How I treat warfarin-associated coagulopathy in patients with intracerebral hemorrhage

Intracerebral hemorrhage in patients with warfarin-associated coagulopathy is an increasingly common life-threatening condition that requires emergent management. The evolution of therapeutic options in this setting, as well as recently published guidelines, has resulted in some heterogeneity in recommendations by professional societies. This heterogeneity can be attributed to lack of evidence-based support for plasma therapy; the variability in availability of prothrombin complex concentrates; the variability in the coagulation factor levels and contents of prothrombin complex concentrates; ambiguity about the optimal dose and route of administration of vitamin K; and the lack of standardized clinical care pathways, particularly in community hospitals, for the management of these critical care patients. In this review, we summarize the relevant literature about these controversies and present recommendations for management of patients with warfarin-associated coagulopathy and intracerebral hemorrhage.     

Time trends in warfarin-associated hemorrhage

The annual incidence of warfarin-related bleeding at Brigham and Women's Hospital increased from 0.97/1,000 patient admissions in the first time period (January 1995 to October 1998) to 1.19/1,000 patient admissions in the second time period (November 1998 to August 2002) of this study. The proportion of patients with major and intracranial bleeding increased from 20.2% and 1.9%, respectively, in the first time period, to 33.3% and 7.8%, respectively, in the second.     

Fatal warfarin-associated intracranial hemorrhage in atrial fibrillation inpatients

Journal of Thrombosis and Thrombolysis - The concept of a pulmonary embolism response team (PERT) is multidisciplinary, with the hope that it may positively impact patient care, hospital...     

Inactivation of viruses in fresh-frozen plasma

Summary Methylene blue (MB) or solvent/detergent (SD) treatment is used for the inactivation of lipid-enveloped viruses in plasma. One important characteristic of the SD treatment is the necessity to pool plasma from different donors, thus inducing the risk of spreading infectious particles. MB treatment can be applied to single-donor plasma, causing no greater infectious risk than conventional fresh-frozen plasma (FFP). However, the virucidal efficacy of the SD method regarding HIV, HBV and HCV has been significantly better examined and proven than the MB treatment. Most of the therapeutic constituents of both plasma products are well maintained; coagulation factors decrease by roughly 5–20%. SD treatment reduces protein S and ₂-antiplasmin by approximately 40%, whereas MB treatment leads to a significant photooxidative alteration of fibrinogen with a disturbance of fibrin polymerization. As current studies show, the use of either plasma product is obviously not limited by acute or chronic toxicity. Several studies are in progress to evaluate the relevance of alterations in FFP quality which may affect the clinical efficacy of virusinactivated plasma.     

The risk of hemorrhage among patients with warfarin-associated coagulopathy.

OBJECTIVES: Among warfarin-treated patients with international normalized ratio (INR) >5, we sought to determine the risk of major bleeding within 30 days. BACKGROUND: For warfarin-treated patients, the risk of bleeding increases as the INR rises, particularly if the INR exceeds 4. The 30-day risk of hemorrhage among outpatients with excessively prolonged INR values is unknown. METHODS: To assess anticoagulation care in the U.S., a cohort of 6,761 patients taking warfarin was prospectively assembled from 101 participating sites (43% were community-based cardiology practices). From this cohort, 1,104 patients were identified with a first episode of INR >5. RESULTS: A total of 979 met eligibility criteria; complete follow-up information was available for 976 (99.7%). Ninety-six percent (n = 937) of patients had an INR value between 5 and 9; 80% of INR values were <7. Thirteen patients (1.3%) experienced major hemorrhage during the 30-day follow-up period; among patients whose INR was >5 and <9, 0.96% experienced major hemorrhage. None of the bleeding events was fatal. Intervention with vitamin K was uncommon (8.7%). Warfarin doses were withheld for the majority of patients. Fifty percent of patients who were managed conservatively and retested on day 4 or 5 had an INR of 2.0 or less. CONCLUSIONS: For warfarin-treated outpatients presenting with an INR >5 and <9, the 30-day risk of major bleeding is low (0.96%). Intervention with vitamin K among asymptomatic patients presenting with an INR <9 is not routine practice in the U.S.     

脑出血患者神经元特异性烯醇化酶的变化

目的探讨脑出血（ICH）患者血浆神经元特异性烯醇化酶（NSE）的含量变化及意义。方法59例ICH患者于发病后24h、第3、7、14天测定NSE的含量，同时进行神经功能缺损程度评分以及头CT检查，观察NSE与神经功能缺损程度以及脑水肿的关系。结果NSE在ICH后24h、第3、7、14天均增高，第3、7、14天时NSE含量与神经功能缺损程度以及脑水肿程度呈正相关（P〈0．01），而ICH24h内NSE含量与神经功能缺损程度以及脑出血量无明显相关性（P〉0．05）。结论ICH患者血浆NSE含量的变化反映脑水肿及神经功能缺损的程度，NSE可以作为判断ICH患者病情及预后的检验指标。     

Transfusion audit of fresh-frozen plasma in southern Taiwan

BACKGROUND AND OBJECTIVES: The demand for transfusions has increased rapidly in southern Taiwan. Between 1993 and 2003, requests for fresh-frozen plasma (FFP) in particular rose dramatically at Kaohsiung Medical University Hospital (KMUH). Transfusion orders were not tightly regulated, and inappropriate use of blood products was common. MATERIALS AND METHODS: We carried out a prospective analysis of transfusion requests from October 2003 to January 2004 at KMUH, and then repeated the audit for another 3-month period after the clinical faculty had undergone five sessions of education on transfusion guidelines. Later, our consultant haematologist applied computerized guidelines to periodic audits. RESULTS: A 5.2% decrease in inappropriate FFP usage followed the educational programme and a further 30% reduction took place after the application of computerized transfusion guidelines. With the guidelines and periodic audits, FFP transfusions decreased by 74.6% and inappropriate requests from 65.2% to 30%. CONCLUSIONS: Hospital policy, computerized transfusion guidelines and periodic audits greatly reduced inappropriate FFP transfusions. An educational campaign had a more limited effect.     

The dynamics of clot formation in fresh-frozen plasma

Background  Factor VIII (FVIII) levels are used as a quality marker of fresh-frozen plasma (FFP); however, other clotting factors are not routinely measured.
Methods  We assessed additional haemostatic parameters and the dynamics of coagulation using Thrombelastography (TEG®) and a thrombin generation test (TGT). FFP was prepared on the day of donation (Day 0) or after overnight hold at 4°C (Day 1).
Results  Factor VIII in Day 1 FFP was 18% lower than in Day 0. TEG® parameters in Day 1 FFP were consistent with increased coagulability and did not correlate with altered levels of clotting factors, but were consistent with the increased levels of microparticles seen in the Day 1 samples. TGT studies exhibited increased lag time, time to peak and reduced peak thrombin generation, but no change in endogenous thrombin potential (ETP) on Day 1. There was a weak association between FVIII level and both ETP and peak thrombin (ETP r _s≥ 0·22, P ≤ 0·003; peak thrombin r _s≥ 0·48, P ≤ 0·0001), which was influenced by ABO group, with the lowest levels in group O.
Conclusion  We conclude that levels of FVIII do not predict the haemostatic potential of FFP and that there may be a role for alternative technologies in monitoring the quality of FFP.     

Cost-effectiveness of solvent/detergent-treated fresh-frozen plasma

BACKGROUND AND OBJECTIVES: Although transfusion-transmitted infections are rare, non-infectious complications occur relatively frequently. Solvent/detergent-treated fresh-frozen plasma (SD-FFP) has been shown to reduce the frequency of both types of complication, although previous economic evaluations failed to consider non-infective events and subsequently underestimated the benefits of SD-FFP. MATERIALS AND METHODS: A time-series analytical model was used to estimate the incremental cost/life year saved for SD-FFP compared with untreated FFP, having controlled for post-transfusion mortality and patient age. Various infective and non-infective transfusion-related complications were considered. RESULTS: The discounted cost/life year saved for SD-FFP use in the UK was pound sterling 22,728 [95% confidence interval (95% CI): pound sterling 22,604-22,853] for neonates and pound sterling 98,465 (95% CI: pound sterling 97,924-99,005) for patients aged 70. The cost-effectiveness ratio was below pound sterling 50,000/life year saved for patients < or = 48 years of age, and below pound sterling 30,000/life year saved for those < or = 21 years of age. In transfusion recipients with no significant morbidity, the cost-effectiveness ratio was pound sterling 12,335 for neonates and pound sterling 61,692 for 70-year olds. The most important driver of cost-effectiveness was transfusion-related acute lung injury (TRALI), on account of its relatively high incidence and mortality rate. CONCLUSIONS: Previous analyses greatly underestimated the cost-effectiveness of SD-FFP. Inclusion of non-infectious complications suggests that SD-FFP is cost-effective in patients < or = 48 years of age and in older patients with good clinical prognosis, which may justify the wider use of this technology.     

Management of intracerebral hemorrhage

Following quickly behind improvements in acute ischemic stroke care have been important advances in the understanding and management of intracerebral hemorrhage (ICH). Among these are accurate diagnosis of cerebral amyloid angiopathy (CAA) during life, recognition of the association between CAA and warfarin-related ICH, use of newer hemostatic treatments, and the combination of minimally invasive surgery with hematoma thrombolysis. Currently recommended management includes prompt evaluation of the patient at a facility with stroke and neurosurgical expertise, consideration of early surgery for patients with clinical deterioration or cerebellar hemorrhages larger than 3 cm, and early treatment of coagulopathies and other neurologic and medical complications. Over the past 2 years, two major randomized studies in ICH (comparing early surgery with best medical management and testing the utility of hemostatic treatment within 4 hours using recombinant factor VIIa) have yielded neutral results. This review focuses on comprehensive management of ICH in light of recent evidence.     

Spontaneous intracerebral hemorrhage in children

We reviewed our experience in 42 children younger than 16 years with spontaneous intracerebral hemorrhage (ICH) treated between January 1989 and December 1997. Glasgow coma scale (GCS) on admission was 15 in 21 (50%) patients. The most frequent presenting symptoms were headache in 28 (67%) patients, followed by loss of consciousness in 22 (52%) patients and vomiting in 21 (50%) patients. Three cases were diagnosed initially as meningitis and two cases as common cold. The locations of ICH were lobar (26 patients) and cerebellar (7). Cerebral angiographies were performed on 28 patients, and were diagnostic in 19 (68%). Magnetic resonance imaging (MRI) scans revealed two cases of cavernous angiomas, which were confirmed by the pathologic studies of surgical specimens. Laboratory examinations detected two cases of acute leukemia. Four categories of the causes of ICH were determined in 23 (55%) patients. The leading cause of bleeding was arteriovenous malformations (AVMs). The in-hospital survival rate of all patients in this study was 79%. Patients with GCS 3-5 on admission and ICH located at brain stem, cerebellum, and multiple subcortical areas had higher mortality rates. On the follow-up (mean 42 months), seventy percent of our cases had made a good recovery, 21% a fair recovery, 3% a poor recovery, and 6% had died. Children with ICH recover motor function more rapidly than adults. However, visual deficits always persist at our long-term follow-up examinations. A physician should keep in mind the diagnosis of ICH in children, even though the presenting symptoms may be non-specific and the incidence of ICH is very low in children.     

脑出血分型研究进展

了解脑出血分型,有助于临床更好地管理脑出血患者,针对不同亚型选择适宜的诊治措施和预防策略,从而改善脑出血的预后和预防再发.文章综述了目前国际上研究和报告较多的脑出血分型方法.     

Microparticle sizing by dynamic light scattering in fresh-frozen plasma

Background We have previously shown that fresh‐frozen plasma (FFP) contains red blood cell‐derived procoagulant microparticles (MPs) that are removable by 0·2 µm filtration. Given the limitations of current methods for accurately sizing MPs, we have applied the novel approach of dynamic light scattering (DLS) to characterize the size distributions of these MPs within FFP. Methods Fresh‐frozen plasma was prepared from blood Group A and O donations (n = 10 of each) after an overnight hold of whole blood at 4°C. On the day of analysis, plasma was thawed to 37°C and daughter aliquots were studied pre‐ and post‐filtration (0·2 µm filtration device, Ceveron® MFU‐500, Technoclone). MP size and dispersity was assessed using a Zetasizer Nano S (Malvern Instruments Ltd), which employs a 173° backscatter detector and an N5 Submicron Particle Size Analyser (Beckman Coulter) using multi‐angle measurements (30·1°, 62·6° and 90°). The analysers presented MP size distribution graphically as intensity plots, mean size, standard deviation and polydispersity index. Results Of the instruments used, only the N5 utilizing a 30·1° angle of measurement could detect MPs of the expected size distribution and demonstrate their removal by filtration. MPs (range of mean particle diameters: pre, 101–464 nm; post, 21–182 nm filtration) were significantly smaller post‐filtration (P < 0·0001), but polydispersity index (median: pre, 0·746, post, 0·769) exhibited no significant change. There was no significant difference between the size of MPs from blood Group O (pre, 247 nm) and Group A (pre, 289 nm) samples (P = 0·44). Conclusion Our data demonstrates that DLS offers a novel approach to assessing MP size and distribution, a technique that could be easily adopted as a means of assessing MPs within either FFP or other blood products.     

大鼠脑出血血肿周围组织内的环状出血现象及其病理机制探讨

目的对大鼠脑出血血肿周围组织内的环状出血现象及其病理机制进行初步研究。方法SD大鼠11只,随机分为模型组(5只),墨汁灌注组(4只),假手术对照组(2只)。动物模型采用大鼠尾状核自体动脉血注射制作脑出血模型,术后6 h灌注并浸泡固定,常规石蜡包埋、切片,HE染色。墨汁灌注组大鼠灌注固定后用印度墨汁右旋糖酐溶液灌注。结果模型组大鼠脑血肿周围组织内小血管周围环状出血灶均广泛存在。出血灶位于血管周围间隙内,围绕在小血管周围呈环状分布。环状出血灶内的血液来自于原发血肿。结论环状出血在血肿周围组织内广泛存在,是原发血肿内的血液沿血管周围间隙向外围扩展所致。     

Quality assessment of seven types of fresh-frozen plasma leucoreduced by specific plasma filtration

BACKGROUND AND OBJECTIVES: A study was undertaken to determine plasma quality after specific filtration. MATERIALS AND METHODS: Seven types of plasma were tested, after filtration of plasma from filtered or non-filtered whole blood. Leucocyte counting was carried out after a 30-fold concentration of the sample. Twenty-nine parameters (including coagulation testing, proteins, coagulation factors and activation markers) were measured before and after filtration, and after 6 months of storage. RESULTS: After specific plasma filtration, the average residual leucocyte counts were less than 2250/l. In spite of small statistically significant changes in proteins, coagulation factors and complement activation, this study showed that plasma filtration did not alter plasma quality. After 6 months of storage at -30 degrees C, factor VIII recovery varied between 91 and 109%. Haemostasis parameters and activation markers remained within the normal range. CONCLUSIONS: Specific plasma filtration reduced the leucocyte number to < 104 leucocytes/l. The quality of plasma was not altered by the additional step of specific plasma filtration.     

脑出血外科手术治疗的进展

出血性卒中患者虽只占全部卒中患者的10 %,但早期病死率可高达49.4%,仅不足半数患者可生活自理,年再出血发生率达2%～6%.因此,早期、正确的处理直接影响着出血性卒中患者的预后.从已发表的文献来看,有关脑出血的研究远远少于缺血性卒中,其比例仅为3：97.作者就自发性脑出血,主要是高血压性脑出血的外科手术治疗进展综述如下.