Pathophysiology, epidemiology, diagnosis and treatment of heparin-induced thrombocytopenia (HIT)

Due to the widespread use of unfractionated (UFH) and low molecular weight heparins (LWH) for prophylaxis and treatment of thrombosis, heparin-induced thrombocytopenia is considered to be the most frequent (and potentially the most devastating) drug-induced thrombocytopenia. Induced by an immune response, excessive activation of platelets and endothelium cells causes massive thrombin generation and, as a result, life-threatening venous and arterial thrombotic vessel occlusion. The rate of mortality and amputation in HIT II is estimated to be 30% and 20%, respectively. The clinical course of HIT II depends highly on early therapeutic intervention consisting of immediate interruption of heparin application and, most important, of compatible thrombin inhibition. All measures implying a potentially procoagulant risk such as begin of oral anticoagulation or platelet substitution may result in disastrous side effects.     

4 例复杂先天性心脏病术后并发肝素诱导的血小板减少症患者的监测

2013年7月至2015年2月中南大学湘雅医院心脏大血管外科收治的复杂先心病接受心脏直视手术的患者中有 4例先后出现肝素诱导的血小板减少症(heparin-induced thrombocytopenia,HIT),通过严密动态监测血小板计数,观察 HIT所致的栓塞性皮肤损伤情况,监测阿加曲班用药效果等综合治疗,3例痊愈,1例死亡。HIT是接受肝素治疗出现 的罕见的严重并发症,栓塞发生率和病死率较高。早期识别、早期诊断高风险人群可以有效改善预后。     

肝素诱导的血小板减少症的临床观察

目的 分析静脉血栓栓塞症肝素诱导的血小板减少症及其治疗.方法 对我院2006年5月至2008年5月临床确诊并以肝素抗凝治疗的静脉血栓栓塞症患者202例进行临床分析,定期监测血常规.结果 其中有6例患者发生肝素诱导的血小板减少症,在应用肝素第3～9天出现血小板数目下降,发生率为2.97%,其下降率为60.4%～82.2%.对需要继续抗凝的4例患者停用肝素后改为阿加曲班继续治疗,第3～7天血小板数目回升至入院时水平.结论 在使用肝素进行抗凝治疗期间,应常规监测血小板数目变化,如发现血小板数目进行性下降大于50%,应及时停用肝素,需继续抗凝的患者可改用阿加曲班治疗.     

利伐沙班与低分子肝素对髋膝关节置换术后下肢深静脉血栓预防的应用评价

目的:通过对髋膝关节置换术术后病人分别使用利伐沙班和注射用低分子量肝素钙,来评价2种药物的临床疗效,进一步探讨临床药师在髋膝关节置换术术后的预防中,如何协助临床医生使用抗凝药物进行治疗。方法:收集100例髋、膝关节置换术的病人,随机分为利伐沙班组50例和低分子肝素组50例。利伐沙班组病人于术后8 h给予利伐沙班片10 mg,每天1次,口服;低分子肝素组病人于术后12 h给予低分子量肝素5 000抗Xa国际单位,每天1次,皮下注射。2组均连续治疗2周。观察比较2组病人的凝血指标血小板（PLT）、活化部分凝血活酶（APTT）、凝血酶原时间（PT）及下肢深静脉血栓（DVT）发生率。临床药师参与治疗过程并提供药学监护。结果:2组病人术前血小板及凝血指标均无异常,且2组间差异无统计学意义（P>0.05）。2组病人术后药物治疗前及治疗后14 d血小板及凝血指标均无异常,且2组间差异无统计学意义（P>0.05）。2组病人中利伐沙班组深静脉血栓形成（DVT）发生率为0%（0/50）,低分子肝素组DVT发生率为8%（4/50）,2组差异有统计学意义（P<0.05）。2组病人中利伐沙班组不良反应发生率为2%（1/50）,低分子肝素组为12%（6/50）,差异无统计学意义（P>0.05）。结论:利伐沙班能有效预防髋膝关节置换术后下肢深静脉血栓的发生,不增加出血风险,具有良好的安全性,其疗效与低分子肝素相当。且利伐沙班具备可口服、固定剂量、疗效满意、无需监测等优点。     

肝素疗法对肾小球肾炎患者血小板活化状态的影响及其临床意义

目的：肝素疗法对不同病理类型肾小球肾炎口才因以活化状态的影响。方法：用全自动血细胞分析仪测定患者血小板计数、体积和分布宽度,用流式细胞技术测定患者血小板表面ＣＤ６２Ｐ、ＣＤ６３和ＣＤ４１表达水平。结果：９５例肾小球肾炎肝素疗法病人发生肝素诱导性血小板减少症４你,发病率４．２％,肝素疗法对ＭＣ病人血以计数、体积、分布宽度,血小板表面ＣＤ６２Ｐ、ＣＤ６３和ＣＤ４１表达水平无显著影响（Ｐ〉０．０５）,部     

激素联合静注免疫球蛋白治疗狼疮合并血小板减少

目的探讨糖皮质激素联合静注免疫球蛋白（IVIG）治疗系统性红斑狼疮（SLE）合并血小板减少的疗效及安全性。方法30例合并中重度血小板减少的SLE患者,随机分为实验组和对照组,每组15例。两组患者均接受糖皮质激素治疗;实验组联合应用静注免疫球蛋白（400mg/Kg/day,连用3天）。观察两组患者血小板计数变化、血小板恢复正常（100×10^9／L）的时间（天）、2周完全缓解率、平均住院日等。结果（1）治疗第4、7、10、14天实验组平均血小板计数高于对照组,差异具有统计学意义;（2）实验组血小板计数恢复正常的时间较对照组缩短（9．7±4．2天VS13．5±5．3天,P〈0．05）;实验组2周完全缓解率显著高于对照组（93．3％vs46．7％,P〈0．05）;（3）对照组患者的平均住院日为16．1±4．4天,实验组平均住院日为12．7±3．7天,两组比较差异具有统计学意义（P〈0．05）。（4）治疗过程中无严重不良反应发生。结论糖皮质激素联合静注免疫球蛋白治疗狼疮合并中重度血小板减少具有较好的疗效及安全性。     

人工髋关节置换术后下肢深静脉血栓的预防

目的预防人工髋关节置换术后下肢深静脉血栓的形成。方法选择本院骨科人工髋关节置术后患者108例,将其随机分为观察组（54例）与对照组（54例）,全部患者运用人工髋关节手术治疗,术后观察组选用利伐沙班和复方丹参滴丸联合预防下肢深静脉血栓形成,对照组单选用利伐沙班预防,比较两组的治疗效果。结果观察组中D-2聚体为（271.0±12.0）ng/mL,与对照组的（350.0±20.2）ng/mL相比差异有高度统计学意义（P〈0.01）,观察组中未出现D-2聚体〉300 ng/mL的患者。结论利伐沙班和复方丹参滴丸联合预防人工髋关节置换术后患者下肢静脉血栓的形成效果显著,值得推广。     

不同时间点利伐沙班预防髋关节置换术后深静脉血栓形成的疗效研究

目的 比较在围手术期不同时间点使用利伐沙班预防髋关节置换术后下肢深静脉血栓（DVT）形成的效果和安全性。方法 选取2014 年1 月-2016 年10 月在该院行髋关节置换手术患者150 例。根据患者入选标准随机分成4 组,A 组术前72 h 使用利伐沙班,B 组术前48 h 使用利伐沙班,C 组术前24 h 使用利伐沙班,D 组术后6 h 使用利伐沙班。观察4 组患者在围手术期的深静脉血栓发生率、出血并发症与记录围手术期出血量。结果 A 组发生DVT 1 例（2.5%）,B 组发生DVT 4 例（11.1%）,C 组发生DVT 5 例（13.2%）,D 组发生DVT 11 例（30.6%）。A 组DVT 发生率与B、C、D 组比较,差异有统计学意义（P <0.05）,A 组低于B、C、D 组。围手术期出血量上4 组间比较差异无统计学意义（P >0.05）。结论 术前72 h 使用利伐沙班预防髋关节置换术后发生DVT 的效果好,安全性高。     

利伐沙班预防股骨颈骨折关节置换术后血栓的临床观察简

目的观察利伐沙班预防股骨颈骨折关节置换术后血栓的临床效果。方法选取2010年9月至2013年2月来我院就诊的股骨颈骨折实行关节置换术的患者120例,将其随机分为实验组和对照组。实验组在实施关节置换术后口服利伐沙班用来预防血栓的形成,对照组术后进行皮下注射低相对分子质量肝素钠治疗,疗程均为2周。观察两组患者在治疗两周后血栓形成情况。结果治疗后,实验组发生血栓的有5例,对照组有11例,实验组血栓发生率（8．3％）明显小于对照组血栓发生率（18．3％）,差异显著具有统计学意义（P〈0．05）;而两组患者术后第3、9天血小板计数和血红蛋白相比,差异无统计学意义（P〉0．05）．结论利伐沙班能够显著降低股骨颈骨折实施关节置换后血栓的形成。     

下肢骨折围术期抗凝治疗对下肢深静脉血栓形成的影响

目的：探讨下肢骨折围术期抗凝治疗对下肢深静脉血栓形成的影响。方法：分析2008～2011年152例接受下肢骨折手术、围术期应用低分子肝素钙或口服利伐沙班片的患者（A组）的临床资料,统计血栓发生率,同2008年152例前下肢骨折围术期未予抗凝药物干预的患者（B组）血栓发生情况进行对比。结果：A组8例（5.26%）发生深静脉血栓,B组38例（25.00%）发生深静脉血栓,两组比较,差异有统计学意义（P〈0.05）;且两组均未发生明显大出血。结论：围术期积极抗凝治疗,可大大降低下肢深静脉血栓形成的发生率。     

Alternative diagnosis to heparin-induced thrombocytopenia in two critically ill patients despite a positive PF4/heparin-antibody test

Abstract

Thrombocytopenia can cause diagnostic challenges in patients who have received heparin. Heparin-induced thrombocytopenia (HIT) is often considered in the differential diagnosis, and a positive screening can be mistaken as confirmation of the disorder. We present two patients who both received low-molecular-weight heparin for several days. In the first patient, clinical judgment rejected the suspicion of HIT despite a positive screening assay, and treatment for the alternative diagnosis of post-transfusion purpura was correctly initiated. In the second patient, the inaccurate diagnosis HIT was pursued due to a positive screening assay, while the alternative diagnosis of drug-dependent thrombocytopenia caused by piperacillin/tazobactam was rejected. This resulted in re-exposure to piperacillin/tazobactam which caused a second episode of severe thrombocytopenia. A positive screening assay for platelet factor 4/heparin-antibody should be verified by a functional assay, especially in patients with low pretest probability for HIT.     

Heparin-induced thrombocytopenia associated with pulmonary embolism after total knee arthroplasty： a case report and review of literatures

Type II heparin-induced thrombocytopenia (HIT) is a life-threatening adverse drug reaction initiated by heparin administration. We described a rare case of LMWH-induced HIT complicated with proven pulmonary embolism (PE) in a 75-year-old male patient who hospitalized with diagnose of right knee osteoarthritis and was underwent total knee arthroplasty. The patient was successfully treated with argatroban. Early recognition and timely alternative therapy are of great importance in the treatment of this severe disorder.     

Antiplatelet effect of aspirin in patients with coronary artery disease

Cardiovascular disease is the number one cause of death globally, and atherothrombosis is the underlying cause of most cardiovascular events. Several studies have shown that antiplatelet therapy, including aspirin (acetylsalicylic acid), reduces the risk of cardiovascular events and death. However, it is well-known that many patients experience cardiovascular events despite treatment with aspirin, often termed "aspirin low-responsiveness". This fact has caused considerable debate: does biochemical aspirin low-responsiveness have prognostic value? Can low-responders be reliably identified? And if so, should antithrombotic treatment be changed? Is the whole discussion of antiplatelet drug response merely a result of low compliance? Compliance should be carefully optimised, before evaluating the pharmacological effect of a drug. It is well-known that cardiovascular disease is multifactorial, and, therefore, total risk reduction is not feasible. Aetiological factors to the variable platelet inhibition by aspirin seem to include genetic factors, pharmacological interactions, smoking, diabetes mellitus, and increased platelet turnover. It is a captivating thought that antiplatelet therapy may be improved by individually tailored therapy based on platelet function testing. Ongoing studies are challenging the current one-size-fits-all dosing strategy, but the preceding evaluation of platelet function assays has not been adequate. The overall objective of this thesis was to evaluate the reproducibility of and aggreement between a number of widely used platelet function tests and to explore the importance of platelet turnover for the antiplatelet effect of aspirin in patients with coronary artery disease. In the intervention studies (studies 1, 3, and 4), optimal compliance was confirmed by measurements of serum thromboxane, which is the most sensitive assay to confirm compliance with aspirin. In study 1, platelet function tests widely used to measure the antiplatelet effect of aspirin were evaluated in healthy individuals and patients with coronary artery disease. Pharmaco-specific metabolites were measured in urine and serum to investigate the pharmacodynamic effect of aspirin and to enable the comparison with the more global tests of platelet function. Based on repeated duplicate measurements, we evaluated the reproducibility of each test. We found that reproducibility of the classical reference method was not impressive and that the newer, so-called point-of-care tests differed markedly on reproducibility. With coefficients of variation of about 3%, the VerifyNow Aspirin test was clearly the most reproducible test - even after correction of the official scale, which begins at about 350 aspirin reaction units and, therefore, results in artificially low coefficients of variation. Among the platelet function tests investigated, Multiplate was most sensitive for aspirin treatment. In study 2 we performed the hitherto largest study of newly released, immature platelets as a marker of platelet turnover. The study population included healthy individuals, patients with stable coronary artery disease, and patients with acute coronary syndromes. The main finding was an increased fraction of immature platelets in patients with ST-segment myocardial infarction, indicating an increased platelet turnover. Smoking and type 2 diabetes were identified as independent determinants of platelet turnover. In study 3 we explored the relationship between platelet turnover and the antiplatelet effect of aspirin in patients with stable coronary artery disease. The study results support the hypothesis that an increased platelet turnover reduces the antiplatelet effect of aspirin. The main findings were: 1) platelet turnover correlated with platelet aggregation measured by Multiplate and with sP-selectin, a marker of platelet activation. 2) Patients with diabetes mellitus type 2 had reduced antiplatelet effect of aspirin compared with patients without diabetes. 3) Widely used platelet function tests differ with respect to dependence on platelet parameters, including platelet count. 4) Smoking, diabetes mellitus type 2, and thrombopoietin were identified as independent determinants of platelet turnover. 5) The relative fraction of immature platelets has been employed in most previous studies, but in stable patients the absolute immature platelet count does not seem dependent on the total platelet count, and it has a stronger correlation with both platelet activation measured by sP-selectin and with platelet aggregation during treatment with aspirin. In study 4 we investigated platelet turnover and the antiplatelet effect of aspirin in a nested case-control study on patients with previous definite stent thrombosis. Patients with stent thrombosis were compared with patients without stent thrombosis, with whom they were matched at a 1:2 ratio with respect to risk factors for stent thrombosis: age, sex, stent type, and indication for percutaneous coronary intervention. The study showed that patients with previous stent thrombosis have reduced antiplatelet effect of aspirin and a tendency towards increased platelet turnover. In conclusion, widely used platelet function tests markedly differ on reproducibility, and the agreement between tests is relatively poor. An increased platelet turnover as suggested by the presence of newly formed immature platelets is important for the antiplatelet effect of aspirin, and, perhaps also for the development of acute coronary thrombosis. In the future, individually tailored antiplatelet therapy may potentially improve the benefit-risk ratio of antiplatelet therapy.     

Reevaluation of the Efficacy of Intravenous Gammaglobulin in the Prevention and Treatment of Coronary Artery Lesion inKawasaki Disease

Kawasaki disease (KD) has received wide con-cernfor its liabilitytoinduce coronary arterylesion(CAL) . Clinical multi-center randomized resear-ches suggest that intravenous gammaglobulin(IVIG) can effectively prevent cardiovascular com-plications of KD[1]. But a number of patients de-veloped coronary artery dilation (CAD) or coro-nary artery aneurysm ( CAA) even after IVIGtreat ment with a varied incidence rate in differentreports . To evaluate the efficacy of IVIGin pre-vention and …     

98例急性特发性血小板减少性紫癜临床分析

目的:分析儿童急性特发性血小板减少性紫癜不同治疗方案的疗效.方法:收集98例我院2005年1月至2007年1月收治的特发性血小板减少性紫癜儿童患者的病历资料,分析儿童急性特发性血小板减少性紫癜不同治疗方案的疗效.结果:①激素组的有效率为:79.59%(39/49),显效率为67.34%(33/49);丙种球蛋白加泼尼松...     

Acute renal failure resulting from intravenous immunoglobulin therapy

Intravenous administration of immunoglobulin is used for the treatment of many conditions, including primary immunodeficiency states, autoimmune disorders, glomerulonephritides and polyneuropathy. Acute renal failure induced by intravenous immunoglobulin is a known but rare adverse reaction. We have a patient who was treated with IVIG for inflammatory polyneuropathy. Intravenous immunoglobulin therapy 0.5 g/kg/ d was given for 4 days. Three days after completion of IVIG therapy, patient developed decreased urine output. His serum creatinine increased from baseline of 1.3 to 7 mg/dL. Even though IVIG was discontinued, patient required hemodialysis. This case illustrated that IVIG can cause acute oliguric renal failure which is reversible after withdrawal of the drug. Risk factors include pretreatment renal impairment, diabetes mellitus, high concentration of sucrose or glucose in IVIG preparation and older age. Awareness of this serious side effects and recognition of predisposing factors provide means of avoiding a known life threatening complication of IVIG therapy.     

肿瘤化疗患者并发输液港导管相关血栓的危险因素及治疗策略

目的 探讨肿瘤化疗患者并发输液港(implantable venous access port,IVAP)导管相关血栓的危险因素,并分析治疗策略。方法 2021年3—7月前瞻性连续纳入复旦大学附属中山医院274例使用输液港化疗的肿瘤患者。超声筛查患者IVAP导管相关血栓发生情况,并以此分为血栓发生组和未发生IVAP导管相关血栓组。搜集患者基线和病历资料,多因素Logistic回归分析肿瘤化疗患者并发IVAP导管相关血栓的危险因素,并对发生血栓的患者进行3个月的初步抗凝治疗(D-二聚体<0.8 mg/L的患者用10 mg/d利伐沙班抗凝,D-二聚体≥0.8 mg/L的患者用20 mg/d利伐沙班抗凝),随访发生血栓组患者的治疗结果。结果 274例肿瘤患者中有35例(12.8%)患者发生IVAP导管相关血栓。多因素Logistic回归分析表明发生相关血栓的独立危险因素包括合并有远处转移(OR=3.013)、化疗前纤维蛋白原≥400 mg/dL(OR=3.226)、新辅助+辅助化疗方式(OR=26.286)。随访发现所有IVAP导管相关血栓阳性患者抗凝用药后无局部症状发生或加重,患者均未出现肺栓塞,1例因肠道出血停药,1例轻度牙龈出血,1例轻度鼻黏膜出血。有超声复查的5位患者在新型口服抗凝药作用下附壁血栓消失或变小。结论 IVAP相关血栓的危险因素为化疗前纤维蛋白原≥400 mg/dL、有远处转移、新辅助+辅助化疗方式,临床应注意筛查。D-二聚体<0.8 mg/L的患者可使用10 mg/d的利伐沙班;D-二聚体≥0.8 mg/L的患者可使用20 mg/d的利伐沙班抗凝。     

Heparin induced thrombocytopenia: diagnosis and management update

Heparin-induced thrombocytopenia (HIT) is a potentially devastating immune mediated adverse drug reaction caused by the emergence of antibodies that activate platelets in the presence of heparin. Despite thrombocytopenia, bleeding is rare; rather, HIT is strongly associated with thromboembolic complications involving both the arterial and venous systems. A number of laboratory tests are available to confirm the diagnosis; however, when HIT is clinically suspected, treatment should not be withheld pending the result. Fortunately, therapeutic strategies have been refined, and new and effective therapeutic agents are available. Treatment options are focused on inhibiting thrombin formation or direct thrombin inhibition. Warfarin should not be used until the platelet count has recovered.     

A rare case of arterial thrombosis due to heparin-induced thrombocytopenia

A 78-year-old man presented with an eight-hour history of chest distress. Electrocardiograph and serum cardiac enzymes were suggestive of acute inferior myocardial infarction with right ventricular infarction. The patient, who underwent emergency percutaneous coronary intervention, suffered from thrombocytopenia presenting with cerebral infarction and myocadial reinfarction during haparin exposure. The laboratory test for heparin-induced thrombocytopenia (HIT) specific antibodies (heparin-platelet factor, PF4) was positive. The case was diagnosed as arteries thrombosis due to heparin-induced thrombocytopenia; the patient died after cessation of heparin.

     

Lysophosphatidic acid is the unique platelet-activating substance in human malignant ascites

Pathological blood platelet activation promotes thrombosis in cancer patients, but the specific substances involved are still under investigation. Tumor exudates have been described to contain lysophosphatidic acid (LPA), a known platelet-activating substance, and the concentration of mediators present in malignant ascites are constantly equilibrated with the concentration in plasma. We hypothesized that the ascites of cancer patients might activate platelets, and that this may be caused by LPA. Indeed, ascites samples from 15 different patients with cancer induced shape change and an increase of cytosolic Ca2+ of isolated platelets; both responses were cross-desensitized by lysophosphatidic acid (LPA), but not by other platelet stimuli. Moreover shape change, Ca2+ mobilization and aggregation induced by ascites could be completely blocked by pretreatment of platelets with specific LPA-receptor antagonists. Phospholipids were extracted from ascites, separated by thin layer chromatography, and individual fractions were tested for activity on platelets. The platelet activating substance co-migrated with LPA, whereas other fractions were inactive. Notably, ascites induced through LPA-receptor activation platelet aggregation in whole blood. Our results suggest that LPA plays an essential role in the pathological platelet activation in cancer patients. We propose that LPA receptor antagonists could be effective in blocking cancer-associated platelet activation and thus preventing thrombosis.