Enoxaparin-sodium/heparin/tocilizumab

Author Information

An event is serious (based on the ICH definition) when the patient outcome is:

• * death

• * life-threatening

• * hospitalisation

• * disability

• * congenital anomaly

• * other medically important event

In a case series, five men (aged 31−79 years) were described, who exhibited masking of inflammatory markers following off-label use with tocilizumab for COVID 19. Additionally, they exhibited lack of efficacy during anticoagulant therapy with heparin or enoxaparin-sodium [not all routes and dosages stated; duration of treatment to reaction onset and outcome not stated].

Patient 1: A 51-year-old man, who had COVID-19 with acute respiratory distress syndrome, started receiving off label treatment with tocilizumab. Then, he was admitted to the ICU for the further management of COVID-19. His medical history was significant for diabetes. After the admission, he was found to have elevated D-dimer levels. Subsequently, he started receiving SC heparin [unfractionated heparin] infusion 5000 units three times a day. On day 2 of admission, his D-dimer level was over 6 times the upper limit of normal. Hence, the dose of SC heparin infusion increased to 7500 units three times a day. His ferritin and Interleukin-6 (IL-6) level were noted to be abnormal, but CRP and fibrinogen were within normal limits. On day 3, ultrasound showed ischaemia of the first three toes with no capillary refill. His anticoagulation plan was changed to heparin DVT/PE protocol (aPTT 60–85s). Subsequently, he underwent CT angiogram of abdomen and pelvis which showed floating thrombi noted 4cm infrarenal abdominal aorta, compromising the lumen and leading to acute limb ischaemia with extensive abdominal and bilateral lower extremity thrombus. It was found that, during the thrombotic event, his inflammatory markers including CRP and fibrinogen were within normal limits (masking of inflammatory markers). Thereafter, he underwent mechanical thrombectomy of the infrarenal aorta and intra-arterial thrombolysis of thrombus of left lower extremity. He developed secondary ischaemia of bilateral lower extremity developing left foot dry gangrene requiring below-knee amputation. He eventually improved and was discharged on day 75 of admission on unspecified oral anticoagulation therapy.

Patient 2: A 79-year-old man, who had COVID-19 with acute respiratory distress syndrome, was admitted to the ICU. His medical history was significant for prostate carcinoma. Upon admission, he was found to have elevated CRP and D-dimer over 6 times the upper limit of normal (ULN). For DVT prophylaxis, he received SC enoxaparin-sodium [enoxaparin] 40 mg/day. On day 3, he started receiving IV tocilizumab 400mg. Due to COVID-19, his condition was critical and he required mechanical ventilation. After 2 weeks of hospitalisation, he had a sudden increase in oxygen requirement due to secondary bacterial infection. However, due to prolonged ICU course and known COVID-19 status, the ultrasound of lower extremities was performed which showed DVT in bilateral calf veins. It was found that, during the thrombotic event, his inflammatory markers including CRP and fibrinogen were within normal limits (masking of inflammatory markers). He started receiving heparin [unfractionated heparin] infusion. His D-dimer, CRP and ferritin were elevated, although these parameters were much lower than those at admission. Approximately 30 days after the ICU admission, he suddenly went into Pulseless Electrical Activity rhythm. Focused ICU ECHO showed very subtle cardiac motion with evidence of large clot in the right atrium, likely representing massive pulmonary embolism (PE). He was pronounced dead [immediate cause of death not stated].

Patient 3: A 31-year-old man, who had history of intermittent asthma, was admitted with flulike symptoms. At admission, he was noted to be hypoxaemic. Therefore, he was transferred to the ICU and received oxygen supplementation. On day 1 of admission, he was diagnosed with COVID-19 by chest X-ray and COVID-19 RT-PCR test. On the same day, he started receiving tocilizumab. During the admission, his D-dimer level was over 3 times the upper limit of normal (ULN). Therefore, he started receiving standard dose for DVT prophylaxis with enoxaparin-sodium [low molecular weight heparin] 40 mg/day. On hospital day 7, he was found have elevated D-dimer level to over 6 times ULN and bilateral lower limb pain. Ultrasound of bilateral lower extremity showed occlusive deep vein thrombosis of the right distal femoral, popliteal, posterior tibial and peroneal veins as well as left popliteal, gastrocnemius and peroneal veins. Therefore, his thromboprophylaxis was escalated to therapeutic dose anticoagulation. It was found that, during the thrombotic event, his inflammatory markers including CRP and fibrinogen were within normal limits (masking of inflammatory markers). On day 10 of admission, due to worsening pleuritic chest pain, a CT pulmonary angiography was performed which showed subsegmental pulmonary embolus within the right lower lobe basilar pulmonary artery. Hence, enoxaparin was switched to heparin IV drip. His condition continued to improve. On hospital day 17, he was discharged on oral anticoagulation with apixaban.

Patient 4: A 36-year-old man, who had fever and chills for 8 days, presented to the hospital. On day 1 of admission, he was diagnosed with COVID-19 by RT-PCR test. Upon admission, he was found to have elevated D-dimer level. Hence, he started receiving DVT prophylaxis therapy with enoxaparin-sodium [enoxaparin] 40 mg/day. On day 3 of admission, he was transferred to the ICU for worsening hypoxia and received tocilizumab. His D-dimer level continued to increase. Hence, on hospital day 7, the frequency of enoxaparin-sodium increased to 40mg two times a day. On day 11 of admission, due to persistent severe hypoxaemia and high D-Dimer level, a CT pulmonary angiography was performed which showed large saddle embolus which extended into the upper and lower lobar pulmonary arteries with right heart strain. It was found that, during the thrombotic event, his inflammatory markers including CRP and fibrinogen were within normal limits (masking of inflammatory markers). He received systemic alteplase followed by heparin drip for therapeutic anticoagulation. Following the corrective measures, his condition improved. On hospital day 21, he was discharged on oral anticoagulation.

Patient 5: A 51-year-old man transferred to the ICU on mechanical ventilation following severe COVID-19 acute respiratory distress syndrome. His medical history was significant for hypertension. Upon admission, he was found to have D-dimer level elevated over 6 times the upper limit of normal (ULN). Therefore, he started receiving thromboprophylaxis therapy with SC heparin 7500 three times day. On the second day of admission, he received tocilizumab therapy. Thereafter, he developed acute kidney injury requiring continuous renal replacement therapy. A chest CT scan was performed on day 11 revealed bilateral pulmonary embolism. It was found that, during the thrombotic event, his inflammatory markers including CRP and fibrinogen were within normal limits (masking of inflammatory markers). Thereafter, IV heparin therapy was initiated. D-dimer continued to be 6 times ULN throughout admission and up until day of event. Thereafter, he developed bacteremia and cavitary lung disease with confirmed aspergillosis. Despite anti-fungal therapy, his condition deteriorated with hemoptysis. On day 76 of admission, he died due to cardiac arrest.