Capillary Plugging Research Articles

Pathological and immunohistochemical findings of lungs, heart, liver, and kidneys, and unexpected findings of fungi and parasites in lungs of deceased COVID-19 patients: A case series

Objective: To define histopathologic and immunohistochemical features of the lungs, heart, liver, and kidneys in patients who died from coronavirus disease 2019 (COVID-19), and to determine the presence of SARS-CoV-2 in all tissues, as well as the presence of fungi and parasites in lung tissues. Methods: This retrospective case study was conducted in the intensive care units of Dokuz Eylül University Hospital, and patients (≥18 years) who died due to COVID-19 between October 2020 and April 2021 were included. The biopsy samples of the patient's lung, heart, liver, and kidney tissues were studied. Results: In the study, we enrolled 12 patients (mean age: 70 years; 50% male). Alveolar epithelial cell damage and diffuse alveolar damage were predominant in lung tissues. Lobular lymphocyte infiltration, centrilobular sinusoidal dilatation, and microvesicular steatosis in the liver, together with pigmented cast, non-isometric vacuolar degeneration, and capillary plugging in the kidneys, were commonly found among the patients. SARS-CoV-2 nucleocapsid protein antibodies were detected in three lung and two kidney tissues, and so did angiotensin-converting enzyme 2 receptor positivity in one lung and more than half of the kidney tissues. The RT-PCR tests were positive in three lungs and one kidney tissue. After DNA isolation from lung tissues, Pneumocystis jirovecii was detected in nine patients, Aspergillus fumigatus in two, Microsporidia in three, and Cryptosporidium in two. Conclusions: SARS-CoV-2 is a multisystemic disease. Fungi and parasites should be investigated in critically ill COVID-19 patients prescribed corticosteroids.

Microvascular Thrombosis as a Critical Factor in Severe COVID-19.

Platelet-endothelial interactions have a critical role in microcirculatory function, which maintains tissue homeostasis. The subtle equilibrium between platelets and the vessel wall is disturbed by the coronavirus disease 2019 (COVID-19), which affects all three components of Virchow's triad (endothelial injury, stasis and a hypercoagulable state). Endotheliitis, vasculitis, glycocalyx degradation, alterations in blood flow and viscosity, neutrophil extracellular trap formation and microparticle shedding are only few pathomechanisms contributing to endothelial damage and microthrombosis resulting in capillary plugging and tissue ischemia. In the following opinion paper, we discuss major pathological processes leading to microvascular endothelial activation and thrombosis formation as a possible major adverse factor driving the deterioration of patient disease course in severe COVID-19.

Vitamin C and its therapeutic potential in the management of COVID19.

COVID19 has emerged as one of the worst pandemics in the history of mankind. Several vaccines have been approved by different government agencies worldwide, but data on their efficacy and safety are limited, and distribution remains a massive challenge. As per WHO, personal immunity is vital for protection against COVID19. Earlier, Vitamin C-mediated pathways have been shown to play critical role in boosting immunity attributed to its antioxidant properties. Recently, the involvement of such pathways in protection against COVID19 has been suggested. The controlled doses of Vitamin C administered through intravenous (IV) injections are being studied for determining its role in the prognosis of COVID19. In this article, we have discussed the potential role of Vitamin C in the management in COVID19 patients and presented recent clinical trials data. Additionally, we have elaborated the possibility of administering Vitamin C through inhalers in order to achieve local high concentration and the challenges of such approach.

Microfluidic capillary networks are more sensitive than ektacytometry to the decline of red blood cell deformability induced by storage

Ektacytometry has been the primary method for evaluating deformability of red blood cells (RBCs) in both research and clinical settings. This study was designed to test the hypothesis that the flow of RBCs through a network of microfluidic capillaries could provide a more sensitive assessment of the progressive impairment of RBC deformability during hypothermic storage than ektacytometry. RBC units (n = 9) were split in half, with one half stored under standard (normoxic) conditions and the other half stored hypoxically, for up to 6 weeks. RBC deformability was measured weekly using two microfluidic devices, an artificial microvascular network (AMVN) and a multiplexed microcapillary network (MMCN), and two commercially available ektacytometers (RheoScan-D and LORRCA). By week 6, the elongation indexes measured with RheoScan-D and LORRCA decreased by 5.8–7.1% (5.4–6.9% for hypoxic storage). Over the same storage duration, the AMVN perfusion rate declined by 27.5% (24.5% for hypoxic) and the MMCN perfusion rate declined by 49.0% (42.4% for hypoxic). Unlike ektacytometry, both AMVN and MMCN measurements showed statistically significant differences between the two conditions after 1 week of storage. RBC morphology deteriorated continuously with the fraction of irreversibly-damaged (spherical) cells increasing significantly faster for normoxic than for hypoxic storage. Consequently, the number of MMCN capillary plugging events and the time MMCN capillaries spent plugged was consistently lower for hypoxic than for normoxic storage. These data suggest that capillary networks are significantly more sensitive to both the overall storage-induced decline of RBC deformability, and to the differences between the two storage conditions, than ektacytometry.

Susceptibility to capillary plugging can predict brain region specific vessel loss with aging

Vessel loss in the aging brain is commonly reported, yet important questions remain concerning whether there are regional vulnerabilities and what mechanisms could account for these regional differences, if they exist. Here we imaged and quantified vessel length, tortuosity and width in 15 brain regions in young adult and aged mice. Our data indicate that vessel loss was most pronounced in white matter followed by cortical, then subcortical grey matter regions, while some regions (visual cortex, amygdala, thalamus) showed no decline with aging. Regions supplied by the anterior cerebral artery were more vulnerable to loss than those supplied by middle or posterior cerebral arteries. Vessel width and tortuosity generally increased with age but neither reliably predicted regional vessel loss. Since capillaries are naturally prone to plugging and prolonged obstructions often lead to vessel pruning, we hypothesized that regional susceptibilities to plugging could help predict vessel loss. By mapping the distribution of microsphere-induced capillary obstructions, we discovered that regions with a higher density of persistent obstructions were more likely to show vessel loss with aging and vice versa. These findings indicate that age-related vessel loss is region specific and can be explained, at least partially, by regional susceptibilities to capillary plugging.

Vitamin C and Microvascular Dysfunction in Systemic Inflammation

Sepsis, life-threatening organ dysfunction caused by a dysfunctional host response to infection, is associated with high mortality. A promising strategy to improve the outcome is to inject patients intravenously with ascorbate (vitamin C). In animal models of sepsis, this injection improves survival and, among others, the microvascular function. This review examines our recent work addressing ascorbate’s ability to inhibit arteriolar dysfunction and capillary plugging in sepsis. Arteriolar dysfunction includes impaired vasoconstriction/dilation (previously reviewed) and impaired conduction of vasoconstriction/dilation along the arteriole. We showed that ascorbate injected into septic mice prevents impaired conducted vasoconstriction by inhibiting neuronal nitric oxide synthase-derived NO, leading to restored inter-endothelial electrical coupling through connexin 37-containing gap junctions. Hypoxia/reoxygenation (confounding factor in sepsis) also impairs electrical coupling by protein kinase A (PKA)-dependent connexin 40 dephosphorylation; ascorbate restores PKA activation required for this coupling. Both effects of ascorbate could explain its ability to protect against hypotension in sepsis. Capillary plugging in sepsis involves P-selectin mediated platelet-endothelial adhesion and microthrombi formation. Early injection of ascorbate prevents capillary plugging by inhibiting platelet-endothelial adhesion and endothelial surface P-selectin expression. Ascorbate also prevents thrombin-induced platelet aggregation and platelet surface P-selectin expression, thus preventing microthrombi formation. Delayed ascorbate injection reverses capillary plugging and platelet-endothelial adhesion; it also attenuates sepsis-induced drop in platelet count in systemic blood. Thrombin-induced release of plasminogen-activator-inhibitor-1 from platelets (anti-fibrinolytic event in sepsis) is inhibited by ascorbate pH-dependently. Thus, under acidotic conditions in sepsis, ascorbate promotes dissolving of microthrombi in capillaries. We propose that protected/restored arteriolar conduction and capillary bed perfusion by ascorbate contributes to reduced organ injury and improved survival in sepsis.

Ascorbate inhibits platelet-endothelial adhesion in an in-vitro model of sepsis via reduced endothelial surface P-selectin expression.

Plugging of the capillary bed can lead to organ failure and mortality in sepsis. We have reported that intravenous ascorbate injection reduces platelet adhesion to the capillary wall and capillary plugging in septic mice. Both platelet adhesion and capillary plugging require P-selectin, a key adhesion molecule. To elucidate the beneficial effect of ascorbate, we hypothesized that ascorbate reduces platelet-endothelial adhesion by reducing P-selectin surface expression in endothelial cells. We used mouse platelets, and monolayers of cultured microvascular endothelial cells (mouse skeletal muscle origin) stimulated with lipopolysaccharide, to examine platelet-endothelial adhesion. P-selectin mRNA expression in endothelial cells was determined by real-time PCR and P-selectin protein expression at the surface of these cells by immunofluorescence. Secretion of von Willebrand factor from cells into the supernatant (a measure of P-selectin-containing granule exocytosis) was determined by ELISA. Lipopolysaccharide (10 μg/ml, 1 h) increased platelet-endothelial adhesion. P-selectin-blocking antibody inhibited this adhesion. Lipopolysaccharide also increased P-selectin mRNA in endothelial cells, P-selectin expression at the endothelial surface, and von Willebrand factor secretion. Ascorbate pretreatment (100 μmol/l, 4 h) inhibited the increased platelet adhesion, surface expression of P-selectin, and von Willebrand factor secretion, but not the increase in P-selectin mRNA. The lipopolysaccharide-induced increase in platelet-endothelial adhesion requires P-selectin presence at the endothelial surface. Ascorbate's ability to reduce this presence could be important in reducing both platelet adhesion to the capillary wall and capillary plugging in sepsis.

Effect of ascorbate on plasminogen activator inhibitor-1 expression and release from platelets and endothelial cells in an in-vitro model of sepsis

The microcirculation during sepsis fails due to capillary plugging involving microthrombosis. We demonstrated that intravenous injection of ascorbate reduces this plugging, but the mechanism of this beneficial effect remains unclear. We hypothesize that ascorbate inhibits the release of the antifibrinolytic plasminogen activator inhibitor-1 (PAI-1) from endothelial cells and platelets during sepsis. Microvascular endothelial cells and platelets were isolated from mice. Cells were cultured and stimulated with lipopolysaccharide (LPS), tumor necrosis factor alpha (TNFα), or thrombin (agents of sepsis), with/without ascorbate for 1-24 h. PAI-1 mRNA was determined by quantitative PCR. PAI-1 protein release into the culture medium was measured by ELISA. In platelets, PAI-1 release was measured after LPS, TNFα, or thrombin stimulation, with/without ascorbate. In endothelial cells, LPS and TNFα increased PAI-1 mRNA after 6-24 h, but no increase in PAI-1 release was observed; ascorbate did not affect these responses. In platelets, thrombin, but not LPS or TNFα, increased PAI-1 release; ascorbate inhibited this increase at low extracellular pH. In unstimulated endothelial cells and platelets, PAI-1 is released into the extracellular space. Thrombin increases this release from platelets; ascorbate inhibits it pH-dependently. The data suggest that ascorbate promotes fibrinolysis in the microvasculature under acidotic conditions in sepsis.

Emergent Therapy with Therapeutic Plasma Exchange in acute pancreatitis due to Severe Hypertriglyceridemia

Hypertriglyceridemia causes acute pancreatitis in 1.3-3.8% of the patients. It is generally believed that the risk of acute pancreatitis increases in patients with severe hypertriglyceridemia (a triglyceride level of more than 1000 mg/dL). Although the mechanism of hypertriglyceridemia-induced acute pancreatitis (HIAP) is not clear, hydrolysis of triglycerides in and around the pancreas by pancreatic lipase seeping out of the acinar cells leads to accumulation of free fatty acids (FFA) in high concentrations. FFA are toxic and destroy acinar cells and capillary endothelium. Moreover, an increased concentrations of chylomicrons causes capillary plugging, ischemia, and acidosis. FFA in acidosis activate trypsinogen and initiate acute edematous and necrotizing pancreatitis . Therapeutic plasma change (TPE) is effective in HIAP in a few case series. According to a committee of the American Society of Apheresis in 2013, TPE is recommended to treat patients with HIAP as Category III indication. In this study, we evaluated the effectiveness of TPE in patients with acute recurrent pancreatitis due to severe hypertriglyceridemia as emergent therapy. Ten patients (8 male and 2 female, mean age 39±9 years) were treated with 14 TPE procedures. All patients were admitted to intensive care unit and treated with serum saline (4-6 L/day) and antibiotics such as meropenem, imipenem, or piperacillin-tazobactam. There was recurrent pancreatitis in six patients’ medical history. According to Balthazar classification, while 4 patients were in stage-C, each 2 patients were in stages-A, D, and E. Mean Ranson’s scores (prognostic scoring system) were 1.3 and 1 in admission and after 48 hours, respectively. Central venous route in 64% of TPE and fresh frozen plasma in 71% of TPE were used. A Haemonetics MCS+ instrument with intermittent flow and acid citrate dextrose solution to whole blood ratio of 1:14 as anticoagulation solution were used. Mean 6280 ml. plasma was exchanged. Mean duration of TPE was 221±79 min. Mean 773 ml. ACD solution was used. In all patients, triglyceride levels lowered less than 1000 mg/dL after one day of TPE. Mean triglyceride levels of the patients significantly decreased from 2876±1701 mg/dL to 1015±1137 mg/dL (p<0.001). Moreover the levels of mean total cholesterol and VLDL-cholesterol were significantly lowered from 483±279 mg/dL to 222±74 mg/dL (p=0.043) and from 574±338 mg/dL to 202±228 mg/dL (p<0.001), respectively. After one hour PE, platelet counts significantly lowered (p=0.007), but the levels of amylase and hemoglobin levels, and white blood cell counts did not change (p>0.05). One patient with necrotizing pancreatitis was died from multi-organ failure after 7 days. Other nine patients were discharged from hospital without local and systemic complication. Two procedures could not be completed due to instrumental problems. Nausea/vomiting and hypotension were seen in each one patient. Hypertriglyceridemia should be considered as a cause of acute recurrent pancreatitis. In conclusion, although now there is no evidence about early application of TPE, this procedure can be of benefit by correcting the clinical course may be effective as adjunctive therapy along with medical treatment in the treatment of acute pancreatitis due to severe hypertriglyceridemia. DisclosuresNo relevant conflicts of interest to declare.

Effect of ascorbate on fibrinolytic factors in septic mouse skeletal muscle

Plugging of the capillary bed in tissues correlates with organ failure during sepsis. In septic mouse skeletal muscle, we showed that blood in capillaries becomes hypercoagulable and that ascorbate injection inhibits capillary plugging. In the present study, we hypothesized that ascorbate promotes fibrinolysis, reversing this plugging. Sepsis in mice was induced by fecal injection into peritoneum. Mice were injected intravenously with a bolus of streptokinase (fibrinolytic agent) or ascorbate at 5-6 h. Both agents reversed capillary plugging in muscle at 7 h. Sepsis increased mRNA expression of urokinase plasminogen activator (u-PA) (profibrinolytic) and plasminogen activator inhibitor 1 (PAI-1) (antifibrinolytic) in muscle and liver homogenates at 7 h. Ascorbate did not affect u-PA mRNA in either tissue, but it inhibited PAI-1 mRNA in muscle, suggesting enhanced fibrinolysis in this tissue. However, ascorbate did not affect increased PAI-1 mRNA in the liver (dominant source of soluble PAI-1 in systemic blood). Consistently, ascorbate affected neither elevated PAI-1 protein/enzymatic activity in septic liver nor lowered plasmin antiplasmin level in septic blood. Furthermore, hypocoagulability of septic blood revealed by thrombelastography and thrombin-induced PAI-1 release from isolated platelets (ex-vivo model of sepsis) were not affected by ascorbate. Based on the PAI-1 protein data, the present study does not support the hypothesis that ascorbate promotes fibrinolysis in sepsis.

Short-term effect of ascorbate on bacterial content, plasminogen activator inhibitor-1, and myeloperoxidase in septic mice

BackgroundSepsis, a potential risk associated with surgery, leads to a systemic inflammatory response including the plugging of capillary beds. This plugging may precipitate organ failure and subsequent death. We have shown that capillary plugging can be reversed rapidly within 1 h by intravenous injection of ascorbate in mouse skeletal muscle. It is unknown whether, in parallel with this effect, ascorbate negatively affects the protective responses to sepsis involving the fibrinolytic and immune systems. We hypothesized that treatment with ascorbate for 1 h does not alter bacterial content, plasminogen activator inhibitor 1 (PAI-1), and neutrophil infiltration in lung, kidney, spleen, and liver (organs with high immune response) of septic mice. Materials and methodsSepsis was induced by feces injection into the peritoneum. Mice were injected intravenously with ascorbate at 6 h (10 mg/kg), and samples of peritoneal fluid, arterial blood, and organs collected at 7 h were subjected to analyses of bacterial content, PAI-1 messenger RNA and enzymatic activity, and myeloperoxidase (MPO) (a measure of neutrophil infiltration). ResultsSepsis increased bacterial content in all fluids and organs and increased PAI-1 messenger RNA and enzymatic activity in the lung and liver. Sepsis increased the myeloperoxidase level in the lung and liver, and lowered it in the spleen. Except for decreasing the bacterial content in blood, these responses to sepsis were not altered by ascorbate. ConclusionsThe rapid effect of ascorbate against capillary plugging in the septic mouse skeletal muscle is not accompanied by alterations in PAI-1 or myeloperoxidase responses in the organs with high immune response.

Ischemia-Reperfusion Injury

Ischemia-reperfusion injury forms the basis of tissue damage and cellular apoptosis in many pathologic and traumatic processes. The tissue damage follows a natural progression of cellular and metabolic events initiated by an ischemic episode. Ischemia causes intracellular/extracellular changes principally resulting in increased intracellular calcium, pH changes, and adenosine triphosphate depletion that end in cell death if the process is not interrupted. This interruption takes the form of reperfusion, characterized by a "flushing" of tissues with toxic metabolites, principally reactive oxygen species. The immediate effect is mitochondrial pore permeability, complement activation, cytochrome release, cytokine activation, inflammation, edema, neutrophil platelet adhesion, capillary plugging, and thrombosis. This sets the stage for the long recognized "no-reflow" phenomenon and progressive tissue death. Current recognition of cellular "cross-talk" and molecular events have introduced new logical strategies to sequentially combat the events occurring in relation to ischemia-reperfusion injury. These include mechanical preconditioning and pharmacological preconditioning and postconditioning strategies. It is likely that success in reversing or limiting tissue damage will be found in a sequential multitargeted approach using a combination of these strategies-clinical trials in this regard are sorely needed.

Otvaranje koronarne arterije u primarnim PCI ne znači uvek i optimalni protok i najpovoljniji ishod za bolesnika - tretman 'no reflow' fenomena

Microvascular obstruction (MVO) commonly occurs following percutaneous coronary interventions (PCI), may lead to myocardial injury, and is an independent predictor of adverse outcome. Severe MVO may manifest angiographically as reduced flow in the patent upstream epicardial arteries, a situation that is termed 'no-reflow.' The no-reflow phenomenon was originally observed in experimental models of acute myocardial infarction (MI) and was described as a failure to restore normal myocardial blood flow despite removal of the coronary obstruction. Defined angiographically, no-reflow manifests as an acute reduction in coronary flow (TIMI grade 0-1) in the absence of dissection, thrombus, spasm, or high-grade residual stenosis at the original target lesion. Lesser degrees of flow impairment (TIMI grade 2) are generally referred to as 'slow-flow'. However, studies of acute MI patients have reported that scintigraphic evidence for no-reflow may occur in the absence of angiographic slow-flow, suggesting that microvascular injury may be angiographically inapparent in some patients. The mechanisms and mediators responsible for noreflow remain speculative, but the end result appears to be severe microvascular dysfunction. Potential mechanisms of microvascular dysfunction include vasospasm, distal embolization of thrombus or other debris, oxygen free radical mediated endothelial injury, capillary plugging by erythrocytes and neutrophils, and intracellular/interstitial edema with intramural hemorrhage. Microvascular obstruction can be broadly categorized according to the duration of myocardial ischemia preceding PCI. In 'interventional MVO' (e.g., elective PCI), obstruction typically involves myocardium that was not exposed to acute ischemia before PCI. Conversely 'reperfusion MVO' (e.g., primary PCI for acute myocardial infarction) occurs within a myocardial territory that was ischemic before the coronary intervention. Interventional and reperfusion MVO have distinct pathophysiological mechanisms and may require individualized therapeutic approaches. Interventional MVO is triggered predominantly by downstream embolization of atherosclerotic material from the epicardial vessel wall into the distal microvasculature. Reperfusion MVO results from both distal embolization and ischemia-reperfusion injury within the subtended ischemic tissue. Randomized clinical trials have studied strategies for prevention of MVO and no-reflow; however, the efficacy of measures for reversing MVO once no-reflow has been demonstrated angiographically is unclear. New approaches for prevention and treatment of MVO will require a better understanding of intracellular cardioprotective pathways such as the blockade of the mitochondrial permeability transition pore.

Ascorbate Reduces Mouse Platelet Aggregation and Surface P‐Selectin Expression in an Ex Vivo Model of Sepsis

Compromised perfusion of the capillary bed can lead to organ failure and mortality in sepsis. We have reported that intravenous injection of ascorbate inhibits platelet adhesion and plugging in septic capillaries. In this study, we hypothesized that ascorbate reduces aggregation of platelets and their surface expression of P-selectin (a key adhesion molecule) in mice. Platelets were isolated from control mice and subjected to agents known to be released into the bloodstream during sepsis (thrombin, ADP or U46619, thromboxane A2 analog). Platelet aggregation was analyzed by aggregometry and P-selectin expression by flow cytometry. Platelet-activating agents increased aggregation and P-selectin expression. Ascorbate inhibited these increases. This inhibitory effect was NOS-independent (LNAME had no effect). In contrast to the platelet-activating agents, direct stimuli lipopolysaccharide, TNFα, or plasma from septic mice did not increase aggregation/expression, a finding consistent with the literature. The results suggest a complex mechanism of platelet aggregation and P-selectin expression in sepsis, where generation of platelet-activating stimuli is required first, before platelet aggregation and adhesion in capillaries occur. The ability of ascorbate to reduce platelet aggregation and P-selectin expression could be an important mechanism by which ascorbate inhibits capillary plugging in sepsis.

Rationale and design of the MGuard for acute ST elevation reperfusion MASTER trial

Primary percutaneous coronary intervention (PCI) improves survival compared with thrombolytic therapy in ST-segment elevation myocardial infarction (STEMI), with much of the benefit attributable to greater rates of normal epicardial and myocardial perfusion resulting in enhanced myocardial salvage. However, reduced tissue reperfusion after primary PCI may occur from distal thromboemboli with capillary plugging. The MGuard stent consists of a balloon-expandable metallic scaffold with mesh sleeve fibers of polyethylene terephthalate attached to its outer surface to trap friable debris/thrombi and reduce distal embolization. The MGuard for Acute ST Elevation Reperfusion (MASTER) trial has been designed to evaluate the MGuard stent in patients with STEMI. The MASTER trial is a prospective, multicenter, randomized study designed to compare the incidence of complete (=70%) ST-segment resolution with PCI using bare metal or drug-eluting stents (the control arm) versus PCI with the MGuard stent, measured 60 to 90 min after the last angiogram (primary endpoint). Secondary endpoints include the rates of TIMI flow and myocardial blush, and clinical outcomes through 1-year follow-up. The study has enrolled 432 patients with STEMI undergoing primary or rescue angioplasty within 12 hr of symptom onset and includes substudies with cardiac magnetic resonance imaging and quantitative coronary angiography to evaluate infarct size, microvascular obstruction, and angiographic restenosis. Distal embolization is common during primary PCI and results in reduced myocardial perfusion and lack of reduction of infarct size. The MASTER trial is a prospective, randomized trial designed to assess the potential of the novel MGuard stent with protective mesh net to reduce embolization and enhance myocardial reperfusion compared with routine PCI in the setting of STEMI.

Prospective, randomized, multicenter evaluation of a polyethylene terephthalate micronet mesh-covered stent (MGuard) in ST-segment elevation myocardial infarction: the MASTER trial

The enemy of revascularization using primary PCI during STEMI intervention is risk of distal embolization with capillary plugging which leads to reduced tissue reperfusion. Several pharmacological agents, as well as mechanical devices (i.e. manual aspiration catheters/mechanical thrombectomy, proximal and distal protection devices) were introduced, in the last years, to reduce the risk of angiographic complications during percutaneous coronary intervention and to improve myocardial reperfusion.1,2 Despite the use of these agents still distal embolization is common which leads to no-reflow phenomenon.1,2 Recently, the MGuard stent (InspireMD, Tel Aviv, Israel), a bare metal stent covered by micron level mesh, which allows to prevent distal embolization by blocking the athero-thrombi prolapse through the stent struts during deployment.3 Dr. Gregg W. Stone presented the late-breaking findings from the MASTER study were presented in a late-breaking session at TCT 2012 that revealed a new stent in STEMI patients undergoing emergent PCI to increase the rate of complete ST-segment resolution compared with conventional BMS and DES.

Cerebral hypoperfusion and white matter disease in healthy elderly and patients with Alzheimer's disease

Click here to view the accompanying paper in this issue.

Update in Pharmacological Management of Coronary No-Reflow Phenomenon

The no-reflow phenomenon (NRP) is defined as the lack of adequate myocardial tissue perfusion despite a patent epicardial coronary artery. The incidence of NRP varies between 2-5% of elective percutaneous coronary interventions (PCI) and 30% in primary PCI. Clinically, it is an independent predictor of myocardial infarction, in-hospital mortality, and long-term mortality. It may be categorized in interventional (after PCI, especially in saphenous venous grafts) or reperfusion NRP (after re-opening of a totally occluded coronary artery, usually during primary PCI or thrombolysis). There are many physiopathological factors implicated: distal microembolization, interstitial and intracellular edema, coronary spasm and capillary plugging. Although reperfusion and no reflow is a field of intense research, no single mechanical or pharmacological therapy has demonstrated a clear efficacy against NRP, probably due to its multifactorial nature. Once established, the treatment of NRP is based on vasodilators like adenosine, verapamil, nitroprusside or nicorandil. However, the efficacy of these measures is poor, so every effort should be made to prevent the apparition of NRP. The objective of this report is to provide an update of the pharmacological armamentarium available for the prevention and treatment of NRP, and suggest a systematic approach of the management of NRP according to the different possible clinical scenarios.

TENECTEPLASE AS A NEW MEDICATION IN MANAGING NO-REFLOW

No-reflow has been defined as “inadequate myocardial perfusion through a given segment of coronary circulation without angiographic evidence of a mechanical obstruction”. Important components of the process are thought to include endothelial ischemic injury producing “blebs” of tissue that directly obstruct the microvasculature, leukocyte plugging of capillaries, and the vascular effects of reactive oxygen species. No-reflow can complicate any percutaneous intervention (PCI), though it is more common following acute myocardial infarctions (MI), particularly with prolonged occlusion times. A 59-year-old woman presented to the hospital after two hours of continuous chest pain. Because of acute myocardial infarction of the inferior and lateral wall, she underwent direct stenting to an occlusion in the right coronary artery. Despite successful implantation of stents revascularization failed. In absence of aspiration devices and other pharmacological agent we decide to apply 30 mg (6000 IU) tenecteplase intracoronary. Three min after administration TIMI flow grade improved from TIMI 0 to TIMI 3. Managing no-reflow can be approached in a number of different ways and needs to be tailored to the type of intervention being performed. As confirmed in practice, prevention is better than cure and both mechanical and pharmacological approaches can be employed in high risk cases. In the setting of acute myocardial infarction the most effective preventative measure is the rapid opening of the vessel and as such the development of a robust and efficient primary PCI service is integral to the avoidance of this complication. Managing no-reflow will become increasingly important with the wider development of primary PCI. Within the setting of acute myocardial infarctions with no reflow as primary percutaneous intervention complication, there are potential important future pharmacological regimens that may become established and one of them can be tenecteplase. Acta Medica Medianae 2012; 51(1):42-45.

Anaerobic storage of red blood cells: the need for caution regarding donor red cells with sickle cell trait.

Dear Sir, We concur with observations made by Dr. Ahmed in his letter “Anaerobic storage of red blood cells: the need for caution regarding donor red cells with sickle cell trait”1 about the potential unsuitability of anaerobic conditions for the storage of sickle cell trait (SCT) blood. Blood containing HbAS is well known to clog up leucoreduction filters and to enable unacceptable levels of leucocytes to escape during the filtering process2. At sufficiently low pO2, pH and high mean corpuscular haemoglobin concentration, HbAS in red blood cells (RBC) of SCT carriers polymerises. Although SCT is considered benign, symptoms and pathology suggesting occurrences of serious sickling events have been reported in numerous cases involving healthy SCT carriers placed under extremely demanding anoxic conditions3. Polymerisation of HbAS is well underway at a pO2 below 35 Torr for RBC with an HbS content of 40% or less, reducing RBC deformability and resulting in the well-described obstruction of leucoreduction filters2. In order to obtain significant anti-oxidative and metabolic benefits, we target anaerobic red blood cells to have less than 3% haemoglobin oxygen saturation (%SO2) before placing units in storage, and then maintain this low SO2 state throughout the storage period4. The pO2 required to achieve an SO2 below 3% is less than 5 Torr at 4 °C, and under such a low pO2, HbAS would polymerise. Even if it was permissible, inclusion of anti-sickling agents would be insufficient to prevent HbAS polymerisation, and storing RBC under a highly sickled state is known to be unacceptable because of prolonged mechanical stress to the cells and resulting haemolysis. If successful collection and storage of SCT blood is specifically desired, a test to exclude units with HbAS will be necessary to avoid subjecting these collected RBC to the anaerobic treatment. Further investigation will be required to determine the feasibility of storing SCT blood with a low HbS content. The AABB guidelines for transfusing erythrocytes containing sickle haemoglobin recommend avoiding transfusion of HbAS blood to foetuses and neonates, as well as to patients with sickle cell disease, but there is no definitive clinical evidence indicating a necessity to exclude RBC units containing HbAS for general transfusion5. Despite the fact that RBC containing HbAS are diluted in the recipient upon transfusion, under anoxic conditions that may exist in the recipient’s capillaries, these RBC may become rigid due to gelation of HbAS resulting in compromised oxygen delivery. Furthermore, RBC sickling in anoxic capillaries may result in capillary plugging and further harm the tissues. The safety of HbAS blood in the context of the general blood supply is an issue that lies outside the scope of Dr. Ahmed’s letter. For the reasons stated above however, we believe it is one that merits further careful scrutiny. In routine transfusion practice, we do not expect any harm to come from transfusing anaerobic blood to recipients, since infused RBC will be fully oxygenated at their first pass through the pulmonary capillaries. The effects of transfusing anaerobic blood to sickle cell disease patients will also need careful investigation.