Full Dose Heparin Vs. Prophylactic Or Intermediate Dose Heparin in High Risk COVID-19 Patients

There are clinical data to support the observation that hospitalized acutely ill medical
patients with severe viral pneumonitis/Acute Respiratory Distress Syndrome (ARDS), such as
those with influenza H1N1 infection, have an over 23-fold increased risk for venous
thromboembolism (VTE) - especially pulmonary embolism (PE) - with an overall 44% incidence of
VTE in ARDS associated with H1N1 pneumonia. Multicenter studies from China report that key
markers of inflammation and/or coagulopathy are associated with morbidity and increased
mortality in COVID-19 patients. Elevated D-dimer levels (that are sometime greater than 4 or
6 times the upper limit of normal [ULN]) are strongly associated with mortality in patients
with severe COVID-19 illness. Recent data also shows that mortality among COVID-19 patients
is markedly higher in patients with elevated Troponin-T (TnT) levels than in patients with
normal TnT levels. Recently a cohort of 81 patients retrospectively evaluated diagnosed with
severe COVID-19 pneumonia and reported a lower extremity VTE incidence of 25% (20/81) and a
mortality of 40% (8/20) in the presence of VTE. Reported a case of bilateral pulmonary
embolism in a 75 year old woman diagnosed with severe COVID-19, in the absence of
predisposing risk factors and a negative lower extremity US. Lastly the investigated use of
Tissue Plasminogen Activator (tPA) in the treatment of COVID-19 associated ARDS and reported
promising, but transient, results in terms of pulmonary function improvement. It appears that
either the SARS-CoV2 infection itself induces a hypercoagulable state, possibly by
hypofibrinolytic mechanisms, or the cytokine storm in COVID-19 patients with severe disease
induces a prothrombotic state, which leads to clinical deterioration, hypoxia and hemodynamic
instability secondary to thromboembolic phenomena and potentially cardiac ischemia.
Preliminary data from Northwell Health System, which has one of the largest populations of
hospitalized COVID-19 patients in the US, reveals a positivity rate for deep vein thrombosis
(DVT) of 40% of those COVID-19 patients screened by Doppler compression ultrasonography of
the lower extremities.

Heparin has been shown to have anti-inflammatory and immunomodulatory properties in addition
to its anticoagulation effect, which could play a beneficial role in sepsis. In addition,
there is in vitro evidence that the large negatively charged sulfated glycosaminoglycans of
unfractionated heparin may act as an alternate ligand for the SARS-CoV2 receptor irrespective
of ACE2. Whether this in vitro evidence supports the role of a protective or deleterious
mechanism in COVID-19 infection is not known. However, an early report with empiric use of
treatment dose unfractionated heparin (UFH) in ARDS from a different viral family, influenza
H1N1, revealed that H1N1 ARDS patients under systemic anticoagulation had 33-fold fewer VTE
events than those treated given prophylactic doses of UFH/low-molecular weight heparin (LMWH)
thromboprophylaxis. Very recent evidence suggests that therapy with prophylactic to
intermediate doses of the LMWH enoxaparin (30mg to 60mg QD) in severe hospitalized COVID-19
patents with a SIC score ≥ 4 or D-dimer (Dd) > 6 X ULN improves outcomes and prognosis.
All-cause mortality at 28 days was reduced from 64.2% to 40.0% in those patients with a SIC
score ≥ 4 (p=0.029), and from 52.4% to 32.8% in those patients with an elevated Dd > 6 x ULN
(P=0.017). Notably, Klok and colleagues investigated 184 ICU patients infected with COVID-19
and reported a 13% mortality rate, a relatively high incidence of CTPA- or
ultrasonography-confirmed VTE rate (27%), and arterial thrombotic events (3.7%) despite the
use of standard dose thromboprophylaxis. Postulated mechanisms for the improved prognosis
with the use of treatment doses of LMWH in the sick COVID-19 population include the decrease
in the risk of microthrombi, especially in the pulmonary vasculature, which can lead to
hypoxemia, pulmonary vasoconstriction and right ventricular dysfunction as well as the
decrease in the risk of progression to disseminated intravascular coagulopathy as a
contributor to the high mortality seen in these patients.

The optimal dose of heparin (either LMWH or UFH) in hospitalized COVID-19 patients is
unknown, as patients on conventional prophylactic dose heparin (UFH or LMWH) as supported by
international guidance statements on hospitalized COVID-19 patients appear to remain at risk
for thromboembolic events. There is data to support improved efficacy with treatment doses of
twice daily enoxaparin versus once-daily weight-adjusted enoxaparin for the management of
VTE, especially with large thrombus burden. There is also long-standing data to support that
treatment-dose heparin can reduce major cardiovascular events. Our current standard of care
in our 24 hospital Northwell Health System, which has a very large hospitalized COVID-19
patient population, is to use Lovenox 40mg SQ QD for patients with a BMI < 30 and Creatinine
Clearance (CrCl) > 15ml/min, Lovenox 40mg SQ BID for patients with a BMI > 30 and CrCl >
15ml/min, and UFH 5000U SQ BID or TID in patients with a CrCl < 15ml/min and BMI < 30 and UFH
7500U SQ BID or TID with a CrCl < 15ml/min and BMI > 30. Large healthcare institutions in the
US and elsewhere have protocols for in-patient thromboprophylaxis ranging from
prophylactic-to-intermediate dose UFH or LMWH for the management of patients with COVID-19
associated coagulopathy. The aim of this study is to test the hypothesis that prophylaxis of
severe COVID-19 patients with treatment dose LMWH leads to better thromboembolic-free
outcomes and associated complications during hospitalization than prophylaxis with
institutional standard of care with prophylactic to intermediate-doses of UFH or LMWH.