In this study, we reported the outcomes of LMWH used at intermediate prophylactic doses in COVID-19 patients, focusing on the safety of this approach in elderly patients.
All of our patients had radiologically confirmed COVID-19-related pneumonia. In this population a marked microvascular thrombosis and haemorrhage linked to extensive alveolar and interstitial inflammation are the most relevant pathological features . These aspects have been associated with worse outcomes especially in older patients, probably because of the reduced functional reserve of spared pulmonary parenchyma .
In our cohort, only one thrombotic event occurred, although the true prevalence may be underestimated since our patients were not extensively screened for deep venous thrombosis or pulmonary embolism, as probably indicated . The patient who developed pulmonary embolism was a 49-year-old female, with history of deep vein thrombosis (more than 10 years before) who developed subsegmental pulmonary embolism 6 days after admission while receiving 80 mg of enoxaparin; she was the only patient with history of venous tromboembolism. Apixaban was started and she was discharged after 13 days, without long-term oxygen needing.
Two patients had a major bleeding event. The first patient was an 87-year-old man with severe COVID-19 and treated with LMWH 40 mg/day (due to CKD), early withdrawn for the development of moderate thrombocytopenia (70 × 103 platelet/mm3 was the lowest count); aspirin was taken as concomitant therapy. He developed spontaneous hematomas of the sternocleidomastoid muscles, bilaterally, and of the left adductor muscles, that required prolongation of the hospital stay and transfusion of three units of packed red blood cells. The patient was discharged in a post-acute care facility seven days after the onset of bleeding, without any recurrence. The second bleeding case was a 66-year-old man with severe COVID-19, who developed hematemesis for acute gastritis with active bleeding erosions. He was transfused (three units of packed red blood cells) and transferred to ICU, where he died 7 days later for a central venous catheter related-septic shock.
Regarding the 21 dead patients, the median age was 81.9 years (11 male) and none of them had evidence of a haemorrhagic death. Five of them had at admission, or developed during hospitalization, a D-dimer level > 5000 ng/ml FEU: all these patients performed a venous Doppler ultrasound exam of legs without evidence of thrombosis. Six of them, all younger than 71 years, was transferred in ICU.
Indeed, the use of intermediate doses of LMWH appears to be feasible and safe also in elderly patients: all the patients treated with a high-risk of bleeding (IBRS ≥ 7) were older than 85 years but none of them developed major bleedings. The cumulative risk of major bleeding in our cohort was low (2%), whereas the overall mortality (21%) was similar to the one reported in previous studies investigating LMWH use in COVID-19 patients . Unfortunately, published studies, mostly observational, reported conflicting results regarding anticoagulation treatment in COVID-19 patients. Notably, even if there are no univocal strategies in the type of heparin and administration protocols, LWMH is widely recommended in all the spectrum of disease severity, particularly in ICU patients [13,14,15]. Unfractionated heparin (UFH) could be used in patients with renal impairment or at high bleeding risk who need rapid reversal ; however, it requires expertise in the management. Some authors also suggested a possible advantage of direct oral anticoagulants in thromboprophylaxis . In our cohort, anticoagulation with intermediate doses of LMWH appears to be feasible and safe also in patients with CKD. In fact, no major bleeding occurred in these patients and, additionally, the proportion of patients requiring transfusion of packed red cells was comparable between patients with or without CKD (5.4% vs 16.7%, p = 0.14). A relevant warning might be the decrease in hemoglobin (≥ 2 g/dl) founded in about a fifth of patients; this could represent a hallmark of clinically overt minor bleedings. Anyway, hospital-acquired anemia (HAA) must be considered as a valid alternative explanation: large cohort studies reported prevalence of HAA between 33 and 74% in medical or critical patients hospitalized without anemia at admission .
Laboratory findings are consistent with literature data . An interesting finding is the decrease of D-dimer level at day 7, particularly in the elderly population. Since higher D-dimer levels have been associated with a poor prognosis, the decrease could reasonably represent a favourable effect of higher-dose heparin, although this remains to be evaluated in proper clinical trials.
Our study has several limitations, that could represent a selection bias: the monocentric cohort, the retrospective design, the small number of patients and the absence of a control group treated with standard therapy.