Table 5.

Areas Requiring Further Investigation

Area	Comment
Patients with mild COVID-19 (outpatient)
To determine the optimal method for risk assessment for outpatients with mild COVID-19 who are at risk of VTE	The options include the Caprini model, the IMPROVE model, and the Padua model, and others for assessment of the risk of VTE. These should be weighed against the risk of bleeding.
To determine the incidence ACS in population-based studies
Patients with moderate or severe COVID-19 without DIC (hospitalized)
To determine the incidence and predictors of VTE among patients with COVID-19 who present with respiratory insufficiency and/or hemodynamic instability; these include lower extremity DVTs, central line–associated DVT in upper or lower extremities, and also PE	Prospective multicenter cohort (observational) data are needed, and these protocols should not interfere, and could run in parallel with, interventional trials that are planned or already underway.
To develop an appropriate algorithm for the diagnosis of incident VTE in patients with COVID-19	D-dimer is elevated in many inpatients with COVID-19, although negative value may still be helpful. In some cases of COVID-19 with worsening hypoxemia, CTPA may be considered instead of noncontrast CT (which only assesses the pulmonary parenchyma). Unresolved issues include diagnostic tests for critically ill patients, including those in prone position, with limited options for CTPA or ultrasonography.
To determine the optimal total duration of prophylactic anticoagulation	Ultrasound screening in select patients may need to be studied.
To determine the optimal dose of prophylactic anticoagulation in specific populations (e.g., those with obesity or advanced kidney disease)	Weight-adjusted prophylactic dosing for patients with obesity, or dosing based on creatinine clearance in patients with kidney disease require further investigation.
To determine if LMWH constitutes the preferred method of pharmacological prophylaxis
To determine the optimal method for risk stratification and VTE prophylaxis after hospital discharge	The options include the Caprini model, the IMPROVE model, and the Padua model, and others for assessment of the risk of VTE. These should be weighed against the risk of bleeding.
To determine if routine use of higher doses of anticoagulants (i.e., higher than prophylactic doses as described in the international guidelines) confer net benefit	An important question would be whether monitoring anti-Xa activity would be preferable over aPTT.
To determine the incidence and predictors of type 1 acute myocardial infarction in patients with COVID-19, and to compare their process measures and outcomes with noninfected patients
To determine the potential role of agents including danaparoid, fondaparinux, and sulodexide in select patients with moderate/severe COVID-19
Patients with moderate or severe COVID-19 and suspected or confirmed DIC (hospitalized)
To determine if routine use of pharmacological VTE prophylaxis or low- or standard-dose anticoagulation with UFH or LMWH is warranted (if no overt bleeding)	A relevant question is whether prophylactic, or other, dose anticoagulation should be given to patients with DIC who do not have bleeding, even without immobility.
To determine if additional clinical characteristics and variables in the setting of DIC (e.g., lymphopenia) should be considered to help risk-stratify and assess prognosis
To determine utility of other interventions including antithrombin concentrates
Patients without COVID-19 but with comorbidities, and homebound during the pandemic
To determine the optimal method of screening and risk stratification for consideration of VTE prophylaxis	The options include the Caprini model, the IMPROVE model, and the Padua model, and others for assessment of the risk of VTE. These should be weighed against the risk of bleeding.
To conduct population-level studies to determine the trends in incidence and outcomes of thrombotic disease in the period of reduced office visits	Although telemedicine is reasonable to control the COVID-19 pandemic, potential adverse consequences on noncommunicable disease, including thrombotic disease deserve investigation.

CTPA = computed tomography pulmonary angiography; IMPROVE = International Medical Prevention Registry on Venous Thromboembolism; LMWH = low-molecular weight heparin; UFH = unfractionated heparin; other abbreviations as in Table 1.