Diagnosis of Disseminated Intravascular Coagulation in Sepsis Scoring System of a Thrombosis-Hemostasis Center

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1 ORIGINAL ARTICLE Diagnosis of Disseminated Intravascular Coagulation in Sepsis Scoring System of a Thrombosis-Hemostasis Center Lugyanti Sukrisman*, Karmel L. Tambunan**, Suhendro***, Nanang Sukmana**** ABSTRACT Background. Disseminated intravascular coagulation (DIC) is a septic complication that is not easily diagnosed. The purpose of the study is to obtain a scoring system to diagnose DIC in sepsis. Subject and methods. An observational study with a cross-sectional design was performed at the Department of Internal Medicine, University of Indonesia, Dr. Cipto Mangunkusumo General Hospital from February to August Subjects were septic patients in the emergency unit or inpatient ward of the Department of Internal Medicine, and were taken consecutively. The criteria of sepsis, severe sepsis and septic shock were based on ACCP/SCCM Consensus The evaluation conformed to the Thrombosis Hemostasis Center (THC) scoring system, compared with modified Bick scoring system as a gold standard. Results. There were 34 subjects ranging from 19 to 78 years old, 32.4% were septic patients, 41.2% with severe sepsis and 26.5% with septic shock. The most common source of infection was pneumonia; where bacterial pathogens were found in 35.2% of blood aerobic culture and 17.7% in pus or urine culture. Gram negative bacteria was the most common pathogen found. According to a modified Bick and THC scoring system, DIC was found in all subjects, consisting of mild and moderate DIC. No severe DIC was found. There was no difference between both scoring systems, with a p value of based on the Mc Nemar test. There was no difference found in mild and moderate DIC in sepsis, severe sepsis and septic shock of modified Bick scoring systems (p value of 0.987) and THC scoring system (p value of 1.000). *Department of Internal Medicine, Faculty of Medicine, University of Indonesia-Dr. Cipto Mangunkusumo Hospital **Division of Hemato logy-medical Oncology***Division of Tropical-Infection Desease****Division Alergy and Immunology, Department of Internal Medicine, Faculty of Medicine, University of Indonesia- Dr. Cipto Mangunkusumo Hospital, Jakarta Conclusion. No difference was found between THC and modified Bick scoring system in diagnosing DIC in septic patients. In sepsis, severe sepsis and septic shock, mild and moderate DIC complications can be diagnosed with THC scoring system, which are of the same potency with the modified Bick, with the assumption that the modified Bick scoring system was the same as the Bick scoring system. Key words: sepsis, DIC, Thrombosis Hemostasis Center scoring system INTRODUCTION Sepsis is a systemic response towards infection characterized by tachycardia, tachypnea, changes in body temperature, reduced peripheral blood vessel resistance, leukocytosis or leukopenia, and is known as a highly fatal health condition. 1,2 The mortality rate of sepsis ranges between 10 to 90%, depending on the underlying illness, the causative microorganism, the host s response to infection, adequate antimicrobial treatment, and the onset of shock. In the United States, the mortality rate due to sepsis is approximately 35%. 2,3 At Cipto Mangunkusumo General Hospital, out of 92 cases of sepsis in 1999, 70 patients, or 78.3%, died, while in the year 2000, 135 patients (84.5%) died out of 160 cases of sepsis. 4 This rate could increase to over 80% for cases with multi-organ dysfunction. 5 Sepsis influences all systemic homeostatic mechanisms and could cause widespread organ dysfunction, known as Multiple Organ Dysfunction Syndrome (MODS) or Multiple Organ Failure (MOF). 6-9 MODS/ MOF is the greatest cause of death among septic patients in the intensive care unit. Disseminated Intravascular Coagulation (DIC) is one of the complications of sepsis that play a role in organ dysfunction that occurs in this condition. Sepsis is almost always accompanied by hemostatic abnormality, ranging from small changes in platelet count and subclinical changes in clotting time to severe DIC, 19

2 Lugyanti Sukrisman, etal Acta Med Indones-Indones J Intern Med characterized by generalized microvascular thrombosis and bleeding in various parts of the body. 10,11 Disseminated Intravascular Coagulation is a condition where the blood clotting and/or fibrinolytic system is systematically activated, causing fibrin formation in the small blood vessels and widespread microvascular thrombosis in various organs. 12 Clinical diagnosis of DIC is not easily established. Thrombosis often do not clinically manifest in DIC, even if we perform microscopic examination in DIC patients, fibrin or thrombus is very hard to find. With a very specific technique, only 35-40% of thrombus can be found. 13 In an effort to assist the diagnosis of DIC in sepsis, several diagnostic criteria or scoring system has been developed, including the Bick criteria, the Schmaier criteria, the DIC scoring system also developed by Bick, the scoring system by Mujun Yu et al, the scoring algorithm DIC criteria issued by The Scientific and Standardization Committee (SSC), the working arm of the International Society of Thrombosis and Haemostasis (ISTH) in July 2001, and the National Consensus on DIC management in sepsis in Up to now, no criteria or scoring system has been established to be the best for the diagnosis of DIC in sepsis. Bearing in mind the high incidence of and mortality rate in sepsis, there needs to be a rapid diagnosis for sepsis as well as its complications, including DIC. The Department of Internal Medicine, Faculty of Medicine of the University of Indonesia/Cipto Mangunkusumo General Hospital has not established a standard criteria for the diagnosis of DIC in sepsis. In this study, we compared the Thrombosis- Hemostasis Center scoring system with the modified Bick scoring system, which is considered to be the gold standard. It is hoped that an appropriate scoring system could be obtained to diagnose DIC in sepsis based on clinical and laboratory findings in line with facilities available at the Department of Internal Medicine, Faculty of Medicine of the University of Indonesia/ Cipto Mangunkusumo General Hospital. SUBJECTS AND METHODS The study was an observational, cross-sectional study performed at the Department of Internal Medicine, Faculty of Medicine of the University of Indonesia/Dr. Cipto Mangunkusumo General Hospital from February to August The target population of the study was septic patients admitted to Cipto Mangunkusumo General Hospital. The study subjects were septic patients at the Emergency Unit or the inpatient ward of Department of Internal Medicine, Faculty of Medicine of the University of Indonesia/ Cipto Mangunkusumo General Hospital. Samples were obtained consecutively. The inclusive criteria were: (1) All patients with sepsis who met the criteria of sepsis, severe sepsis, and septic shock, (2) willing to participate in the study (received approval from the patient or closest family member), and (3) is willing to undergo laboratory examinations related to sepsis and coagulation disorders. The exclusion criteria were: (1) The patient/patient s family refused to participate in the study or have blood samples taken for laboratory examination; or those with (2) acute leukemia/suspicions of acute leukemia, Idiopathic Thrombocytopenic purpura (ITP), Dengue hemorrhagic fever, (3) decompensated liver cirrhosis, (4) nephrotic syndrome, (5) chronic renal failure, (6) pregnancy ; and those (7) undergoing anticoagulant treatment. Subjects who met the sepsis criteria based on ACCP-SCCM 1991 and met the inclusion and exclusion criteria underwent the following clinical assessments: mean blood pressure, pulse rate, respiratory rate, and body temperature. Their blood samples were then taken to determine hematocryte level, white blood cell count, platelet count, prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, D-dimer, antithrombin, prothrombin fragments 1 and 2, alpha-2 antiplasmin, blood gas analysis (PH, PaO2), electrolyte (sodium, potassium), creatinine, LDH and albumin, in accordance with the variables of the scoring system assessed. In order to support the diagnosis of sepsis, chest x-ray, blood and/or urine or pus culture, and ultrasound were performed. After the results of the clinical and laboratory assessments were recorded, the results were scored and the score was calculated according to the modified Bick DIC scoring system, the HTP scoring system, compared with the degree of sepsis, which were sepsis, severe sepsis, and septic shock. Hematocryte level, white blood cell count, platelet count, prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, D-dimer, antithrombin, prothrombin fragments 1 and 2, and alpha-2 antiplasmin were assessed at the hematological laboratory of the Department of Internal Medicine, Faculty of Medicine of the University of Indonesia/Cipto Mangunkusumo General Hospital. For Hematocryte level, white blood cell count, and platelet count, 1 mil of venous blood sample was obtained and mixed with EDTA. Creatinine, LDH, and albumin were examined at the laboratory of the 20

3 Vol 36 Number 1 January-March 2004 The Thrombosis-Hemostasis Center Scoring System Department of Pediatrics of the Faculty of Medicine of the University of Indonesia/Cipto Mangunkusumo General Hospital from 4 ml of frozen venous blood sample, while blood gas analysis and electrolyte were examined at the laboratory of the Emergency Unit of Cipto Mangunkusumo General Hospital from 2 ml of arterial blood mixed with heparin. For prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, D-dimer, antithrombin, prothrombin fragments 1 and 2, and alpha-2 antiplasmin evaluation, 4.5 ml of venous blood was obtained and mixed with 0.5 ml of 3.5% citric sodium solution with a vacutainer. Prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, D-dimer, antithrombin, and alpha-2 antiplasmin were examined using the Behring Coagulation Timer from Dade-Behring with a chromogenic method, while prothrombin fragments 1 and 2 were assessed using the ELISA (Enzyme-linked Immunosorbent Assay) method using Behring ELISA Processor II. A blood sample of 5 ml for culture was taken and sent using a BacT/Alert culture media to the Microbiology laboratory of the Faculty of Medicine of the University of Indonesia, or 5 ml of urine in a sterile container, or pus obtained using a sterile culture swab. The criteria of sepsis, severe sepsis, and septic shock 21

4 Lugyanti Sukrisman, etal Acta Med Indones-Indones J Intern Med was based on the 1991 ACCP/SCCM Consensus, as follows: 20 sepsis: SIRS due to infection, characterized by two or more of the following conditions: (1) a temperature of over 38ºC or <36º C, (2) a pulse rate of over 90 times/minute, (3) a respiratory rate of over 20 times/minute or PaCO2 <32 mmhg, (4) a white blood cell count of over 12,000/mm 3, less than 4,000/mm 3 or over 10% immature neutrophil (rods). While the criteria of severe sepsis were: sepsis accompanied with organ dysfunction, which encompassed: metabolic acidosis, acute encephalopathy, olyguria, hypoxemia or DIC or hypotension. The criteria of septic shock were hypotension due to sepsis (systolic blood pressure of less than 90 mmhg or a drop of ³ 40 mmhg) occurring for over 1 hour despite adequate fluid therapy. Early sepsis pertained to sepsis that has not met the criteria of severe sepsis or septic shock. Infection was established clinically and microbiologically. Infection was established clinically or considered a probable infection if there were appropriate clinical findings, while it was established microbiologically or considered as a definite infection if a bacterial pathogen was found in blood, urine, pus or sputum culture. 21 The scoring system used to diagnose DIC was the scoring system DIC developed by Bick which was then modified and known as the modified Bick scoring system, and the Hemostasis-Thrombosis Center (HTC) scoring system, as found in Tables 1, 2 and 3. 14,15 The modified Bick scoring system was developed because not all variables in the Bick scoring system can be performed at Cipto Mangunkusumo General Hospital and the normal laboratory values at Cipto Mangunkusumo General Hospital were not the same as the normal values in the Bick scoring system. This modified scoring system was assumed to be the same as the actual Bick scoring system, even though this has not been validated. The variables evaluated in this scoring system were variables that could be assessed at Cipto Mangunkusumo General Hospital, and whose values were adjusted to the normal values at the Cipto Mangunkusumo General Hospital laboratory, as found in Table Mild, moderate, severe DIC or no DIC is determined the same way in this scoring system as in the original Bick scoring system. The HTC scoring system consists of the variables that can routinely be examined at the Department of 22

5 Vol 36 Number 1 January-March 2004 The Thrombosis-Hemostasis Center Scoring System Internal Medicine of the Faculty of Medicine of the University of Indonesia/Cipto Mangunkusumo General Hospital. In this scoring system, the variables prothrombin fragments 1and 2 and alpha-2 antiplasmin were eliminated and replaced by PT and APTT. Mild, moderate, severe DIC or no DIC is determined the same way in this scoring system as in the original Bick scoring system. 22 Data management and analysis were performed using a computer program. The statistical analysis used consisted of univariant analysis to obtain a mean average, standard deviation, a confidence interval of 95%; minimum, maximum, and median values. The McNemar paired-test was used to compare the modified Bick scoring system with the HTC scoring system. aerobic blood culture and in 17.7% pus or urine culture. The most common bacteria was Gram-negative. The distribution of DIC based on the Bick scoring system, the modified Bick scoring system and the HTC scoring system are illustrated in the following table. Analysis was performed between the DIC obtained based on the modified Bick scoring system and the HTC scoring system. Using the McNemar test, no difference was found between mild and moderate DIC based on the modified Bick scoring system and that based on the HTC scoring system, with a p value of Analysis was performed in mild and moderate DIC based on the two scoring systems above in sepsis, severe sepsis and septic shock. RESULTS This study was performed in 34 subjects, with an age range of years, 32.4% with sepsis, 41.2% with severe sepsis, and 26.5% septic shock. The most common cause of infection in the subjects was pneumonia. Definite infection was found in 52.9% subjects with bacterial pathogens found in 35.2% of DISCUSSION Based on the modified Bick scoring system and the HTC scoring system, DIC was found in all of the study subjects, in the form of mild and moderate DIC. No subject suffered from severe DIC. Using the McNemar statistical test, no difference was found between the modified Bick scoring system and the HTC scoring 23

6 Lugyanti Sukrisman, etal Acta Med Indones-Indones J Intern Med In this study, the HTC scoring system was proposed as a new diagnostic criteria for DIC in sepsis. The modifications were made based on the consideration that most of the clinical and laboratory variables in this scoring system is widely used in the hospitals in Indonesia and could be performed in daily practice. The study results demonstrate no difference between this HTC scoring system and the modified Bick scoring system, which are assumed to be the same with the original Bick scoring system. The limitations of the HTC scoring system are as follows: 1. It is not simple to perform. 2. The laboratory variables needed to be modified from the original due to differences in normal value at the Cipto Mangunkusumo General Hospital laboratory. Based on the findings above, it was found that diagnosis DIC in early sepsis is not easy. An important thing that needs to be remembered in establishing a diagnosis of DIC, is that DIC is always associated with a primary illness, and the coagulation process in sepsis is a dynamic process. 23 However accurate or complete the examination, regular monitoring is more important. Thus, the diagnosis could be better established in accordance with whatever facilities available. system, with a p value of No difference was found between mild and moderate DIC in sepsis, severe sepsis and septic shock, both using the modified Bick scoring system and the HTC score, demonstrating a p value of and CONCLUSION No difference was found between the HTC scoring system and the modified Bick scoring system in establishing the diagnosis of DIC in septic patients. In sepsis, severe sepsis and septic shock, mild and moderate DIC complications could be diagnosed using the HTC scoring system, which has the same strength as the modified Bick scoring system. 24

7 Vol 36 Number 1 January-March 2004 The Thrombosis-Hemostasis Center Scoring System SUGGESTION To further test the modified Bick scoring system and the HTC scoring system to find a comparison in patients with severe DIC and in a greater number of subjects. Bearing in mind that the scoring system is not easily conducted, further research should be conducting for rapid or bedside diagnosis of DIC in sepsis. REFERENCES 1. Fisher Jr.CJ, Yan B. Protein C levels as a prognostic indicator of outcome in sepsis and related disease. Crit Care Med 2000; 28 (suppl 9) : Thijs LG, Dhainaut JF. Definitions and epidemiology. In: Dhainaut JF, Thijs LG, Park G, eds. Septic shock. London: W.B. Saunders company limited; p Balk RA. Severe sepsis and septic shock. Definitions, epidemiology, and clinical manifestations. In: Balk RA, Casey LC, eds. Critical care clinics. Septic and septic shock. Philadelphia: W.B. Saunders company; p Data rekam medik RSUPN Cipto Mangunkusumo, Jakarta , tidak dipublikasikan. 5. Lynn WA. Sepsis. In: Armstrong D, Cohen J, editors. Infectious diseases. London: Mosby; p Balk RA. Pathogenesis and management of multiple organ dysfunction or failure in severe sepsis and septic shock. In: Balk RA, Casey LC, eds. Critical care clinics. Septic and septic shock. Philadelphia: W.B. Saunders company; p Piper RD, Sibbald WJ. Multiple organ dysfunction syndrome. In: Fein AM, Abraham EM, Balk RA, Bernard GR, Bone RC, Dantzker DR, et al, eds. Sepsis and multiorgan failure. Baltimore: Williams and Wilkins; p Marshall JC. Criteria for the description of organ dysfunction in sepsis and SIRS. In: Fein AM, Abraham EM, Balk RA, Bernard GR, Bone RC, Dantzker DR, et al, eds. Sepsis and multiorgan failure. Baltimore: Williams and Wilkins; p Levy B, Bollaert PE. Clinical manifestations and complications of septic shock. In: Dhainaut JF, Thijs LG, Park G, eds. Septic shock. London: W.B. Saunders company limited; p Levi M. Sepsis and the coagulation system. Advances in Sepsis 2000;1 (1): Poll Tvd, Levi M, Deventer SJHV. Coagulopathy: disseminated intravascular coagulation. In: Fein AM, Abraham EM, Balk RA, Bernard GR, Bone RC, Dantzker DR, et al, eds. Sepsis and multiorgan failure. Baltimore: Williams and Wilkins; p Vervloet MG, Thijs LG, Hack CE. Derangement of coagulation and fibrinolysis in critically ill patients with sepsis and septic shock. Semin Thromb Hemost 1998; 24 (1): Bell WR. The pathophysiology of disseminated intravascular coagulation. Sem Hematol 1994;31 (2 suppl 1): Bick RL. Disseminated intravascular coagulation: pathophysiological mechanisms and manifestations. Semin Thromb Hemost 1998; 24 (1): Bick RL. Disseminated intravascular coagulation: objective criteria for clinical and laboratory diagnosis and assessment of therapeutic response. Clin Appl Thromb Hemost 1995;1 (1): Schmaier AH. Disseminated intravascular coagulation, November [cited 7 March 2002]. Available from: Yu M, Nardella A, Pechet L. Screening tests of disseminated intravascular coagulation: guidelines for rapid and specific laboratory diagnosis. Crit care med 2000;2: Levi M. Disseminated intravascular coagulation: new diagnostic criteria and supportive treatment strategies. Conference report, 47 th scientific and standardization committee meeting of the International Society of Thrombosis and Haemostasis, July 6-7,2001. [cited 18August 2001].Availablefrom: 19. Tambunan KL, Sudoyo AW, Mustafa I, Pudjiadi A, Chen K, Govinda A, Sukrisman L, eds. Konsensus nasional tatalaksana KID (DIC) pada sepsis American college of chest physicians / society of critical care medicine consensus conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992;20 (6): Onderdonk AB. Laboratory diagnosis of infectious diseases. In: Fauci AS, Braunwald E, Isselbacher KJ, Wilson JD, Martin JB, Kasper DL, et al, eds. Harrison s principles of Internal Medicine 14 th ed. New York: McGraw-Hill 1998;255:p Tambunan KL. Subbagian Hematologi-Onkologi Medik Bagian Ilmu Penyakit Dalam, Fakultas Kedokteran Universitas Indonesia, Jakarta Komunikasi pribadi. 23. Seligsohn U. Disseminated intravascular coagulation. In: Beutler E, Lichtman MA, Coller BS, Kipps TJ, Seligsohn U, eds. Williams hematology. 6 th ed. New York: The McGraw-Hill companies; p