Disseminated Intravascular Coagulation (DIC) 武汉大学基础医学院病理生理学教研室 李银萍 2014.04

一、凝血通路 (coagulation pathway） 正常机体凝血和抗凝血的平衡 (Balance between coagulation and anticoagulaiton) 一、凝血通路 (coagulation pathway） 外源性凝血通路（ Extrinsic Pathway ） Initiated by tissue factor (TF,组织因子); Can be activated quickly; Primary pathway in physiological conditions. 外源性凝血系统: 15 seconds;内源性凝血系统, 1-6 min Clotting factors from livers: I, II, V, VII, IX, X, XI, XII, XIII From Platelet: III, IV(Ca2+), VIII, XIII From endothelial cells: VIII 内源性凝血通路（Intrinsic Pathway ） Initiated by factor Ⅻ Slow in activation speed

Intrinsic Pathway Extrinsic Pathway prekallikrein kallikrein Ⅸ Ⅹ TF Ⅶa Ca2+ Ⅶ Intrinsic Pathway Ⅸa Ⅷa PL+ Ca2+ Ⅺa Ⅺ Ⅻa Ⅻ collagen kallikrein prekallikrein Extrinsic Pathway Blood coagulation fibrin Ⅹa Ⅴa thrombin prothrombin fibrogen Common pathway ⅩⅢa ⅩⅢ Ⅻa、Ⅹa、thrombin

凝血反应的三个阶段（Main Steps of coagulation) 1. Formation of Xa-Va-PF3-Ca2+ complex 3. Fibrinogen 2. prothrombin thrombin Fibrin

二、抗凝血系统 (anti-coagulation system) Cellular anticoagulation system Humoral anticoagulation system 组织因子途径抑制物(tissue factor pathway inhibitor (TFPI) 丝氨酸蛋白酶抑制物：如抗凝血酶Ⅲ （antithrombin Ⅲ，AT-Ⅲ) 3. 蛋白C系统（protein C system) 4. 肝素 (heparin) 5. 纤溶系统(fibrinolytic system ) Cellular anticoagulation system 1. Monocytes/macrophages 2. Liver cells 3. Endothelial cells

Humoral anticoagulation Anti- coagulation system Cellular TFPI TFPI-Ⅹa TFPI-Ⅹa-TF-Ⅶa Ⅹa TF-Ⅶa heparin ATⅢ↑↑ Humoral anticoagulation PC system Ⅱa、Ⅶa、Ⅸa、Ⅹa、Ⅺa、Ⅻa fibrinolytic system Anti- coagulation system Monocytes/macrophages：phagocytosis of activated coagulation factors and endotoxin, etc Liver cells：synthesis of anticoagulation factors as PC、 ATⅢ，inactivate coagulation factors as Ⅸa、Ⅹa、Ⅺa Endothelial cells: Cellular anticoagulation

Fibrinolytic system 纤溶酶原(plaminogen )、纤溶酶原激活物（ plaminogen activator, PA）， 纤溶酶原激活物抑制剂（ plaminogen activator inhibitor, PAI）。 激肽释放酶 激肽释放酶原 纤维蛋白沉积 组织型纤溶酶原激活物（t-PA) Ⅻa 尿激酶型纤溶酶 原激活物（u-PA) PAI 抑制作用 纤溶酶 纤溶酶原 The injured tissues and endothelium very slowly release tissue plasminogen activator (t-PA；组织纤溶酶原激活物) a day or later after clot is formed and convert plasminogen to plasmin. Plasmin具有广泛的丝氨酸水解酶活性，能水解凝血终产物fibrin生成可溶性的纤维蛋白降解产物（fibrin degradation products, FDP），也能水解fibrinogen和其他多种coagulation factors、血浆蛋白与组织蛋白。 尿激酶原 is from kidney. 纤溶酶原激活物抑制物(PAIs)：from endothelium and platelets Ⅺa、Ⅻa及凝血酶 抑制血小板聚集 水解Ⅴ,Ⅶ、Ⅷ、Ⅸ、Ⅹ、 Ⅻ，凝血酶原 纤维 蛋白(原) 纤维蛋白 降解产物

Disseminated Intravascular Coagulation (DIC) 弥散性血管内凝血 Disseminated Intravascular Coagulation (DIC)

Definition of DIC DIC (Disseminated Intravascular Coagulation,DIC）是一种由不同原因引起的以全身性血管内凝血系统活化为特征的临床综合征，因促凝物质暴露或产生增多，内源性抗凝因子及纤溶不足，导致广泛微血管内微血栓形成，同时或相继发生大量凝血因子和血小板消耗并可伴有纤溶亢进，导致多部位出血、休克、多器官功能障碍及微血管病性溶血性贫血。

Definition Disseminated Intravascular Coagulation (DIC) is a life-threatening acquired syndrome characterized by systematic activation of intravascular coagulation arising from different causes. It is manifestated by widespread microthrombosis and subsequent hemorrage, shock, multiorgan dysfunction and microangiopathic hemolytic anemia, which result from consumption and exhaustion ofcoagulation factors and platelets. DIC can present with a simultaneously occurring microthrombotic and bleeding problem.

Etiology of DIC

Precipitating causes Severe dysfunction of liver Dysfunction of monocytes/macrophages，eg. Severe infection Severe dysfunction of liver Hypercoagulatory status：pregnancy and acidosis Dysfunction of microcirculation Dysfunction of fibrinolysis 一）单核吞噬系统功能受损（Impairment of Mononuclear Phagocyte System） Mononuclear phagocyte能吞噬、清除血液中多种促凝物质、活化的凝血因子、fibrin和FDP等，发挥物理抗凝作用，防止凝血活化失控。长期大量使用糖皮质激素、严重肝功能障碍等使单核吞噬功能明显降低；反复感染使单核吞噬功能被大量吞噬物所封闭，导致体内防止凝血失控的能力降低。在此种情况下，若有激活凝血的因素在体内出现，易激起广泛失控的凝血，发生DIC。 （二）肝功能障碍（Hepatic Insufficiency） 肝脏是体内单核吞噬系统的主要脏器，同时是antithrombin Ⅲ、protein C、protein S和绝大多数coagulation factors的生成场所。急性、亚急性肝脏损伤：会释放出大量tissue factors；造成肝细胞损伤的病毒、化学物质可损伤内皮细胞；同时使antithrombin Ⅲ生成严重减少；使吞噬功能显著降低。虽然肝脏损伤同时造成coagulation factors生成明显减少，但因coagulation factors的半衰期多为3~6天，此时血浆中尚能保持它们的一定浓度水平。故急性、亚急性肝脏损伤，易发生DIC。慢性肝功能障碍时，因合成障碍使血液中coagulation factors缺乏，凝血功能降低，易发生出血倾向。但因慢性肝功障碍使细胞抗凝能力降低，加上肠源性内毒素、细菌等促凝物质可通过门-体侧支循环绕过肝脏进入体循环，当强促凝病因在体内出现时也易发生DIC。 （三）血液高凝状态（Hypercoaguloble State） 在某些生理和病理情况下，血液中凝血物质增多或/和抗凝血及纤溶能力减弱，使血液处于凝血活性显著增强而易发生凝血的状态，即高凝状态（hypercoagulable state）。体内处于hypercoagulable state时，若有启动凝血因素出现则容易引起广泛失控的凝血反应。 妊娠后期血液中fibrinogen、prothrombin、凝血因子Ⅴ、Ⅶ、Ⅷ、Ⅸ、Ⅹ、plasminogen activator inhibitor等含量增多，platelets粘附、聚集性能显著增强，血浆中出现较多可溶性纤维蛋白复合物。与此同时，血浆中antithrombin Ⅲ减少；plasminogen含量虽有所增加，但plasminogen activator inhibitor的量也显著增加，使总的纤溶活力有所减弱。妊娠后期孕妇体内的这种变化是一种生理变化，使孕妇处于hypercoagulable state，对预防分娩时子宫过量出血有积极的保护意义。但此时若有激活凝血的因素在孕妇体内出现，如发生羊水栓塞、宫内死胎、胎盘早期剥离等，则很容易发生DIC。 酸中毒除造成内皮细胞损伤外，还可降低肝素活性，使coagulation factors活性和platelets聚集性加强。因此酸中毒，特别是严重酸中毒也会使机体处于hypercoagulable state，成为促使DIC发生的一个重要诱发因素。另外，强烈应激反应时交感-肾上腺髓质系统兴奋，血浆儿茶酚胺浓度增高，使platelets数量增多，聚集性增强；急性期反应使血浆中fibrinogen、prothrombin和凝血因子Ⅷ的含量显著增高；内皮细胞中plasminogen activator含量和分泌显著增多。故强烈应激使血液总体凝血活性增高，成为严重创伤和感染时容易发生DIC的重要条件之一。 （四）微循环障碍（Disorder of Microcirculation） 微循环血管功能障碍，无论血管持续收缩还是舒张，或有效循环血量减少，都造成微循环灌流量减少、流速缓慢，毛细血管和微静脉中血液淤滞，血粘度增高。因此，在微循环灌流障碍局部，促凝物质、活化的coagulation factors和纤维蛋白聚合物不能及时随血流清除、稀释，有利于platelets粘附、聚集和fibrin沉积；同时微循环灌流障碍局部缺血、缺氧和酸中毒，可造成内皮细胞损伤及局部凝血活性增强；严重全身微循环灌流障碍，导致肝、肾功能降低，使机体清除促凝物质、活性凝血因子能力降低。因而在微循环灌流障碍部位，易发生凝血。 （五）纤溶功能降低（Impairment of Fibrinolytic Ability） 机体fibrinolysis功能正常时，血流中形成的microthrombus在微循环中仅约存在1h，即被激活的plasmin水解。高龄、吸烟、糖尿病和妊娠后期，体内的纤溶功能常明显降低；过量使用对羧基苄胺、氨基已酸等纤溶抑制药物，使体内纤溶功能过度被抑制。当体内fibrinolysis功能主动或被动降低时，一旦有强烈激活凝血的因素在体内出现，如感染、创伤等，体内容易发生DIC。 在不同疾病中，影响DIC发生、发展的因素可以是某一因素起主要作用，也可以是几个因素综合发挥作用，促进DIC的发生、发展。

Dysfunction of monocytes/macrophages Inability or decreased ability in remove activated coagulation factors Mononuclear phagocyte能吞噬、清除血液中多种促凝物质、活化的凝血因子、fibrin和FDP等，发挥物理抗凝作用，防止凝血活化失控。长期大量使用糖皮质激素、严重肝功能障碍等使单核吞噬功能明显降低；反复感染使单核吞噬功能被大量吞噬物所封闭，导致体内防止凝血失控的能力降低。在此种情况下，若有激活凝血的因素在体内出现，易激起广泛失控的凝血，发生DIC。 Phagocytose of macrophage

Hypercoagulatory status Decreased synthesis and activation of anticoagulation factors, eg. AT-III and plasminogen。 Increase synthesis of coagulation factors,eg.Ⅰ、Ⅱ、Ⅶ、Ⅸ、Ⅹ、Ⅻ Increased synthesis of PAI by placenta. Increased aggregation of platelets and increased number of RBC Pregnancy Acidosis Damage of endothelial cells Decrease activation of anticogulaiton factors, eg. heparin Increase activation of coagulation factors Increase aggregation of platelets

Mechanisms of DIC initiation of DIC：hyperactivation of coagulation system 1. Tissue injury, release of TF Causes： infection,severe trauma, surgical operation, necrosis of tumor cells, obstetric complications Massive release of TF, formaiton of TF-FⅦa-FⅦa complex, initiation of extrinsic coagulation pathway Release of lysoenzymes by injuried cells，hydrolysis of activated coagulation factors

TF Tran-membrane glycoprotein; Expressed by damaged endothelial cells； Constitutively expressed by tissues, eg. placenta, lung, liver, pancreas, brain, etc.

2. Extensive damage of vascular endothelial cells causes：endotoxin, virus, inflammation, hypoxia, radiation

1. Release of TF by injuried EC, activation of extrinsic coagulation system 2. Exposing of collagen, and activation of intrinsic coagulation system 3. increased adhesion and activation of platelets induced by collagen and ADP 4. Activation of white blood cells by inflammatory factors induced by infection 5. Disorders of coagulation factors and anticoagulation factors released by EC Redued TFPI,AT-Ⅲ,TM， PGI2,,t-PA ； Increased PAI

3. Massive destruction of blood cells 1) Injury of red blood cells Causes：hemolysis。 Release of ADP and phospholipid，induction of aggregation of platelets and coagulation 2) Activation and injury of white blood cells Causes：infection, leukemia Release of TF，and intiation of extrinsic coagulation pathway

3) Activation of platelets Activation of platelets by thrombin, ADP, collagen

Effects of cytokines TNFα、IL-1、IL-6、IL-8，etc 5. Effects of activated coagulation factors and platelets positive feedback 6. Interactions among coagulation system /anti-coagulation system/kinin /inflammatory factors 7. Dysfunction in fibrinolysis Defects or hyperfunction 8. Consumption of coagulation factors and platelets 9. Oxidative stress and damage to VEC

10. Other thromboplastic materials entering the blood 1) Acute pancreatitis： Directe activation of FⅩand prothrombin by Trypsin； Increase activation of FⅧ and FⅤ by trypsin; Massive release of TF. 2) 羊水栓塞(amniotic fluid embolism)： Massive release of TF； Activation of fibrinolysis by PA, induction of bleeding 3) Entrance of large quantities of negatively charged materials into blood Carcinoma cells in hematogenous metastasis Particles as bacterials 4) Entrance of exogenuous toxin into blood Activation of FⅩ and prothrombin by certain apisin and venomous

Secondary fibrinolysis Activation by Ⅺa, Ⅻa, thrombin and kallikrein Accompanied by reduced activity of coagulation VEC受损后丧失了正常的抗凝功能，如合成分泌AT-III， TM，TFPI等，PAI合成相对t-PA多，局部抗凝减弱而凝血增强。 继而凝血因子大量消耗，凝血活性下降，凝血酶启动的纤溶相对增强，

Clinical stages of DIC 1. Hypercoagulation stage thrombin，activation of platelets，hypercoagulation，low activity of fibrinolysis，massive microthrombus in microcirculaiton 2. Consumed hypocoagulation stage coagulation factors and platelets  ，activation of secondary fibrinolysis，activity of coagulation， bleeding 3. Vigorous secondary fibrinolysis stage plasmin  ，FDP ；coagulation activity   ，bleeding  。 VEC受损后丧失了正常的抗凝功能，如合成分泌AT-III， TM，TFPI等，PAI合成相对t-PA多，局部抗凝减弱而凝血增强。 继而凝血因子大量消耗，凝血活性下降，凝血酶启动的纤溶相对增强，

Consequences of DIC Bleeding Shock Dysfunction of multiple organs Microangiopathic hemolytic anemia

Mechanism of bleeding Coagulation substances are largely consumed and exhausted, particularly fibrinogen, prothrombin and platelets Activation of secondary fibrinolytic system, massive FDP are produced Impairment of endothelial cells induced by ischemia, hypoxia and acidosis secondary to widespread microthrombus High permeability of vascular endothelium kinin, bradykinin, complements and other inflammatory factors activated during coagulation process and fibrinolysis

Clinical Features of DIC 1. Bleeding Petechiae (瘀点) Purpura (紫癜) Hemorrhagic bullae (出血性水泡) Surgical & traumatic wound bleeding (创伤性出血） Venipuncture site bleeding （注射部位出血） Arterial oozing （动脉渗血） Subcutaneous hematoma （皮下血肿）

DIC患者出血部位分布（%） 部位 百分率（%） 部位 百分率（%） 皮肤紫癜或出血点 63 咯血 24 胃肠道出血 50 粘膜出血 20 伤口面出血 46 阴道出血 10 血尿 32 鼻出血 9 血肿 26 眼底出血 7

2. Shock Over 50% of acute DIC are accompanied by shock Mechanisms: Cardiac insufficiency induced by widespread microthrombi in microvessels Decreased blood volume resulting from bleeding Activation and release of kinin and bradykinin contribute to dilation of microvessels, leading to increased volume of peripheral vessels. DIC shock

3. Multiple organ dysfunction 60% of DIC patients Kidney and lung suffer the most frequently Mechanisms: widespread occlusion of microvessels by microthrombi induces ischemia, hypoxia of tissue cells, leading to disorders in metabolism, functions. Kinin, bradykinin, complement and inflammatory factors generated during onset and development of DIC Reperfusion induced by fibrinolysis of thrombus can produce oxygen free radical, which may lead to further damage to organs

DIC导致的常见器官功能障碍 累及器官 功能变化及常见临床表现 肾 脏 急性肾功能障碍：少尿、氮质血症、水肿等 肝 脏 胃肠道 累及器官 功能变化及常见临床表现 肾 脏 急性肾功能障碍：少尿、氮质血症、水肿等 肝 脏 胃肠道 消化道出血、溃疡 心 脏 心脏功能障碍：低血压、心功能指标异常等 肺 急性呼吸功能障碍：呼吸困难、低氧血症 神经系统 脑出血、脑栓塞 急性肝功能障碍：血清转氨酶升高、黄疸

4. microangiopathic hemolytic anemia (MAHA ) 概念： 纤维蛋白丝在微血管腔内形成网状结构，红细胞流过网孔时受到机械性损伤而破坏所导致的溶血性贫血。 Schistocytes (裂体细胞）in peripheral blood Mechanisms： physical damage to red blood cells during their passage through net of fibrin deposited in the microvessels Reduced deformability of RBC

DIC发生、发展的机制及对机体影响 原发疾病 组织损伤 VEC损伤 血细胞损伤、活化 促凝物质入血 凝血系统活化 凝血酶形成 继发性纤溶 FDP形成 血小板活化 纤维蛋白形成 MAHA 微血栓形成 凝血因子消耗、破坏 血小板消耗、减少 出血 组织细胞缺血坏死 器官功能障碍 出血

六、DIC的诊断和防治原则 （一） DIC的诊断依据 1. 原发病 2. 临床表现 3. 实验室凝血指标检查阳性 1) 血小板减少（<100×109/L或进行性下降） 2）血浆纤维蛋白原减少（<1.5g/L或进行性下降) 3) 凝血酶原或活化的部分凝血酶原时间异常 4）3P试验阳性，或DD升高 4. 抗凝治疗有效

FDP 概念： 纤维蛋白降解产物，指纤维蛋白（原）被纤溶酶分解后形成的多肽碎片 作用： 1 裂解产物X片段与纤维蛋白单体结合，抑制纤维蛋白单体聚合；D片段抑制纤维蛋白交联形成不溶性纤维蛋白。 2 片段Y、E抑制纤维蛋白单体聚合，并能拮抗凝血酶。 3 抑制血小板黏附聚集。

FDP检测 可溶 X FM X FM FM 沉淀 3P 试验 (plasma protamin paracoagunation test， 鱼精蛋白副凝试验) ： 鱼精蛋白 X FM FM 沉淀 D-二聚体检查(Detection of D-dimer )：纤溶酶水解纤维蛋白多聚体产生D-二聚体。 是继发性纤溶亢进指标

(二) DIC的治疗原则 1. 防治原发病 2. 改善微循环 3. 重新建立凝血和纤溶间的动态平衡 1）早期进行抗凝治疗——肝素 2）在肝素治疗基础上，补充凝血因子和血小板 3）在肝素治疗基础上，加用抗纤溶药 4. 保护重要器官