A Persistent Nightmare: A Case of Recurrent Brachial Artery Thrombosis

Background Brachial artery thrombosis can be seen with thromboembolism, hypercoagulability, and arterial thoracic outlet syndrome. Case A 33-year-old healthy female construction worker presented with right hand discoloration and pain. She suffered a COVID-19 infection 8 weeks prior with hand symptoms developing shortly thereafter. She could no longer work due to the pain. Duplex ultrasound and CTA of the right upper extremity (Figure) demonstrated localized thrombosis of the right brachial artery. The workup yielded no aortic or intracardiac thrombus, and cardiac event monitor showed no atrial arrhythmia. She underwent thrombectomy with brachial artery stenting and was found, during surgery, to have distal ulnar artery occlusion. Two days post-op, she had recurrent pain and was found to have brachial artery recurrent thrombosis. She underwent urgent brachial-brachial bypass. Arm pain continued despite graft patency, so ulnarpalmar bypass was performed. Decision-making Hypercoagulability workup, including antiphospholipid antibody, protein C, protein S, homocysteine, and Lp(a), was negative. Neither central thrombus on TEE nor evidence of thoracic outlet syndrome was found. As a diagnosis of exclusion, brachial artery thrombosis was ascribed to COVID infection. Despite rivaroxaban, the patient developed gangrene (Panel C) requiring partial digit amputation. Conclusion We present a case of COVID-19-induced recurrent brachial artery thrombosis despite surgical intervention. [Formula presented]Copyright © 2023 American College of Cardiology Foundation

Diagnostic and Therapeutic Potential for HNP-1, HBD-1 and HBD-4 in Pregnant Women with COVID-19.

Pregnancy is characterized by significant immunological changes and a cytokine profile, as well as vitamin deficiencies that can cause problems for the correct development of a fetus. Defensins are small antimicrobial peptides that are part of the innate immune system and are involved in several biological activities. Following that, this study aims to compare the levels of various cytokines and to investigate the role of defensins between pregnant women with confirmed COVID-19 infection and pregnant women without any defined risk factor. TNF-α, TGF-ß, IL-2 and IL-10, ß-defensins, have been evaluated by gene expression in our population. At the same time, by ELISA assay IL-6, IL-8, defensin alpha 1, defensin beta 1 and defensin beta 4 have been measured. The data obtained show that mothers affected by COVID-19 have an increase in pro-inflammatory factors (TNF-α, TGF-ß, IL-2, IL-6, IL-8) compared to controls; this increase could generate a sort of "protection of the fetus" from virus attacks. Contemporarily, we have an increase in the anti-inflammatory cytokine IL-10 and an increase in AMPs, which highlights how the mother's body is responding to the viral attack. These results allow us to hypothesize a mechanism of "trafficking" of antimicrobial peptides from the mother to the fetus that would help the fetus to protect itself from the infection in progress.

Severe Hypertriglyceridemia as a Cause of Arterial Thrombosis with Peripheral Embolic Complications

Lead Author's Financial Disclosures: Nothing to disclose. Study Funding: None. Background/Synopsis: Extensive evidence exists in support of a causal association of elevated triglyceride-rich lipoprotein (TRL) levels with the risk of atherosclerosis progression. Hypertriglyceridemia has been established as a risk factor for venous thrombosis, including a 2- fold increase in the risk of venous thrombosis in postmenopausal women. However, there is limited data on the role of hypertriglyceridemia in the arterial thrombosis. Objective/Purpose: Not Applicable. Methods: Case description: A 51-year-old white female with hypertension and type 2 diabetes (hemoglobin A1C, 7.4%) was transferred for further management of newly diagnosed bilateral renal and splenic infarcts. No risky habits were elicited except for the use of combined hormonal contraceptives over the past two years to control menorrhagia. Family history was significant for hypertriglyceridemia. Her physical exam was unremarkable. Testing for COVID-19 was negative. An extensive hypercoagulable and autoimmune work-up was unremarkable. Fasting lipid profile was significant for elevated levels of triglycerides, 1,274 mg/dL (replicated on two separate occasions), very low-density lipoprotein-cholesterol, 255 mg/dL, and non-high-density lipoprotein-cholesterol, 214 mg/dL, directly measured low-density lipoprotein cholesterol, 39 mg/dL and lipoprotein(a), 6 mg/dL. There was no structural pathology on the echocardiogram, including no interatrial shunt or intracardiac thrombus. Her whole-body computed tomography angiography revealed a focal calcified protruding thrombus in the distal thoracic aorta. No significant plaque was seen elsewhere in the aorta. Results: Decision-making. The posterior thrombus in the distal thoracic and proximal abdominal aorta was determined as a culprit for the visceral organ infarcts. Over the course of the hospital stay her abdominal pain gradually resolved. Treatment with low dose aspirin and therapeutic dose of low-molecular weight heparin was initiated followed by apixaban and aspirin on discharge. She was started on atorvastatin 40 mg, fenofibrate 145 mg, icosapent ethyl 4 g, resulting in a 70% reduction in the triglycerides levels (306 mg/dL). In 3 months, her repeat CT angiography showed significant resolution of the aortic atherothrombosis with no signs of aortic wall inflammation. At the 6-month follow-up visit she was switched to dual antiplatelet therapy with a plan to repeat imaging in 6 months. Conclusions: This case illustrates challenges in managing patients with arterial thrombosis in the setting of familial hypertriglyceridemia. Apart from severely elevated triglycerides no other etiology was evident. We propose further investigation of the prothrombotic properties of TRL and the role of targeted triglyceride-lowering therapies on atherothrombotic outcomes.

Protective and therapeutic potentials of HDL and ApoA1 in COVID-19 elderly and chronic illness patients.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for coronavirus disease-2019 (COVID-19). Elderly subjects, obese, and patients with chronic illnesses, are the most affected group. HDL has pleiotropic physiological functions that are affected with alteration(s) in its structure. Main text: Inflammation whether septic, immune, or other affects HDL structure and function. COVID-19 is associated with systemic immune-inflammation due to cytokine surge. Viral interaction with erythrocytes and hemoglobin-related compounds (may cause anemia and hypoxia) and other factors may affect HDL function. Trials have been conducted to resume HDL functions using peptide preparation, nutritional, and herbal elements. Conclusions: In this review article, I'll discuss the use of reconstituted HDL (rHDL), Apo-A1 mimetic peptide D-4F, ω-3 polyunsaturated fatty acids, and the powdered roots and/or extract of Saussurea lappa (costus) to avoid comorbidity and mortality of COVID-19 in patients with chronic illness or elderly-age mortality.

"COVID toes": A true viral phenomenon or a diagnosis without a leg to stand on?

"COVID toes" is the colloquial name of chilblain-like lesions thought to be a sequela of COVID-19 infection. Over two years and approximately 300 publications later, this association remains controversial. Here, we summarize key clinical, serological, biological, histological, and immunological evidence that supports and rejects this relationship and discuss alternate theories underlying the pathogenesis of chilblain-like lesions.

Lipoprotein(a), venous thromboembolism and COVID-19: A pilot study.

BACKGROUND AND AIMS: Thrombosis is a major driver of adverse outcome and mortality in patients with Coronavirus disease 2019 (COVID-19). Hypercoagulability may be related to the cytokine storm associated with COVID-19, which is mainly driven by interleukin (IL)-6. Plasma lipoprotein(a) [Lp(a)] levels increase following IL-6 upregulation and Lp(a) has anti-fibrinolytic properties. This study investigated whether Lp(a) elevation may contribute to the pro-thrombotic state hallmarking COVID-19 patients. METHODS: Lp(a), IL-6 and C-reactive protein (CRP) levels were measured in 219 hospitalized patients with COVID-19 and analyzed with linear mixed effects model. The baseline biomarkers and increases during admission were related to venous thromboembolism (VTE) incidence and clinical outcomes in a Kaplan-Meier and logistic regression analysis. RESULTS: Lp(a) levels increased significantly by a mean of 16.9 mg/dl in patients with COVID-19 during the first 21 days after admission. Serial Lp(a) measurements were available in 146 patients. In the top tertile of Lp(a) increase, 56.2% of COVID-19 patients experienced a VTE event compared to 18.4% in the lowest tertile (RR 3.06, 95% CI 1.61-5.81; p < 0.001). This association remained significant after adjusting for age, sex, IL-6 and CRP increase and number of measurements. Increases in IL-6 and CRP were not associated with VTE. Increase in Lp(a) was strongly correlated with increase in IL-6 (r = 0.44, 95% CI 0.30-0.56, p < 0.001). CONCLUSIONS: Increases in Lp(a) levels during the acute phase of COVID-19 were strongly associated with VTE incidence. The acute increase in anti-fibrinolytic Lp(a) may tilt the balance to VTE in patients hospitalized for COVID-19.

Airborne particles and cardiovascular morbidity in severe inherited hypercholesterolemia: Vulnerable endothelium under multiple attacks.

Despite recent advances in the research related to air pollution and associated adverse cardiovascular events, the combined effects of air pollution, climate change, and SARS-CoV-2 infection on cardiovascular health need to be researched further. This Commentary addresses their impacts on cardiovascular health in the approximately 25 million people with a severe form of inherited hypercholesterolemia, called familial hypercholesterolemia (FH). The arterial endothelium in these individuals is potentially under multiple attacks caused by particles of both endogenous and exogenous origin. Thus, they have a lifelong highly elevated level of circulating low density lipoprotein (LDL) cholesterol which drives premature atherosclerosis. The high levels of LDL particles, often associated with an elevated level of circulating lipoprotein(a) particles, are both capable of inducing and maintaining endothelial dysfunction. Such pre-existing endothelial dysfunction can be exacerbated by exposure to SARS-CoV-2 viral particles, by exposure to fine particulate matter generated by climate change-associated wildfires, and by dehydration during deadly heatwaves linked to the globally rising temperatures. The external factors can severely worsen the pre-existing endothelial dysfunction, and thereby significantly increase the risk of a cardiovascular event in the exposed FH patients.

High Plasma Apolipoprotein(a) Concentration and Low Plasmin Tpa Enzymatic Activity in Hospitalized Patients with COVID-19

Thrombotic and thromboembolic complications in patients diagnosed with coronavirus disease 2019 (COVID-19) are emerging as important sequelae that contribute to mortality, including disseminated intravascular coagulation, pulmonary embolism, deep vein thrombosis, ischemic stroke, and myocardial infraction. Reported incidence of thrombotic and thromboembolic complications in moderate/severe COVID-19 patients is from 21% to 49%, while even higher incidence in non-surviving COVID-19 patients. However, the underlying mechanism between thrombosis and COVID-19 is still unclear. Tissue-type plasminogen activator (tPA) plays an important role on initiating fibrinolysis by converting zymogen plasminogen to plasmin, a serine protease that degrades the fibrin clot, and therefore preventing excessive pathological blood clots. A homologous protein to plasminogen is apolipoprotein(a) [apo(a)], a major component of lipoprotein(a). The apo(a) inhibits fibrinolysis and exacerbates thrombosis through blocking the conversion from Glu-plasminogen to Lys-plasminogen, which has a higher binding affinity to fibrin and is a better substrate to tPA. The population distribution of plasma apo(a) level is positively skewed (most values are clustered around the left tail of the distribution close to zero), and the plasma apo(a) level in most people is less than 300 μg/mL. High plasma concentration of apo(a) (> 300 μg/mL), or genetic variants of LPA, the gene that encodes for apo(a), correlates with thrombotic cardiovascular risk and thromboembolic risk in many population-based clinical or genetic studies. To investigate the potential correlation between infection of SARS-COV-2 and thrombosis, we tested de-identified plasma samples collected from hospitalized patients with or without positivity of SARS-CoV-2 testing results and COVID-19 diagnosis (ICD10CM:U07.1) through the COVD-19 Tissue Bank at the Medical College of Wisconsin. The tPA enzymatic activity was measured by the release of p-nitroaniline chromophore from a plasmin-specific synthetic substrate with exogenous human plasminogen, with the intensity of color proportional to tPA activity. The apo(a) concentration is measured by ELISA capturing total apo(a) antigen. Our results show that the SARS-CoV-2-positive inpatients have higher plasma tPA concentration than the SARS-CoV-2 negative inpatients (6.0 versus 3.0 ng/mL, p<0.05), while plasma tPA enzymatic activity is lower in SARS-CoV-2-positive inpatients than the SARS-CoV-2 negative inpatients (15.2 versus 25.5 ΔA/min/mL/10 4, p<0.0001) (Figure A). The plasma apo(a) concentration is significantly higher in SARS-CoV-2-positive inpatients than in the plasma from SARS-CoV-2-negative inpatients (the median of the two groups are 114.8 versus 34.4 μg/mL, p<0.05) (Figure B). Among the 20 hospitalized patients with COVID-19, 13 survived. The 13 survived patients have one additional plasma sample collected after recovering from COVID-19 (date range between the two blood collections of onset and after recovery is from 19 to 87 days, the mean duration is 42 days). After recovery, 11 out of 13 surviving patients have increased plasma tPA enzymatic activity (the mean value at onset versus recovery is 5.2 versus 7.1 ΔA/min/mL/10 4, p<0.05) (Figure C). Consistently, 11 out of 13 surviving patients have decreased plasma apo(a) concentration compared to the plasma collected during the onset of COVID-19 from the same individuals (the median values of the onset and recovery are 141.1 versus 106.5 μg/mL, p<0.001) (Figure D). In summary, our study shows lower tPA enzymatic activity and higher apo(a) concentration in SARS-CoV-2-positive hospitalized patients compared to SARS-CoV-2-negative hospitalized patients. Among the survived patients, the reduction of apo(a) concentration after recovering from COVID-19 is accordance with the increase of tPA enzymatic activity. Considering the role of apo(a) in inhibiting fibrinolysis through limiting tPA-mediated plasminogen to plasmin conversion, the alteration in apo(a) concentration provide a possible explana ion of change of tPA activity in patients with severe COVID-19. [Formula presented] Disclosures: Baumann Kreuziger: CSL Behring: Consultancy;Quercegen Pharmaceuticals: Consultancy;Vaccine Injury Compensation Program: Consultancy.

Beyond Lipoprotein(a) plasma measurements: Lipoprotein(a) and inflammation.

Genome wide association, epidemiological, and clinical studies have established high lipoprotein(a) [Lp(a)] as a causal risk factor for atherosclerotic cardiovascular disease (ASCVD). Lp(a) is an apoB100 containing lipoprotein covalently bound to apolipoprotein(a) [apo(a)], a glycoprotein. Plasma Lp(a) levels are to a large extent determined by genetics. Its link to cardiovascular disease (CVD) may be driven by its pro-inflammatory effects, of which its association with oxidized phospholipids (oxPL) bound to Lp(a) is the most studied. Various inflammatory conditions, such as rheumatoid arthritis (RA), systemic lupus erythematosus, acquired immunodeficiency syndrome, and chronic renal failure are associated with high Lp(a) levels. In cases of RA, high Lp(a) levels are reversed by interleukin-6 receptor (IL-6R) blockade by tocilizumab, suggesting a potential role for IL-6 in regulating Lp(a) plasma levels. Elevated levels of IL-6 and IL-6R polymorphisms are associated with CVD. Therapies aimed at lowering apo(a) and thereby reducing plasma Lp(a) levels are in clinical trials. Their results will determine if reductions in apo(a) and Lp(a) decrease cardiovascular outcomes. As we enter this new arena of available treatments, there is a need to improve our understanding of mechanisms. This review will focus on the role of Lp(a) in inflammation and CVD.

The role of lipoprotein(a) in coronavirus disease 2019 (COVID-19) with relation to development of severe acute kidney injury.

Lipoprotein(a) (Lp(a)) is a prothrombotic and anti-fibrinolytic lipoprotein, whose role has not been clearly defined in the pathogenesis of coronavirus disease 2019 (COVID-19). In this prospective observational study, serum Lp(a) as well as outcomes were measured in 50 COVID-19 patients and 30 matched sick controls. Lp(a) was also assessed for correlation with a wide panel of biomarkers. Serum Lp(a) did not significantly differ between COVID-19 patients and sick controls, though its concentration was found to be significantly associated with severity of COVID-19 illness, including acute kidney failure stage (r = 0.380, p = 0.007), admission disease severity (r = 0.355, p = 0.013), and peak severity (r = 0.314; p = 0.03). Lp(a) was also positively correlated with interleukin (IL)-8 (r = 0.308; p = 0.037), fibrinogen (r = 0.344; p = 0.032) and creatinine (r = 0.327; p = 0.027), and negatively correlated with ADAMTS13 activity/VWF:Ag (r = - 0.335; p = 0.021); but not with IL-6 (r = 0.241; p = 0.106). These results would hence suggest that adverse outcomes in patients with COVID-19 may be aggravated by a genetically determined hyper-Lp(a) state rather than any inflammation induced elevations.

Lipoprotein(a) and SARS-CoV-2 infections: Susceptibility to infections, ischemic heart disease and thromboembolic events.

BACKGROUND: Comorbidities including ischemic heart disease (IHD) worsen outcomes after SARS-CoV-2 infections. High lipoprotein(a) [Lp(a)] concentrations are a strong risk factor for IHD and possibly for thromboembolic events. We therefore evaluated whether SARS-CoV-2 infections modify the risk of high Lp(a) concentrations for IHD or thromboembolic events during the first 8.5 months follow-up of the pandemic. METHOD: Cohort study using data from the UK Biobank during the SARS-CoV-2 pandemic. Baseline Lp(a) was compared between SARS-CoV-2 positive patients and the population controls. RESULTS: SARS-CoV-2 positive patients had Lp(a) concentrations similar to the population controls. The risk for IHD increased with higher Lp(a) concentrations in both, the population controls (n = 435,104) and SARS-CoV-2 positive patients (n = 6937). The causality of the findings was supported by a genetic risk score for Lp(a). A SARS-CoV-2 infection modified the association with a steeper increase in risk for infected patients (interaction p-value = 0.03). Although SARS-CoV-2 positive patients had a five-times higher frequency of thromboembolic events compared to the population controls (1.53% vs. 0.31%), the risk was not influenced by Lp(a). CONCLUSIONS: SARS-CoV-2 infections enforce the association between high Lp(a) and IHD but the risk for thromboembolic events is not influenced by Lp(a).

Lipoprotein(a) and Its Potential Association with Thrombosis and Inflammation in COVID-19: a Testable Hypothesis.

PURPOSE OF REVIEW: The COVID-19 pandemic has infected over > 11 million as of today people worldwide and is associated with significant cardiovascular manifestations, particularly in subjects with preexisting comorbidities and cardiovascular risk factors. Recently, a predisposition for arterial and venous thromboses has been reported in COVID-19 infection. We hypothesize that besides conventional risk factors, subjects with elevated lipoprotein(a) (Lp(a)) may have a particularly high risk of developing cardiovascular complications. RECENT FINDINGS: The Lp(a) molecule has the propensity for inhibiting endogenous fibrinolysis through its apolipoprotein(a) component and for enhancing proinflammatory effects such as through its content of oxidized phospholipids. The LPA gene contains an interleukin-6 (IL-6) response element that may induce an acute phase-type increase in Lp(a) levels following a cytokine storm from COVID-19. Thus, subjects with either baseline elevated Lp(a) or those who have an increase following COVID-19 infection, or both, may be at very high risk of developing thromboses. Elevated Lp(a) may also lead to acute destabilization of preexisting but quiescent atherosclerotic plaques, which might induce acute myocardial infarction and stroke. Ongoing studies with IL-6 antagonists may be informative in understanding this relationship, and registries are being initiated to measure Lp(a) in subjects infected with COVID-19. If indeed an association is suggestive of being causal, consideration can be given to systematic testing of Lp(a) and prophylactic systemic anticoagulation in infected inpatients. Therapeutic lipid apheresis and pharmacotherapy for the reduction of Lp(a) levels may minimize thrombogenic potential and proinflammatory effects. We propose studies to test the hypothesis that Lp(a) may contribute to cardiovascular complications of COVID-19.

Lessons from dermatology about inflammatory responses in Covid-19.

The SARS-Cov-2 is a single-stranded RNA virus composed of 16 non-structural proteins (NSP 1-16) with specific roles in the replication of coronaviruses. NSP3 has the property to block host innate immune response and to promote cytokine expression. NSP5 can inhibit interferon (IFN) signalling and NSP16 prevents MAD5 recognition, depressing the innate immunity. Dendritic cells, monocytes, and macrophages are the first cell lineage against viruses' infections. The IFN type I is the danger signal for the human body during this clinical setting. Protective immune responses to viral infection are initiated by innate immune sensors that survey extracellular and intracellular space for foreign nucleic acids. In Covid-19 the pathogenesis is not yet fully understood, but viral and host factors seem to play a key role. Important points in severe Covid-19 are characterized by an upregulated innate immune response, hypercoagulopathy state, pulmonary tissue damage, neurological and/or gastrointestinal tract involvement, and fatal outcome in severe cases of macrophage activation syndrome, which produce a 'cytokine storm'. These systemic conditions share polymorphous cutaneous lesions where innate immune system is involved in the histopathological findings with acute respiratory distress syndrome, hypercoagulability, hyperferritinemia, increased serum levels of D-dimer, lactic dehydrogenase, reactive-C-protein and serum A amyloid. It is described that several polymorphous cutaneous lesions similar to erythema pernio, urticarial rashes, diffuse or disseminated erythema, livedo racemosa, blue toe syndrome, retiform purpura, vesicles lesions, and purpuric exanthema or exanthema with clinical aspects of symmetrical drug-related intertriginous and flexural exanthema. This review describes the complexity of Covid-19, its pathophysiological and clinical aspects.

Are the cutaneous manifestations during or due to SARS-CoV-2 infection/COVID-19 frequent or not? Revision of possible pathophysiologic mechanisms.

BACKGROUND: SARS-Cov-2 is a single-stranded RNA virus, a Betacoronavirus, composed of 16 non-structural proteins, with specific roles in replication of coronaviruses. The pathogenesis of COVID-19 is not yet fully understood. The virus and host factors interplay among distinct outcomes of infected patients. METHODS: Using MeSH (Medical Subject Headings) in PubMed, authors searched for articles cotaining information on COVID-19 and the skin. RESULTS: The pathophysiology of the disease is multifactorial: association with innate immune response, hypercoagulability state, lung tissue damage, neurological and/or gastrointestinal tract involvement, monocytic/macrophage activation syndrome, culminating in exaggerated cytokine secretion, called "cytokine storm", which leads to worsening and death. These systemic conditions may be associated with cutaneous lesions, that have polymorphic aspects, where at histopathological level show involvement in different skin changes. These lesions may be associated with multisystemic manifestations that could occur due to angiotensin-converting enzyme 2 receptor and transmembrane serine protease action, allowing the pulmonary infection and possibly skin manifestation. Several reports in literature show cutaneous lesions similar to chilblain, urticarial eruptions, diffuse or disseminated erythema, livedo racemosa, blue toe syndrome, retiform purpura, vesicle trunk, purpuric exanthema or exanthema with clinical aspects of symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) and others. CONCLUSIONS: This review describes the complexity of Covid-19, pathophysiological and clinical aspects, dermatological finding and other dermatological conditions associated with SARS-CoV-2 infection or COVID-19.