The HIT Expert Probability (HEP) Score: a novel pre‐test probability model for heparin‐induced thrombocytopenia based on broad expert opinion

Summary. Background: The diagnosis of heparin‐induced thrombocytopenia (HIT) is challenging. Over‐diagnosis and over‐treatment are common. Objectives: To develop a pre‐test clinical scoring model for HIT based on broad expert opinion that may be useful in guiding clinical decisions regarding therapy. Patients/methods: A pre‐test model, the HIT Expert Probability (HEP) Score, was constructed based on the opinions of 26 HIT experts. Fifty patients referred to a reference laboratory for HIT testing comprised the validation cohort. Two hematology trainees scored each patient using the HEP Score and a previously published clinical scoring system (4 T’s). A panel of three independent experts adjudicated the 50 patients and rendered a diagnosis of HIT likely or unlikely. All subjects underwent HIT laboratory testing with a polyspecific HIT ELISA and serotonin release assay (SRA). Results: The HEP Score exhibited significantly greater interobserver agreement [intraclass correlation coefficient: 0.88 (95% CI 0.80–0.93) vs. 0.71 (0.54–0.83)], correlation with the results of HIT laboratory testing and concordance with the diagnosis of the expert panel (area under receiver‐operating curve: 0.91 vs. 0.74, P = 0.017) than the 4 T’s. The model was 100% sensitive and 60% specific for determining the presence of HIT as defined by the expert panel and would have allowed for a 41% reduction in the number of patients receiving a direct thrombin inhibitor (DTI). Conclusion: The HEP Score is the first pre‐test clinical scoring model for HIT based on broad expert opinion, exhibited favorable operating characteristics and may permit clinicians to confidently reduce use of alternative anticoagulants. Prospective multicenter validation is warranted.     

HCMV INFECTION: MODULATING THE CELL CYCLE AND CELL DEATH

Human cytomegalovirus (HCMV) is a member of the Herpesviridae family and is recognized as a significant pathogen to certain subgroups of the human population. It has become apparent that HCMV manipulation of the host cell cycle as well as the immune response promotes the replication and propagation of the virus. The ability of HCMV to modulate components of the host immune system and the response to infection most likely contributes to the pathology associated with this virus. This review will address the mechanisms HCMV has adapted to modulate the cell cycle to promote viral replication as well as the different ways it can prevent the “death” of an infected cell.     

ATP1A3 mutations in infants: a new rapid‐onset dystonia–Parkinsonism phenotype characterized by motor delay and ataxia

We report new clinical features of delayed motor development, hypotonia, and ataxia in two young children with mutations (R756H and D923N) in the ATP1A3 gene. In adults, mutations in ATP1A3 cause rapid‐onset dystonia–Parkinsonism (RDP, DYT12) with abrupt onset of fixed dystonia. The parents and children were examined and videotaped, and samples were collected for mutation analysis. Case 1 presented with fluctuating spells of hypotonia, dysphagia, mutism, dystonia, and ataxia at 9 months. After three episodes of hypotonia, she developed ataxia, inability to speak or swallow, and eventual seizures. Case 2 presented with hypotonia at 14 months and pre‐existing motor delay. At age 4 years, he had episodic slurred speech, followed by ataxia, drooling, and dysarthria. He remains mute. Both children had ATP1A3 gene mutations. To our knowledge, these are the earliest presentations of RDP, both with fluctuating features. Both children were initially misdiagnosed. RDP should be considered in children with discoordinated gait, and speech and swallowing difficulties.     

The Origin of Epicardial Ventricular Tachycardia Revealed by Entrainment From a Permanent Epicardial Left Ventricular Pacing Lead

Entrainment From Left Ventricular Pacing Lead. Recognizing ventricular tachycardias (VTs) that require epicardial ablation is desirable, but challenging when prior surgery prevents percutaneous epicardial mapping. This patient had cardiomyopathy, prior cardiac surgery, and VT that failed endocardial ablation. Observing that the Bi‐V implantable cardioverter defibrillator (ICD), left ventricular (LV) lead was epicardial to the area of infarct scar, it was used to pace during VT. Entrainment with concealed fusion with long stimulus to QRS interval, consistent with an epicardial VT circuit, was observed. Surgical cryoablation targeting the area around the LV lead eliminated VT. Thus pacing maneuvers from permanent epicardial leads can occasionally help identify an epicardial VT origin. (J Cardiovasc Electrophysiol, Vol. 21, pp. 1293‐1295, November 2010)     

Bleeding risk in randomized controlled trials comparing warfarin and aspirin: a systematic review and meta‐analysis

Summary. Background: Warfarin and aspirin (acetylsalicylic acid [ASA]) are the most commonly used anticoagulant and antiplatelet drugs in the treatment of cardiovascular disease.Objectives: To provide a pooled estimate of the bleeding risk from randomized controlled trials (RCTs) comparing warfarin and ASA at the dose ranges recommended in evidence‐based guidelines.Patients/Methods: Ovid MEDLINE, Embase and the Cochrane Library, up to September 2011, were searched for RCTs comparing bleeding rates in adult patients randomized to warfarin, target International Normalized Ratio (INR) 2.0–3.5, and ASA, 50–650 mg daily, with at least 3 months of follow‐up. Pooled odds ratios (ORs) and associated 95% confidence intervals (CIs) were calculated with the inverse variance method and the random effects model.Results: Four thousand four hundred and forty‐two abstracts were screened, resulting in eight included studies for final analysis. A pooled estimate derived from the 2904 patients enrolled indicated a trend towards an increase in major bleeding risk in those randomized to warfarin (OR 1.27; 95% CI 0.83–1.94). The pooled OR for intracranial hemorrhage in patients treated with warfarin vs. ASA was 1.64 (95% CI 0.71–3.78), and that for extracranial major bleeding was 1.03 (95% CI 0.61–1.75). Minor bleeding, from a 1748‐patient sample, was more common in warfarin patients (OR 1.50; 95% CI 1.13–2.00).Conclusions: This meta‐analysis failed to find a statistically significant difference in major bleeding between warfarin, target INR 2.0–3.5, and ASA, 50–650 mg daily. The trend towards increased bleeding with warfarin appears to be explained by an excess of intracranial bleeding in warfarin patients.     

Cell-to-Cell Electrical Interactions During Early and Late Repolarization

Cardiac electrical activity is significantly affected by variations in the conductance of gap junctions that connect myocytes to one another. To better understand how intrinsic (single cell) electrical activity is modulated by junctional conductance, we used a two-myocyte coupling system in which physically separate cells were electrically coupled via a variable resistance set by the investigator. This brief review summarizes our findings regarding: (1) the effect of the early phase of action potential repolarization (phase 1) and transient outward current ( I _to) on action potential conduction, and (2) the effect of coupling on the action potential plateau (late repolarization). We found that inhibition of I _to markedly increased the ability of action potentials to propagate from cell-to-cell when junctional conductance was low. Electrically coupling two myocytes together also suppressed their beat-to-beat variability in action potential duration and contraction. Similarly, early afterdepolarizations (EADS) were readily suppressed by connecting a normal myocyte to one generating EADs. This high sensitivity of the plateau to variations in junctional interactions arises from the large increase in membrane resistance that occurs during this phase of the action potential.     

Anticoagulant prophylaxis to prevent asymptomatic deep vein thrombosis in hospitalized medical patients: a systematic review and meta-analysis

Summary.  Background:  The effect of anticoagulant prophylaxis on the prevention of deep vein thrombosis (DVT) should include an investigation of both clinical and subclinical DVT. We conducted a systematic review to determine whether anticoagulant prophylaxis reduces the risk of asymptomatic DVT compared to no prophylaxis in at-risk hospitalized medical patients. Methods:  MEDLINE, EMBASE, and the Cochrane Library were searched through March 2007 for randomized trials of anticoagulant prophylaxis for the prevention of asymptomatic DVT, assessed by venogram or ultrasound. We assessed four outcomes: all asymptomatic DVT, asymptomatic proximal DVT, major bleeding and mortality. Random effects meta-analyses were performed and results were expressed using relative risk (RR) and 95% confidence intervals (95% CIs). Results:  Four trials including 5516 patients were eligible. Our pooled analysis demonstrated that compared to placebo, anticoagulant prophylaxis was associated with a significantly lower risk of any asymptomatic DVT (RR 0.51; 95% CI 0.39–0.67) and asymptomatic proximal DVT (RR 0.45; 95% CI 0.31–0.65). Anticoagulant prophylaxis was associated with a significantly increased risk of major bleeding compared to placebo (RR 2.00; 95% CI 1.05–3.79). There was no significant difference in the pooled estimate for all-cause mortality. Anticoagulant prophylaxis conferred an absolute risk reduction of any DVT and proximal DVT of 2.6% and 1.8%, respectively, and was associated with a 0.5% absolute risk increase in major bleeding. Conclusions:  Anticoagulant prophylaxis is effective in preventing asymptomatic DVT in at-risk hospitalized medical patients but is associated with an increased bleeding risk. The therapeutic benefits of anticoagulant prophylaxis appear to outweigh the risks of bleeding.     

Pulmonary Vein Isolation Alone in Patients with Persistent Atrial Fibrillation: An Ablation Strategy Facilitated by Antiarrhythmic Drug Induced Reverse Remodeling

PVI Alone in Patients with Persistent AF . Introduction: Pulmonary vein isolation (PVI) alone has been thought to be insufficient in patients with persistent atrial fibrillation (PersAF). We hypothesized that preablation treatment of PersAF with a potent antiarrhythmic drug (AAD) would facilitate reverse atrial remodeling and result in high procedural efficacy after PVI alone. Methods and Results: Seventy‐one consecutive patients (59.4 ± 9.8 years) with PersAF and prior AAD failure were treated with oral dofetilide (768 ± 291 mcg/day) for a median of 85 days pre‐PVI. P‐wave duration (Pdur) on ECG was used to assess reverse atrial remodeling. Thirty‐five patients with paroxysmal (P) AF not treated with an AAD served as controls. All patients underwent PVI alone; dofetilide was discontinued 1–3 mos postablation. In the PersAF patients, the Pdur decreased from 136.3 ± 21.7 ms (assessed postcardioversion on dofetilide) to 118.6 ± 20.4 ms (assessed immediately prior to PVI) (P < 0.001). In contrast, no change in Pdur (122.6 ± 11.5 ms vs. 121.3 ± 13.7 ms, P = NS) was observed in PAF patients. The 6 and 12 mos AAD‐free response to ablation was 76% and 70%, respectively, in PersAF patients, similar to the 80% and 75%, response in PAF patients (P = NS). A decline in Pdur in response to dofetilide was the only predictor of long‐term clinical response to PVI in patients with PersAF. Conclusions: Pre‐treatment with AAD resulted in a decrease in Pdur suggesting reverse atrial electrical remodeling in PersAF patients. This may explain the excellent clinical outcomes using PVI alone, and may suggest an alternative ablation strategy for PersAF. (J Cardiovasc Electrophysiol, Vol. 22, pp. 142‐148, February 2011)     

The interaction of human T-lymphocytes and Entamoeba histolytica: killing of virulent amoebae by lectin-dependent lymphocytes

Clinical and experimental studies indicate that following invasive disease due to Entamoeba histolytica, development of human cell-mediated immune mechanisms may provide protective immunity. Activated, human monocyte-derived macrophages in vitro can kill virulent axaenic amoebic trophozoites. This study describes the interaction of lectin-stimulated T-lymphocytes and E. histolytica trophozoites (virulent strain HM1-IMSS). Amoebae progressively killed unstimulated nonimmune T-lymphocytes over 18 h incubation with no effect on amoebic viability. T-lymphocytes, stimulated with phytohaemagglutinin (PHA), were progressively cytotoxic for virulent HMI amoebae over 18 h incubation, but were also reduced in viability themselves. Lymphocyte cytotoxicity for amoebae was absent if PHA was removed before or added only during the assay. PHA-stimulated T-lymphocytes killed amoebae at cell ratios of lymphocytes to amoebae as low as 50:1 and cytotoxicity was antibody-independent. PHA-stimulated T-lymphocytes, depleted of T8-bearing cells by complement-mediated lysis, were unable to kill amoebae. Adherence of PHA-stimulated T-lymphocytes to amoebae was greater than with unstimulated T-lymphocytes. Inhibition of the amoebic adherence lectin with N-acetyl-D-galactosamine decreased lymphocyte-amoebic adherence and resulted in increased lymphocyte amoebicidal activity and lymphocyte survival. Suspension of amoebae with or without adherent PHA-stimulated T-lymphocytes in a 10% dextran solution indicated that cytotoxicity was contact dependent. In summary, PHA-stimulated T-lymphocytes of the T8-phenotype can kill virulent axaenic E. histolytica trophozoites through a contact-dependent, antibody-independent mechanism.