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Disseminated intravascular coagulation (DIC). Jørn Dalsgaard Nielsen Thrombosis Centre Gentofte Hospital Denmark. Characteristics of DIC. DIC. Arterial thrombosis. Venous thrombosis. DIC Increased fibrin formation. Trombotic microangiopathy Increased platelet aggregation. Introduction.
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Disseminated intravascular coagulation(DIC) Jørn Dalsgaard Nielsen Thrombosis Centre Gentofte Hospital Denmark
Characteristics of DIC DIC Arterial thrombosis Venous thrombosis
DICIncreased fibrin formation TromboticmicroangiopathyIncreased platelet aggregation Introduction • Thrombotic microangiopathy (TMA) and disseminated intravascular coagulation (DIC) are disorders causing obstruction of the microvascular circulation
TromboticmicroangiopathyIncreased platelet aggregation TTP HELLP HUS Thrombotic microangiopathy TTP: Thrombotic Thrombocytopenic Purpura HELLP: Haemolysis, Elevated Liver enzymes, Low Platelets HUS: Haemolytic Uremic Syndrome
TromboticmicroangiopathyIncreased platelet aggregation TTP HELLP HUS Thrombotic microangiopathy Type Symp. Etiology TTP: CNS vW cleaving factor deficiency, cong/aquired HELLP: Liver Pregnant women HUS: Kidney +/- diarrhoea associated (E coli 0157)
TromboticmicroangiopathyIncreased platelet aggregation TTP HELLP HUS Thrombotic microangiopathy • Treatment: TTP HELLP HUS • Eliminate the causal factor + • Plasmapheresis (or FFP or cryosupernatant transfusion) + • Corticosteroids (+) + (+) • IV gamma globulin (+) (+) • Rituximab + (+) • Avoid platelet transfusions + + +
DIC DIC is a complication Banal Serious illness Critical illness
Causes of DIC Other causes Sepsis
Severe sepsis The Vicious Cycle of Inflammation and Coagulation Septic shock Sepsis
The Vicious Cycle of Inflammation and Coagulation Infection Inflammation Organ Failure Coagulation Ischemia Death Endothelial Dysfunction Inflammation Coagulation Inflammation Inflammation Coagulation Esmon. Immunologist. 1998;6:84.
Bacteria Cytokines Tissue factor Accelerates coagulation Progression of SEPSIS Platelets Monocytes Endothelial cells Endothelial cells Non-adhesive surface Adhesive surface Leuko- cytes Activation of coagulation Thrombin Fibrin
Surface contact Tissue factor XII XIIa XI XIa IX IXa II IIa I Ia (fibrin) THE ”CLASSIC” COAGULATION SYSTEM APTT Prothrombin time VIIa VII Ca++ Phospholipid, Ca++, VIII X Xa X Phospholipid, Ca++, V
IL-1 TNF-C5a EXPRESSION OF TISSUE FACTOR CONSTITUTIVEe.g.:epithelial cellsglial cells INDUCEDe.g.:monocytic cellsendothelial cells PROHIBITEDe.g.:lymphocyteserythrocytes
TF Local clot formation TF TF Cytokines TF TF Endothelial damage SUBENDOTHELIAL TISSUE ENDOTHELIAL CELLS NORMAL HAEMOSTASIS Haemostatic mechanisms Intravascular clot formation Activated monocyte Monocyte Activation of monocytes SYSTEMIC INFLAMMATION
Causes of DIC (mechanisms) • Extensive release of tissue factor • Increased formation of tissue factor • Abnormal activators of coagulation • Contact activation hypotension
Causes of DIC (Clinical conditions, I) • Infections • Sepsis • Gram negative (endotoxin) • Gram positive (polysaccharides, peptides) • Viremias • Varicella • Hepatitis • Cytomegalovirus • HIV
Causes of DIC (Clinical conditions, II) • Trauma • Crush injuries • Other trauma with tissue necrosis • Severe burns • Extensive surgery • Obstetric complications • Amniotic fluid embolism • Placental abruption • (Pre)eclampsia • Dead fetus syndrome
Causes of DIC (Clinical conditions, III) • Hemolysis • Hemolytic transfusion reactions • Massive transfusions • Malaria • Other severe hemolysis • Malignant disorders • Metastatic malignancy • Tumors producing cancer procoagulant • Tumor with tissue necrosis
Causes of DIC (Clinical conditions, IV) • Vascular abnormalities • Giant hemangioma • Heriditary teleangiectasis • Prosthetic devices • Aortic balloon assist devices • Denver shunts • Other conditions • Pancreatitis • Acute liver necrosis • Transplant rejection • Heat stroke
Systemic fibrin formation Systemic inflammation Multiple organ dysfunction Systemic bleeding Progression of DIC Onset of DIC Time
Systemic inflammation Multiple organ dysfunction High fibrinolytic activity Low fibrinolytic activity Systemic bleeding Progression of DIC Systemic fibrin formation Abrupt onset of DIC Onset of DIC Time
Examples of hyperfibrinolytic DIC • DIC in women with post-partum bleeding • DIC in patients with promyelocytic leukaemia • Early after severe trauma • Contact with Lonomia caterpillars
Thrombin- and stasis-induced release of tissue plasminogen activator FXII FXIIa PrekallikreinKallikrein Plasminogen activator inhibitor-1 2-Plasmin inhibitor During DIC PC APC inhibits PAI-1 Fibrinolytic activity in patients with DIC Abrupt onset of DIC Plasminogen Plasmin Fibrin Fibrin degradation products
Hyper- and non-hyperfibrinolytic DIC • Hyperfibrinolytic DIC • Main problem: Severe bleeding • Non-hyperfibrinolytic DIC • Main problem: Microvascular occlusion • DIC in septic patients is a • non-hyperfibrinolytic type of DIC
TF and LPS induced DIC DIC was induced in rats by infusion of TF or LPS TF LPS p Platelets *109/l 204 177 ns Fibrinogen mg/dl <50 <50 ns TAT ng/ml 162 170 ns D-dimer g/ml 12,4 1,2 0,001 PAI U/ml 22 245 0,001 Glomerular fibrin 12% 73% 0,001 Asakura et al. Crit Care Med 2002; 30: 161-4
Symptoms of DIC • Dysfunction of multiple organs • The pulmonary microembolism syndrome • Acute: vascular and bronchial constriction • Late: ARDS • Acute renal failure • Oliguria, increasing serum creatinine, haematuria • Cerebral dysfunction • Confusion, blurred consciousness, coma • Cutane haemorrhagic necroses • Failure of liver, endocrine glands etc.
Circulating mediators Circulating mediators Local haemostatic response to an injury Local immunological response to an injury Modification (Amplification) DIC SIRS Ischaemia Destruction MODS
SIRS+DIC = hyperproteolysis Coagulation Fibrinolysis Complement Kinines Cytokines
Platelet count Activated partial thromboplastin time (APTT) Prothrombin time (PT) Fibrin D-dimer fragment Antithrombin Fibrinogen BLOOD TESTS WHEN DIC IS SUSPECTED Simple screening Extended screening Supplementary tests Further evidence for activation of coagulation and fibrinolysis
D fragmentsE fragments Activation of coagulation Fibrinogen Prothrombin Fragment 1+2 THROMBIN Fibrino-peptideA + B Antithrombin Fibrin Plasmin FXIII FXIIIa Thrombin-Antithrombincomplex(TAT) Cross-linkedfibrin D dimerE fragments
Soluble fibrin monomer as predictor for DIC in neonatal sepsis • Healthy neonates: 24,5 ± 6,09 mg/l • Sepsis, no DIC: 33,7 ± 11,9 mg/l • Sepsis + DIC*: 73,2 ± 31,6 mg/l *ISTH DIC score 5 Critical level: 48,5 mg/l Sensitivity: 100% Specificity: 93% Overall accuracy: 97,5% Selim et al. Haematologica 2005;90:419-20
FIBRIN THROMBUS SCHISTOCYTES Longitudinally cut blood vessel
Definition of disseminated intravascular coagulation DIC is an acquired syndrome characterized by the intravascular activation of coagulation with loss of localization arising from different causes. It can originate from and cause damage to the microvasculature, which if sufficiently severe, can produce organ dysfunction ISTH´s Scientific Subcommittee on DIC, July 2001
Scoring system for overt DIC • Underlying disorder known to be associated with overt DIC YES NO continue stop • Platelet count • (>100=0, <100=1, <50=2) .............................. • Soluble fibrin/D-dimer • (normal=0, =2, =3) ............................. • Prolongation of PT • (<3s=0, 3-6s=1, >6s=2) ................................ • Fibrinogen • (>1g/l=0, <1g/l=1) .......................................... • Calculate sum ........................................ ISTH´s Scientific Subcommittee on DIC, July 2001
Scoring system for overt DIC - Example - • Underlying disorder known to be associated with overt DIC YES NO Polytrauma continue stop • Platelet count • (>100=0, <100=1, <50=2) .............................. • Soluble fibrin/D-dimer • (normal=0, =2, =3) ............................. • Prolongation of PT • (<3s=0, 3-6s=1, >6s=2) ................................ • Fibrinogen • (>1g/l=0, <1g/l=1) .......................................... • Calculate sum ........................................ 85 1 8 3 +3 1 2,2 0 5 ISTH´s Scientific Subcommittee on DIC, July 2001
Scoring system for overt DIC • If the calculated score is • 5: compatible with overt DIC repeat scoring daily • <5: suggestive (not affirmative) for non-overt DIC repeat next 1-2 days. ISTH´s Scientific Subcommittee on DIC, July 2001
Scoring system for non-overt DIC • Presence of underlying disorder • (no=0, yes=2) .......................................................... • Platelet count + changes • (100=0, <100=1) + (=-1, stable=0, =1) ....... • Sol.fibrin/D-dimer + changes • (normal=0, =1) + (=-1, stable=0, =1) ........ • Prolongation of PT + changes • (3s=0, >3s=1) + (=-1, stable=0, =1) ........... • Antithrombin • (normal=-1, low=1) ................................................. • Protein C • (normal=-1, low=1) ................................................. • TAT complexes • (normal=-1, high=1) ................................................. • Calculate sum ................................................ ISTH´s Scientific Subcommittee on DIC, July 2001
Validation of the ISTH scoring system for overt DIC Distribution of DIC scores in 217 patients in intensive care unit Bakhtiari et al. Crit Care Med 2004; 32:2416 –2421
Validation of the ISTH scoring system for overt DIC Bakhtiari et al. Crit Care Med 2004; 32:2416 –2421
Validation of the ISTH scoring system for non-overt DIC Survivors Deaths Non-overt DIC scores in 490 patients in intensive care unit Toh & Downey. Blood Coagul Fibrinolysis 2005;16:69–74
Validation of the ISTH scoring system for non-overt DIC Toh & Downey. Blood Coagul Fibrinolysis 2005;16:69–74
Validation of the ISTH scoring system for non-overt DIC • The mortality rate for non-overt DIC was • 29% (105 of 360) for scores below 5 • 78% (70 of 90) for scores of 5 or above • The mortality rate for overt DIC was also 78% (38 of 49). • The non-overt DIC scoring template is workable and has prognostic relevance. • A score of 5 and greater is recommended as diagnostic of non-overt DIC. Toh & Downey. Blood Coagul Fibrinolysis 2005;16:69–74
Scoring system for overt DIC • Underlying disorder known to be associated with overt DIC YES NO continue stop • Platelet count • (>100=0, <100=1, <50=2) .............................. • Soluble fibrin/D-dimer • (normal=0, =2, =3) ............................. • Prolongation of PT • (<3s=0, 3-6s=1, >6s=2) ................................ • Fibrinogen • (>1g/l=0, <1g/l=1) .......................................... • Calculate sum ........................................ ISTH´s Scientific Subcommittee on DIC, July 2001
D-dimer- low cutoff - • A low cutoff of 1 mg/l was used by: • Dempfle et al. Thromb Haemost 2004; 91: 812–8 • Toh et al. Blood Coagul Fibrinolysis 2005; 16: 69-74 • Angstwurm et al. Crit Care Med 2006; 34: 314–20
Interassay variation of D-dimer D-dimer was determined in 39 plasma samples with 23 D-dimer assays Dempfle et al. Thromb Haemost 2001; 85: 671–8
Stago Liatest D-Di Roche Tinaquant Roche Cardiac D-dimer D-dimer tests giving comparable results Suggested cutoffs: Low: 1 mg/l High: 4 mg/l BioMérieux Vidas D-dimer BioMérieux MDA D-dimer