Hereditary thrombocytopenia with platelet sialic acid deficiency and mutations in the GNE genes.

BACKGROUND: The inherited macrothrombocytopenias are rare disorders and the underlying cause can be identified in many cases but in some, this can remain enigmatic. Platelet transfusions are often administered during hemorrhagic events. METHODS: A patient with previously unexplained inherited macrothrombocytopenia with a platelet count between 3-20 × 109 /L is described in which studies were performed using exome sequencing (ES) and platelet flow cytometry. RESULTS: Both the hemoglobin and white cell counts were normal. ES revealed two suspicious variants, one likely pathogenic and one a variant of uncertain significance, in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene, and flow cytometry showed diminished expression of surface platelet sialic acid (about 5%) but normal red cell sialic acid. The Thrombopoietin (TPO) level was low, and the patient responded to TPO-mimetic treatment with an increase in the platelet count. CONCLUSION: Two variants in the GNE gene were able to be upgraded to pathogenic with apparently restricted expression to the megakaryocyte lineage. Platelet transfusion may be avoided in these patients with TPO-mimetic treatment.

In vitro comparison of CPD whole blood with conventional blood components.

INTRODUCTION: Resuscitation of severely injured trauma patients is commonly performed using red blood cells in additive solution supplemented with plasma and platelet concentrates. There is an increasing interest in the use of low anti-A titer Group O whole blood (LTOWB) in the early management of the resuscitation. It is unclear whether clinical outcome is improved using this approach. METHODS: Expired units of CPD-LTOWB were studied on Day 22 and expired units of thawed plasma on Day 6 and Day 7. LTOWB was assessed for hemoglobin content, clotting factor levels and platelet numbers and function using thromboelastography (TEG) and impedance aggregation. Assays of fibrinogen and FV, FVIII, FVII and FX were performed on the expired plasma. The LTOWB hemoglobin was compared to red cells in additive solution (AS-RBCs) and the clotting factor levels to those of expired thawed plasma. Platelet function was compared to fresh whole blood samples from healthy subjects. RESULTS: LTOWB contained slightly more hemoglobin than the AS-RBCs (Medians, 66 v 59 G), and the plasma content of fibrinogen was similar. Other clotting factors were reduced by approximately 15% except for FVIII which was 30% less. Both TEG and impedance aggregometry showed evidence of residual platelet function despite the prolonged period of refrigerator storage. CONCLUSION: LTOWB contains higher hemoglobin and adequate clotting factors, and residual platelet function is demonstrated indicating that this product would be expected to be at least equivalent to a single unit of each of the conventional components commonly used in trauma resuscitation.

Influenza-associated thrombotic thrombocytopenic purpura: A report of two cases and a brief review of the literature.

BACKGROUND AND OBJECTIVES: Thrombotic thrombocytopenic purpura (TTP) is often preceded by a recent history of an acute infection and influenza is the most implicated virus. MATERIALS AND METHODS: We identified two cases of TTP, which were preceded by influenza between 2010 and 2021. In one patient, we epitope mapped the binding specificity of antibodies using an overlapping peptide approach of the stalk protein of Influenza B and the cysteine-rich spacer domain (CRSD) of ADAMTS13. A literature search was performed for reports of influenza-associated TTP over the period 1980-2021. RESULTS: Two patients were identified in which TTP was preceded by influenza, one Influenza A and the other Influenza B. Epitope mapping of the latter's plasma identified target epitopes in both the stalk protein of Influenza B and CRSD of ADAMTS13. The literature review revealed only seven case reports, all but one from Europe or Asia and associated with Influenza A. Severe ADAMTS13 deficiency was demonstrated in only four cases. CONCLUSION: We report the first small case series of influenza-associated TTP. Moreover, it is the first case implicating Influenza B and a mechanism favouring polyclonal B-cell proliferation rather than molecular mimicry as the stimulus to form anti-ADAMTS13 auto-antibodies is suggested.

Causes of an elevated international normalized ratio in the intensive care unit and the implications for plasma transfusion.

BACKGROUND: The presence of an elevated international normalized ratio (INR) is common in patients in the intensive care unit (ICU), but the cause rarely determined. These patients are at risk to receive prophylactic plasma prior to invasive procedures. STUDY DESIGN AND METHODS: Samples from patients with an INR of 1.5 or greater were frozen and subsequently thawed and assayed for procoagulant and anticoagulant clotting factors and anti-Xa to determine the likely cause of the INR. Samples showing a low FVII, FX, PC, and PS were categorized as a vitamin K deficiency pattern. Samples showing a low FV, low or normal fibrinogen, and high FVIII were categorized as a liver disease pattern. Samples showing an anti-Xa >0.01 IU/ml were assayed for anti-Xa DOACs. Samples which could not be categorized were grouped as equivocal. RESULTS: A total of 48 samples were obtained over a 6-month period. Nineteen showed a Vitamin K deficiency pattern, 17 a liver disease pattern, 7 showed an anti-Xa DOAC and 5 were equivocal. High FVIII and D-dimers and reduced levels of the anticoagulant proteins were present in the majority of the samples. FVII levels correlated inversely with the INR (r = -0. 81), as did FX (r = -0.67) but not FV (r = -0.04) nor fibrinogen (r = -0.15). CONCLUSION: Transfusion of plasma to reverse an elevated INR in the ICU should be discouraged since such a practice is either avoidable by the use of vitamin K or inappropriate in the case of liver disease or an anti-Xa DOAC.

Adjunctive treatment of clinically severe babesiosis with red blood cell exchange: a case series of nineteen patients.

BACKGROUND: Infection with the protozoan parasite Babesia, the causative agent of babesiosis, can result in asymptomatic to life-threatening illness. Severe cases of babesiosis are characterized by high levels of parasitemia (>4%-10%) and commonly treated with adjunctive red blood cell exchange (RCE) in addition to antimicrobial therapy. The efficacy of RCE in this context is unknown. STUDY DESIGN AND METHODS: Blood bank records were examined for requests for RCE during a 10-year period from 2007 to 2017. Relevant clinical and laboratory variables were extracted from medical records from presentation to 35 days after RCE and analyzed in univariate and multivariate models. RESULTS: Nineteen cases of babesiosis were identified in which RCE was performed. The median age of patients was 77 years, 74% of whom were male. A total of 37% of patients were asplenic. RCE was performed on average 1.3 days after presentation, with procedural urgency driven mainly by the level of parasitemia. Mean pre- and post-RCE levels of parasitemia were 12.9 and 3.4%, respectively, resulting in a mean percent reduction in parasitemia of 75%. Preprocedural parasitemia (p = 0.047) and age (p = 0.028) were both significant predictors of postprocedural hospital length of stay (post-RCE LOS). Neither postprocedural parasitemia (p = 0.12) nor percent reduction in parasitemia (p = 0.72) correlated with post-RCE LOS. Four patients died, none of whom were asplenic. Mortality was not correlated with hematologic, parasitologic, or clinical variables analyzed. CONCLUSIONS: Reduction in the level of parasitemia is the only known benefit of RCE in severe babesiosis.

Heavy parasitemia in babesiosis treated without adjunctive red cell exchange.

Babesiosis is a tick-borne infectious disease caused by the protozoa Babesia but transplacental, and transfusion transmission may occur. While most infections are asymptomatic, rarely, it can present with a severe, life-threatening illness. Treatment is primarily with antibiotics, but red cell exchange (RCE) has been used in more severe cases which are characterized by high-grade parasitemia, evidence of severe hemolysis and or multi-organ failure. A threshold parasite level of 10% has arbitrarily been applied as an indication for RCE; however, this threshold is not evidence-based. We report on three cases of severe babesiosis in which we considered the use of RCE on the basis of a parasite level greater than 10%, but the procedure was not performed. We deferred RCE on account of the good clinical state of the patient and the absence of end-organ failure. All patients were followed daily until discharge. Two of these patients had been splenectomized, and each received a single unit of red blood cells during the hospitalization. The third patient had a long history of refractory lymphoma and was pancytopenic requiring multiple transfusions during the years before the diagnosis of babesiosis. She had transfusion-transmitted babesiosis from a red blood cell transfused 46 days prior to diagnosis. All three patients responded well to antibiotics, and none expired. This small case series suggests that requests for RCE solely on the basis of an arbitrary level of parasitemia should be questioned and the clinical state and evidence of end-organ failure considered in the decision to perform RCE.

Refractoriness to red blood cell transfusion therapy due to hypersplenism.

BACKGROUND: A 55-year-old male presented with myelodysplastic/myeloproliferative neoplasm and severe splenomegaly. The patient is blood group O, D+ with a negative indirect antiglobulin test. Transfusion of 5 units of red blood cells (RBCs) increased the hemoglobin (Hb) level from 6.7 to 7.2 g/dL. No active bleeding or hemolysis was evident. The patient was readmitted 1 week later with a Hb level of 3.3 g/dL. An additional 6 units of RBCs showed only an increase from 3.3 to 3.5 g/dL. Partial splenic embolization was performed, which resulted in a stabilization of the Hb level at approximately 7 g/dL. Because of this, total splenectomy was performed, which resulted in a gradual increase in Hb level to approximately 13 g/dL. The patient remains transfusion independent 160 days postsplenectomy. RESULTS: RBC transfusion increases Hb concentration by 1 g/dL per unit in a typical adult. This increase is attenuated in the presence of ongoing hemolysis or active blood loss. Occasionally, a low-RBC-volume unit transfused to a recipient with a large intravascular blood volume may show an unexpectedly small increase. In rare situations, however, the etiology of a greatly attenuated response is more perplexing. The pattern of Hb concentration posttransfusion was suggestive of splenic sequestration in our patient. CONCLUSION: Severe refractoriness to RBC transfusion attributable to severe hypersplenism is a rare event. Our case suggests that splenic artery embolization may be a useful initial approach in individual cases and a potential predictor of the utility of a subsequent surgical splenectomy.

False-negative compatible antiglobulin crossmatches in samples with alloantibodies to cognate red blood cell antigens.

BACKGROUND: Patient samples showing a positive indirect antiglobulin test are further tested to identify alloantibody specificity using a panel of phenotypically characterized group O reagent red blood cells (RBCs). Donor RBCs phenotypically negative for the antibody specificity are then serologically crossmatched using an antiglobulin reagent. This latter test is performed to identify any incompatibility due to the presence of undetected minor blood group antibodies and considered an important step in patient safety. STUDY DESIGN AND METHODS: Samples with well-characterized alloantibodies were intentionally crossmatched against donor RBCs expressing the cognate antigen. In a separate set of specimens, the alloantibody was titered and crossmatched against both heterozygous and homozygous cells. RESULTS: Thirty-five samples containing 10 common alloantibodies crossmatched against 240 ABO-compatible donor cells phenotypically positive for the cognate antigen showed compatible crossmatches in 89 of 240 (37%). Antibody titering of 12 alloantibodies showed that a titer of 2 or more was required for incompatibility of all homozygous cells and a titer of 8 or more for incompatibility of all heterozygous cells. CONCLUSION: The antiglobulin crossmatch has a high failure rate (false-negatives) related to antibody titer and donor cell zygosity and is not reliable in interdicting incompatibility due to minor blood group antibodies.

Rapid response to intravenous vitamin K may obviate the need to transfuse prothrombin complex concentrates.

BACKGROUND: Patients on warfarin who present with bleeding or who require an urgent procedure are commonly treated with intravenous (IV) vitamin K, which is supplemented with repletion of the vitamin K factors using either plasma or a prothrombin complex concentrate (PCC). In some such cases, use of vitamin K alone could be adequate to achieve acceptable hemostasis. STUDY DESIGN AND METHODS: An algorithm emphasizing the use of vitamin K alone in patients presenting with non-life-threatening bleeding was encouraged, with repeat testing of the international normalized ratio (INR) within 5 hours. Depending on the INR result, patients received no factor repletion or plasma or PCC, as judged by the physician. Leftover samples from a separate cohort of patients with supratherapeutic INRs (INR > 4.0) were studied for clotting factor evaluation. RESULTS: A total of 46 pre- and postinfusion INRs were evaluable from 41 patients. Median INR decreased from 5.8 to 2.5, with a median dose of 5 mg after a median time of 4.0 hours postinfusion. A total of 27 of 46 (59%) postinfusion samples showed an INR of 2.5 or less. Samples from patients with the highest INR showed the greatest decline in INR. Samples from supratherapeutic INR patients showed very high Factor VIII:C (200%) and a normal activated partial thromboplastin time in 23 of 50 (46%). CONCLUSION: Use of IV vitamin K as sole therapy for urgent partial reversal of warfarin for non-life-threatening bleeding may provide adequate hemostasis within 5 hours, avoiding the need for clotting factor repletion.

How do we reduce plasma transfusion in Rhode Island?

BACKGROUND: Plasma transfusions are given to patients with coagulopathy, either prophylactically, before an invasive procedure; or therapeutically, in the presence of active bleeding; and as an exchange fluid in therapeutic plasma exchange for disorders such as thrombotic thrombocytopenic purpura. There is consensus that many prophylactic plasma transfusions are non-efficacious, and the misdiagnosis of thrombotic thrombocytopenic purpura results in unnecessary therapeutic plasma exchange. STUDY DESIGN AND METHODS: Beginning in 2001, programs to reduce plasma transfusion in the three major teaching hospitals in Rhode Island were initiated. The programs evolved through the establishment of guidelines, education for key prescribers of plasma, screening of plasma prescriptions, and engagement of individual prescribing physicians for out-of-guidelines prescriptions with modification or cancellation. Establishment of an in-house ADAMTS13 (ADAM metallopeptidase with thrombospondin type 1, motif 13) assay in 2013 was used to prevent therapeutic plasma exchange in patients with non-thrombotic thrombocytopenic purpura microangiopathy. Transfusion service data were gathered at the hospital level regarding blood component use, hospital data for discharges, inpatient mortality, and mean case-mix index, and, at the state level, for units of plasma shipped from the community blood center to in-state hospitals. RESULTS: Between 2006 and 2016, a reduction in plasma use from 11,805 to 2677 units (a 77% decrease) was observed in the three hospitals and was mirrored in the state as a whole. This decline was not associated with any increase in red blood cell transfusion. Inpatient mortality either declined or was unchanged. CONCLUSION: An active program focused on education and interdiction can achieve a large decrease in plasma transfusions without evidence of patient harm.

Acquired Factor XIII inhibitor associated with mantle cell lymphoma.

BACKGROUND: Acquired Factor (F)XIII deficiency is a very rare bleeding diathesis with a potentially fatal outcome, previously described in the context of autoimmune disorders and leukemias. There is minimal information on autoantibody characterization and the role of antifibrinolytic therapy in patient management. CASE REPORT: A 79-year-old woman with a 3-month history of bruising and heavy menorrhagia presented with ongoing vaginal bleeding, symptomatic anemia, and a right thigh hematoma. Initial management included an axillary lymph node biopsy and coagulation evaluation. Pathologic examination of the biopsy specimen revealed mantle cell lymphoma. Clot solubility assay was consistent with a FXIII activity of less than 3%. An anti-FXIII inhibitor was suspected, the epitope specificity of which was mapped by micropeptide array analysis to regions in the ß-sandwich and catalytic core domain of the FXIII-A subunit. Management with cryoprecipitate, steroids, rituximab, and antifibrinolytic therapy resolved the bleeding diathesis and suppressed the inhibitor. CONCLUSION: This is the first reported case of an acquired FXIII inhibitor associated with mantle cell lymphoma in which the epitope specificity of the pathologic autoantibody was accurately defined. Antifibrinolytic therapy played a prominent role in the prevention of bleeding complications in the window period between initiation of immunosuppression and disappearance of the pathologic anti-FXIII autoantibody.

Effect of ADAMTS13 activity turnaround time on plasma utilization for suspected thrombotic thrombocytopenic purpura.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) due to deficiency of the von Willebrand-cleaving protease ADAMTS13 is a hematologic emergency that requires prompt initiation of therapeutic plasma exchange (TPE). Long turnaround times (TATs) have precluded the use of pre-TPE measurement of ADAMTS13 activity for the initial diagnosis in most institutions. STUDY DESIGN AND METHODS: An in-house rapid TAT (r-TAT) assay for ADAMTS13 activity was implemented after 18 months of validation. In a quasi-experimental design using interrupted time series analysis, patterns of plasma utilization in patients with suspected TTP were assessed after implementation of this assay for ADAMTS13 activity and compared to utilization patterns for patients who received plasma exchange before r-TAT assay implementation designated the standard TAT period. RESULTS: In the 18 months after implementation of the r-TAT ADAMTS13 assay, there was a significant reduction in plasma utilization per patient suspected of having TTP (mean, 144.5 units vs. 63.3 units of plasma per patients suspected of having TTP; p = 0.002). The mean number of exchanges per patient and mean number of exchanges after achieving a platelet count of at least 150 × 10(9) /L were lower in the r-TAT cohort (p < 0.001 for both). There was no significant difference in 30-day mortality. CONCLUSIONS: Implementation of a rapid turnaround assay for ADAMTS13 resulted in a significant reduction in plasma utilization for patients with suspected TTP, without an increase in mortality. This study demonstrates that these data, provided in a timely fashion, can avoid unnecessary plasma exchange in patients who do not have TTP.

Transfusion-transmitted anaplasmosis from a leukoreduced platelet pool.

BACKGROUND: Human granulocytic anaplasmosis is an emerging tick-borne illness. Anaplasma phagocytophilum resides intracellularly, can cause asymptomatic infection, and can survive blood component refrigeration conditions for at least 18 days. To date, eight cases of transfusion-transmitted anaplasmosis (TTA) have been reported: seven attributed to red blood cell (RBC) units, five of which were prestorage leukoreduced using RBC leukoreduction filters, and one involving a process leukoreduced apheresis platelet (PLT) unit. Here, we report a case of TTA from a whole blood-derived PLT pool. STUDY DESIGN AND METHODS: Donation segments from the 7 units of RBCs and two PLT pools transfused were examined. Fast protocol multiplex real-time A. phagocytophilum polymerase chain reaction (PCR) and serologic testing for immunoglobulin (Ig)M and IgG antibodies to A. phagocytophilum by enzyme immunoassay were performed. RESULTS: Transmission was confirmed by positive A. phagocytophilum PCR and serology in one of 16 donors and by positive PCR and seroconversion in the recipient. CONCLUSION: This is the first confirmed case of TTA from a whole blood-derived PLT pool prepared from PLT concentrates leukoreduced by in-line filtration of PLT-rich plasma.

Sulfamethoxazole-induced thrombocytopenia masquerading as posttransfusion purpura: a case report.

BACKGROUND: Drug-induced immune thrombocytopenia (DITP) is a rare clinical disorder characterized by accelerated platelet (PLT) clearance in the presence of drug-dependent antibodies. Distinguishing DITP from other immune-mediated disorders such as posttransfusion purpura (PTP) and autoimmune thrombocytopenia can represent a clinical challenge. CASE REPORT: A 68-year-old male with no prior transfusion history presented to the emergency department (ED) with dyspnea, epistaxis, and severe thrombocytopenia (<10 × 10(9)/L) 12 days after discharge from a hospital admission for a coronary artery bypass graft. Evaluation of the degree of thrombocytopenia and the temporal association between the peri- and postoperative receipt of multiple transfusions and the acute decrease in PLT count indicated PTP as a possible cause of the severe thrombocytopenia. Treatment with 1 g/kg intravenous immunoglobulin (IVIG) was initiated and followed by a rapid 48-hour increase in the PLT count. PLT antibodies lacking serologic specificity were subsequently identified in a sample collected upon presentation. Two weeks later he again presented to the ED with epistaxis and severe thrombocytopenia (<10 × 10(9)/L). Clinical history now revealed that the patient had been treated with trimethoprim-sulfamethoxazole by his primary care physician after his first hospitalization for a "cellulitic-appearing" leg and again before his final presentation for surgical site erythema and edema. IVIG was administered again with a rapid return of PLT count to baseline. Sulfamethoxazole-dependent PLT antibodies were subsequently identified in the original patient sample. CONCLUSION: This case report documents a case of IVIG-responsive DITP initially misdiagnosed as PTP, highlighting the clinical overlap of these immunologic-mediated phenomena.

Reduction in red blood cell transfusion associated with engagement of the ordering physician.

BACKGROUND: Data on red blood cell (RBC) transfusion in the United States show variation in practice and overprescribing or overdosing is considered to be prevalent. Education or restrictive interventions could modify practice. STUDY DESIGN AND METHODS: RBC transfusion and mortality rates were recorded in a single institution over a 15-year period. The first 3 years were used as a baseline. Education measures were used to influence practice for 3 years followed by a 9-year period when questionable RBC orders in nonbleeding inpatients resulted in prospective physician notification for potential modification. Physician notification was done by blood bank technologists with transfusion medicine physician support, if needed. Pretransfusion hemoglobin levels of more than 9 g/dL were recommended for cancellation and levels between 8 and 9 g/dL advised for a single unit, if 2 or more units were requested. RBC transfusion rates were described as inpatient units per 1000 discharges to allow for interyear comparison. RESULTS: A downward trend in RBC transfusion was noted for the intervention period. Comparison of the baseline period with the past 3 years of the intervention period showed an approximate 33% decrease, which was highly significant (508 ± 66 vs. 341 ± 32, p < 0.01). Inpatient mortality rates declined over this period. CONCLUSION: Physician education in appropriate transfusion practice is desirable but may not greatly impact RBC use. Engagement of physicians who prescribe RBCs that appear inappropriate for indication or dose was associated with a significant decline in RBC use without evidence of a change in mortality.

Residual plasma in red blood cells and transfusion-related acute lung injury.

BACKGROUND: Transfusion-related acute lung injury (TRALI) is the most common cause of death from blood transfusion and red blood cells (RBCs) now account for approximately 50% of these fatalities. RBCs from female donors have been implicated in large series and HLA Class II antibodies to cognate recipient antigens identified in small series and case reports. The absolute volume of residual plasma in these RBCs is unknown. STUDY DESIGN AND METHODS: Two confirmed cases of RBC-associated TRALI in which the implicated donors had Class II antibodies were investigated, and the antibody strength against recipient cognate antigens was assessed using a fluorescent bead assay. RBCs in additive solution (AS) were studied on Day 42 of liquid storage to calculate residual anticoagulated plasma. RESULTS: Both RBC units were stored in AS-1 and were from female donors who had anti-HLA Class II antibodies of high strength against cognate antigens in the recipients. Anti-DR4 was identified in both cases. Nineteen AS-1 RBC units manufactured from whole blood donations using a hard spin had a mean (±1SD) residual plasma content of 38 ± 8 mL, and 26 AS-3 RBC units manufactured using a soft spin had 66 ± 13 mL (p < 0.01). CONCLUSION: RBCs continue to be manufactured from female donors of unknown or even known anti-HLA status. The residual plasma content of these RBCs may approach 100 mL. A combination of a high-strength antibody and large residual plasma volume could explain severe or even fatal RBC-associated TRALI.

Effects of red wine and vodka on collateral-dependent perfusion and cardiovascular function in hypercholesterolemic swine.

BACKGROUND: Moderate consumption of alcohol, particularly red wine, has been shown to decrease cardiac risk. We used a hypercholesterolemic swine model of chronic ischemia to examine the effects of 2 alcoholic beverages on the heart. METHODS AND RESULTS: Yorkshire swine fed a high-cholesterol diet underwent left circumflex ameroid constrictor placement to induce chronic ischemia at 8 weeks of age. One group (HCC, n=9) continued on the diet alone, the second (HCW, n=8) was supplemented with red wine (pinot noir, 12.5% alcohol, 375 mL daily), and the third (HCV, n=9) was supplemented with vodka (40% alcohol, 112 mL daily). After 7 weeks, cardiac function was measured, and ischemic myocardium was harvested for analysis of perfusion, myocardial fibrosis, vessel function, protein expression, oxidative stress, and capillary density. Platelet function was measured by aggregometry. Perfusion to the ischemic territory as measured by microsphere injection was significantly increased in both HCW and HCV compared with HCC at rest, but in only the HCW group under ventricular pacing. Microvessel relaxation response to adenosine 5'-diphosphate was improved in the HCW group alone as was regional contractility in the ischemic territory, although myocardial fibrosis was decreased in both HCW and HCV. Expression of proangiogenic proteins phospho-endothelial nitric oxide synthase and vascular endothelial growth factor was increased in both HCW and HCV, whereas phospho-mammalian target of rapamycin was increased only in the HCV group. Expression of Sirt-1 and downstream antioxidant phospho-FoxO1 was increased only in the HCW group. Protein oxidative stress was decreased in the HCW group alone, whereas capillary density was increased only in the HCV group. There was no significant difference in platelet function between groups. CONCLUSION: Moderate consumption of red wine and vodka may reduce cardiovascular risk by improving collateral-dependent perfusion through different mechanisms. Red wine may offer increased cardioprotection related to its antioxidant properties.