Evidence Of Disseminated Intravascular Coagulation Research Articles

Intracranial hemorrhage (ICH) in acute leukemia (AL): A single-center study from a general hospital with two cases managed with middle meningeal artery (MMA) embolization.

e19033 Background: ICH is a devastating and potentially fatal complication in patients with AL. Contributing factors for ICH include thrombocytopenia, hyperleukocytosis, and coagulopathy. Acute promyelocytic leukemia (APL) has a higher risk of disseminated intravascular coagulation (DIC) and fatal ICH, contributing to early deaths from the disease. At our institution, we have incorporated MMA embolization into traditional methods of observation and surgery for the management of ICH in AL patients. Methods: We performed a single-center retrospective study of adult AL patients with ICH at Memorial Hermann Hospital Texas Medical Center from January 1, 2013, to December 31, 2022. Data collected included: age at diagnosis, type of AL, white blood cell count (WBC), platelet count, coagulation profile, Glasgow Coma Scale score at presentation, response to platelet transfusion, need for surgical, minimally invasive intervention, and mortality rates at 72 hours and 30 days. Descriptive statistics were used to analyze the data. Results: Among 160 consecutive AL patients, we identified 22 (13.75%) with ICH at presentation (APL = 11, AML = 6, B-ALL = 3, Burkitt leukemia = 1, myeloid sarcoma = 1). All were newly diagnosed except for one (an intracranial relapse of AML). Median age was 54 (range, 20–82) years; 60% were women. Subject races included white (n = 10), Asian (n = 5), Hispanic (n = 2), African American (n = 2), and others (n = 3). Median WBC count at admission was 23 (range, 0.2–400) × 109/L. Thrombocytopenia (platelet levels < 50,000/μL) was present in 16 patients (72%), and 3 had platelet counts < 10,000/μL. Twelve patients (54%) had evidence of DIC. Sites of ICH included intraparenchymal (n = 8), subarachnoid (n = 3), subdural (n = 10), cerebellum (n = 1). In 3 patients, ICH extended into the ventricles. Three patients had ≥2 types of ICH. Three patients had middle cerebral artery ischemic stroke in addition to ICH. One patient with myelofibrosis and myeloid sarcoma had bilateral subdural hematomas (SDHs) on admission and developed a fatal basal ganglia ICH during induction chemotherapy. All APL patients were promptly started on all-trans retinoic acid. Two patients had refractory thrombocytopenia. Five patients required craniotomy, with 2 deaths from recurrent ICH. Two patients with SDH underwent MMA embolization with favorable outcomes. Four patients (18%) died within 72 hours of admission (APL = 3, AML = 1). The 30-day mortality rate among patients presenting with ICH was 31% (n = 7). Conclusions: ICH in AL continues to be a major cause of mortality and morbidity. Early diagnosis, transfusion support, correction of coagulopathy, and neurosurgical expertise are critical in improving outcomes in AL-associated ICH. MMA embolization is a new, minimally invasive strategy for the management of SDH in these critically ill patients.

A Systematic Review and Meta-Analysis of the Proportion Estimates of Disseminated Intravascular Coagulation (DIC) in Malaria.

Disseminated intravascular coagulation (DIC) is a potentially life-threatening condition that causes systemic coagulation to be turned on and coagulation factors to be used up. However, the evidence for DIC in malaria patients is still not clear, and small case series and retrospective studies have shown varying results. This meta-analysis was intended for the evaluation of the evidence of DIC among malaria patients using a meta-analysis approach. The protocol for the systematic review was registered at PROSPERO as CRD42023392194. Studies that investigated DIC in patients with malaria were searched in Ovid, Scopus, Embase, PubMed, and MEDLINE. The pooled proportion with 95% confidence intervals (CI) of DIC among malaria patients was estimated using a random-effects model. A total of 1837 articles were identified, and 38 articles were included in the meta-analysis. The overall proportion of DIC in malaria was 11.6% (95% CI: 8.9%-14.3%, I2: 93.2%, 38 studies). DIC in severe falciparum malaria and fatal malaria was 14.6% (95% CI: 5.0-24.3%, I2: 95.5%, 11 studies) and 82.2% (95% CI: 56.2-100%, I2: 87.3, 4 studies). The estimates of DIC among severe malaria patients who had multi-organ dysfunction with bleeding, cerebral malaria, acute renal failure, and ≥2 complications were 79.6% (95% CI: 67.1-88.2%, one study), 11.9% (95% CI: 7.9-17.6%, one study), 16.7% (95% CI: 10.2-23.3%, ten studies), and 4.8% (95% CI: 1.9-7.7%, nine studies), respectively. The proportion estimates of DIC among the patients with malaria depended on the Plasmodium species, clinical severity, and types of severe complications. The information from this study provided useful information to guide the management of malaria patients. Future studies are needed to investigate the association between Plasmodium infection and DIC and to understand the mechanism of malaria-induced DIC.

Could Transfusion be Restricted for Acute Promyelocytic Leukemia in the Era of Diffetentiating Agents?

BACKGROUNDWith the advent of differentiating agents (DA) like all-trans-retinoic-acid (ATRA), and arsenic trioxide (ATO), acute promyelocytic leukemia (APL) has become one of the best prognostic type of acute myeloid leukemia (AML) even in the under-developed countries. In Myanmar, APL is recognized as a common form of AML and managing APL in the resource limited setting particularly for aggressive transfusion support according to current guidelines is difficult and therefore transfusion requirement of APL treated in our center were analyzed with an aim to find evidence for restrictive transfusion policy. MATHODSCases of APL complicated by disseminated intravascular coagulation (DIC) treated during November 2014 to April 2017 were retrospectively reviewed in this study. All cases were treated with combined ATRA and ATO and conventional chemotherapy was added in high risk patients and those who developed rapid rise in white cell counts. Recommended target platelet count of 30-50 x 109/L and fibrinogen level of 100-150 mg/dl were maintained only for WHO grade 3 to 4 bleeding while the rest were transfused with platelet target of 20 x 109/L and fixed dose of FFP 2 -4 units per day until bleeding subsided. Prophylactic platelet was given for counts below 10 x 109/L. RESULTSAmong 33 APL admitted during two and half year's period, 29 presented with evidence of DIC, of them 4 had already developed intracerebral haemorrhage at presentation and died within 24 hours. In remaining molecularly confirmed 25 patients with APL, 14 males and 11 females, with median age of 28 years (range 12 -58) with initial performance status of 3 to 4 in 8 cases (32%) were classified as low, intermediate and high risk in 1 (4%), 13 (52%) and 11 (44%) cases respectively. Presenting blood counts were median hemoglobin - 5.9 mg/dl (3.2 - 10.6), median white cell count 7.23 x 109/L (0.43 - 110.8) and median platelet count 29 x 109/L (2 - 121). Regarding coagulation profile median PT - 15.6 second (9.9 - 21), median APTT - 28.4 second (20 - 46), median fibrinogen 160 mg/dl (82 - 900) and median D-Dimer - 8700 ng/ml (1917 - 19166). Median lowest platelet was 6 x 109/L (2 - 37) and median days of platelet count less than 10 x 109/L and less than 20 x 109/L were 4 days (0 - 10) and 8 days (2 - 26) respectively. Median number blood products transfused were of 6 units (3 - 12) of red cell, 10 units (6 - 15) of platelets and 10 unit (4 - 24) of FFP in total for each patient. Most bleeding and DIC subsided within first week and there were no haemorrhagic death during induction. CONCLUSIONRestricted transfusion policy may be possible in APL provided close monitoring of clinical and laboratory parameters and transfusion of blood products are tailored according to the risk and clinical condition. DisclosuresNo relevant conflicts of interest to declare.

Abstract 5854: BT5528, a Bicycle Toxin Conjugate targeting EphA2 has potent anti-tumor activity without bleeding or coagulation abnormalities in preclinical models

Abstract Ephrin receptor A2 (EphA2) is a member of the Ephrin receptor family of cell-cell junction proteins and is both highly overexpressed in several solid tumors and associated with poor prognosis in patients. EphA2 is considered a high-value target for cancer therapeutics, but development of an antibody drug conjugate targeting EphA2 (MEDI-547) was stopped in early clinical development after severe adverse events, including bleeding toxicity were seen (Annunziata et al, 2013). We have developed a series of Bicycle Toxin Conjugates comprising a constrained bicyclic peptide (Bicycle®) that binds with high affinity and specificity to EphA2, which is covalently linked to a toxin payload via a cleavable linker. The small size of BTCs offers a significant advantage over other targeted cytotoxic approaches such as antibody-drug conjugates due to rapid extravasation, renal clearance and improved tumor penetration. BT5528 was selected from a panel of >75 Bicycle Toxin Conjugates (BTCs) with variations in Bicycle binder, molecular spacer, cleavable linker and toxin payload, based on in vivo efficacy and tolerability. BT5528 is effective in EphA2-expressing xenograft models, with efficacy seen from 1mg/kg qw and complete tumor regression at 3mg/kg qw. Rapid, complete regression of tumors is seen across a range of EphA2-expressing cell lines, including HT1080 fibrosarcoma line, MDA-MB-231 triple negative breast cancer line and NCI-H1975 lung cancer line and NSCLC PDX models. In order to test the benefit of the enhanced tumor penetration of BTCs, NSCLC PDX tumors were grown to >1000mm3 before commencing treatment. Complete regression of tumor was seen following 3 weeks of dosing. The bleeding events reported in early clinical trials of MEDI-547 (EphA2 ADC) were consistent with effects on the coagulation system in preclinical models. Dose-limiting toxicology in non-human primate (NHP) was reportedly Disseminated Intravascular Coagulation (DIC) and changes were seen in APTT and D-Dimer, with associated elevations in liver enzymes. Toxicology studies of BT5528 in rat and NHP showed no laboratory or clinical evidence of DIC, with normal levels of platelets, D-Dimer, APTT, and other coagulation-related parameters. Bicycle Toxin Conjugates (BTC) targeting EphA2 show potent antitumor activity in a range of solid tumor xenograft models. The BTCs show profound efficacy, without the limiting toxicity observed with previous Antibody Drug Conjugate approaches. IND-enabling studies for BT5528 are currently underway. Citation Format: Gavin Bennett, Philip Huxley, Amy Brown, Gemma Mudd, Peter U. Park, Nicholas Keen. BT5528, a Bicycle Toxin Conjugate targeting EphA2 has potent anti-tumor activity without bleeding or coagulation abnormalities in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5854.

Coagulation abnormality as a complication of L-asparaginase therapy in childhood lymphoblastic leukemia

Background Bleeding, one of the most common symptoms ofacute leukemia in untreated patients, is mostly due to thrombocy-topenia as a result of myeloinvasion by leukemic cells. Neverthe-less, a further contributory factor for the additional hemorrhagiccomplication during intensive chemotherapy is the myelosuppressiveeffect of most active drugs. L-asparaginase, one of the cytostaticsused during remission induction therapy for childhood of acutelymphoblastic leukemia (ALL), is widely reported to impair the he-mostatic system.Objective To determine the influence of shorter courses of L-as-paraginase (L-Ase) on some of the hemostatic parameters in thetreatment of childhood ALL.Methods A prospective analytical study was carried out in theDepartment of Child Health, Cipto Mangunkusumo Hospital Jakartafrom July 1, 1999 to June 30, 2001 on newly diagnosed ALL pa-tients with normal liver function tests treated according to our na-tional ALL protocol which one of its composition contained 6 in-stead of 9 injections of L-asparaginase.Results All of 30 children with ALL included in the study, experi-enced prolongation of prothrombin time (PT), activated partialthromboplastin time (aPTT), and decreased fibrinogen concentra-tion, markedly during the administration of L-asparaginase. How-ever, none of the patients had additional hemorrhage or evidenceof disseminated intravascular coagulation (DIC).Conclusion The use of shorter courses of L-asparaginase, 6 in-jections, in the remission induction chemotherapy of childhood ALLin our department may reduce the blood clotting factors withoutfurther hemorrhage complication or evidence of DIC

Factor XI Deficiency Alters the Cytokine Response and Activation of Contact Proteases during Polymicrobial Sepsis in Mice.

Sepsis, a systemic inflammatory response to infection, is often accompanied by abnormalities of blood coagulation. Prior work with a mouse model of sepsis induced by cecal ligation and puncture (CLP) suggested that the protease factor XIa contributed to disseminated intravascular coagulation (DIC) and to the cytokine response during sepsis. We investigated the importance of factor XI to cytokine and coagulation responses during the first 24 hours after CLP. Compared to wild type littermates, factor XI-deficient (FXI-/-) mice had a survival advantage after CLP, with smaller increases in plasma levels of TNF-α and IL-10 and delayed IL-1β and IL-6 responses. Plasma levels of serum amyloid P, an acute phase protein, were increased in wild type mice 24 hours post-CLP, but not in FXI-/- mice, supporting the impression of a reduced inflammatory response in the absence of factor XI. Surprisingly, there was little evidence of DIC in mice of either genotype. Plasma levels of the contact factors factor XII and prekallikrein were reduced in WT mice after CLP, consistent with induction of contact activation. However, factor XII and PK levels were not reduced in FXI-/- animals, indicating factor XI deficiency blunted contact activation. Intravenous infusion of polyphosphate into WT mice also induced changes in factor XII, but had much less effect in FXI deficient mice. In vitro analysis revealed that factor XIa activates factor XII, and that this reaction is enhanced by polyanions such polyphosphate and nucleic acids. These data suggest that factor XI deficiency confers a survival advantage in the CLP sepsis model by altering the cytokine response to infection and blunting activation of the contact (kallikrein-kinin) system. The findings support the hypothesis that factor XI functions as a bidirectional interface between contact activation and thrombin generation, allowing the two processes to influence each other.

Evidence of disseminated intravascular coagulation in a porcine model following radiation exposure

Recent evidence has suggested that disseminated intravascular coagulation (DIC) plays an integral role in death at the LD50 dose of either gamma or solar particle event (SPE)-like proton radiation in ferrets. In these studies, Yucatan minipigs were evaluated to determine whether they were susceptible to the development of radiation induced DIC. Yucatan minipigs were exposed to a dose of 2.5 Gray (Gy) with X-rays and monitored over the course of 30 days. Evidence of DIC was evaluated by way of thromboelastometry parameters, platelet counts, fibrinogen concentration, and the d-dimer assay. Pigs exposed to X-rays developed signs of DIC within 2 days' post-irradiation. The development of DIC was exacerbated over the course of the studies, and one of the pigs died at day 14 and another had to be euthanized on day 16 post-irradiation. For both of these pigs, DIC was evident at the time of death. The following observations were indicated or were suggestive of DIC: whole blood clotting was impaired (as evidenced by thromboelastometry alterations), there were decreased platelet counts, elevated d-dimer concentrations in the blood, and/or hemorrhaging and the presence of fibrin in tissues observed during post-mortem examination. The extrapolation of data from these studies, in combination with other published data, have led to the hypothesis that there could be a correlation between the propensity to develop DIC, as indicated by hemorrhaging at death at relatively low doses of radiation, and the LD50 for a particular species. Our data suggest that the development of DIC may contribute to death at the LD50 dose in large mammals.

Factor XI Deficiency Reduces The Inflammatory Response To Polymicrobial Sepsis In Mice

Sepsis is a systemic host inflammatory response to entry and dissemination of an infectious agent. Interconnected pathways including inflammation, coagulation, and complement that serve protective functions when activated locally, contribute to morbidity and mortality when activated systemically during sepsis. Factor XIa (fXIa), the active form of the zymogen factor XI (fXI), contributes to thrombin generation in response to tissue injury. Prior work using a model of polymicrobial sepsis induced by cecal ligation and puncture (CLP) in mice suggests that fXI contributes to the pathology of sepsis by promoting disseminated intravascular coagulation (DIC) and inflammation (Tucker et al. J Infect Dis 2008;198:271 and Blood 2012;119:4762). We investigated the role of fXI in the CLP model, concentrating on the first 24 hours post-injury, using a high-level ligation that affects ≥75% of the length of the cecum. This level of injury causes near-100% mortality in wild type (WT) C57Bl/6 mice (median survival 42 hrs). Survival 7 days post-CLP was significantly greater for fXI-deficient (fXI-/-, 30% p=0.002) and partially deficient (fXI+/-, 17% p=0.003) mice compared to WT littermates (3%). For animals dying after CLP, median time to death was similar in the three groups. Four hours post-CLP, there were peaks in TNFα and IL-10 plasma levels in WT mice that were significantly smaller in fXI-/- mice (TNFα 76 ± 44 and 24 ± 22 pg/mL [p=0.009]; IL-10 10,000 ± 11,000 and 1,000 ± 900 pg/mL [p=0.0003], respectively), with levels also higher in WT mice 24 hrs post-CLP. There was significant white blood cell accumulation in the peritoneum 24 hrs post-CLP in WT and fXI-/- mice, with the lymphocyte fraction significantly elevated only in WT mice (p=0.008). The major rodent acute phase protein serum amyloid P was 5-fold higher in WT mice than in sham-treated mice, while levels in fXI-/-mice were indistinguishable from shams, 24 hrs post-CLP.In contrast to the indicators of inflammation, evidence for DIC was not strong for either genotype 24 hours post-CLP. Platelet counts were reduced similarly in both groups from a baseline mean of ∼600,000/μL, but mean counts remained above 300,000/μL. In both groups, plasma thrombin-antithrombin complex levels did not increase above baseline over the first 24 hrs post-CLP, and fibrinogen levels, which often decrease during DIC, increased modestly. No evidence of gross hemorrhage was noted at necropsy 4, 8, or 24 hrs post-CLP, and there was no histologic evidence of microvascular thrombosis (considered a “gold standard” for diagnosing DIC in laboratory animals) in kidney, liver or brain.The contact system zymogens factor XII (fXII) and prekallikrein (PK) are activated on bacterial surfaces during infection, resulting in cleavage of high molecular weight kininogen (HK) to produce antimicrobial peptides and the pro-inflammatory peptide bradykinin. We measured plasma fXII, PK, and fXI using western blots and densitometry. FXI decreased by ∼30% on average 24 hrs post-CLP in WT mice, consistent with protease activation. PK levels decreased by ∼50% in WT mice 24 hrs post-CLP (p 0.007), but were unchanged in fXI-/- mice. FXII levels decreased slightly in WT mice post-CLP, but increased in fXI-/-mice 4 hrs after CLP, returning to baseline 8 hrs post-CLP. FXI, PK and fXII levels were unchanged in sham-treated animals. The data suggest that fXI contributes to contact activation after CLP, and its absence leads to reduced PK and fXII activation.Previously, we reported that fXI deficiency reduced mortality after CLP (Tucker et al. J Infect Dis 2008;198:271) and infection with the gram-positive organism Listeria monocytogenes (Luo et al., Infect Immun. 2012;80:91), and proposed that this was in part related to down-regulation of coagulation, mitigating consumptive coagulopathy. The data presented here suggest that the high-level injury employed in the CLP-model produces an intense early systemic inflammatory response that leads to early death, before changes characteristic of DIC become obvious. The survival benefit conferred by fXI deficiency in this model then, may be primarily due to early modulation of inflammation, perhaps by altering contact activation, rather than to a prominent antithrombotic effect. Given the relatively mild bleeding diathesis associated with fXI deficiency, pharmacologic inhibition of fXIa may be a safe option for reducing the inflammatory response in septic patients. Disclosures:Tucker:Aoronora, Inc.: Employment. Gruber:Aronora, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Gailani:Aronora, Inc.: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy; Bayer Pharma: Consultancy; Novartis: Consultancy.

Successful renal transplantation from a brain-dead deceased donor with head injury, disseminated intravascular coagulation and deranged renal functions

Deceased donors (DDs) with the brain death due to head injury are the major source of organs for transplantation. The incidence of post-head injury disseminated intravascular coagulation (DIC) ranges from 24% to 50%. Many centers do not accept organs from donors with DIC due to increased risk of primary graft non-function and/or high chances of morbidity/mortality. We performed two successful renal transplants from a DD with head injury with DIC and deranged renal function. One of the recipients developed transient thrombocytopenia, but there was no evidence of DIC or delayed graft functions in either of the recipients. Over a follow-up of 1 month, both are doing well with stable graft function and hematological profile. Thus, a carefully selected DD with severe DIC even with deranged renal function is not a contraindication for organ donation if other risk factors for primary non-function are excluded. This approach will also help in overcoming organ shortage.

Prothrombin Fragment 1.2 and Modified Antithrombin as Predictors of Disseminated Intravascular Coagulation and Thrombotic Risk in Thermal Injury

Patients with thermal injury have subclinical disseminated intravascular coagulation (DIC) and increased hypercoagulability. This study was undertaken to determine whether prothrombin fragment 1.2 (F1.2) or modified antithrombin (ATM) were predictive of DIC or thrombotic risk in thermal injury. Sixty burn patients had F1.2 and ATM plasma levels drawn within 36 hours and between days 5 and 7 after injury. Additional hemostatic parameters were evaluated in a subset of nine patients with abnormal global coagulation markers (an elevated prothrombin time [PT], or activated partial thromboplastin time [aPTT]) or decreased platelets, but without clinical evidence of DIC, and three patients with DIC at admission. These patients were matched for age and %TBSA with 12 control patients who had normal PT, aPTT, and platelets. Blood was drawn for hemostatic factors: fibrinogen, antithrombin, F1.2, ATM, and D-dimer. F1.2 plasma levels increased in proportion to the severity of the %TBSA. The levels were significantly increased among burn patients with 20 to 40% and >40% TBSA at admission compared with normal (P < .01). ATM showed a significant decrease (P < .02) compared with normal levels and remained decreased for the first 5 to 7 days of the acute clinical phase in all the groups. Control patients and those with DIC had significantly increased D-dimer (P < .0001) and F1.2, (P < .03) plasma levels, and decreased antithrombin (P < .0001) compared with normal values; ATM plasma levels were not significantly different among the groups (P < .28). Burn patients with abnormal global coagulation markers had significantly increased D-dimer (P < .0001) and ATM (P < .005) plasma levels and decreased antithrombin levels (P < .0001) compared with normal values; F1.2 plasma levels were not significantly different (P < .15). Neither F1.2 nor ATM plasma levels showed any advantage in predicting thrombosis or DIC compared with PT, aPTT, and platelet count in conjunction with the patient's clinical presentation.

Outcome of advanced gastric cancer patients with disseminated intravascular coagulation and bone marrow metastasis is improved by weekly 24-Hour infusional high-dose 5-fluorouracil and leucovorin (HDFL)-based chemotherapy

14132 Background: Advanced gastric cancer (AGC) patients manifesting with acute disseminated intravascular coagulation (DIC) and diffuse bone marrow metastasis have inevitably led a fatal outcome within a median of 2–4 weeks. We previously reported that weekly 24-hour infusional high-dose 5-fluorouracil (5-FU) and leucovorin (LV) (HDFL: 5-FU of 2,000–2,600 mg/m2/wk and LV 300 mg/m2/wk) chemotherapy with negligible myelosuppression has been successfully used in the treatment of these patients (Yeh KH &amp; Cheng AL, Br J Haematol 1998;100:769–72). The study planned to determine the treatment outcome in a larger group of this disease entity being treated with HDFL-based chemotherapy. Methods: This is a retrospective study. Bone marrow study is routinely done for gastric cancer patients with DIC in our institute. We searched for gastric cancer patients with DIC or bone marrow metastasis from 1994 to 2005. Results: A total of 21 AGC patients (M: 13, F: 8) who had unequivocal evidence of DIC or biopsy-proven bone marrow metastasis have been diagnosed at National Taiwan University Hospital between 1994 and 2005. At initial presentations, 18 patients had evident laboratory findings of DIC. Nine of them had symptomatic DIC and 8 patients had significant thrombocytopenia (&lt; 50,000/mm3). All patients received HDFL-based chemotherapy as the initial treatment. Seventeen of them showed significant improvement in both clinical symptoms and laboratory abnormalities of DIC. The median overall survival (OS) of the whole group of patients since the diagnosis of DIC or bone marrow metastasis was 7 months (range: 1 week–3 years). Conclusions: Manifestations with acute DIC and bone marrow metastasis in AGC patients constitute a rare disease entity with a grave prognosis. Before introduction of HDFL for the treatment of AGC at our institute, this group of patients was extremely difficult to treat, and usually died within 2–4 weeks. Current analysis revealed that OS of this group of patients has been improved up to a median of 7 months, suggesting a significant improvement in the treatment outcome. No significant financial relationships to disclose.

A Case of Heparin-Induced Thrombocytopenia With Sepsis and Congestive Heart Failure-First Autopsy Report in Japan-

An 84-year-old man was referred to the emergency department with severe dyspnea. Based on his physical findings, electrocardiogram, X-ray and echocardiographic findings, congestive heart failure was suspected and drip infusion of prophylactic heparin against intracardiac thrombosis was commenced together with dopamine, nitroglycerin and furosemide. Diuresis occurred and the pulmonary congestion ameliorated remarkably. Starting on the 20th hospital day, the platelet count was gradually reduced (from 256,000 to 55,000 /microl) and the fibrin degradation product concentration rose (27.6 microg/ml). However, prothrombin time was not prolonged (89%), the concentration of antithrombin III was low -normal (69%) and the fibrinogen concentration was high (650 mg/dl). Thus, heparin-induced thrombocytopenia (HIT), rather than disseminated intravascular coagulation (DIC), was suspected. Heparin was withdrawn on the 24th hospital day and replaced by nafamostat mesilate after which the platelet count was restored to 100,000 /microl. Enzyme-linked immunosorbent assay for HIT antibodies was positive. Unfortunately, the patient died from uncontrolled sepsis on the 29th hospital day. At autopsy, platelet-rich thrombi were found in the small pulmonary arteries and intestinal arteries. No evidence of DIC, such as fibrin-rich thrombosis, was observed. This is the first autopsy report of HIT in Japan.

CIVD et défaillance d’organes : arguments expérimentaux et cliniques

Disseminated intravascular coagulation (DIC) is thought to contribute to multiple organ failure in a variety of underlying conditions for several reasons. First, clinical studies have found that, in patients with severe sepsis or septic shock, those with DIC exhibited more acquired organ failures than those without DIC, and their mortality rate was higher. Second, experimental studies of DIC associated with sepsis or low-grade activation of coagulation have repeatedly indicated that effective inhibition of DIC can indeed reduce organ failures and mortality. The mechanisms by which this role could be effectuated, however, are not clearly understood. The repeatedly demonstrated microvascular fibrin deposition in tissues of patients who have died from an illness with evidence of DIC may deprive downstream cells of oxygen, and cellular hypoxia could be a mechanism by which cells are damaged. In contrast, many investigators currently believe that it is not fibrin formation itself that is harmful, but rather is the generation of serine proteases and their interactions with pro-inflammatory mediators that contributes to organ failure and death. With the emergence of powerful anticoagulant strategies, aspects involving ischemia-reperfusion damage and organ recovery become important to investigate.

Serum and plasma latex agglutination tests for detection of fibrin(ogen) degradation products in clinically ill dogs.

An increased concentration of fibrin(ogen) degradation products (FDPs) commonly is used in conjunction with other hemostatic test abnormalities to identify patients with disseminated intravascular coagulation (DIC). Positive FDP results, however, have been observed in dogs without clinical evidence of DIC. The purpose of this study was to evaluate FDP concentrations in a group of clinically ill dogs with a variety of disorders. Dogs included in the study had the following hemostatic parameters evaluated: prothrombin time, activated partial thromboplastin time, fibrinogen concentration, platelet count, and FDP concentration. Two rapid latex agglutination methods were compared for detecting FDP in serum samples (Thrombo-Wellcotest, International Murex Technologies Corp) and plasma samples (FDP Plasma, American Bioproducts Inc). Results of the serum FDP method were positive in 8% (4/50) of the dogs tested: 3 with DIC and 1 with immune-mediated hemolytic anemia and liver disease. Results of the plasma FDP test were positive in 60% (30/50) of the animals tested: 6 with DIC, 3 with confirmed thrombosis, and 21 with a variety of conditions, including neoplasia, immune-mediated hemolytic anemia, pancreatitis, gastric dilatation-volvulus, heat stroke, severe trauma, sepsis, protein-losing nephropathy, liver disease, hyperadrenocorticism, and chronic heart failure. Because the plasma FDP test was positive more frequently than the serum FDP test in ill dogs, it may be more sensitive for the detection of canine FDP.

D-Dimer Measurements Unhelpful for Ruling In DIC

Physicians often use D-dimer assay results to corroborate the diagnosis of disseminated intravascular coagulation (DIC). We determined whether the results of this nonspecific assay helped to diagnose DIC in a group of patients admitted to the intensive care unit (a setting in which patients are often evaluated for this condition). We defined DIC in accordance with the following findings: systemic bleeding, prothrombin time (PT) more than 3 seconds above the reference range (or both); a fibrinogen level less than 150 mg/dL (1.5 g/L); and a platelet count less than 100 × 103/μL (100 × 109/L). For each patient, we calculated the Acute Physiological and Chronic Health Evaluation (APACHE) II score for illness and measured the PT, fibrinogen level, platelet count, and (semiquantitative) D-dimer level. The D-dimer result was positive in 31 of 50 patients (62%); for all 50 patients, the PT, fibrinogen level, and platelet count were within the reference ranges. None of these patients had clinical or laboratory evidence of DIC. We found no correlation between D-dimer results and (1) clinically observed deep venous thrombosis or pulmonary embolus; and (2) PT, level of fibrinogen, or platelet count. The mean ± SD APACHE II scores of D-dimer–negative patients were lower than those of the D-dimer–positive patients (13.4 ± 1.4 vs 16.2 ± 1.1, P = .006) but did not correlate with the degree of D-dimer positivity. The mean ± SD fibrinogen level of the D-dimer–negative group (456 ± 295 mg/dL [4.6 ± 3.0 g/L]) was not significantly different from that of the D-dimer–positive group (393 ± 187 mg/dL [3.9 ± 1.9 g/L], P = .36). We conclude that D-dimer levels are elevated in most critically ill patients irrespective of their hemostatic or thrombotic symptoms. The D-dimer assay should not be used to diagnose DIC in this patient population because it adds no specificity; it should be used only to rule out DIC.

Disseminated intravascular coagulation in liver cirrhosis

We measured thrombin-antithrombin III complex (TAT), soluble fibrin (SF) and D-dimer levels in 51 patients with liver cirrhosis to determine whether these tests provide new evidence for the presence of disseminated intravascular coagulation (DIC) in liver cirrhosis. TAT levels (median, range) were increased in the patient group (4.2 μg/l, 1.8–60.0) compared to the reference group (2.0 μg/l, range 1.5–7.6 μg/l). SF levels (0 nmol/l, range 0–80 nmol/l) were also increased in the patients as compared to the controls (0 nmol/l, 0), but there was no correlation between TAT and SF levels ( r = 0.23, p < 0.98). TAT levels did not correlate with AT-III levels ( r = −0.36, p < 0.49), but there was an inverse correlation between SF and AT-III ( r = 0.60, p < 0.001). If AT-III levels were above 0.30 U/ml, SF levels remained low, whereas SF levels were increased in patients with AT-III levels below 0.30 U/ml. These findings suggest that if sufficient AT-III is present, thrombin formation is adequately controlled, whereas at low levels of AT-III, thrombin escapes inactivation by AT-III and may act upon fibrinogen, leading to the formation of SF and a low-grade DIC. SF levels correlated well with D-dimer levels ( r = 0.55, p < 0.001), which is consistent with DIC and secondary fibrinolysis. In conclusion: (1) thrombin formation is increased in liver cirrhosis, as indicated by increased TAT levels in 21 of 51 patients; (2) the plasma concentration of AT-III appears to be of major importance for the development of DIC. The present study provides evidence for DIC in severe liver cirrhosis when AT-III levels are less than 0.30 U/ml.

High incidence of disseminated intravascular coagulation during remission induction of adult patients with acute lymphoblastic leukemia [see comments

We determined the incidence and complications of disseminated intravascular coagulation (DIC) at presentation and during remission induction of previously untreated adults with acute lymphoblastic leukemia (ALL) or de novo Philadelphia chromosome-positive ALL (PCALL) seen at Memorial Hospital between January 1, 1978 and December 31, 1989. DIC was diagnosed in the presence of (1) low fibrinogen (less than or equal to 160 mg/dL), (2) prolonged prothrombin time (PT) and falling fibrinogen, or (3) prolonged PT and positive fibrin split products (FSP). L-Asparaginase was not used during remission induction. Among adequately screened patients with ALL, DIC was detected in 7 of 58 (12%) before initiation of chemotherapy and in 35 of 45 (78%) during remission induction. DIC was not simply the result of infection because clinical and laboratory signs of infection were absent in 16 patients, whereas only 2 of the 22 febrile patients with DIC had positive cultures. Among the 38 patients with DIC at presentation or during remission induction, serious complications were seen in 13 in temporal association with DIC (pulmonary embolus in one, sagittal sinus thrombosis in three, and serious hemorrhage in nine) and were major factors in the deaths of three patients. Among the 10 patients with thorough screening but no evidence of DIC there was only one hemorrhage during the same time interval. In patients with PCALL, DIC was detected in 9% at presentation and in 80% during remission induction. We conclude that DIC is rare at presentation but common during remission induction of adult ALL and PCALL and may be associated with significant thrombotic and hemorrhagic complications. We suggest daily screening for DIC during the first 14 days of remission induction. The treatment of DIC in ALL and PCALL should be a subject of future clinical studies.

High Incidence of Disseminated Intravascular Coagulation During Remission Induction of Adult Patients With Acute Lymphoblastic Leukemia

We determined the incidence and complications of disseminated intravascular coagulation (DIC) at presentation and during remission induction of previously untreated adults with acute lymphoblastic leukemia (ALL) or de novo Philadelphia chromosome-positive ALL (PCALL) seen at Memorial Hospital between January 1, 1978 and December 31, 1989. DIC was diagnosed in the presence of (1) low fibrinogen (less than or equal to 160 mg/dL), (2) prolonged prothrombin time (PT) and falling fibrinogen, or (3) prolonged PT and positive fibrin split products (FSP). L-Asparaginase was not used during remission induction. Among adequately screened patients with ALL, DIC was detected in 7 of 58 (12%) before initiation of chemotherapy and in 35 of 45 (78%) during remission induction. DIC was not simply the result of infection because clinical and laboratory signs of infection were absent in 16 patients, whereas only 2 of the 22 febrile patients with DIC had positive cultures. Among the 38 patients with DIC at presentation or during remission induction, serious complications were seen in 13 in temporal association with DIC (pulmonary embolus in one, sagittal sinus thrombosis in three, and serious hemorrhage in nine) and were major factors in the deaths of three patients. Among the 10 patients with thorough screening but no evidence of DIC there was only one hemorrhage during the same time interval. In patients with PCALL, DIC was detected in 9% at presentation and in 80% during remission induction. We conclude that DIC is rare at presentation but common during remission induction of adult ALL and PCALL and may be associated with significant thrombotic and hemorrhagic complications. We suggest daily screening for DIC during the first 14 days of remission induction. The treatment of DIC in ALL and PCALL should be a subject of future clinical studies.

Immunohistochemical Diagnosis of Disseminated Intravascular Coagulation in Newborns

Disseminated intravascular coagulation (DIC) and other clotting abnormalities are common in sick newborn infants who have a variety of conditions. To document evidence of DIC at autopsy, immunoperoxidase staining of fibrin-related antigens (FRA) was used to detect intravascular microthrombi in liver, kidney, and lung from 127 newborns. Patients were selected from seven major disease groups: hyaline membrane disease/bronchopulmonary dysplasia, infection, meconium aspiration, necrotizing enterocolitis, congenital heart disease, other congenital anomalies, and extreme prematurity. Staining for FRA in intravascular microthrombi was seen in 40% of cases studied. The liver showed the highest frequency of intravascular microthrombi, located predominantly in the sinusoids. Unlike the adult kidney, the newborn kidney seldom had evidence of intravascular coagulation. Extravascular staining of FRA was observed in the renal distal tubular epithelium in 48 cases, many of which also had evidence of intravascular FRA staining. No significant differences in FRA staining patterns were seen among the disease groups except for cases of extreme prematurity in which all tissues showed minimal staining. Control tissues from SIDS patients also showed minimal FRA staining. Hepatic sinusoidal staining was the only tissue finding that correlated with thrombocytopenia, a clinical indicator of DIC. Despite the use of this immunohistochemical staining method, discrepancies between the clinical and autopsy diagnosis of DIC remain.

Is Heparin Administration Necessary During Induction Chemotherapy for Patients With Acute Promyelocytic Leukemia?

The role of heparin in the treatment of the disseminated intravascular coagulation (DIC) associated with acute promyelocytic leukemia (APL) remains unclear. Between 1974 and 1985, we treated 27 patients with APL using four different chemotherapeutic regimens; 23/27 (85%) had evidence of DIC either at presentation or following the initiation of induction chemotherapy. The coagulopathy was treated primarily with fresh frozen plasma and platelet transfusions; only 2/27 (7%) patients received heparin. Twenty of 27 patients (74%) entered complete remission. Major bleeding or thrombotic complications occurred in 5/27 patients (19%), but 2 of these 5 patients presented after hemorrhage had already occurred. None of the 5 patients with bleeding or thrombosis entered complete remission. All of the hemorrhagic complications due to DIC in our study occurred before 1979, which may reflect changes in the management of leukemic patients. This observation emphasizes the risks inherent in the use of historical controls in this population. In conclusion the DIC associated with APL can be successfully treated with intensive blood product support without the use of heparin.