Safety of plasma-derived protein C for treating disseminated intravascular coagulation in adult patients with active cancer

Severe and recurrent purpura fulminans developed in a Chinese boy at one day of age. Results of coagulation studies performed on the patient during attacks were compatible with the diagnosis of disseminated intravascular coagulation. Subsequent investigations have revealed that the patient is homozygous and that his parents are heterozygous for protein C deficiency. Cryoprecipitate and fresh frozen plasma induced a remission, and administration of warfarin has been successful in preventing recurrence of attacks for as long as 8 months without infusion of any plasma components. None of the family members who are heterozygous for protein C deficiency have had thrombotic episodes.

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Endothelial Dysfunction Is Associated with Mortality and Severity of Coagulopathy in Patients with Sepsis and Disseminated Intravascular Coagulation

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/1076029619852163 ◽

2019 ◽

Vol 25 ◽

pp. 107602961985216 ◽

Cited By ~ 7

Author(s):

Amanda Walborn ◽

Matthew Rondina ◽

Michael Mosier ◽

Jawed Fareed ◽

Debra Hoppensteadt

Keyword(s):

Disseminated Intravascular Coagulation ◽

Protein C ◽

High Mobility ◽

Severity Of Illness ◽

Endothelial Activation ◽

Endothelial Damage ◽

Intravascular Coagulation ◽

Angiopoietin 2 ◽

Von Willebrand ◽

Relationship Of

The role of the endothelium in sepsis-associated disseminated intravascular coagulation (DIC) is multifaceted and may contribute substantially to disease severity and outcome. The purpose of this study was to quantify measures of endothelial function, including markers of activation (endocan, Angiopoietin-2 [Ang-2], and von Willebrand Factor), endogenous anticoagulants (tissue factor pathway inhibitor and protein C), and damage-associated factors (High Mobility Group Box 1 [HMGB-1]) in the plasma of patients with sepsis and DIC, and to determine the relationship of these factors with severity of illness and outcome. Plasma samples were collected from 103 adult patients with sepsis within 48 hours of intensive care unit admission. Biomarker levels were measured using commercially available, standardized methods. Disseminated intravascular coagulation was diagnosed according to the International Society of Thrombosis and Hemostasis scoring algorithm. Twenty-eight-day mortality was used as the primary end point. In this study, endothelial damage and dysfunction were associated with the severity of coagulopathy and mortality in DIC patients. Loss of the endogenous anticoagulant protein C and elevation in the vascular regulator Ang-2 were associated with the development of overt DIC. In addition to Ang-2 and protein C, endocan, a biomarker of endothelial activation, and HMGB-1, a mediator of endothelial damage and activation, were significantly associated with mortality. This underscores the contribution of the endothelium to the pathogenesis of sepsis-associated DIC.

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Decreased plasma activity of antithrombin or protein C is not due to consumption coagulopathy in septic patients with disseminated intravascular coagulation

European Journal Of Haematology ◽

10.1034/j.1600-0609.2001.5790508.x ◽

2001 ◽

Vol 67 (3) ◽

pp. 170-175 ◽

Cited By ~ 43

Author(s):

Hidesaku Asakura ◽

Yasuo Ontachi ◽

Tomoe Mizutani ◽

Minori Kato ◽

Takako Ito ◽

...

Keyword(s):

Disseminated Intravascular Coagulation ◽

Protein C ◽

Consumption Coagulopathy ◽

Intravascular Coagulation ◽

Plasma Activity

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Dysregulation of Inflammatory and Hemostatic Markers in Sepsis Associated Disseminated Intravascular Coagulation.

Blood ◽

10.1182/blood.v120.21.2223.2223 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2223-2223 ◽

Cited By ~ 1

Author(s):

Jawed Fareed ◽

Debra Hoppensteadt ◽

Josephine Cunanan ◽

Michael Mosier ◽

Yutaka Osawa ◽

...

Keyword(s):

Disseminated Intravascular Coagulation ◽

Inflammatory Mediators ◽

Protein C ◽

Control Group ◽

Functional Protein ◽

Double Blind ◽

Intravascular Coagulation ◽

Hemostatic Markers ◽

Circulating Levels ◽

Pai 1

Abstract Abstract 2223 Disseminated intravascular coagulation (DIC) represents a complex pathophysiologic syndrome where marked alterations in the hemostatic system are manifested. As a result several inflammatory mediators are up regulated through multiple mechanisms. The up regulation of inflammatory mediators such as anaphylatoxin C5a (C5a), procalcitonin (PCT), interleukin 6 (IL-6), interleukin 10 (IL-10), myeloperoxidase (MPO), C reactive protein (CRP), and circulating levels of hemostatic markers including protein C inhibitor (PCI), plasminogen activator inhibitor 1 (PAI-1), and protein C (Pr C) were evaluated in 758 subjects enrolled in a randomized, double-blind, placebo-controlled, Phase-2B study evaluating the safety and efficacy of recombinant thrombomodulin (ART-123) in subjects with sepsis and suspected DIC. Thirty healthy male and female volunteers served as the control group. Commercially available ELISA methods were used to measure the various mediators. Marked deviations in the circulating levels of these markers, as compared to controls, were noted as shown in the following table. Compared with controls, subjects in DIC showed an increase in the circulating levels of most inflammatory markers. The levels of PCT, IL-6 and CRP, where considerably higher in the DIC subjects whereas PCI, Pr C and AT exhibited slight decreases. Wide individual variations were present. The PAI-1 levels were also increased in the DIC subjects. These results are tabulated below. These results clearly indicate that inflammation and impairment of fibrinolysis play a key role in the pathogenesis of DIC Parameter Nomal (NHP Mean+SEM) DIC (Baseline Mean+SEM) % Change Protein C (% Ag) 82.5 ± 13.6 47.6 ± 23.7 −42.2% Functional Protein C (%) 83.4 ± 13.2 46.2 ± 29.8 −44.6% PCI (% Inhibition) 130.0 ± 24.6 79.4 ± 105.5 −38.9% PAI-1 (ng/ml) 35.4 ± 10.8 140.6 ± 165.6 297.1% CRP (ug/ml) 2.6 ± 0.4 48.0 ± 14.2 1736.9% C5a (ng/ml) 9.2 ± 3.2 17.2 ± 13.3 85.1% IL-6 (pg/ml) 9.3 ± 3.7 620.3 ± 1883.4 6583.9% IL-10 (pg/ml) 13.9 ± 13.1 130.2 ± 118.6 836.1% MPO (ng/ml) 16.0 ± 4.2 108.1 ± 68.6 574.6% PCT (ng/ml) 0.2 ± 0.13 21.9 ± 43.3 14514.5% Disclosures: Osawa: Asahi Kasei Pharma America Corporation: Employment. Kaul:Asahi Kasei Pharma America Corporation: Employment.

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The Leiden Mutation and Activated Protein C Resistance as Risk Factors for Disseminated Intravascular Coagulation in Acutely Poisoned Patients

Clinical Toxicology ◽

10.1080/15563650500394845 ◽

2006 ◽

Vol 44 (1) ◽

pp. 53-57

Author(s):

Mirosław Prazanowski ◽

Barbara Kur ◽

Małgorzata Barańska ◽

Waldemar Lutz ◽

Bożena Piłacik ◽

...

Keyword(s):

Risk Factors ◽

Disseminated Intravascular Coagulation ◽

Protein C ◽

Activated Protein C ◽

Activated Protein C Resistance ◽

Intravascular Coagulation

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The withdrawal of Activated Protein C from the use in patients with severe sepsis and DIC [Amendment to the BCSH guideline on disseminated intravascular coagulation]

British Journal of Haematology ◽

10.1111/j.1365-2141.2011.09019.x ◽

2012 ◽

Vol 157 (4) ◽

pp. 493-494 ◽

Cited By ~ 40

Author(s):

Jecko Thachil ◽

Cheng Hok Toh ◽

Marcel Levi ◽

Henry G Watson

Keyword(s):

Severe Sepsis ◽

Disseminated Intravascular Coagulation ◽

Protein C ◽

Activated Protein C ◽

Intravascular Coagulation

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Aggravation of endotoxin-induced disseminated intravascular coagulation and cytokine activation in heterozygous protein-C–deficient mice

Blood ◽

10.1182/blood-2002-10-3254 ◽

2003 ◽

Vol 101 (12) ◽

pp. 4823-4827 ◽

Cited By ~ 108

Author(s):

Marcel Levi ◽

Janine Dörffler-Melly ◽

Pieter Reitsma ◽

Harry Büller ◽

Sandrine Florquin ◽

...

Keyword(s):

Inflammatory Response ◽

Disseminated Intravascular Coagulation ◽

Protein C ◽

Activated Protein C ◽

Intravascular Coagulation ◽

Cytokine Activation ◽

Tnf Α ◽

Single Allele ◽

Factor Α ◽

Heterozygous Deficiency

Abstract In the pathogenesis of sepsis and disseminated intravascular coagulation (DIC), dysfunctional anticoagulant pathways are important. The function of the protein C system in DIC is impaired because of low levels of protein C and down-regulation of thrombomodulin. The administration of (activated) protein C results in an improved outcome in experimental and clinical studies of DIC. It is unknown whether congenital deficiencies in the protein C system are associated with more severe DIC. The aim of the present study was to investigate the effect of a heterozygous deficiency of protein C on experimental DIC in mice. Mice with single-allele targeted disruption of the protein C gene (PC+/–) mice and wild-type littermates (PC+/+) were injected with Escherichia coli endotoxin (50 mg/kg) intraperitoneally. PC+/–mice had more severe DIC, as evidenced by a greater decrease in fibrinogen level and a larger drop in platelet count. Histologic examination showed more fibrin deposition in lungs, kidneys, and liver in mice with a heterozygous deficiency of protein C. Interestingly, PC+/– mice had significantly higher levels of proinflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1β, indicating an interaction between the protein C system and the inflammatory response. Survival was lower at 12 and 24 hours after endotoxin in the PC+/– mice. These results confirm the important role of the protein C system in the coagulative-inflammatory response on endotoxemia and may suggest that congenital deficiencies in the protein C system are associated with more severe DIC and adverse outcome in sepsis.

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