Diagnosis and treatment of disseminated intravascular coagulation文档格式.docx

1、 2014 John Wiley & Sons LtdKeywords:Disseminated intravascular coagulation;platelets;coagulation factors;fibrin degradation products;tissue factor;antithrombin;activated protein C;thrombomodulinSummaryDisseminated intravascular coagulation （DIC） is a condition in which systemic activation of coagula

2、tion without a specific localization occurs, resulting in extensive formation of intravascular fibrin, particularly in small and midsize vessels. Disseminated intravascular coagulation may lead to several altered coagulation parameters, including a low platelet count, abnormal global clotting assays

3、, low levels of physiological anticoagulant proteases, or increased fibrin degradation products. Also, more complex assays for activation of coagulation factors or pathways may indicate involvement of these molecules in DIC. None of these tests alone, however, can accurately ascertain or rebuff a di

4、agnosis of DIC. Nonetheless, a combination of readily available routine assays may be instrumental in establishing a diagnosis of DIC and can also be useful to point to a subset of patients with DIC that may need definite, often costly, interventions in the hemostatic system. Current insights on rel

5、evant etiological pathways that may contribute to the occurrence of DIC have led to innovative therapeutic and adjunctive approaches to patient with DIC. Management options directed at the amelioration of hemostatic activation may tentatively be indicated and were found to be advantageous in experim

6、ental and clinical investigations. These treatments encompass elimination of tissue factor-mediated thrombin generation or restitution of normal anticoagulant function.IntroductionDisseminated intravascular coagulation （DIC） is an intense manifestation of hemostatic activation that may occur in a va

7、riety of clinical settings, most of which imply some degree of local or widespread inflammation. Activation of coagulation in the systemic circulation, inefficiently counteracted by coagulation inhibitors and amplified by decreased physiological fibrin-degrading potential, may result in fibrin forma

8、tion in small and midsize vessels and microvascular thrombotic microangiopathy 1. The substantial and continuing thrombin generation may result in exhaustion of coagulation proteases and platelets, leading to an increased risk of serious hemorrhagic complications, which sometimes may be the most imp

9、ressive clinical presentation. Currently, most etiological factors in DIC have been identified, which may lead to a more accurate diagnosis of the disorder. Nevertheless, the precise diagnosis of DIC may be tricky, as most assays demonstrate exhaustion of coagulation proteases or indicate thrombocyt

10、openia, while biomarkers that indicate specific activation of a coagulation factor or pathway are mostly inaccurate and are often not accessible in most hospitals on a 24 h basis 2, 3. In this overview, we will discuss both widely available and more complex laboratory assays that may be helpful in t

11、he diagnosis of DIC.With growing understanding that the simultaneous activation of systemic inflammatory activity and activation of hemostasis may lead to organ failure in critically ill patients, the adjunctive management of DIC has been intensely studied recently 4. Current thinking about the path

12、ophysiology of DIC has resulted in novel strategies directed at inhibiting the initiation or propagation of fibrin formation. The most important therapeutic options will be reviewed in this study.Laboratory Findings in DICPlateletsLow platelets or a rapidly developing thrombocytopenia is a central c

13、haracteristic of DIC （Table 1）. As a platelet count of 150 109/L in intensive care patients frequently occurs 5, 6, a low platelet count is not a specific feature of DIC. Moderate-to-severe thrombocytopenia （platelets 100 109/L） is observed in the majority of patients with DIC, whereas a smaller pro

14、portion of patients （about 1015%） have severe thrombocytopenia （50 109/L）. In critically ill postoperative patients with DIC, thrombocytopenia （80% 7. The importance of a low platelet count in DIC is associated with an increased risk of hemorrhagic complications, especially patients with a thrombocy

15、topenia of 109/L have a fourfold to fivefold increased risk for hemorrhage in comparison with patients with normal platelet numbers, above all when the patient uses antithrombotic agents 5. The risk of intracranial hemorrhage in patients with DIC is relatively modest （0.30.5%）, but more than 85% of

16、patients with DIC with this event, a moderate or severe thrombocytopenia （ 109/L） is present. In spite of the origin, a low platelet count is an independent prognostic factor in ICU survival with a relative risk of 24 in various investigations 5, especially, a sustained low platelet count during mor

17、e than 4 days after admission to a critical care department or a worsening thrombocytopenia during admission of a critically ill patient is related to a fivefold increased risk of death 5, 8.Table 1. Routine laboratory value abnormalities in DICTest Abnormality Causes other than DIC contributing to

18、test resultae.g., protein C, AT, protein S.Platelet count Decreased Sepsis, impaired production, major blood loss, hypersplenismProthrombin time Prolonged Vitamin K deficiency, liver failure, major blood lossaPTT Prolonged Liver failure, heparin treatment, major blood lossFibrin degradation products

19、 Increased HematomaProtease inhibitorsa Decreased Liver failure, capillary leakageCoagulation factors and global clotting timesOngoing activation and subsequent exhaustion of coagulation proteases results in decreased concentrations of these factors in patients with DIC （Table 1）. Also, reduced prod

20、uction of clotting factors, caused by attenuated liver function and/or shortage of vitamin K, and simultaneous coagulation factor reductions, due to substantial hemorrhage, may be important in DIC （Table 2） 9. Despite the fact that the preciseness of one-stage clotting measurements in consumption co

21、agulopathies has been debated （due to interference with activated coagulation factors in the assay）, the concentration of clotting factors seems to show a fairly good relationship with the intensity of DIC. The reduced level of clotting factors is readily detected by abnormal coagulation screening t

22、ests, including the prothrombin time （PT） or the activated partial thromboplastin time （aPTT）. An abnormal PT or aPTT can be found in 1530% of critically ill patients and occurs in the vast majority of patients with DIC 10. However, it should be mentioned that overall clotting assays, such as the PT

23、 and aPTT, not very well mirror in vivo coagulation. Nevertheless, these assays are a readily available means to swiftly assess the level of one or more clotting factors 11. Usually, global clotting assays will become abnormal if the concentration of clotting proteins is 50% and for some reagents on

24、ly 3040%. This is important because the concentrations of clotting factors, that are required for correct functioning of coagulation, are approximately in the range of 2550%. Various reagents may produce highly variable normal values and abnormal levels. Because of this, a growing number of laborato

25、ries are employing the international normalized ratio （INR） as a substitute of the PT. The advantage of enhanced comparability between centers, however, should be offset against the fact that the INR has not been developed as a screening test for clotting abnormalities 12, 13.Table 2. Differential d

26、iagnosis of suspected DICDifferential diagnosis Additional diagnostic cluesDIC Prolonged aPTT and PT, increased fibrin split products, low levels of physiological anticoagulant factors （antithrombin, protein C）Massive blood loss Major bleeding, low hemoglobin, prolonged aPTT and PT,Thrombotic microa

27、ngiopathy Schistocytes in blood smear, Coombs-negative hemolysis, fever, neurologic symptoms, renal insufficiency, coagulation times usually normal, ADAMTS13 levels decreased; PT and aPTT normalHeparin-induced thrombocytopenia Use of heparin, venous or arterial thrombosis, positive HIT test （usually

28、 ELISA for heparin-platelet factor IV antibodies）, rebound of platelets after cessation of heparin; coagulation times usually normal; PT normal （aPTT may be prolonged due to heparin）Vitamin K deficiency PT prolonged, aPTT normal or slightly prolonged, normal platelet countLiver insufficiency PT and

29、aPTT prolonged, platelets （moderately） low, liver test abnormalities, hypersplenism, jaundiceIn contradiction to most other coagulation factors, plasma concentrations of factor VIII are markedly increased in most patients with DIC, presumably caused by substantial release of von Willebrand factor fr

30、om vascular endothelial cells and acute phase properties of factor VIII. Previous investigations have directed at a relative deficiency of the von Willebrand factor cleaving protease ADAMTS-13, which may result in increased levels of very large von Willebrand multimers in plasma, promoting platelet-

31、vessel wall binding and the ensuing occurrence of a thrombotic microangiopathic condition, which may also be a factor in organ failure 14.In older literature, assessment of fibrinogen is often mentioned as a valuable assay to ascertain the presence of DIC; however, this marker is not useful to estab

32、lish DIC in the vast majority of patients. Fibrinogen behaves as an acute phase protein, and therefore, its concentration can be completely normal for a long time despite massive consumption levels. The accuracy of a low fibrinogen concentration in case of DIC was 30%, and low levels of fibrinogen were only established in patients