Improvement in plasma D-dimer level in severe SARS-CoV-2 infection can be an indicator of fibrinolysis suppression

Abstract

Rationale: Fibrinolysis shutdown associated with severe thrombotic complications is a recently recognized syndrome that was previously seldom investigated in patients with severe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. It presents a unique therapeutic dilemma, as anticoagulation with heparin alone is insufficient to address the imbalance in fibrinolysis. And while the use of fibrinolytic agents could limit the disease severity, it is often associated with bleeding complications. There is a need for biomarkers that will guide the timely stratification of patients into those who may benefit from both anticoagulant and fibrinolytic therapies. Patient concerns: All 3 patients presented with shortness of breath along with comorbidities predisposing them to severe SARS-CoV-2 infection. One patient (Patient 3) also suffered from bilateral deep venous thrombosis. Diagnoses: All 3 patients tested positive for SARS-CoV-2 RNA by reverse transcription polymerase chain reaction (RT-PCR) and were eventually diagnosed with respiratory failure necessitating intubation. Interventions: All 3 patients required mechanical ventilation support, 2 of which also required renal replacement therapy. All 3 patients were also placed on anticoagulation therapy. Outcomes: In Patients 1 and 2, the initial D-dimer levels of 0.97 μg/ml fibrinogen equivalent units (FEU) and 0.83 μg/ml FEU were only slightly elevated (normal <0.50 μg/ml FEU). They developed rising D-dimer levels to a peak of 13.21 μg/ml FEU and >20.0 μg/ml FEU, respectively, which dropped to 1.34 μg/ml FEU 8 days later in Patient 1 and to 2.94 μg/ml on hospital day 13 in Patient 2. In Patient 3, the D-dimer level on admission was found to be elevated to >20.00 μg/ml FEU together with imaging evidence of thrombosis. And although he received therapeutic heparin infusion, he still developed pulmonary embolism (PE) and his D-dimer level declined to 5.91 μg/ml FEU. Despite “improvement” in their D-dimer levels, all 3 patients succumbed to multi-system organ failure. On postmortem examination, numerous arterial and venous thromboses of varying ages, many consisting primarily of fibrin, were identified in the lungs of all patients. Lessons: High D-dimer levels, with subsequent downtrend correlating with clinical deterioration, seems to be an indicator of fibrinolysis suppression. These findings can help form a hypothesis, as larger cohorts are necessary to demonstrate their reproducibility.

Role of Fibrinolysis in the Management of Patients with COVID-19 and Thromboembolic Complications: A Review

“…Moreover, the lag times to plasmin, thrombin and fibrin formation were prolonged with the increasing severity of COVID-19 [ 24 ]. Coagulation disorders with systemic microthrombi and increased incidence of VTE were also confirmed by autopsy studies in patients with COVID-19 [ 12 , 25 , 26 ]. In a systematic review and meta-analysis, Suh et al [ 27 ] assessed the incidence of PE and DVT in patients with COVID-19.…”

“…SARS-CoV-2 infection leads to acute inflammation, which leads to an increase in bradykinin and tPA. However, increased tPA levels are not sufficient to counterbalance the high levels of PAI-1, which likely explains the impaired fibrinolysis and fibrin accumulation in the lung alveoli [ 12 ]. Fibrin deposits enhance inflammation and fibrosis, and lead to lung surfactant damage [ 9 ].…”

“…Plasmin, along with other proteases, may contribute to increased SARS-CoV-2 infectivity, and antiproteases targeting the plasmin(ogen) system may be a promising therapeutic option in patients with COVID-19 [ 13 ]. There is also an increasing body of evidence that systemic fibrinolysis may be an effective therapeutic approach in critically ill patients with COVID-19 [ 12 , 13 , 14 ]. Medcalf et al [ 15 ] described the so-called plasmin paradox in patients with COVID-19, wherein plasmin formation can be either harmful or beneficial, although not at the same time.…”

“…Manzoor et al [ 12 ] suggested that, similar to fibrinogen, a reduction in D-dimer levels correlating with clinical deterioration may indicate the suppression of the fibrinolytic system. However, Tang et al [ 4 ] reported moderately or markedly elevated levels of D-dimer and fibrin degradation products in all patients who died from novel coronavirus pneumonia, which suggests coagulation activation and secondary hyperfibrinolysis in these patients [ 4 ].…”

The Cause–Effect Dilemma of Hematologic Changes in COVID-19: One Year after the Start of the Pandemic

“…On the other hand, less evidence is found concerning vaccine-induced immune thrombotic thrombocytopenia (VITT), and the issue of anticoagulation with or without the use of IVIG still remains controversial [ 7 ]. Some authors have even argued that the addition of fibrinolytic agents to heparin can increase the incidence of bleeding and, in this case, the improvement in the D-dimer can exceptionally be used as a biomarker of fibrinolysis suppression in high-risk patients [ 37 ].…”