Cuba has been affected by coronavirus disease 2019 (COVID-19) with more than 2,400
cases diagnosed, 87 deaths, and 3.55% lethality, by July 17, 2020.[1] COVID-19 is a gradually evolving pathology, characterized by a series of stages
sustained by different molecular and biological mechanisms. The disease can be divided
in at least five different phases: incubation, respiratory, proinflammatory, prothrombotic,
and death or remission.[2]
COVID-19 may predispose patients to thrombotic disease, both in venous and arterial
circulation, due to excessive inflammation, endothelial dysfunction, platelet activation,
and many other prothrombotic factors such as tissue injury, decrease of natural anticoagulants,
and stasis.[3] Despite the use of antiviral, anti-inflammatory drugs, anticoagulant therapy, and
even invasive mechanical ventilation, many patients progress to a critical stage,
characterized by acute respiratory distress syndrome (ARDS) and shock.[4] We describe here two patients, in whom thrombolysis using recombinant streptokinase[5] was used to treat refractory hypoxemia after suspecting pulmonary micro- and macrothrombotic
disease.
Patient 1: A 53-year-old woman with previous history of hypertension and type 2 diabetes
mellitus was admitted at the intensive care unit (ICU) after moderate hypoxemia and
respiratory alkalosis. Her initial oxygenation index (PaO2/FiO2) was 191. Diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
infection was confirmed with real time polymerase chain reaction (RT-PCR) on a nasopharyngeal
sample. Upon admission, she was receiving treatment with lopinavir/ritonavir, chloroquine,
interferon α, and ceftriaxone. She developed several COVID-19 complications including
nosocomial respiratory infection (Pseudomonas aeruginosa, Staphylococcus aureus, and Candida albicans), requiring endotracheal intubation and mechanical ventilation. Chest X-rays showed
interstitial lesions in both lung fields (matching with stage II of physiopathology).
She was hence treated with the anti-CD6 antibody itolizumab,[6] which significantly reduced interleukin-6 serum concentration. Patient experienced
radiological and clinical improvement, though definitive ventilator weaning was not
possible. After three unsuccessful extubation attempts in 15 days, radiological and
clinical deterioration developed, including hypotension requiring dobutamine administration
at a dose of 20 µg/kg/min. A computer tomography (CT) scan showed ground glass images
at both lung fields ([Fig. 1A], [B]). D-dimer was 2.32 µg/mL, PaO2/FiO2 decreased to 100, the alveolar-arterial oxygen gradient [D(A-a)O2] was 483, pulmonary shunt fraction (Qs/Qt) ratio was 57.9%, the arterial-venous O2 content difference (Ca-vO2) was 5.14, and the positive end-expiratory pressure (PEEP) was 8 cm of water. After
the patient respiratory worsening together with the increase in the D-dimer, the ICU's
expert committee decided to start thrombolysis with recombinant streptokinase[7] at a dose of 250,000 IU in the first hour followed by 100,000 IU every hour for
24 hours. Streptokinase infusion was only administered for 6 hours due to oral cavity
bleeding. Hemorrhage was rapidly controlled after stopping infusion. The use of tranexamic
acid was not required. In spite of the premature streptokinase discontinuation, D-dimer
values decreased to 0.7 µg/mL (D-dimer units), PaO2/FiO2 raised to 410, blood pressure normalized, and dobutamine could be withdrawn. In parallel,
alternative prone (12–16 hours) and supine ventilation (8 hours) was established.
After thrombolysis, the fraction of inspired oxygen was reduced (FiO2 = 0.4) and ventilation parameters began to improve: PaO2 was 164 mm Hg and oxygen saturation reached 99.2%. Patient also showed a remarkable
clinical and radiological improvement ([Fig. 1C]). Twenty-four hours later, the prone and supine ventilation continued to alternate,
the attendance rate of the assistance mechanical ventilator was gradually reduced
to 30%, PEEP was decreased to 5 cm of water, and FiO2 to 0.30. In the next 5 days, complete ventilator weaning was achieved. A third CT
scan was performed 10 days after the thrombolysis ([Fig. 1D]), showing sustained radiological improvement. After 39 days in ICU, the patient
was transferred to hospital conventional ward to continue pulmonary and neuromuscular
rehabilitation.
Fig. 1 Patient 1. (A, B) Multislice computed tomography (CT) scan before thrombolysis: Ground glass images
are observed in both lung fields, with small areas of hyperlucency toward the vertex.
(C) Multislice CT image performed 48 hours after thrombolysis, with clear tomographic
improvement. (D) Multislice CT image performed 7 days after thrombolysis, where the tomographic improvement
becomes more evident.
Patient 2: An 86-year-old man with a personal history of essential hypertension, generalized
atherosclerosis, and cognitive disorder, was admitted at the “Celestino Hernandez
Robau” University Hospital of Santa Clara. Upon admission, RT-PCR for SARS-CoV-2 was
positive on a nasopharyngeal sample and the patient showed polypnea (32 rotations
per minute) and ancillary respiratory musculature use for breathing. His blood pressure
was 90/60 mm Hg. He was hence treated according the Cuban national protocol including
chloroquine, lopinavir/ritonavir, recombinant erythropoietin (EPO) (cytoprotective
dose), and low molecular weight heparin (fraxiparine), at 0.6 IU every 12 hours. EPO
was included in the protocol for COVID-19 considering its cytoprotective capacity
including anti-ischemic, antiapoptotic, and regenerative effect in several tissues
such as the lung, kidney, heart, nervous system, retina, pancreas, and endothelial
cells. EPO acts through a special receptor, EPOR-βcR, which mediated its protective
effects in critically ill patients and following trauma.[8] Patient also received CIGB258,[9] a peptide with immune-regulatory properties, as part of an expanded access protocol.
Despite treatment, patient suffered COVID-19 complications including nosocomial respiratory
infection (Pseudomonas aeruginosa was isolated in blood culture and bronchial secretions) requiring antibiotic therapy,
endotracheal intubation, and mechanical ventilation. The initial evaluation of the
arterial blood gases showed severe hypoxemia with PaO2/FiO2 of 68. Chest X-rays showed interstitial lesions in both lung fields. Ventilator was
used in volume-control mode, PEEP was adjusted to 10 cm of water, and FiO2 was 0.60. Urine output gradually decreased, creatinine reached 224 μmol/mL, glomerular
filtration rate was 20.59 mL/min, and patient showed signs of hypovolemia. Due to
these hemodynamic changes, treatment with norepinephrine (0.2 µg/kg/min) and dobutamine
(10 μg/kg/min) was initiated. Patient also had radiologic and respiratory worsening,
including tracheobronchial secretions and leukocytosis of 18.0 × 109/L. X-rays showed triangular images at the base of the right lung suggestive of pulmonary
infarction or pulmonary thromboembolism. A PaO2 of 58 mm Hg and PaO2/FiO2 of 96, forced to keep FiO2 high (0.8) and to start maneuvers of alveolar recruitment. PEEP was increased to
12 cm of water, CIGB-258 dose augmented, and alternating prone and supine ventilation
started. As a result, oxygen saturation improved to 98 to 99%. However, after an elevated
D-dimer (8 µg/mL; D-dimer units), arterial hypotension, D(A-a)O2 of 486, and Qs/Qt of 57% together with a significant clinical-radiological worsening,
thrombolysis was proposed as therapeutic alternative. At that point, a confirmatory
CT scan of the pulmonary thrombosis or microthrombosis was not feasible, due to the
patient's extreme poor condition. Thrombolysis with recombinant streptokinase[5] at 250,000 IU for 1 hour followed by 100,000 IU every 1 hour for 24 hours was planned.
Streptokinase administration was interrupted due to onset of oral and endotracheal
bleeding that was rapidly contained with tranexamic acid (1.0 g). Shortly after and
even though the full streptokinase dose was not administered, a remarkable clinical
and radiological improvement occurred; PaO2 increased to 79.2 mm Hg and PaO2/FiO2 raised to 158. Seventy-two hours after thrombolysis, a CT scan (120-slice) combined
with a dual energy CT scan, was performed ([Fig. 2]). Patient subsequently had negative RT-PCR for SARS-CoV-2 on a nasopharyngeal sample,
15 days after admission. CT scan showed areas of pulmonary infarcts, microthrombi,
and diffuse inflammatory lesions of both lung bases. After initial improvement, a
persistent multidrug-resistant Pseudomonas aeruginosa was isolated from the respiratory secretion. At that time, he had received therapy
with meronem, colistina, and piperacillin-tazobactam. Patient had progressive radiological
and clinical worsening associated with severe bronchopneumonia. The patient remained
ventilated and unresponsive to any of the antibiotic schemes used. He died 40 days
after his admission in the hospital and 25 days after thrombolysis. Death was attributed
to septic shock. Necropsy was not performed.
Fig. 2 Patient 2. (A) Multislice computerized axial tomography (120 cuts), with dual energy tomographic
views, showing a zone of pulmonary infarction (black) at the base of the right and
left lung. Thrombus zone with laterobasal ischemia of the left lung (violet) and multiple
and small areas of purplish color, pulmonary microthrombi, in both lung fields predominate
on the right side. (B) Anterior view of multiplanar airways, with black areas of pulmonary infarcts and
diffuse inflammatory lesions of both lung bases. (C) Another anterior view of axial tomography computed with dual energy, with pulmonary
infarcts (black) and areas of diffuse inflammatory lesions predominantly of the lower
lobes. (D) Computerized axial tomography, shaggy aorta with diffuse atheromatosis in all segments
of the aorta.
Patients admitted to the ICU for COVID-19, following an infection by the SARS-CoV-2,
have a considerably increased risk of thrombotic events, both arterial and venous.[4]
SARS-CoV-1 and -2 show tropism for angiotensin-converting enzyme 2 on type II pneumocytes.[10] This tropism, along with the close anatomical juxtaposition of type II pneumocytes
and pulmonary vascular network, together with a severe inflammatory reaction, is likely
to drive the generalized pulmonary hypercoagulable state seen in patients with COVID-19.[10] Development of hypoxemia, secondary to ARDS induced by COVID-19 might also activate
the coagulation cascade and could be important in endothelial dysfunction beyond the
capillary network.[3]
Although the number of postmortem pathologic reports are limited, Luo et al described
vascular wall thickening, stenosis of the vascular lumen, and microthrombus formation
accompanying the findings of ARDS.[11] Similar pathologic findings are found in small vessels of other organs.[12]
[13]
[14] Ackermann et al reported that alveolar capillary microthrombi were more prevalent
in patients with COVID-19 than in patients with influenza.[15] The frequency of venous thromboembolism in critically ill patients with COVID-19,
including deep vein thrombosis and pulmonary embolism, is becoming better understood,
ranging from 25 to 27% in recent publications.[16]
[17] Besides these pathology findings, many physicians have reported D-dimer elevation
in COVID-19 patients, mainly in those bearing severe and critical disease.[18] Although D-dimer is not a specific indicator of thrombosis, in combination with
other parameters, its elevation may suggest a systemic coagulation activation with
increased thrombin generation and fibrinolysis.[19]
Here, we present the results of the first two Cuban patients carrying COVID-19, in
whom thrombolysis was attempted (considering their extreme severity, their refractory
hypoxemia, and high suspicion of micro- and macrothrombosis).
A few reports on thrombolysis for COVID-19, using tissue plasminogen activator as
a thrombolytic agent, have been published.[20] Our two patients were treated with recombinant streptokinase, which has been the
thrombolytic of choice to treat coronary thrombosis and pulmonary or peripheral venous
macrothrombi in Cuba.[5]
[7] Both patients had hemorrhagic complications that precluded administering the full
dose. Other thrombolytic agents are unavailable in Cuba.
Confirming multiple pulmonary microthrombi is challenging. In COVID-19, clinical and
laboratory manifestations can raise the index of diagnostic suspicion. A thoracic
angio-tomography can confirm a diagnosis of pulmonary thromboembolism of thick or
medium branches or multiple pulmonary microthrombi disseminated in both lung fields.
A multislice CT with dual energy has the potential to improve the detection of pulmonary
thrombosis.[21]
We hence conclude that the two patients took some advantages from the thrombolysis,
since this therapeutic strategy was effective to improve their respiratory function
and chest images. Unfortunately, one patient died due to septic respiratory complications.
In both cases, rescue thrombolysis was done on compassionate basis after interdisciplinary
discussion. We advise, however, that this procedure should not be done routinely unless
in the setting of a clinical trial.
Bleeding occurred in both cases but was controlled after stopping infusion or with
the use of tranexamic acid. We therefore believe that thrombolysis might be a valuable
alternative for COVID-19 patients with pulmonary micro- or macrothrombosis that have
failed anti-inflammatory and anticoagulant therapy. Nevertheless, the effectiveness
of thrombolysis for COVID-19 patients should be confirmed in randomized clinical trials.
