Disseminated Intravascular Coagulation
Subcommittee Minutes
24 July 2011
08:00-12:00
Room Sakura
Chairman: Hideo Wada (JP)
Co-chairman: Satoshi Gando (JP), Hyun Kyung Kim (KR), Jorn Nielsen (DK), Jecko Thachil (UK), Cheng-Hock Toh (UK)
In the education session, Dr. Shinichiro Kurosawa made a presentation, entitled, “Disseminated Intravascular Coagulation due to Anthrax; A Pre-Clinical In Vivo Study” The causative agent of Anthrax, B. anthracis was actually used for bioterrorism on the U.S. ground in 2001. National Institute of Health considers B. anthracis as the most important agent of bioterrorism and the development of countermeasures against Anthrax is a national priority. Anthrax is an acute infection and without proper treatment, it leads to sepsis, DIC, organ failure (OF) and shock, and ultimately death. It is well documented that B. anthracis produces both Lethal toxin and Edema toxin. The paradigm of the field is that the toxin is the primary cause of death. This is evidenced by the fact that most of the efforts are directed toward targeting and neutralizing protective antigen (PA), a common and required component of Anthrax toxin. In case reports from 2001 attack, all the fatal cases had bacteremia, and almost all patients had DIC, coagulation abnormalities including prolonged prothrombin time (PT) and activated partial thromboplastine time (APTT), elevated D-dimer or microangipathic hemolytic anemia (MAHA). Dr. Kurosawa established a non-human primate model of anthrax sepsis similar to the E-coli-injected baboon model established by Drs. Hinshow-Taylor. The intravenous challenged model caused dose-dependent DIC similar to that observed in patients and also the original baboon E-coli model. In order to delineate the role of Anthrax toxin, the animals were challenged with toxin-negative B. anthracis strain and compared with toxin-positive strain. The difference between the lethal doses of these two groups was not striking, indicating that the role of toxin may not be as great as previously thought. In order to test whether animals were dying from sepsis, the animals were treated with activated protein C (APC), the only FDA approved drug for severe sepsis. All baboons without APC died, while those pre-treated with APC survived.
Taken together, a conclusion was made that Anthrax causes septic DIC and APC may be a potential therapeutic.
Dr Marcel Levi talked about the “Pathogenesis of septic DIC”. DIC in sepsis causes OF and bleeding. In sepsis, endotoxin and inflammatory cytokines activate monocytes and endothelial cells to express tissue factor (TF). It has been reported that the messenger RNA levels in monocytes were elevated in menningococemia and TF was detected by an anti-TF antibody in several tissues such as kidneys in these patients. TF, Xa and thrombin activate protease activated receptor (PAR). P selectin released from activated platelets induces TF expression. Decreased ADAMTS13 increases the ultra large multimer of von Willebrand factor (ULM-VWF), and this was observed in sepsis. APC, TF pathway inhibitor (TFPI), antithrombin (AT) and thrombomodulin (TM) have both anti-coagulant and anti- inflammatory activities. As a potential, new factor, the volume loss of the Glycocalyx was observed in sepsis as a result of the activation of coagulation.
In the chairperson’s report, Dr Wada introduced 4 working parties for examining the relationship between trauma and DIC, standardization of fibrin related markers (FRMs), establishment of non-overt DIC and establishment of DIC treatment guidelines.
Dr. Jecko Thachil talked about “Mimics of DIC in the intensive care unit”. He showed the hemostatic abnormalities present in critically-ill patients with DIC and those present in patients with liver disorders, macrophage activation syndrome, MHAH, systemic vasculitis and massive blood loss.
Dr. Satoshi Gando presented “DIC in trauma” It was reported that the administration of tranexamic acid reduced the risk of death in bleeding trauma patients associated with DIC. He showed that the plasma levels of tissue type plasminogen activator (tPA), fibrinopeptide Bβ15-42 (FP Bβ15-42) and plasmin plasmin inhibitor complex (PPIC) were markedly increased during the early phase of trauma thereafter depressed, while those of PA inhibitor-1 (PAI-I) and FPA were persistently increased during all phase of trauma. A trauma patient's survival may depend on the ability to control two opposing conditions; bleeding during the early phase and thrombosis during the late phase of trauma. He stated that most hemostatic abnormalities in trauma were due to DIC. After the presentation, it was discussed whether the hemostatic abnormalities were due to trauma or DIC in trauma?
Dr. Toshiaki Iba presented “Multicenter prospective analysis of the efficacy and safety of AT treatment”. He analyzed the resolution rate, survival rate and bleeding in 1435 cases treated with 1,500 units or 3,000 units of AT. The resolution rate was 55.4% in those treated with 1,500 units of AT and 69.6% in those treated with 3,000 units of AT. The survival rate was 65.2% in those treated with 1,500 units of AT and 75.4% in those treated with 3,000 units of AT. The frequency of bleeding was low in patients treated with either dose. These data suggest that administration of 3,000 units of AT should be recommended.
Dr. Shousaku Nomura talked about the “Therapeutic effects of recombinant thrombomodulin (rhTM) in DIC patient with hematologic malignancy”.?He classified DIC in hematological malignancy into 4 types; the leukemia type, tumor-lysis type, infection type and transplantation type. TF and Anexin II mainly cause DIC in the leukemia or tumor-lysis type. DIC due to infection is generally caused by inflammatory cytokines and is frequently associated with systemic immune response syndrome (SIRS) and OF. He introduced many markers, such as sP-selectin, CD40L, PDMP, RANTES, MCP-1, microparticle (MP), HMGB-1 and sVCAM-1, which increased in DIC due to infection. The transplantation-related DIC may include vascular occlusion disorder (VOD), graft versus host disease (GVHD) and thrombotic microangiopathy (TMA). Finally, he reported that rhTM was effective for DIC due to hematological malignancy.
Dr. Nigel Key talked about “Microparticle assays in human endotoxemia.”?In this model, MPs may be released from platelets, monocytes, and endothelial cells. A new functional assay for TF activity on MPs demonstrates findings that are analogous to a previously publish assay from his lab (Aras O, et al, Blood 2004). After LPS infusion, MPs-TF levels peaked at 2-4 hours, with a decline thereafter. However, using the recently standardized ISTH approach to measure platelet-derived MPs by flow cytometry (Lacroix, R et al. JTH 2010), the number of MPs was surprisingly most elevated at the 24 hour time point in 2 of the 5 subjects thus far.
Dr. Jorn Nielsen talked about “Controversies in DIC scoring”. The mortality was significantly higher in DIC patients in a RCT for APC and AT. Both APC and AT significantly improved the survival rate in the patients with DIC. In the non-overt DIC scoring system, the mortality was significantly higher in the patients with high non-overt DIC scores. He stated that the DIC related states, such as TTP, capillary leak syndrome (CLS) and hyperfibrinolytic state are important for the diagnosis of DIC. He proposed simplify the scoring system to include platelet activation, CLS and FRMs. The platelet activation marker includes the platelet number and ADAMTS13. The CLS markers are PT, albumin, AT and PC. The marker for FRMs is D-dimer.
Dr Zhaoyue Wang talked about the “Involvement of tissue factor and annexin II in pathoclinical profiles of acute promyelocytic leukemia”. He retrospectively examined the frequency of DIC in more than 1,400 cases of leukemia. The frequency of DIC was 39.6% in leukemia and 80% in patients with acute promyelocytic leukemia (APL). He examined the levels of TF and anexin II in leukemic cells, and NB4 and HL-60 cell lines based on the Xa activity, flow cytometry results, mRNA and western blotting analysis. ATRA and ASO improved DIC by inhibiting the expression of TF and Anexin II. The hypofibrinogenemia in APL is suggested to be caused by Anexin II.
