TR-05969; No of Pages 4 Thrombosis Research xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Management of disseminated intravascular coagulation: A survey of the International Society on Thrombosis and Haemostasis Marcello Di Nisio a,b,⁎, Jecko Thachil c, Alessandro Squizzato d a
Department of Medical, Oral and Biotechnological Sciences, University "G. D'Annunzio" of Chieti-Pescara, Chieti, Italy Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands Department of Haematology, Manchester Royal Infirmary, Oxford road, Manchester, United Kingdom, M13 9WL d Research Center on Thromboembolic Disorders and Antithrombotic Therapies, Department of Clinical and Experimental Medicine, University of Insubria, Varese, Italy b c
a r t i c l e
i n f o
Article history: Received 31 March 2015 Received in revised form 18 May 2015 Accepted 21 May 2015 Available online xxxx Keywords: Disseminated intravascular coagulation Venous thrombosis Arterial thrombosis Management
a b s t r a c t Introduction: It is not clear if and how international guidelines on the management of disseminated intravascular coagulation (DIC) are translated in routine clinical practice. Materials and Methods: A survey was conducted among different specialists who treat DIC. The survey examined six hypothetical case scenarios including the diagnosis of DIC, the treatment of non-overt and overt DIC with or without thrombosis, and the management of DIC patients at risk of bleeding or actively bleeding. Results: There were 191 respondents and 73 returned complete questionnaires. Most of respondents were specialists in hematology (48%) or intensive care (30%). In suspected overt or non-overt DIC, only one third use formal diagnostic scores while two thirds rely on a broad panel of coagulation tests independently of any score. In non-overt DIC, 68% provide no treatment, but monitor laboratory tests. Monitoring was considered by 48% of respondents in overt DIC without thrombosis or bleeding. When a thrombotic or bleeding complication ensues, 29% consider intervening only if the event is major. In DIC patients judged at risk of bleeding, 67% use prophylactic transfusions, mostly fresh-frozen plasma (73%) and platelets (65%). Active bleeding is often managed with fresh-frozen plasma (83%) and platelet transfusions (68%) as first line and recombinant activated factor VII (31%) as second line treatment. Conclusions: This survey shows a largely heterogeneous approach of clinicians to the diagnosis and management of DIC. There is limited use of diagnostic scores despite guidelines' recommendations. The prevalent attitude seems monitoring DIC and limiting treatment to the underlying disease, unless thrombosis or bleeding develop, but modalities varied considerably. © 2015 Elsevier Ltd. All rights reserved.
Introduction Disseminated intravascular coagulation (DIC) is a systemic activation of blood coagulation that may complicate a wide spectrum of disorders such as sepsis or malignancy [1]. The term “non-overt DIC” is usually used to indicate a compensated activation of the hemostatic system, whereas “overt DIC” designates a decompensated state that may lead to thrombosis of small- and medium-sized vessels and bleeding due to the consumption of platelets and coagulation factors. There is no gold standard for the diagnosis of DIC and no single laboratory test has shown sufficiently high diagnostic accuracy to establish or rule out the diagnosis of DIC [2]. While diagnostic scores combining clinical and laboratory parameters have been proposed [2–4], it is uncertain if and how often these scores are applied in clinical practice. ⁎ Corresponding author at: Department of Medical, Oral and Biotechnological Sciences, University G. D’Annunzio, Chieti, Italy. E-mail addresses: [email protected] (M. Di Nisio), [email protected] (J. Thachil), [email protected] (A. Squizzato).
Once DIC is diagnosed, physicians have to decide whether any treatment aiming at improving the haemostatic abnormalities needs to be added to the treatment of the condition underlying DIC as the latter will often lead to a spontaneous resolution of the coagulopathy. In the presence of thrombotic or bleeding complications, the decision of treating or refraining from giving any therapy may be challenging as scarce information is available in the literature to guide decision making, and recommendations remain largely based on expert opinion [2–4]. The objective of the present worldwide survey was to investigate current diagnostic approaches and management practice patterns for DIC patients with or without concomitant thrombotic or bleeding complications.
Materials and Methods The survey was published online on the website of the International Society on Thrombosis and Haemostasis (ISTH) (http://www.isth.org)
http://dx.doi.org/10.1016/j.thromres.2015.05.022 0049-3848/© 2015 Elsevier Ltd. All rights reserved.
Please cite this article as: M. Di Nisio, et al., Management of disseminated intravascular coagulation: A survey of the International Society on Thrombosis and Haemostasis, Thromb Res (2015), http://dx.doi.org/10.1016/j.thromres.2015.05.022
2
M. Di Nisio et al. / Thrombosis Research xxx (2015) xxx–xxx
with the purpose to reach a large number of physicians practicing in several countries and specialties potentially related to DIC. The questionnaire examined six hypothetical case scenarios (Table 1 and online supplementary material): the diagnostic approach to patients with suspected DIC (hypothetical case scenario 1); treatment of non-overt DIC (hypothetical case scenario 2); approach to overt DIC without (hypothetical case scenario 3) or with arterial thrombosis or venous thromboembolism (VTE) (hypothetical case scenario 4); management of patients at risk of bleeding (hypothetical case scenario 5) or actively bleeding (hypothetical case scenario 6). Data were analyzed using descriptive statistics. Since not all participants fully completed the survey, proportions were calculated based on the number of respondents for each question. Results There were 191 respondents of whom 73 returned complete questionnaires available for analysis. Most of the participants were specialists in hematology (48%), intensive care (30%), internal medicine (12%), and emergency unit (7%), while the remaining practiced in oncology (1%), infectious diseases (5%), trauma (3%) and pulmonary medicine (1%) units. The participants were mostly from Asia (mainly Japan, 28%), Europe (23%), North America (16%), with a minority from South America (7%) or Africa (4%). Sepsis or septic shock was reported as the most frequent underlying cause of DIC in the physicians’ practice (88%) followed by hematological cancer (29%), pregnancy or obstetric complications (18%). Lower proportions of respondents reported other causes of DIC including solid cancer (11%), trauma (11%), advanced liver disease (8%), surgery (7%), vascular malformations (4%), and severe toxic or immunologic reactions (3%). Hypothetical case scenario 1 In patients with suspected overt DIC, 37% of the respondents would use a formal diagnostic score, namely the score of the ISTH (62%), of the Japanese Association for Acute Medicine (29%), or of the Japanese Ministry of Health and Welfare (10%). Table 2 presents an overview of the diagnostic scores. Up to 60% of participants do not calculate any score and request a number of coagulation tests which include in more than two-thirds of cases the D-dimer, platelet count, prothrombin time, fibrinogen, and the activated partial thromboplastin time (Table 3). The international normalised ratio, fibrin degradation products, schistocytes, hemoglobin, and antithrombin are requested by about one-third whereas less than 10% of the respondents use tests such as the wave-form analysis, protein S/C, thromboelastography, or thrombin-antithrombin complexes.
Once DIC is diagnosed, 94% of physicians monitor DIC evolution by repeating laboratory testing on a daily basis (67%). Frequency of monitoring was decided on case-by-case in one-fourth of the cases. In patients with suspected non-overt DIC, 31% use a formal diagnostic score while 66% rely on a combination of coagulation tests independently of any score. Hypothetical case scenario 2 In patients with non-overt DIC, 68% of participants would not provide any treatment, but monitor laboratory tests; 29% would treat, most frequently with low-molecular-weight heparin (LMWH) (Table 4). The dose of LMWH is frequently decided on case-by-case basis in relation to the bleeding risk of the patient (73%). If a decision is made to treat, 25% provide therapy until resolution of DIC, 29% until clinical improvement of the underlying condition, and 42% consider both to decide on the duration. VTE prophylaxis in non-overt DIC patients is practiced by 86% of the respondents irrespective of other co- morbidities (27%) or only if other co-morbidities suggest a high risk of VTE (59%). LMWH is the preferred type of prophylaxis (54%), followed by mechanical prophylaxis, with elastic stockings (27%) or pneumatic compression (19%), unfractionated heparin (UFH, 16%), and fondaparinux (6%). One fourth uses a combination of both pharmacological and nonpharmacological prophylaxis (25%). Hypothetical case scenario 3 In patients with overt DIC without evidence of thrombosis or bleeding, half of the respondents (48%) would only monitor laboratory tests while 49% treat (Table 4) until DIC resolution (38%), clinical improvement of the underlying condition (20%), or both (35%). Only 10% choose not to give any VTE prophylaxis while all others would use it, irrespective of co- morbidities (31%) or depending on VTE risk (59%). As for nonovert DIC, the most frequently used types of VTE prophylaxis included LMWH (42%), elastic stockings (27%), pneumatic compression (17%), a combination of pharmacological and non-pharmacological prophylaxis (23%), UFH (18%), and fondaparinux (5%). Hypothetical case scenario 4 In patients with overt DIC and thrombosis, 71% of respondents provide treatment independently of the type of event, while 29% consider treating only major thrombotic events such as pulmonary embolism (90%), proximal deep vein thrombosis (86%), arterial thrombosis (myocardial infarction, stroke, acute visceral and leg ischemia, 86%). A lower
Table 1 Synopsis of the six hypothetical case scenarios evaluated in the questionnaire. DIC = disseminated intravascular coagulation; ISTH = International Society on Thrombosis and Haemostasis; JMHW = Japanese Ministry of Health and Welfare; VTE = venous thromboembolism. Scenario
Diagnosis of DIC
Treatment of DIC
Case
Case 1 Suspected DIC
Case 2 Non-overt DIC
Information inquired in the questionnaire
Diagnostic test(s) used for suspected overt-DIC:
1. Diagnostic score (e.g. ISTH, JMHW) 2. Combination of coagulation tests independently of any score If and how often monitoring of DIC evolution by laboratory tests Diagnostic test(s) used for suspected non-overt DIC
Case 4 DIC and thrombosis
Case 5 DIC at risk of bleeding
Case 6 DIC and active bleeding
Treatment provided, if any
Case 3 DIC without thrombosis or bleeding Treatment provided, if any
Treatment provided, if any
Treatment provided, if any
Treatment provided, if any
Type, dose, and duration of treatment Prophylaxis for VTE, if any
Type, dose, and duration of treatment Prophylaxis for VTE, if any
Type of arterial or venous event prompting intervention Additional treatment for DIC
Type and duration of treatment
Type, dose, and duration of treatment Therapy, if any, after bleeding resolves
Please cite this article as: M. Di Nisio, et al., Management of disseminated intravascular coagulation: A survey of the International Society on Thrombosis and Haemostasis, Thromb Res (2015), http://dx.doi.org/10.1016/j.thromres.2015.05.022
M. Di Nisio et al. / Thrombosis Research xxx (2015) xxx–xxx
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Table 2 Overview of diagnostic scores for Disseminated Intravascular Coagulation. DIC = disseminated intravascular coagulation; ISTH = International Society on Thrombosis and Haemostasis; JMHW = Japanese Ministry of Health and Welfare; JAAM = Japanese Association for Acute Medicine. ISTH
JMHW
JAAM
Underlying disorder known to be associated with DIC Bleeding
Mandatory
1 point
0 points
0 points
0 points
Thrombosis-related organ failure
0 points
Systemic inflammatory response syndrome criteria Prolonged thrombin time
0 points
No hematological malignancy: 1 point Hematological malignancy: 0 point Present: 1 point Absent: 0 point 0 points
b3 sec: 0 points ≥3 sec: 1 point ≥6 sec: 2 points
Fibrinogen level (g/L)
N1: 0 points ≤1: 1 point
Fibrin related marker (e.g. d-dimer)
No increase: 0 point Moderate increase: 2 points (D-dimer: increase ≤10 fold limit of normal) Marked increase: 3 points (N10 fold limit of normal)
Platelet count (x109/μL)
N100: 0 point ≤100: 1 point ≤50: 2 points
Total
DIC ≥ 5 points No DIC b 5 points
proportion of physicians consider treatment of cerebral sinus vein thrombosis (62%), visceral thrombosis (57%), or distal deep vein thrombosis (29%). The preferred types of treatment for an arterial or venous thrombotic event are shown in Table 4. The majority of physicians chose to continue antithrombotic therapy until the Table 3 Diagnostic scoring systems and laboratory tests used for the diagnosis of DIC. Data are reported as percentage of respondents using the specific test. Each respondent could indicate more than one test. DIC = disseminated intravascular coagulation; ISTH = International Society on Thrombosis and Haemostasis. % of respondents Any formal diagnostic score ISTH Japanese Ministry of Health and Welfare Japanese Association for Acute Medicine Laboratory test independently of any score Prothrombin time Activated partial thromboplastin time International normalized ratio Wave-form analysis D-dimer Fibrinogen Soluble fibrin monomers Fibrin degradation products Platelet count Hemoglobin Schistocytes Antithrombin Protein C Protein S Thrombin-antithrombin complexes Platelet aggregation test Thrombelastography Other
37 62 10 29 63 74,2 65,2 39,4 3 84,9 75,8 10,6 31,8 87,9 39,4 39,4 34,9 13,6 4,6 7,6 0 7,6 6,1
Prothrombin time ratio: b1.25: 0 points 1.25-1.67: 1 point ≥1.67: 2 points N1.5: 0 points 1.0-1.5: 1 point ≤1: 2 points Fibrin degradation product (μg/mL): b10: 0 point 10–20: 1 point 20–40: 2 points ≥40: 3 points Hematological malignancy: 0 points No hematological malignancy: N120: 0 points 80–120: 1 point 50–80: 2 points ≤50: 3 points Hematological malignancy: ≥4 points No hematological malignancy: ≥7 points
0 points 0-2: 0 points ≥3: 1 points Prothrombin time ratio: b1.2: 0 points ≥1.2: 1 point ≥3.5: 0 points b3.5: 1 point Fibrin/fibrinogen degradation products (mg/L) b10: 0 point ≥10 and b25: 1 point ≥25: 3 points ≥120: 0 point ≥80 and b120 or N30% decrease within 24 hrs: 1 point b80 or N50% decrease within 24 hrs: 3 points
DIC ≥ 5 points No DIC b 5 points
resolution or improvement of the thrombotic event (49%) or till clinical improvement (24%) while one fourth awaits the resolution of the DIC (26%). In addition to the treatment for the thrombotic event, half (51%) of respondents consider therapy for DIC and most often use antithrombin (40%), transfusions of plasma (40%) or platelets (16%), LMWH (30%), or recombinant thrombomodulin (19%).
Table 4 Treatment options for non overt DIC, overt DIC with or without thrombotic complications. Data are reported as percentage of respondents using the specific treatment. Each respondent could indicate more than one test. DIC = disseminated intravascular coagulation.
Low molecular weight heparin Unfractionated heparin Fondaparinux Direct factor Xa inhibitor Direct thrombin inhibitor Thrombolytic agent Antiplatelet agent Dermatan sulphate Antithrombin Recombinant human activated protein C Recombinant soluble thrombomodulin Protein C concentrate Gabexate Antifibrinolytic agents Platelet transfusion Plasma Transfusion Other
Non-overt DIC
Overt DIC with no thrombosis
DIC and arterial thrombosis
DIC and VTE
42,9 23,8 4,8 19,1 4,8
33,3 19,4 8,3 2,8 22,2 2,8
48 27,4 2,7 9,6 21,9 2,7 40,5 -
60,3 32,9 2,7 4,1 2,7 2,7 40,5 -
14,3
13,9
18,9
18,9
4,8 14,3 28,6 14,3
2,8 5,6 8,3 22,2 33,3 5,6
2,7 8,1 2,7 16,2 40,5 2,7
2,7 8,1 2,7 16,2 40,5 2,7
Please cite this article as: M. Di Nisio, et al., Management of disseminated intravascular coagulation: A survey of the International Society on Thrombosis and Haemostasis, Thromb Res (2015), http://dx.doi.org/10.1016/j.thromres.2015.05.022
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M. Di Nisio et al. / Thrombosis Research xxx (2015) xxx–xxx
Hypothetical case scenario 5 In patients with overt DIC who are regarded to be at risk of bleeding, 67% consider treatment with either transfusion of fresh-frozen plasma (73%), platelets (65%), plasma (29%), cryoprecipitate (35%), and less frequently anti-fibrinolytic agents (22%), fibrinogen concentrate (16%), recombinant activated factor VII (6%) or coagulation factors concentrate (4%). Laboratory test results (60%) or personal clinical experience (29%) guide the decision on the length of treatment. Hypothetical case scenario 6 In patients with DIC and active bleeding, 71% of the respondents provide treatment while 29% consider treating only if the bleeding is regarded as major. First line treatments were most often fresh-frozen plasma (84%) and platelet transfusion (68%), whereas the most used second line treatment was recombinant activated factor VII (31%). When the bleeding has resolved, 68% would not provide additional transfusion of platelets, plasma or coagulation factors while 31% would continue transfusing until laboratory tests improve further. Discussion Results of the current survey suggest a rather heterogeneous approach of clinicians to the management of DIC. International guidelines, which recommend adopting diagnostic scores for suspected DIC [2–4], seem poorly implemented in clinical practice where the majority of the respondents prefer the use of multiple coagulation tests independently of any score. Furthermore, when the diagnosis of DIC is attempted through a formal diagnostic score, the choice of the score appears relatively heterogeneous possibly due to country-specific practices. The sparse use of diagnostic scores may be the consequence of their limited validation among populations of different ethnicities or various conditions underlying DIC, the emerging role of dynamic scores, or the uncertain reliability of these scores in the absence of a reference standard. A number of studies found that increasing values of the scores of the ISTH, Japanese Ministry of Health and Welfare, or of the Japanese Association for Acute Medicine Additional predict a worse outcome, which may increase their clinical usefulness and applicability [6–10]. This prognostic value and the possibility to identify DIC patients who may benefit from additional diagnostic and/or therapeutic procedures need further confirmation and direct comparison against dynamic scores [11]. Interestingly, half of the respondents provide no specific treatment aiming at DIC resolution in patients with overt DIC and two thirds would feel comfortable not giving any therapy in non-overt DIC. Thus, in the absence of thrombotic or bleeding complications, a substantial proportion of clinicians would limit the intervention to the laboratory monitoring of the coagulopathy and treatment of the underlying disorder. This approach appears, at least partly, in conflict both with the guidelines advocating a number of interventions to improve the haemostatic abnormalities [5], and observational studies which often report multiple treatments for DIC [12,13]. To the best of our knowledge, there are no specific guidelines looking at bleeding or thrombosis management in DIC against which we could compare the results of the survey. While most of the physicians provides mechanical and/or pharmacological VTE prophylaxis to DIC patients, there was poor agreement about the type and doses of drugs. Finally, substantial heterogeneity was observed for the management of thrombosis or bleeding with regard to the need of, type and duration of treatment. Some of the reasons that could explain the discrepant approaches are the lack of solid evidence to guide decision-making in such challenging scenarios as well as the between-country differences in terms of policies and regulations. A limitation of the present survey was the relatively small size
that did not allow to explore potential variations in DIC management according to different disorders underlying DIC. Responses may be in part driven by different perception of what constitutes overt vs. nonovert DIC and what constitutes a bleeding risk. In summary, this survey showed a broad heterogeneity in the management of DIC suggesting that physician's approach is often based on personal experience with poor translation of international guidelines into clinical practice. As most of the clinical evidence on DIC comes from studies that enrolled patients with sepsis or septic shock, an even greater heterogeneity can be expected in the management of DIC caused by other underlying diseases, which could be the focus of future prospective studies. Disclosure of Conflict of interest The authors state that they have no conflict of interest. Acknowledgements The authors would like to thank all respondents who kindly consented to participate in this survey. The authors also thank Dr. Satoshi Gando, Dr. Steven Opal, Dr. Jerrold Levy, and Dr. Andrea De Gasperi for helping with spreading the survey among colleagues of the ISTH and Dr. Lacey Schmeidler for the support with the preparation of the online survey. Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.thromres.2015.05.022. References [1] M. Levi, H. ten Cate, Disseminated intravascular coagulation, N. Engl. J. Med. 341 (1999) 586–592. [2] M. Di Nisio, F. Baudo, B. Cosmi, A. D'Angelo, A. De Gasperi, A. Malato, et al., on behalf of the Italian Society for Thrombosis and Haemostasis, Diagnosis and treatment of disseminated intravascular coagulation: Guidelines of the Italian Society for Haemostasis and Thrombosis (SISET), Thromb. Res. 129 (2012) e177–84. [3] M. Levi, C.H. Toh, J. Thachil, H.G. Watson, Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology, Br. J. Haematol. 145 (2009) 24–33. [4] H. Wada, H. Asakura, K. Okamoto, T. Iba, T. Uchiyama, K. Kawasugi, et al., Japanese Society of Thrombosis Hemostasis/DIC subcommittee, Expert consensus for the treatment of disseminated intravascular coagulation in Japan, Thromb. Res. 125 (2010) 6–11. [5] H. Wada, J. Thachil, M. Di Nisio, P. Mathew, S. Kurosawa, S. Gando, et al., Guidance for diagnosis and treatment of disseminated intravascular coagulation from harmonization of the recommendations from three guidelines, J. Thromb. Haemost. 11 (2013) 761–767. [6] K. Bakhtiari, J.C.M. Meijers, E. de Jonge, M. Levi, Prospective validation of the International Society of Thrombosis and Haemostasis scoring system for disseminated intravascular coagulation, Crit. Care Med. 32 (2004) 2416–2421. [7] M.W.A. Angstwurm, C.-E. Dempfle, M. Spannagl, New disseminated intravascular coagulation. score: A useful tool to predict mortality in comparison with Acute Physiology and Chronic Health Evaluation II and Logistic Organ Dysfunction scores, Crit. Care Med. 34 (2006) 314–320. [8] S. Gando, D. Saitoh, H. Ogura, T. Mayumi, K. Koseki, T. Ikeda, et al., Natural history of disseminated intravascular coagulation diagnosed based on the newly established diagnostic criteria for critically ill patients: Results of a multicenter, prospective survey, Crit. Care Med. 36 (2008) 145–150. [9] T. Takemitsu, H. Wada, T. Hatada, Y. Ohmori, K. Ishikura, T. Takeda, et al., Prospective evaluation of three different diagnostic criteria for disseminated intravascular coagulation, Thromb. Haemost. 105 (2011) 40–44. [10] K. Iwai, S. Uchino, A. Endo, K. Saito, Y. Kase, M. Takinami, Prospective external validation of the new scoring system for disseminated intravascular coagulation by Japanese Association for Acute Medicine (JAAM), Thromb. Res. 126 (2010) 217–221. [11] G.T. Kinasewitz, J.G. Zein, G.L. Lee, S.A. Nazir, F.B. Taylor, Prognostic value of a simple evolving disseminated intravascular coagulation score in patients with severe sepsis, Crit. Care Med. 33 (2005) 2214–2221. [12] H. Asakura, H. Takahashi, H. Tsuji, T. Matsushita, H. Ninomiya, G. Honda, et al., Postmarketing surveillance of thrombomodulin alfa, a novel treatment of disseminated intravascular coagulation - safety and efficacy in 1,032 patients with hematologic malignancy, Thromb. Res. 133 (2014) 364–370. [13] T. Iba, D. Saito, H. Wada, H. Asakura, Efficacy and bleeding risk of antithrombin supplementation in septic disseminated intravascular coagulation: A prospective multicenter survey, Thromb. Res. 130 (2012) e129–e133.
Please cite this article as: M. Di Nisio, et al., Management of disseminated intravascular coagulation: A survey of the International Society on Thrombosis and Haemostasis, Thromb Res (2015), http://dx.doi.org/10.1016/j.thromres.2015.05.022
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Management of disseminated intravascular coagulation: A survey of the International Society on Thrombosis and Haemostasis Marcello Di Nisio a,b,⁎, Jecko Thachil c, Alessandro Squizzato d a
Department of Medical, Oral and Biotechnological Sciences, University "G. D'Annunzio" of Chieti-Pescara, Chieti, Italy Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands Department of Haematology, Manchester Royal Infirmary, Oxford road, Manchester, United Kingdom, M13 9WL d Research Center on Thromboembolic Disorders and Antithrombotic Therapies, Department of Clinical and Experimental Medicine, University of Insubria, Varese, Italy b c
a r t i c l e
i n f o
Article history: Received 31 March 2015 Received in revised form 18 May 2015 Accepted 21 May 2015 Available online xxxx Keywords: Disseminated intravascular coagulation Venous thrombosis Arterial thrombosis Management
a b s t r a c t Introduction: It is not clear if and how international guidelines on the management of disseminated intravascular coagulation (DIC) are translated in routine clinical practice. Materials and Methods: A survey was conducted among different specialists who treat DIC. The survey examined six hypothetical case scenarios including the diagnosis of DIC, the treatment of non-overt and overt DIC with or without thrombosis, and the management of DIC patients at risk of bleeding or actively bleeding. Results: There were 191 respondents and 73 returned complete questionnaires. Most of respondents were specialists in hematology (48%) or intensive care (30%). In suspected overt or non-overt DIC, only one third use formal diagnostic scores while two thirds rely on a broad panel of coagulation tests independently of any score. In non-overt DIC, 68% provide no treatment, but monitor laboratory tests. Monitoring was considered by 48% of respondents in overt DIC without thrombosis or bleeding. When a thrombotic or bleeding complication ensues, 29% consider intervening only if the event is major. In DIC patients judged at risk of bleeding, 67% use prophylactic transfusions, mostly fresh-frozen plasma (73%) and platelets (65%). Active bleeding is often managed with fresh-frozen plasma (83%) and platelet transfusions (68%) as first line and recombinant activated factor VII (31%) as second line treatment. Conclusions: This survey shows a largely heterogeneous approach of clinicians to the diagnosis and management of DIC. There is limited use of diagnostic scores despite guidelines' recommendations. The prevalent attitude seems monitoring DIC and limiting treatment to the underlying disease, unless thrombosis or bleeding develop, but modalities varied considerably. © 2015 Elsevier Ltd. All rights reserved.
Introduction Disseminated intravascular coagulation (DIC) is a systemic activation of blood coagulation that may complicate a wide spectrum of disorders such as sepsis or malignancy [1]. The term “non-overt DIC” is usually used to indicate a compensated activation of the hemostatic system, whereas “overt DIC” designates a decompensated state that may lead to thrombosis of small- and medium-sized vessels and bleeding due to the consumption of platelets and coagulation factors. There is no gold standard for the diagnosis of DIC and no single laboratory test has shown sufficiently high diagnostic accuracy to establish or rule out the diagnosis of DIC [2]. While diagnostic scores combining clinical and laboratory parameters have been proposed [2–4], it is uncertain if and how often these scores are applied in clinical practice. ⁎ Corresponding author at: Department of Medical, Oral and Biotechnological Sciences, University G. D’Annunzio, Chieti, Italy. E-mail addresses: [email protected] (M. Di Nisio), [email protected] (J. Thachil), [email protected] (A. Squizzato).
Once DIC is diagnosed, physicians have to decide whether any treatment aiming at improving the haemostatic abnormalities needs to be added to the treatment of the condition underlying DIC as the latter will often lead to a spontaneous resolution of the coagulopathy. In the presence of thrombotic or bleeding complications, the decision of treating or refraining from giving any therapy may be challenging as scarce information is available in the literature to guide decision making, and recommendations remain largely based on expert opinion [2–4]. The objective of the present worldwide survey was to investigate current diagnostic approaches and management practice patterns for DIC patients with or without concomitant thrombotic or bleeding complications.
Materials and Methods The survey was published online on the website of the International Society on Thrombosis and Haemostasis (ISTH) (http://www.isth.org)
http://dx.doi.org/10.1016/j.thromres.2015.05.022 0049-3848/© 2015 Elsevier Ltd. All rights reserved.
Please cite this article as: M. Di Nisio, et al., Management of disseminated intravascular coagulation: A survey of the International Society on Thrombosis and Haemostasis, Thromb Res (2015), http://dx.doi.org/10.1016/j.thromres.2015.05.022
2
M. Di Nisio et al. / Thrombosis Research xxx (2015) xxx–xxx
with the purpose to reach a large number of physicians practicing in several countries and specialties potentially related to DIC. The questionnaire examined six hypothetical case scenarios (Table 1 and online supplementary material): the diagnostic approach to patients with suspected DIC (hypothetical case scenario 1); treatment of non-overt DIC (hypothetical case scenario 2); approach to overt DIC without (hypothetical case scenario 3) or with arterial thrombosis or venous thromboembolism (VTE) (hypothetical case scenario 4); management of patients at risk of bleeding (hypothetical case scenario 5) or actively bleeding (hypothetical case scenario 6). Data were analyzed using descriptive statistics. Since not all participants fully completed the survey, proportions were calculated based on the number of respondents for each question. Results There were 191 respondents of whom 73 returned complete questionnaires available for analysis. Most of the participants were specialists in hematology (48%), intensive care (30%), internal medicine (12%), and emergency unit (7%), while the remaining practiced in oncology (1%), infectious diseases (5%), trauma (3%) and pulmonary medicine (1%) units. The participants were mostly from Asia (mainly Japan, 28%), Europe (23%), North America (16%), with a minority from South America (7%) or Africa (4%). Sepsis or septic shock was reported as the most frequent underlying cause of DIC in the physicians’ practice (88%) followed by hematological cancer (29%), pregnancy or obstetric complications (18%). Lower proportions of respondents reported other causes of DIC including solid cancer (11%), trauma (11%), advanced liver disease (8%), surgery (7%), vascular malformations (4%), and severe toxic or immunologic reactions (3%). Hypothetical case scenario 1 In patients with suspected overt DIC, 37% of the respondents would use a formal diagnostic score, namely the score of the ISTH (62%), of the Japanese Association for Acute Medicine (29%), or of the Japanese Ministry of Health and Welfare (10%). Table 2 presents an overview of the diagnostic scores. Up to 60% of participants do not calculate any score and request a number of coagulation tests which include in more than two-thirds of cases the D-dimer, platelet count, prothrombin time, fibrinogen, and the activated partial thromboplastin time (Table 3). The international normalised ratio, fibrin degradation products, schistocytes, hemoglobin, and antithrombin are requested by about one-third whereas less than 10% of the respondents use tests such as the wave-form analysis, protein S/C, thromboelastography, or thrombin-antithrombin complexes.
Once DIC is diagnosed, 94% of physicians monitor DIC evolution by repeating laboratory testing on a daily basis (67%). Frequency of monitoring was decided on case-by-case in one-fourth of the cases. In patients with suspected non-overt DIC, 31% use a formal diagnostic score while 66% rely on a combination of coagulation tests independently of any score. Hypothetical case scenario 2 In patients with non-overt DIC, 68% of participants would not provide any treatment, but monitor laboratory tests; 29% would treat, most frequently with low-molecular-weight heparin (LMWH) (Table 4). The dose of LMWH is frequently decided on case-by-case basis in relation to the bleeding risk of the patient (73%). If a decision is made to treat, 25% provide therapy until resolution of DIC, 29% until clinical improvement of the underlying condition, and 42% consider both to decide on the duration. VTE prophylaxis in non-overt DIC patients is practiced by 86% of the respondents irrespective of other co- morbidities (27%) or only if other co-morbidities suggest a high risk of VTE (59%). LMWH is the preferred type of prophylaxis (54%), followed by mechanical prophylaxis, with elastic stockings (27%) or pneumatic compression (19%), unfractionated heparin (UFH, 16%), and fondaparinux (6%). One fourth uses a combination of both pharmacological and nonpharmacological prophylaxis (25%). Hypothetical case scenario 3 In patients with overt DIC without evidence of thrombosis or bleeding, half of the respondents (48%) would only monitor laboratory tests while 49% treat (Table 4) until DIC resolution (38%), clinical improvement of the underlying condition (20%), or both (35%). Only 10% choose not to give any VTE prophylaxis while all others would use it, irrespective of co- morbidities (31%) or depending on VTE risk (59%). As for nonovert DIC, the most frequently used types of VTE prophylaxis included LMWH (42%), elastic stockings (27%), pneumatic compression (17%), a combination of pharmacological and non-pharmacological prophylaxis (23%), UFH (18%), and fondaparinux (5%). Hypothetical case scenario 4 In patients with overt DIC and thrombosis, 71% of respondents provide treatment independently of the type of event, while 29% consider treating only major thrombotic events such as pulmonary embolism (90%), proximal deep vein thrombosis (86%), arterial thrombosis (myocardial infarction, stroke, acute visceral and leg ischemia, 86%). A lower
Table 1 Synopsis of the six hypothetical case scenarios evaluated in the questionnaire. DIC = disseminated intravascular coagulation; ISTH = International Society on Thrombosis and Haemostasis; JMHW = Japanese Ministry of Health and Welfare; VTE = venous thromboembolism. Scenario
Diagnosis of DIC
Treatment of DIC
Case
Case 1 Suspected DIC
Case 2 Non-overt DIC
Information inquired in the questionnaire
Diagnostic test(s) used for suspected overt-DIC:
1. Diagnostic score (e.g. ISTH, JMHW) 2. Combination of coagulation tests independently of any score If and how often monitoring of DIC evolution by laboratory tests Diagnostic test(s) used for suspected non-overt DIC
Case 4 DIC and thrombosis
Case 5 DIC at risk of bleeding
Case 6 DIC and active bleeding
Treatment provided, if any
Case 3 DIC without thrombosis or bleeding Treatment provided, if any
Treatment provided, if any
Treatment provided, if any
Treatment provided, if any
Type, dose, and duration of treatment Prophylaxis for VTE, if any
Type, dose, and duration of treatment Prophylaxis for VTE, if any
Type of arterial or venous event prompting intervention Additional treatment for DIC
Type and duration of treatment
Type, dose, and duration of treatment Therapy, if any, after bleeding resolves
Please cite this article as: M. Di Nisio, et al., Management of disseminated intravascular coagulation: A survey of the International Society on Thrombosis and Haemostasis, Thromb Res (2015), http://dx.doi.org/10.1016/j.thromres.2015.05.022
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Table 2 Overview of diagnostic scores for Disseminated Intravascular Coagulation. DIC = disseminated intravascular coagulation; ISTH = International Society on Thrombosis and Haemostasis; JMHW = Japanese Ministry of Health and Welfare; JAAM = Japanese Association for Acute Medicine. ISTH
JMHW
JAAM
Underlying disorder known to be associated with DIC Bleeding
Mandatory
1 point
0 points
0 points
0 points
Thrombosis-related organ failure
0 points
Systemic inflammatory response syndrome criteria Prolonged thrombin time
0 points
No hematological malignancy: 1 point Hematological malignancy: 0 point Present: 1 point Absent: 0 point 0 points
b3 sec: 0 points ≥3 sec: 1 point ≥6 sec: 2 points
Fibrinogen level (g/L)
N1: 0 points ≤1: 1 point
Fibrin related marker (e.g. d-dimer)
No increase: 0 point Moderate increase: 2 points (D-dimer: increase ≤10 fold limit of normal) Marked increase: 3 points (N10 fold limit of normal)
Platelet count (x109/μL)
N100: 0 point ≤100: 1 point ≤50: 2 points
Total
DIC ≥ 5 points No DIC b 5 points
proportion of physicians consider treatment of cerebral sinus vein thrombosis (62%), visceral thrombosis (57%), or distal deep vein thrombosis (29%). The preferred types of treatment for an arterial or venous thrombotic event are shown in Table 4. The majority of physicians chose to continue antithrombotic therapy until the Table 3 Diagnostic scoring systems and laboratory tests used for the diagnosis of DIC. Data are reported as percentage of respondents using the specific test. Each respondent could indicate more than one test. DIC = disseminated intravascular coagulation; ISTH = International Society on Thrombosis and Haemostasis. % of respondents Any formal diagnostic score ISTH Japanese Ministry of Health and Welfare Japanese Association for Acute Medicine Laboratory test independently of any score Prothrombin time Activated partial thromboplastin time International normalized ratio Wave-form analysis D-dimer Fibrinogen Soluble fibrin monomers Fibrin degradation products Platelet count Hemoglobin Schistocytes Antithrombin Protein C Protein S Thrombin-antithrombin complexes Platelet aggregation test Thrombelastography Other
37 62 10 29 63 74,2 65,2 39,4 3 84,9 75,8 10,6 31,8 87,9 39,4 39,4 34,9 13,6 4,6 7,6 0 7,6 6,1
Prothrombin time ratio: b1.25: 0 points 1.25-1.67: 1 point ≥1.67: 2 points N1.5: 0 points 1.0-1.5: 1 point ≤1: 2 points Fibrin degradation product (μg/mL): b10: 0 point 10–20: 1 point 20–40: 2 points ≥40: 3 points Hematological malignancy: 0 points No hematological malignancy: N120: 0 points 80–120: 1 point 50–80: 2 points ≤50: 3 points Hematological malignancy: ≥4 points No hematological malignancy: ≥7 points
0 points 0-2: 0 points ≥3: 1 points Prothrombin time ratio: b1.2: 0 points ≥1.2: 1 point ≥3.5: 0 points b3.5: 1 point Fibrin/fibrinogen degradation products (mg/L) b10: 0 point ≥10 and b25: 1 point ≥25: 3 points ≥120: 0 point ≥80 and b120 or N30% decrease within 24 hrs: 1 point b80 or N50% decrease within 24 hrs: 3 points
DIC ≥ 5 points No DIC b 5 points
resolution or improvement of the thrombotic event (49%) or till clinical improvement (24%) while one fourth awaits the resolution of the DIC (26%). In addition to the treatment for the thrombotic event, half (51%) of respondents consider therapy for DIC and most often use antithrombin (40%), transfusions of plasma (40%) or platelets (16%), LMWH (30%), or recombinant thrombomodulin (19%).
Table 4 Treatment options for non overt DIC, overt DIC with or without thrombotic complications. Data are reported as percentage of respondents using the specific treatment. Each respondent could indicate more than one test. DIC = disseminated intravascular coagulation.
Low molecular weight heparin Unfractionated heparin Fondaparinux Direct factor Xa inhibitor Direct thrombin inhibitor Thrombolytic agent Antiplatelet agent Dermatan sulphate Antithrombin Recombinant human activated protein C Recombinant soluble thrombomodulin Protein C concentrate Gabexate Antifibrinolytic agents Platelet transfusion Plasma Transfusion Other
Non-overt DIC
Overt DIC with no thrombosis
DIC and arterial thrombosis
DIC and VTE
42,9 23,8 4,8 19,1 4,8
33,3 19,4 8,3 2,8 22,2 2,8
48 27,4 2,7 9,6 21,9 2,7 40,5 -
60,3 32,9 2,7 4,1 2,7 2,7 40,5 -
14,3
13,9
18,9
18,9
4,8 14,3 28,6 14,3
2,8 5,6 8,3 22,2 33,3 5,6
2,7 8,1 2,7 16,2 40,5 2,7
2,7 8,1 2,7 16,2 40,5 2,7
Please cite this article as: M. Di Nisio, et al., Management of disseminated intravascular coagulation: A survey of the International Society on Thrombosis and Haemostasis, Thromb Res (2015), http://dx.doi.org/10.1016/j.thromres.2015.05.022
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Hypothetical case scenario 5 In patients with overt DIC who are regarded to be at risk of bleeding, 67% consider treatment with either transfusion of fresh-frozen plasma (73%), platelets (65%), plasma (29%), cryoprecipitate (35%), and less frequently anti-fibrinolytic agents (22%), fibrinogen concentrate (16%), recombinant activated factor VII (6%) or coagulation factors concentrate (4%). Laboratory test results (60%) or personal clinical experience (29%) guide the decision on the length of treatment. Hypothetical case scenario 6 In patients with DIC and active bleeding, 71% of the respondents provide treatment while 29% consider treating only if the bleeding is regarded as major. First line treatments were most often fresh-frozen plasma (84%) and platelet transfusion (68%), whereas the most used second line treatment was recombinant activated factor VII (31%). When the bleeding has resolved, 68% would not provide additional transfusion of platelets, plasma or coagulation factors while 31% would continue transfusing until laboratory tests improve further. Discussion Results of the current survey suggest a rather heterogeneous approach of clinicians to the management of DIC. International guidelines, which recommend adopting diagnostic scores for suspected DIC [2–4], seem poorly implemented in clinical practice where the majority of the respondents prefer the use of multiple coagulation tests independently of any score. Furthermore, when the diagnosis of DIC is attempted through a formal diagnostic score, the choice of the score appears relatively heterogeneous possibly due to country-specific practices. The sparse use of diagnostic scores may be the consequence of their limited validation among populations of different ethnicities or various conditions underlying DIC, the emerging role of dynamic scores, or the uncertain reliability of these scores in the absence of a reference standard. A number of studies found that increasing values of the scores of the ISTH, Japanese Ministry of Health and Welfare, or of the Japanese Association for Acute Medicine Additional predict a worse outcome, which may increase their clinical usefulness and applicability [6–10]. This prognostic value and the possibility to identify DIC patients who may benefit from additional diagnostic and/or therapeutic procedures need further confirmation and direct comparison against dynamic scores [11]. Interestingly, half of the respondents provide no specific treatment aiming at DIC resolution in patients with overt DIC and two thirds would feel comfortable not giving any therapy in non-overt DIC. Thus, in the absence of thrombotic or bleeding complications, a substantial proportion of clinicians would limit the intervention to the laboratory monitoring of the coagulopathy and treatment of the underlying disorder. This approach appears, at least partly, in conflict both with the guidelines advocating a number of interventions to improve the haemostatic abnormalities [5], and observational studies which often report multiple treatments for DIC [12,13]. To the best of our knowledge, there are no specific guidelines looking at bleeding or thrombosis management in DIC against which we could compare the results of the survey. While most of the physicians provides mechanical and/or pharmacological VTE prophylaxis to DIC patients, there was poor agreement about the type and doses of drugs. Finally, substantial heterogeneity was observed for the management of thrombosis or bleeding with regard to the need of, type and duration of treatment. Some of the reasons that could explain the discrepant approaches are the lack of solid evidence to guide decision-making in such challenging scenarios as well as the between-country differences in terms of policies and regulations. A limitation of the present survey was the relatively small size
that did not allow to explore potential variations in DIC management according to different disorders underlying DIC. Responses may be in part driven by different perception of what constitutes overt vs. nonovert DIC and what constitutes a bleeding risk. In summary, this survey showed a broad heterogeneity in the management of DIC suggesting that physician's approach is often based on personal experience with poor translation of international guidelines into clinical practice. As most of the clinical evidence on DIC comes from studies that enrolled patients with sepsis or septic shock, an even greater heterogeneity can be expected in the management of DIC caused by other underlying diseases, which could be the focus of future prospective studies. Disclosure of Conflict of interest The authors state that they have no conflict of interest. Acknowledgements The authors would like to thank all respondents who kindly consented to participate in this survey. The authors also thank Dr. Satoshi Gando, Dr. Steven Opal, Dr. Jerrold Levy, and Dr. Andrea De Gasperi for helping with spreading the survey among colleagues of the ISTH and Dr. Lacey Schmeidler for the support with the preparation of the online survey. Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.thromres.2015.05.022. References [1] M. Levi, H. ten Cate, Disseminated intravascular coagulation, N. Engl. J. Med. 341 (1999) 586–592. [2] M. Di Nisio, F. Baudo, B. Cosmi, A. D'Angelo, A. De Gasperi, A. Malato, et al., on behalf of the Italian Society for Thrombosis and Haemostasis, Diagnosis and treatment of disseminated intravascular coagulation: Guidelines of the Italian Society for Haemostasis and Thrombosis (SISET), Thromb. Res. 129 (2012) e177–84. [3] M. Levi, C.H. Toh, J. Thachil, H.G. Watson, Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology, Br. J. Haematol. 145 (2009) 24–33. [4] H. Wada, H. Asakura, K. Okamoto, T. Iba, T. Uchiyama, K. Kawasugi, et al., Japanese Society of Thrombosis Hemostasis/DIC subcommittee, Expert consensus for the treatment of disseminated intravascular coagulation in Japan, Thromb. Res. 125 (2010) 6–11. [5] H. Wada, J. Thachil, M. Di Nisio, P. Mathew, S. Kurosawa, S. Gando, et al., Guidance for diagnosis and treatment of disseminated intravascular coagulation from harmonization of the recommendations from three guidelines, J. Thromb. Haemost. 11 (2013) 761–767. [6] K. Bakhtiari, J.C.M. Meijers, E. de Jonge, M. Levi, Prospective validation of the International Society of Thrombosis and Haemostasis scoring system for disseminated intravascular coagulation, Crit. Care Med. 32 (2004) 2416–2421. [7] M.W.A. Angstwurm, C.-E. Dempfle, M. Spannagl, New disseminated intravascular coagulation. score: A useful tool to predict mortality in comparison with Acute Physiology and Chronic Health Evaluation II and Logistic Organ Dysfunction scores, Crit. Care Med. 34 (2006) 314–320. [8] S. Gando, D. Saitoh, H. Ogura, T. Mayumi, K. Koseki, T. Ikeda, et al., Natural history of disseminated intravascular coagulation diagnosed based on the newly established diagnostic criteria for critically ill patients: Results of a multicenter, prospective survey, Crit. Care Med. 36 (2008) 145–150. [9] T. Takemitsu, H. Wada, T. Hatada, Y. Ohmori, K. Ishikura, T. Takeda, et al., Prospective evaluation of three different diagnostic criteria for disseminated intravascular coagulation, Thromb. Haemost. 105 (2011) 40–44. [10] K. Iwai, S. Uchino, A. Endo, K. Saito, Y. Kase, M. Takinami, Prospective external validation of the new scoring system for disseminated intravascular coagulation by Japanese Association for Acute Medicine (JAAM), Thromb. Res. 126 (2010) 217–221. [11] G.T. Kinasewitz, J.G. Zein, G.L. Lee, S.A. Nazir, F.B. Taylor, Prognostic value of a simple evolving disseminated intravascular coagulation score in patients with severe sepsis, Crit. Care Med. 33 (2005) 2214–2221. [12] H. Asakura, H. Takahashi, H. Tsuji, T. Matsushita, H. Ninomiya, G. Honda, et al., Postmarketing surveillance of thrombomodulin alfa, a novel treatment of disseminated intravascular coagulation - safety and efficacy in 1,032 patients with hematologic malignancy, Thromb. Res. 133 (2014) 364–370. [13] T. Iba, D. Saito, H. Wada, H. Asakura, Efficacy and bleeding risk of antithrombin supplementation in septic disseminated intravascular coagulation: A prospective multicenter survey, Thromb. Res. 130 (2012) e129–e133.
Please cite this article as: M. Di Nisio, et al., Management of disseminated intravascular coagulation: A survey of the International Society on Thrombosis and Haemostasis, Thromb Res (2015), http://dx.doi.org/10.1016/j.thromres.2015.05.022
