危重患者血小板减少的诊治

1、危重患者血小板减少的诊治,.,1,概述血小板减少的定义、机制、诊断思路、常用的检查方法 危重患者中血小板减少的诊断和治疗 总结 病例讨论,.,2,血小板减少（thrombocytopenia）定义为各种遗传或获得性因素导致的血小板减少，血小板计数150.0 x 10(9)/L，通常小于100.0 x 10(9)/L. 其主要机制为破坏增加（hyperdestructive ）、生成减少（ hypoproductive ）和分布异常（altered distribution,常见于充血性脾大或低体温）。,.,3,.,Hospital-acquired thrombocytopenia. Hosp

2、 Pract , 2014 Oct;42(4):142-52.,4,.,5,.,6,血小板减少的病因多样，涉及多个学科，常规检查特异性和敏感性不高，特异性检查受到技术条件和标准化的制约难以开展，导致诊断及鉴别诊断困难。 同一病因导致血小板减少的时间、程度个体差异大，发生严重出血受到患者年龄、基础疾病（心、肝、肾等）和有创操作等的影响，及时评估、干预非常重要。,.,7,相关病史（基础疾病、药物史、 出血事件） 查体（出血倾向、 肝脾淋巴结、免疫相关疾病、 皮肤巩膜黄染）,.,8,外周血涂片,.,EDTA抗凝剂导致的血 小板 聚集（clumping），自动血细胞计数仪中血小板计数下降，称为假性血小

3、板减少（pseudothrombocytopenia） 人工计数或枸橼酸抗凝可以识别,9,.,裂红细胞（破碎红细胞）,10,.,球形红细胞,11,骨髓涂片/活检,.,了解巨核细胞系（巨核细胞数量及产板情况），还可发现粒系/红系异常,12,.,破坏增多骨髓检查巨核细胞数量正常或增加。部分 ITP可见巨核细胞成熟障碍，产板少。,13,.,生成减少骨髓涂片巨核细胞减少。 再障患者活检增生极度低下，造血组织少。,14,抗人球蛋白试验,即Coombs直接试验:将洗涤过的红细胞2%混悬液加入Coombs试剂，混和后离心一分钟促进凝集。如果肉眼或显微镜下能见到红细胞凝集，即为阳性，说明红细胞表面有抗体或补体

4、。 Coombs间接试验:先将受试的血清加入等量5%适当的正常红细胞(Rh阳性的O型红细胞)，在37温育3060分钟，以促使血清中的半抗体结合于红细胞上(致敏)，将红细胞充分洗涤，以后同直接试验。,.,15,.,血小板减少诊断简易流程,16,以下的实验室方法能帮助我们进一步明确诊断,.,17,平均血小板容积（MPV，meanplateletvolume ） One hundred two patients were completely evaluated. When compared with the BM examination, the MPV of 7.9 fl could predi

5、ct hyperdestructive sensitivity of 82.3% (95% CI: 70.5-90.8), specificity of 92.5% (95% CI: 79.6-98.4), positive predictive value of 94.4% (95% CI: 84.6-98.8), negative predictive value of 77.1% (95% CI: 62.7-88.0) A prospective evaluation of normal mean platelet volume in discriminating hyperdestru

6、ctive thrombocytopenia from hypoproductive 0thrombocytopenia.International journal of laboratory hematology,2008 Oct;30(5):408-14.,.,18,血小板指数（platelet indices），包括MPV, 血小板体积变异宽度（platelet size deviation width ，PDW) 和大血小板比率（ platelet-to-large-cell ratio ，P-LCR) The study group was divided into two cate

7、gories: hypoproliferative and destructive thrombocytopenia All the threeplateletindiceswere significantly higher in destructive group as compared to the hypoproliferative category,.,19,134 thrombocytopenic patients (69 men, 65 women) who were divided into two groups group I (n = 63) included ITP pat

8、ients group II (n = 71) included patients with HT due to myelosuppression secondary to chemotherapy Concerning MPV and PDW indices, sensitivity, specificity, positive prognostic value, negative prognostic value, efficiency and Youden index were 100% for thediagnosisof ITP. On the contrary, the value

9、s for P-LCR were significantly lower。,.,20,血小板指数的局限性在于血小板严重下降的患者（10 x 10(9)/L ）结果有较大的偏差，输血等治疗措施影响对结果的判断。 在ICU的应用价值需要再评估。 Role of platelet volume indices in the differential diagnosis of thrombocytopenia: a simple and inexpensive method.Hematology (Amsterdam, Netherlands) ,2009 Jun;14(3):182-6. Incre

10、ased values of mean platelet volume and platelet size deviation width may provide a safe positive diagnosis of idiopathic thrombocytopenic purpura.Acta Haematol. 2008;119(3):173-7.,.,21,未成熟血小板比例和网织血小板比例 Group 1. Centralthrombocytopenia IPF 8.67% (6.49-10.46%) RP 4.08% (2.86- 5.30%) Group 2. Thromboc

11、ytopenia as a result of enhanced peripheralplateletdestruction 6.80% (12.20-21.39%) ，16.14% (9.89-22.40%). (P 0.01). Group 3. Peripheral non-immune thrombocytopenia by abnormaldistribution 9.04% (6.95-11.14%) ，5.23% (3.41-7.05%). Correlation between immature platelet fraction and reticulated platele

12、ts. Usefulness in the etiology diagnosis of thrombocytopenia.Eur J Haematol. 2010 Aug;85(2):158-63.,.,22,促血小板生成素（Thrombopoietin，TPO)在生成障碍患者，特别是再障患者明显升高，但在鉴别诊断中的价值有限。 血小板相关抗体在免疫性血小板减少中有一定的价值，但检测方法的标准化和特异性需要再评估。 Is the thrombopoietin assay useful for differential diagnosis of thrombocytopenia? Analysi

13、s of a cohort of 160 patients with thrombocytopenia and defined platelet life span.Clin Chem. 2001 Sep;47(9):1660-5. Attempt to improve the diagnosis of immune thrombocytopenia by combined use of two different platelet autoantibodies assays (PAIgG and MACE).Haematologica. 2002 Oct;87(10):1046-52. Qu

14、antification of platelet-associated IgG for differential diagnosis of patients with thrombocytopenia.Thromb Haemost. 2000Nov;84(5):779-83.,.,23,以上是简易流程，最常见的几种疾病。针对住院特别是ICU患者情况可能更复杂，更多的是基础疾病和治疗性因素导致的血小板减少，医院获得性血小板减少（Hospital-acquired thrombocytopenia）。 Hospital-acquired thrombocytopenia.Hosp Pract (1

15、995). 2014 Oct;42(4):142-52. Thrombocytopenia in the intensive care unit patient.Hematology Am Soc Hematol Educ Program. 2010;2010:135-43.,.,24,1.感染,Infection is a common cause of thrombocytopenia. Viral infections associated with thrombocytopenia include the human immunodeficiency virus, hepatitis

16、C virus, and Epstein-Barr virus，cytomegalovirus Thrombocytopenia is also frequent in patients with bacterial infections and sepsis or severe sepsis. Mechanisms of infection-induced thrombocytopenia are multiple and may include bone marrow suppression, peripheral immune destruction, and activation an

17、d consumption. The fall in platelet count associated with sepsis is typically gradual, occurring over 5 to 7 days, and the thrombocytopenia is characteristically mild. Management consists of treatment of the underlying infection and supportive care.,.,25,2.药物诱导免疫性血小板减少,2 primary mechanisms ：decrease

18、d platelet production secondary to bone marrow suppression (eg, chemotherapeutic agents) and increased platelet destruction caused by drug-induced immune thrombocytopenia (DITP) 后者更难以识别。,.,26,Drug-induced immune thrombocytopenia typically presents in a delayed fashion, 5 to 10 days after initiation

19、of the offending drug. There are 2 exceptions to this rule: (1) patients previously exposed to a drug （2）patients may develop thrombocytopenia immediately after initiation of a glycoprotein IIb/IIIa inhibitor (eg, eptifibatide, tirofiban, and abciximab),.,27,The following clinical criteria have been

20、 proposed to estimate the likelihood that a given drug is the cause of DITP: (1) thrombocytopenia occurs after exposure to the drug and improves after the drug is stopped; (2) the candidate drug is the only drug used before the onset of thrombocytopenia, or other drugs are continued or reintroduced

21、without affecting the platelet count; (3) other causes of thrombocytopenia are excluded; (4) thrombocytopenia recurs if the drug is restarted 但在ICU的环境下，多种药物使用，合并多种疾病，可能难以判断。,.,28,.,万古霉素 青霉素 哌拉西林 头孢曲松 甲氧苄氨嘧啶/磺胺甲恶唑 利福平 卡马西平 苯妥英 丙戊酸 阿昔单抗 替罗非班 依替巴肽 奎宁 对乙酰氨基酚 布洛芬 米氮平 雷尼替丁,29,Suspected DITP is treated by

22、discontinuing the potentially offending drug. The platelet count typically begins to improve within 1 to 2 days after the drug is stopped .The median time to recovery of platelet count is 7 days. Patients with severe thrombocytopenia and bleeding may be treated with platelet transfusion. In particul

23、arly severe cases, corticosteroids, intravenous immunoglobulin, and plasma exchange have been used, although there is limited evidence of efficacy with these,.,30,肝素诱导的血小板减少,Heparin-induced thrombocytopenia (HIT) is an immune-mediated disorder that occurs after exposure to unfractionated heparin or

24、low molecular weight heparin. Unlike most other forms of DITP, HIT is generally prothrombotic rather than prohemorrhagic. Thrombotic complications, include deep venous thrombosis, pulmonary embolism, peripheral arterial thrombosis, ischemic stroke, and myocardial infarction.,.,31,.,32,an intermediat

25、e or high probability of HIT, heparin should be discontinued the patient should be treated with a nonheparin anticoagulant（argatroban, danaparoid ，bivalirudin fondaparinux） Once the platelet count has recovered, patients may be transitioned to warfarin.,.,33,3.弥散性血管内凝血,Disseminated intravascular coa

26、gulation (DIC) occurs not in isolation but secondary to an underlying disorder These conditions may generate procoagulant substances, leading to widespread activation of coagulation and deposition of fibrin in the microvasculature. The end result is thrombosis of small vessels and end-organ ischemic

27、 injury. Accelerated consumption of coagulation factors and platelets may also produce a concomitant bleeding tendency,.,34,.,DIC的病理生理机制,35,.,36,.,37,The cornerstone of therapy for DIC is treatment of the underlying condition. Transfusion is indicated in patients who are bleeding or otherwise at hig

28、h risk for bleeding. Therapeutic heparin should be considered in patients with DIC complicated by overt thrombosis. Antifibrinolytic treatments are generally contraindicated in patients with DIC due to an increased risk of thrombosis.,.,38,4.血栓性血小板减少性紫癜,Thrombotic thrombocytopenic purpura (TTP) is a

29、 thrombotic microangiopathy It is characterized by thrombocytopenia and microangiopathic hemolytic anemia and may also include neurologic symptoms, fevers, and renal impairment TTP is caused by a deficiency of ADAMTS13, a protease that cleaves von Willebrand factor. In the absence of ADAMTS13, ultra

30、large von Willebrand factor multimers promote formation of platelet aggregates in the microvasculature, causing shear stress and mechanical fragmentation of erythrocytes in areas of high flow.,.,39,.,40,.,TTP患者肺栓塞病理,TTP患者肾小球病变,41,Diagnosis of TTP is based on a combination of clinical signs and sympt

31、oms and laboratory values. The median platelet count at presentation is 10 to 30 109/L. The median hemoglobin is 8 to 10 g/dL and is accompanied by markers of intravascular hemolysis. Schistocytes, and often nucleated red cells, are found in the peripheral blood smear. The PT and aPTT are typically

32、normal, and the direct Coombs test is negative. Patients may have acute kidney injury or proteinuria.,.,42,Thrombotic thrombocytopenic purpura is a medical emergency, and treatment of suspected TTP must be commenced immediately. daily plasma exchange (PEX) decreases mortality rates from 80%90% to un

33、der 20%. plasma infusion while awaiting exchange therapy. Plasma exchange is continued until platelet count recovery. high-dose corticosteroids, which have been shown in some studies to improve outcomes. Rituximab, a monoclonal antibody that targets CD20 on B lymphocytes, is widely used in patients

34、with refractory or relapsed disease. platelet transfusion is relatively contraindicated unless serious bleeding is present.,.,43,5. 输血后紫癜,Posttransfusion purpura (PTP) is a rare complication of blood transfusion that causes acute, severe thrombocytopenia with a median nadir platelet count , 10 109/L. occurs 5 to