1 Introduction

The elevated risk of thrombosis associated with COVID-19 has led frontline providers to consider the empiric use of therapeutic anticoagulation for hospitalized patients even in the absence of documented or clinically suspected thrombosis. The reported incidence of venous thromboembolism in critically ill patients with COVID-19 is around 30% which is significantly higher than non-COVID-19 critically ill populations.1 In April 2020, the International Society on Thrombosis and Haemostasis developed guidelines for thromboprophylaxis with enoxaparin for patients with COVID-19.2

Patients receiving some form of anticoagulation therapy are predisposed to more risks of bleeding complications. These bleeding may range from minor to major, or even life-threatening events. Major bleeding has a significant risk of immediate morbidity and mortality. LMWH is being widely used in clinical practice because of its greater bioavailability, optimum antith-rombotic effect, and fewer bleeding side effects in contrast to unfractionated heparin.3 The main sites of subcutaneous injection in the anterior abdominal wall, anterolateral aspect of the thigh, and the upper arm. The reported incidence of bruises and hematomas after the subcutaneous injection of LMWH is 26.6%–88.9% and 40%–88%, respectively.4

2 Case report

A 75-year-old male COVID-19 patient weighing 85 kg was admitted to our ICU with shortness of breath, dry cough, and myalgia. At admission his vitals were, heart rate 88 bpm, non-invasive blood pressure 138/88 mm Hg, oxygen saturation was 90% on room air, respiratory rate was 28 rates per minute and temperature 37.8°C. He underwent a post-coronary artery bypass graft 5 years back. He was regularly taking tablet ecospirin 75 mg. He was a known hypertensive and diagnosed with type II diabetes mellitus. We initiated our clinical management of COVID-19 in the form of oxygen therapy, antibiotics (cefoperazone), steroids (dexamethasone), anticoagulants (enoxaparin), and awake proning as a part of our standard operating institute policy. All baseline investigations were within normal limits except renal profile. The serum urea 45 mg/dL, serum creatinine 1.90 mg/dL, serum Sodium 139 meq/L, and serum potassium were 3.2meq/L. His creatinine clearance was 40 mL/min. On the 10th day of treatment (Day 8 on enoxaparin), we noticed a multiple, flat, blue, or purple painful ecchymotic patch measuring 1–2 cm or more in diameter over the anterior abdominal wall above and below the umbilicus (Fig. 1). These ecchymotic patches appeared possibly after the administration of enoxaparin. The patient also complained of generalized abdominal tenderness at the site of injection. The bedside ultrasound scan of the whole abdomen and pelvis were normal ruling out the possibilities of any rectus sheath hematoma or any intrabdominal collections. He had no previous history of drug allergies or cutaneous reactions following enoxaparin. Soon the medication was stopped and on further examination, the ecchymotic patches progressively faded and on 13th day patient discharged from our intensive care unit.

Figure 1:

Arrow showing multiple, flat, blue, or purple ecchymotic patches over the anterior abdominal wall following enoxaparin administration.

3 Discussion

The role of anticoagulation in preventing and treating thrombo-embolic events especially in COVID-19 patients as the presence of micro thrombosis may affect various end-organs. SARS-CoV-2 has been strongly associated with risks of venous thromboem-bolism, deep venous thrombosis, pulmonary thromboembolism, and stroke.5

Bleeding is less common than thrombosis in patients with COVID-19, but it may occur, especially in the setting of anticoagulation. Bleeding diathesis is likely multifactorial, related to the COVID-19 illness severity or anticoagulation. In our case, the patients received prophylactic anticoagulation and showed significant ecchymosis events at unusual locations.

Enoxaparin is used as a prophylaxis to prevent thromboem-bolism, deep vein thrombosis, and the formation of coagulation during the hemodialysis of patients with chronic kidney failure, with one dose every 24 hours. Enoxaparin is slowly absorbed following subcutaneous administration. The drug is injected under the epidermis, between the fat and the connective tissue underlying the skin, where the blood flow is less. There may be accidental administration of this medication in the muscle tissue, affecting absorption and further harming the patient.6

The adverse effects of subcutaneously administering enox-aparin include haemorrhagic complications, severe hematomas of the abdominal wall, necrosis of the skin and subcutaneous tissue, and, over the longer term, osteoporosis, and thrombocy-topenia.7

Kim et al.8 reported the first case of a generalized maculopapular rash due to subcutaneous enoxaparin injections in the literature.

The most common adverse events after subcutaneous administration of low molecular weight heparin (LMWH) are thrombocytopenia, anemia, bruises, and the rare ones are ecchymosis and/ or hematoma.9

These ecchymoses occur due to leakage of blood from a broken capillary into surrounding tissue under the skin. It develops from days to weeks after drug exposure and typically takes between 1 and 3 weeks to spontaneously resolve.

Chan et al.10 reported that keeping the needle in the tissue after administering heparin increases the absorption of the heparin by the tissue and decreases the leak of heparin into the cutaneous tissue which further decreases the risks of ecchymosis.

Uzun et al.11 found that the size of the ecchymosis formation near the anterior abdominal wall may decreased with a longer (30 seconds) administration time and delayed needle withdrawal (10 seconds) from the tissue.

Middeldorp et al.12 reported that about 20% of the included COVID-19 patients had venous thromboembolism despite routine thromboprophylaxis with prophylactic doses of LMWH.

Most studies believe that the incidence of enoxaparin bruising at the injection site can be affected by several factors such as needle gauge, proper injection site, decreasing the volume of solution, and the mode of anticoagulant injection.9 Some of the additional risks factors may be age, hyperlipidemia, and hypertension.13

Simulations have shown that individualized dosing decreased the probability of a bleeding or major bruising event with enoxaparin when compared with conventional dosing, which was most noticeable in subjects with obesity and renal impairment.14

In our case, the patient was obese, having multiple comorbid-ities with deranged renal functions. As current FDA labeling does not recommend dose reduction in moderate renal impairment, we were continuing with normal dosing. Multiple factors and concomitant antiplatelets might have contributed to these complications. Because high body weight correlates with low anti-factor Xa levels, an anti-factor Xa-guided individualized dosing approach with LMWH may also be adopted in the obese hospitalized COVID-19 population to further reduce the risk of thromboprophylaxis failure but it may lead to major bruising.15

This bruising can cause discomfort to the patient and it reduces the available space for subsequent injections and it may negatively affect the patient leading to stress, anxiety, loss of confidence, and fear leading to discontinuation of treatment, especially during the COVID-19 pandemic which may endanger the safety of the patient. Cold application is a useful non-pharmacological treatment for reducing the severity of pain, tissue temperature, blood flow, and cell metabolism, thereby reducing the occurrences of bruises and hematomas.16

As enoxaparin sodium is a hydrophilic drug that is dispensed into non-fat and plasma tissue, these ecchymotic patches may be associated with delayed drug dispersion leading to increased anticoagulant effects of the drug at the injection site and would aggravate these bruising. So health care providers should be adequately trained to identify high risks patients and individuali-zation of dose of enoxaparin may be considered.

Major Highlights of this report

1. LMWH is one of the commonly used treatment modalities in COVID-19 and its complications are thrombocytopenia, anemia, bruises, and the rare ones are ecchymosis and/or hematoma. 2. Clear etiology of ecchymosis is not known at present. Probable causes may be multiple comorbidities, high dose, renal impairment, high BMI, and concomitant antiplatelet drugs. 3. Dose of LMWH needs to be individualized according to risk factors to avoid this ecchymosis and bruises as one of the complications. 4. Nurses working in the intensive care unit should be trained enough to identify high-risk cases, be an expert in dose modification, and should be competent enough for an alternative site of subcutaneous injection, especially during the COVID-19 Pandemic. 4 Conclusion

In conclusion, significant bleeding at unusual sites can occur in COVID-19 patients upon anticoagulation treatment (both prophylactic and therapeutic) and, therefore, a high degree of suspicion and careful clinical monitoring is required. This case describes that multiple comorbidities, high dose LMWH, renal impairment, high BMI, and concomitant antiplatelet drugs need to be individualized according to these risk factors to avoid these ecchymoses and bruises as one of the complications. Health care providers should be adequately trained during the COVID-19 pandemic to identify these high risks patients.

Informed consent

Informed consent was taken.

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