Septic Shock, Multiple Organ Failure, and Disseminated Intravascular Coagulation: Compared Patterns of Antithrombin III, Protein C, and Protein S Deficiencies

BACKGROUND: Coagulopathy is present at admission in 25% of trauma patients, is associated with shock and a 5-fold increase in mortality. The coagulopathy has recently been associated with systemic activation of the protein C pathway. This study was designed to characterize the thrombotic, coagulant and fibrinolytic derangements of trauma-induced shock. METHODS: This was a prospective cohort study of major trauma patients admitted to a single trauma center. Blood was drawn within 10 minutes of arrival for analysis of partial thromboplastin and prothrombin times, prothrombin fragments 1 + 2 (PF1 + 2), fibrinogen, factor VII, thrombomodulin, protein C, plasminogen activator inhibitor-1 (PAI-1), thrombin activatable fibrinolysis inhibitor (TAFI), tissue plasminogen activator (tPA), and D-dimers. Base deficit was used as a measure of tissue hypoperfusion. RESULTS: Two hundred eight patients were studied. Systemic hypoperfusion was associated with anticoagulation and hyperfibrinolysis. Coagulation was activated and thrombin generation was related to injury severity, but acidosis did not affect Factor VII or PF1 + 2 levels. Hypoperfusion-induced increase in soluble thrombomodulin levels was associated with reduced fibrinogen utilization, reduction in protein C and an increase in TAFI. Hypoperfusion also resulted in hyperfibrinolysis, with raised tPA and D-Dimers, associated with the observed reduction in PAI-1 and not alterations in TAFI. CONCLUSIONS: Acute coagulopathy of trauma is associated with systemic hypoperfusion and is characterized by anticoagulation and hyperfibrinolysis. There was no evidence of coagulation factor loss or dysfunction at this time point. Soluble thrombomodulin levels correlate with thrombomodulin activity. Thrombin binding to thrombomodulin contributes to hyperfibrinolysis via activated protein C consumption of PAI-1.

https://www.zora.uzh.ch/id/eprint/4784/2/Ganter_JTrauma_2008Vo.pdf

Acute Coagulopathy of Trauma: Hypoperfusion Induces Systemic Anticoagulation and Hyperfibrinolysis

Purpose of reviewAcute coagulopathy of trauma has only been described relatively recently. Developing early in the postinjury phase, it is associated with increased transfusion requirements and poor outcomes. This review examines the possible initiators, mechanism and clinical importance of acute co

Acute coagulopathy of trauma: mechanism, identification and effect.

Background: Loading doses of warfarin that are larger than those used for maintenance therapy are widely used in clinical practice, but they have never been prospectively evaluated. Objective: To c...

Comparison of 5-mg and 10-mg loading doses in initiation of warfarin therapy

Venous thromboembolism, which includes deep-vein thrombosis (usually involving leg veins) and pulmonary embolism, is a common cause of death. Treatment of affected patients reduces the incidence of fatal pulmonary embolism, but therapy should be based on the severity of disease and the potential for side effects. Decisions about the duration of therapy should be made by balancing the risks of continuing therapy against the risk of recurrence. In this review, the care of patients with venous thromboembolism will be discussed, with emphasis on recent advances. Diagnosis Approximately 75 percent of patients who present with suspected venous thrombosis or pulmonary embolism . . .

Management of Venous Thromboembolism

Although protein C (PC) and activated protein C (APC) have been postulated to be useful for treating patients with thrombosis, their critical effect remains to be studied in human subjects. To examine whether purified PC or APC are useful for treating patients with thrombosis without showing any adverse effect, we studied effects on coagulation and fibrinolysis in normal human subjects. When highly purified human PC was administered intravenously to healthy subjects, plasma levels of immunoreactive PC decreased with a half-life of 10.9 h. Intravenously administered APC decreased with a half-life of 23 min as measured by prolongation of activated partial thromboplastin time (APTT). However, 1.7 h was obtained for the plasma half-life of APC when it was measured immunologically. These findings suggested that a significant fraction of the administered APC was rapidly inhibited by plasma inhibitor. Upon administration of APC, APTT was prolonged and plasma levels of clotting factor VIII (F-VIII) decreased transiently as measured by clotting assay. However, when determined by a chromogenic assay method in which 120-fold diluted plasma samples were used, plasma levels of F-VIII remained unchanged. Plasma levels of F-V did not decrease after APC administration. These findings suggested that prolongation of APTT and apparent decrease in plasma F-VIII clotting activity might be due to the in vitro-effect of APC present in plasma samples used. Diurnal fluctuation of plasminogen activator inhibitor in normal subject was not affected by administration of APC. Thus, PC or APC seems to function selectively at the site of thrombin-formation without lowering plasma levels of coagulation factors.

Effect of protein C and activated protein C on coagulation and fibrinolysis in normal human subjects.

The therapeutic effect of highly purified protein C (PC) or activated protein C (APC) on three patients with disseminated intravascular coagulation (DIC) was tested. In two out of three cases, although therapeutic dose of heparin was not effective, PC or APC administration significantly improved the hypercoagulable state. In one case with acute leukemia who developed DIC with the severe gastrointestinal bleeding, APC corrected the hypercoagulable state without aggravating bleeding. These findings suggested that PC and/or APC might be effective in correcting hypercoagulable state without any adverse effect.

Treatment of patients with disseminated intravascular coagulation by protein C.

Plasma samples from patients with disseminated intravascular coagulation (DIC) associated with acute promyelocytic leukemia (APL) exhibited higher levels of the D-fragment of fibrin and fibrinogen deg

Characterization of the fibrinolytic state by measuring stable cross-linked fibrin degradation products in disseminated intravascular coagulation associated with acute promyelocytic leukemia.

A 75-year-old man was diagnosed with alcaptonuria by direct identification of homogentisic acid in the urine using gas chromatography-mass spectrometry. Complications included valvular heart disease with marked calcification detected by two-dimensional color-Doppler echocardiography and recurrent bacterial infection. Immunological analyses revealed a reduced number of T cells with compensatory expansion of CD56+, CD57+ natural killer (NK) cell population and impaired functions of cellular immunity such as phytohemagglutinin response, antibody-dependent cellular cytotoxicity, NK activity and interleukin-2 production. Humoral immunity and neutrophil functions were considered to be normal. This is the first reported case of alcaptonuria to our knowledge in which immunological abnormality was documented.

Shin Koga

Papers

Effect of protein C and activated protein C on coagulation and fibrinolysis in normal human subjects.

Treatment of patients with disseminated intravascular coagulation by protein C.

Characterization of the fibrinolytic state by measuring stable cross-linked fibrin degradation products in disseminated intravascular coagulation associated with acute promyelocytic leukemia.

Alcaptonuria : a case complicated with valvular heart disease and immunodeficiency

Plasma polymorphonuclear leukocyte elastase-α1-proteinase inhibitor complex in patients with gastric ulcer