rate of 2.3% (5.6% in critically ill patients, including one fatal bleed)
  • The rate of disseminated intravascular coagulation was low (2% of critically ill patients)
  • Elevated D-dimer levels at presentation predicted thrombotic complications, bleeding complications and critical illness

Elevated circulating D-dimer levels and prolonged prothrombin time were associated with a greater risk of death in early studies of COVID-19. Moreover, one paper reported laboratory signs of disseminated intravascular coagulation (DIC) in more than 70% of patients who died of COVID-19.

Nevertheless, routine administration of intensive prophylactic anticoagulation is premature, based on study results reported in Blood by Hanny Al-Samkari, MD, a classical hematologist and clinical investigator, at the Center for Hematology at the Mass General Cancer Center, and Rachel Rosovsky, MD, of the Division of Hematology/Oncology at the Mass General Cancer Center, and colleagues.

Study Details

The study involved 400 adults who were admitted to Mass General or one of its partner hospitals with confirmed COVID-19 between March 1 and April 5, 2020, and had a D-dimer test on initial evaluation. 144 of the patients were critically ill.

Thrombosis

Venous thromboembolism: The radiographically confirmed rate was 4.8% (3.1% of non-critically ill patients; 7.6% of critically ill patients). The overall rate—radiographically confirmed and clinically suspected—was 6.0% (3.5% of non-critically ill patients; 10.4% of critically ill patients). All but one patient was receiving standard prophylactic doses of unfractionated heparin or low molecular weight heparin at the time of the event; the other was receiving therapeutic-dose apixaban.

Arterial thrombosis: The rate was 2.8% (1.2% of non-critically ill patients; 5.6% of critically ill patients). All of these patients were receiving prophylactic anticoagulation.

Line clotting: 12 critically ill patients needed continuous veno-venous hemofiltration (CWH). Eight had recurrent clotting despite prophylactic-dose anticoagulation and required a change to therapeutic-dose heparin; two of those patients continued to have recurrent clotting. Five of the eight patients also had venous or arterial thrombotic events.

Of the four patients placed on CVVH who did not have recurrent line clotting, three were already on therapeutic-dose heparin for other indications.

Two other critically ill patients had recurrent thrombosis of arterial lines or central venous catheters that required repeated replacement of lines.

Bleeding

Bleeding events: The overall rate was 4.8% (3.1% of non-critically ill patients; 7.6% of critically ill patients). The rate of major bleeding (WHO grade 3/4) was 2.3%, and all but one patient with major bleeding was critically ill, for a rate of 5.6%. One event, an intracranial hemorrhage, was fatal.

DIC: Only three critically ill patients (2%) had clinical and laboratory evidence of DIC. All had grade 3/4 bleeding events.

Predictors at Initial Presentation

Predictors of thrombotic complications:

  • D-dimer 1001–2500 ng/mL (adjusted OR, 3.04)
  • D-dimer >2500 ng/mL (aOR, 6.79)

Predictors of bleeding complications:

  • D-dimer >2500 ng/mL (aOR, 3.56)
  • Platelet count <150 × 109/L (aOR, 2.90)

Predictors of critical illness:

  • D-dimer 1001–2500 ng/mL (aOR, 2.58)
  • D-dimer >2500 ng/mL (aOR, 2.05)
  • Procalcitonin >0.50 ng/mL (aOR, 4.92)
  • C-reactive protein >100 mg/L (aOR, 3.03)
  • Erythrocyte sedimentation rate >40 mm/h (aOR, 2.85)
  • High-sensitivity cardiac troponin >20 ng/L (aOR, 1.91)

Recommendations

Given the risk of bleeding, anticoagulation should be escalated beyond the standard of care only in randomized trials, even for critically ill patients with COVID-19. Data in this study support an exception to this being patients receiving renal replacement therapy with CVVH who have multiple episodes of line clotting.

7.6%
of critically ill COVID-19 patients developed venous thromboembolism

5.6%
of critically ill COVID-19 patients had a major bleeding event

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