Cerebral infarction following administration of andexanet alfa for anticoagulant reversal in a patient with traumatic acute subdural hematoma.

Background: Anticoagulants prevent thrombosis in patients with atrial fibrillation (AF) and venous thromboembolism but increase the risk of hemorrhagic complications. If severe bleeding occurs with anticoagulant use, discontinuation and rapid reversal are essential. However, the optimal timing for resuming anticoagulants after using reversal agents remains unclear. Here, we report early cerebral infarction following the use of andexanet alfa (AA), a specific reversal agent for factor Xa inhibitors, in a patient with traumatic acute subdural hematoma (ASDH). The possible causes of thromboembolic complication and the optimal timing for anticoagulant resumption are discussed. Case Description: An 84-year-old woman receiving rivaroxaban for AF presented with impaired consciousness after a head injury. Computed tomography (CT) revealed right ASDH. The patient was administered AA and underwent craniotomy. Although the hematoma was entirely removed, she developed multiple cerebral infarctions 10 h after the surgery. These infarctions were considered cardiogenic cerebral embolisms and rivaroxaban was therefore resumed on the same day. This case indicates the possibility of early cerebral infarction after using a specific reversal agent for factor Xa inhibitors. Conclusion: Most studies suggest that the safest time for resuming anticoagulants after using reversal agents is between 7 and 12 days. The present case showed that embolic complications may develop much earlier than expected. Early readministration of anticoagulant may allow for adequate prevention of the acute thrombotic syndromes.

Primary Antiphospholipid Antibody Syndrome Complicated with Cerebellar Hemorrhage and Aortic Dissection: A Case Report.

BACKGROUND Antiphospholipid antibody syndrome (APS) is a systemic autoimmune disease associated with arterial and venous thromboembolism and pregnancy complications. There have been several reports of APS with systemic lupus erythematosus (SLE) complicated with aortic dissection. However, none of them has been primary APS, which is APS without SLE. CASE REPORT A 42-year-old woman with primary APS and APS nephropathy on warfarin and aspirin therapy presented with coma due to cerebellar hemorrhage. The effect of warfarin was immediately reversed with prothrombin complex concentrate. We performed emergent evacuation of the hematoma, and her level of consciousness improved to normal on postoperative day (POD) 1. She had acute hypertension on arrival, which was resistant to multiple antihypertensives and was stabilized on POD 3. She also had exacerbation of chronic kidney disease after using contrast and prothrombin concentrate complex, and was on temporary renal replacement therapy from POD 3. Aortic dissection was found accidentally on echocardiography on POD 7, and she was subsequently treated medically. She was transferred to the rehabilitation hospital with mild dysarthria and truncal ataxia on POD 59. CONCLUSIONS We report the first case in the English literature of primary APS complicated with cerebellar hemorrhage and aortic dissection. Acute hypertension following hemorrhage and exacerbation of APS nephropathy likely triggered the dissection of the aortic wall, the integrity of which might have been compromised by longstanding antiphospholipid antibody and vasa vasorum thrombosis.

Add-on Antiplatelet Effects of Eicosapentaenoic Acid With Tailored Dose Setting in Patients on Dual Antiplatelet Therapy.

The aim of this study was to investigate the antiplatelet effects of eicosapentaenoic acid (EPA) at a sufficient dose following coronary stent implantation. Thirty-one patients on dual antiplatelet therapy with aspirin and clopidogrel were treated with highly purified EPA-E (Epadel®) for 12 weeks. Based on our previous study, patients with a high baseline EPA/arachidonic acid (AA) ratio (≥ 0.37; n = 11) were given a standard dose (1800 mg daily) of EPA-E, whereas those with a low EPA/AA ratio (< 0.37; n = 20) were given a high dose (2700 mg daily) to reach the target value of > 0.92. Platelet function was then evaluated with agonist-induced aggregation using light transmittance aggregometry and VerifyNow®. After EPA-E treatment, the EPA/AA ratio significantly increased from 0.28 to 1.31 (P < 0.001). Collagen (1, 2, and 4 µg/mL)-induced maximal platelet aggregation (MPA) was significantly suppressed after EPA-E administration (from 28.0 to 24.0, P = 0.033; from 44.0 to 40.0, P = 0.016; from 60.0 to 56.0, P = 0.010; respectively). However, there were no changes in MPA induced by adenosine diphosphate and AA and in P2Y12 reaction units (PRU) and aspirin reaction units. After EPA-E treatment, PRU was significantly suppressed in 8 patients showing high on-treatment platelet reactivity (HTPR) (baseline 305; 266-321 versus on-treatment 256; 233-261, P = 0.012), but not in those without HTPR (201; 156-220 versus 183; 159-233, P = 0.212). In conclusion, EPA treatment at a sufficient dose suppressed platelet aggregation and showed possible add-on effects in patients with clopidogrel hyporesponsiveness.

Hyper-Response to Clopidogrel in Japanese Patients Undergoing Transcatheter Aortic Valve Implantation.

Dual antiplatelet therapy is empirically recommended following transcatheter aortic valve implantation (TAVI). The aims of the present study were to analyze the effect of clopidogrel on platelet function and to determine the relative contribution of each CYP2C19 loss-of-function genotype undergoing TAVI.Thirty-two patients undergoing TAVI and with clopidogrel treatment were studied. All patients were treated with an Edwards SapienXT valve. Platelet reactivity was measured by the VerifyNow P2Y12 point-of-care assay at 7 days and 30 days after the procedure and a cutoff value of 95 PRU was used to identify a hyper-response of platelet reactivity. The Spartan RX(TM) sample-to-result point-of-care DNA testing system was used to identify CYP2C19 loss-of-function genotypes. Hyper-response of platelet reactivity was identified in 11 (34.3%) patients, although 24 (80%) were carriers of at least one CYP2C19 reduced-function allele. The PRU values did not change significantly from 7 days to 30 days after TAVI (136.7 ± 73.4 versus 150.4 ± 83.2, P = 0.13). The incidences of life-threatening bleeding, minor bleeding, and transfusion were significantly higher among the hyper-response of platelet reactivity group (27.3% versus 0%, P = 0.03, 36.4% versus 4.8%, P = 0.04, 81.8% versus 42.9%, P = 0.04, respectively).A hyper-response to clopidogrel was observed in one-third of patients undergoing TAVI and was related to bleeding events, even though 80% of the patients were carriers of the CYP2C19 reduced-function allele.

Quantitative optical coherence tomography analysis for late in-stent restenotic lesions.

Coronary optical coherence tomography (OCT) has the potential to identify in-stent neoatherosclerosis, which is a possible risk factor for late acute coronary events after drug-eluting stent implantation. The purpose of this study was to investigate differences between mid-term and late in-stent restenosis after stent implantation by quantitative and semiautomated tissue property analysis using OCT. In total, 1063 OCT image frames of 16 lesions in 15 patients were analyzed. This included 346 frames of 6 lesions in late in-stent restenosis, which was defined as restenosis that was not detected at 6 to 12 months but ≥ 12 months after follow-up coronary angiography. Signal attenuation was circumferentially analyzed using a dedicated semiautomated software. Attenuation was assessed along 200 lines delineated radially for analysis of the in-stent restenotic lesions (between the lumen and stent contours). All lines were anchored by the image wire to avoid artifacts resulting from wire location. Stronger signal attenuation at the frame level (2.46 ± 0.78 versus 1.47 ± 0.32, P < 0.001) and higher maximum signal intensity at the lesion level (9.19 ± 0.19 versus 8.84 ± 0.32, P = 0.018) were observed in late in-stent restenotic lesions than in mid-term in-stent restenotic lesions. OCT demonstrated stronger signal attenuation and higher maximum signal intensity in late in-stent restenotic lesions than in mid-term in-stent restenotic lesions, indicating the possibility of neoatherosclerosis.

Effects of eicosapentaenoic acid on platelet function in patients taking long-term aspirin following coronary stent implantation.

Eicosapentaenoic acid (EPA) has been widely accepted to have antiatherosclerotic effects. The aim of this study was to investigate the antiplatelet effect of EPA combined with acetylsalicylic acid (ASA) following stent implantation. Eighteen patients who had undergone coronary stent implantation at least 8 months previously were included. All patients were given EPA ethyl ester (EPA-E) 1.8 g/day in addition to ASA 100 mg/day for 12 weeks. After the treatment, the plasma EPA/arachidonic acid (AA) ratio increased significantly from 0.40 ± 0.2 to 1.08 ± 0.39 (P < 0.001). There were no changes in the maximum platelet aggregation (MPA) induced by adenosine diphosphate (5 and 20 µmol/L), AA (0.3 and 0.5 mg/mL), or collagen (2 and 4 µg/mL). Furthermore, no significant differences were observed in the expression of PAC-1 and CD62P on the platelet surface membranes or in the soluble P-selectin concentration. With further analysis, a significant negative correlation was found between collagen (2 µg/mL)-induced MPA and plasma EPA/AA ratio (r = -0.507, P = 0.032). The patients were then divided into 2 groups according to the median EPA/AA ratio value of 0.92. In the high EPA/AA ratio group (n = 10), collagen-induced MPA was significantly suppressed after EPA-E administration (45.3 ± 15.9 versus 39.0 ± 16.3, P = 0.033). In contrast, there were no significant changes in platelet aggregation (56.0 ± 9.8 versus 57.1 ± 11.4, P = 0.745) in the low EPA/AA ratio group (n = 8). EPA treatment had a potential to suppress collagen-induced platelet aggregation in patients with a high plasma EPA/AA ratio.

Predominant microvessel proliferation in coronary stent restenotic tissue in patients with diabetes: insights from optical coherence tomography image analysis.

BACKGROUND: Coronary optical coherence tomography (OCT) enables virtual depiction of histological findings of in-stent restenotic tissue. The aim of this study was to investigate the microvessel proliferation within in-stent restenotic tissue and the influence of diabetes mellitus (DM). METHODS: We examined 54 in-stent restenotic coronary artery lesions (stenotic area>50%) from 50 consecutive patients including 28 with DM (56%) and 9 insulin-treated DM patients (18%); who underwent coronary time-domain OCT imaging with automatic pull back (1mm/s, 20 frames/s). Microvessels were defined as low-signal cavities with a diameter of 50-150 microns and a trajectory parallel to the lumen recognized on 3 consecutive cross-sectional OCT image frames. The microvessel index was calculated as the number of frames with microvessel/total number of frames × 100. Patients were stratified into 3 groups: 1) without microvessels, 2) with a low (< median value) microvessel index, 3) with a high microvessel index. RESULTS: Microvessels were detected in 566 frames (3.1%) from 26 lesions (48%) in 24 patients (48%). A greater incidence of DM and higher serum glucose levels were observed in the high microvessel index group (DM: 42% vs 58% vs 83%, p=0.049; serum glucose level: 118.2 ± 44.6 vs 122.6 ± 31.0 vs 172.8 ± 63.1mg/dL, p=0.03 between low and high microvessel index group, p=0.005 between no microvessel and high microvessel index group). CONCLUSIONS: Microvessel formation may be a unique pathophysiological factor of in-stent restenoses in patients with DM.

Effect of cilostazol on optimized standard antiplatelet therapy in a patient with a cytochrome P450 2C19 *2/*2 genotype.

A 54-year-old man with acute coronary syndrome underwent primary percutaneous coronary intervention (PCI) to implant a bare metal stent. Three weeks later, a subclinical in-stent thrombus was found at staged PCI despite dual antiplatelet therapy with aspirin and clopidogrel. Platelet function tests revealed high post-treatment platelet reactivity, indicating an inadequate response to clopidogrel. The patient's cytochrome P450 2C19 genotype was *2/*2. Cilostazol at 200 mg/day was initiated in addition. Three months later, platelet inhibition was enhanced, and no thrombus was detectable by coronary angiography. Our experience suggests that triple antiplatelet therapy with cilostazol as well as aspirin and clopidogrel could prevent stent thrombosis with improved clopidogrel responsiveness.

Angiographic and clinical outcomes of 100 consecutive severe calcified lesions requiring rotational atherectomy prior to sirolimus-eluting stent implantation in hemodialysis and non-hemodialysis patients.

Both severe calcified lesions and hemodialysis (HD) are predictors for high rates of restenosis, even in the drug-eluting stent era. We sought to investigate the angiographic and clinical outcome in a population of HD versus non-hemodialysis (non-HD) patients with severe calcified lesions requiring rotational atherectomy. One hundred consecutive lesions (28 lesions in the HD group, 72 in the non-HD group) from 82 patients (19 patients in the HD group, 63 in the non-HD group) requiring rotational atherectomy prior to sirolimus-eluting stent (SES) implantation were analyzed post-procedure and at 8 months. Clinical outcomes were assessed at 12 months. Inclusion criteria were calcified lesions with >270° of superficial calcification on the intravascular ultrasound (IVUS), lesions that the IVUS could not cross, or undilatable lesions. There were no differences in patient characteristics except for age. Although both baseline and post-procedure angiographic findings were similar between the two groups, late loss in stented segment was significantly greater in the HD group than in the non-HD group (HD vs. non-HD: 0.69 ± 0.74 mm vs. 0.34 ± 0.50; P = 0.030). Also, the HD group revealed significantly worse clinical outcomes. In conclusion, mid-term results of highly complex, severely calcified lesions requiring rotational atherectomy in non-HD patients were permissible as compared to on-label lesions. However, in HD patients, both angiographic and clinical outcomes were still suboptimal in this lesion subset, even using SES.

Comparison of platelet P2Y(12) ADP receptor-mediated pathway inhibition in triple versus dual antiplatelet therapy as assessed by VASP-phosphorylation in Japanese patients undergoing coronary stenting.

Despite wide interindividual variability in response to clopidogrel, platelet P2Y(12) ADP receptor inhibition in Japanese patients has not been fully studied using specific methodology. This study compared platelet P2Y(12) ADP receptor inhibition during treatment with clopidogrel versus clopidogrel plus cilostazol in patients undergoing coronary stenting. Forty-two patients in whom platelet function was measured within 2 months after coronary stenting were enrolled. All patients were treated with aspirin 100 or 200 mg/day, and were divided into a dual therapy group (aspirin plus clopidogrel 75 mg/day; n = 34) and a triple therapy group (aspirin plus clopidogrel 75 mg/day plus cilostazol 200 mg/day; n = 8). Vasodilator-stimulated phosphoprotein (VASP) phosphorylation analysis and 5 and 20 µmol/L-induced maximal platelet aggregation were assessed. No differences were found in baseline characteristics except for a higher incidence of diabetes mellitus (DM) in the triple therapy group. Although there were no differences in platelet aggregation between the 2 groups, VASP index was significantly lower in the triple therapy group than in the dual therapy group (23.1 ± 15.3% versus 51.2 ± 19.9%; P = 0.001). The rate of low responsiveness to clopidogrel, defined by VASP index > 50%, was lower in the triple therapy group than in the dual therapy group (12.5% versus 55.9%; P = 0.047). Similarly, in DM patients the triple therapy group had a lower VASP index compared with the dual therapy group (23.1 ± 15.3% versus 47.0 ± 23.5%; P = 0.015).Clopidogrel plus cilostazol is more effective in inhibiting the platelet P2Y(12) ADP receptor pathway than clopidogrel alone. This may be useful for reducing clopidogrel resistance in Japanese patients.

Enhanced platelet activation following coronary stent implantation in patients on hemodialysis.

Hemodialysis ("HD") has been suggested as a risk factor for stent thrombosis. However, platelet function in HD patients after coronary stent implantation remains unclear. The aim of this study was to evaluate platelet function following coronary stent implantation in HD patients. A total of 10 HD and 31 non-HD patients who underwent a first coronary stent implantation were studied. All patients received 100 or 200 mg of asprin and thienopiridine (either ticlopidine 200 mg or clopidogel 75 mg) daily. Platelet function was assessed 2-6 weeks (21 ± 8 days) after stent implantation by: (1) platelet maximal aggregation, using light transmittance aggregometry; (2) platelet aggregation threshold index, which was defined as putative concentration of agonist giving 50% maximum aggregation using whole-blood aggregometry; and (3) platelet activation markers (PAC-1 and CD62p), using whole blood flow cytometry. There were no differences between the two groups in baseline and procedure characteristics, except for a greater prevalence of hypertension and calcification in the HD group. Early stent thrombosis and bleeding did not occur in either group. Although no differences in platelet maximal aggregation or whole-blood aggregation were observed, expression of PAC-1 (39.6 ± 9.1 vs 24.2 ± 13.2%) and CD62p (10.4 ± 5.5 vs 5.4 ± 2.3%) were significantly increased in the HD group compared with the non-HD group. HD patients exhibited enhanced platelet activation after coronary stent implantation, but suppression of platelet aggregation was achieved by the current dual antiplatelet therapy.

Serial quantitative coronary analyses for the evaluation of one-year change in saphenous vein grafts.

BACKGROUND: A paucity of data exists with respect to changes in whole saphenous vein grafts (SVGs) despite accelerated atherosclerosis within grafted saphenous vein conduits. In the present study, we evaluated the one-year change in SVGs by means of quantitative coronary analysis. METHODS: This study enrolled consecutive 52 patients with 109 SVGs, who underwent coronary artery bypass graft surgery successfully. A follow-up study was performed in 33 patients with 65 SVGs after one year because 16 SVGs were obstructed (baseline, 8; follow-up period, 8), and 15 patients with 28 SVGs dropped out within one year. RESULTS: Both minimal and mean lumen diameters decreased significantly (3.17 +/- 0.64 mm vs 2.41 +/- 0.57 mm, p < 0.001; 3.70 +/- 0.69 mm vs 2.92 +/- 0.70 mm, p < 0.001; respectively). Graft length also decreased significantly (107.1 +/- 25.8 vs 100.6 +/- 25.2 mm, p < 0.001). The graft shortening rate (graft shortening length/baseline graft length x 100) was greater than 5% in 33 vessels (51%) and greater than 10% in 23 vessels (35%). Coronary risk factors (smoking, diabetes mellitus, hypertension, dyslipidemia) did not reveal significant relationship with late loss of minimal and mean lumen diameters. CONCLUSIONS: The present study showed a considerable and uniform lumen loss of SVGs after one year, irrespective of coronary risk factors. Graft length shortening was seen more than elongation.

[A case of infant epidural hematoma treated by continuous drainage of cephalohematoma].

A female infant was born at 36 weeks with vacuum extraction. Her weight was 2.216 g and Apgar score was 9. She had a cephalohematoma at right parietal region. The cephalohematoma grew during 6 days after birth, then she came to our hospital. On arrival, her consciousness was alert and there were no neurological deficits. Her head circumference was 22.5 cm, and she had a pulsatile soft cephalohematoma, 7 cm in diameter, at right parietal region. Ultrasound examination showed a midline shift of the brain and CT scan revealed an epidural hematoma with bone fracture and cephalohematoma. We chose the puncture and continuous drainage of cephalohematoma as a primary therapy, because cephalohematoma was considered to be liquified and to be continuous to the epidural hematoma. The reason was that the pulsatile cephalohematoma became harder when she cried. The epidural hematoma was completely reduced on the next day's CT and then drainage was removed. She discharged on 15th post-operative day. We conclude that the puncture and continuous drainage of cephalohematoma may be one of the good therapeutic methods for the mild symptomatic neonate who has epidural hematoma with the cephalohematoma and bone fracture.

Intravascular ultrasound analysis of the radial artery for coronary artery bypass grafting.

BACKGROUND: The radial artery has become a popular conduit for coronary artery bypass surgery. However, limited information has been provided regarding the atherosclerotic nature of this artery, which may affect both the immediate intraoperative difficulties and long-term graft patency. METHODS: We examined intravascular ultrasound (IVUS) images of the radial artery in patients with coronary artery diseases. Cross sections of the radial artery were assessed using the following factors: lumen diameter, lumen area, vessel diameter, vessel area, plaque area, percent plaque area, and extent of calcium deposition. RESULTS: The IVUS images were obtained from radial arteries of 58 patients (47 men, average 67 +/- 9 years) during transradial procedures; ie, transradial coronary angiography and/or transradial coronary intervention. Mean luminal diameter was 3.28 +/- 0.69 mm and 3.00 +/- 0.70 mm at the proximal and distal segments, respectively, and 2.58 +/- 0.73 mm at the minimal lumen cross section. A percent plaque area greater than 50% was seen in five radial arteries (8.6%) whose average plaque length was 26.4 +/- 30.8 mm. Of these, one showed a plaque length greater than 50 mm, and another showed vessel caliber less than 2.0 mm. Five of 58 radial arteries (8.6%) showed calcium deposition, two of which showed diffuse calcification (> 50 mm). Thus, among 58 radial arteries, four (6.9%: one with diffuse arteriosclerosis, one small radial artery, two with diffuse calcification) were considered unsuitable for bypass conduit. CONCLUSIONS: Preoperative evaluation of the radial artery is recommended in order to prevent unnecessary exploration of the forearm and to improve graft patency.

[Changes in peripheral lymphocytes count in unconscious patients treated at home with Japanese herbal medicines (Hozai)].

We investigated changes in peripheral white blood cells count, lymphocytes count, and serum albumin level in five unconscious patients administered Japanese herbal medicines (Hozai). The causes of unconsciousness were intracerebral hemorrhage in 3, cerebral infarction in 1, and craniopharyngioma in 1. The administered Hozai were Hotyu-ekki-to in 4 and Jyuzen-taiho-to in 1. To assess the effect of Hozai on the immune system of unconscious patients, we investigated these parameters before and after treatment. We observed normalization of WBC counts, increase of lymphocytes count, and unchanged levels of serum albumin after Hozai treatment. These findings suggest that Hozai may improve the immunological competence of unconscious patients. One of the problems affecting unconscious patients treated at home is infectious diseases, especially respiratory infections. It is considered that improvement of their immunological competence would contribute to prevent infections. These results suggest that Hozai treatment might be useful adjuvants to support the general condition of the patients treated at home.