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Coagulation Disorders
Figure 1: Pathogenesis of Disseminated Intravascular persistent generation of thrombin and plasmin.
10
However, studies in
Coagulation in Sepsis
experimental models of sepsis have put forward the concept that
thrombin generation might largely exceed that of plasmin.
Sepsis Convincing evidence also indicated that such an imbalance between
coagulation and fibrinolysis might be due to increased levels of
plasminogen activator inhibitor type 1 (PAI-1).
11
A constellation of
Protein C
Plasminogen
biological mechanisms has been advocated to trigger and/or boost
Antithrombin
PAI-1 DIC in patients with sepsis, including:
Tissue factor/factor VIIa
• increased thrombin generation mediated predominantly by
Inflammation
Activation of Activation of
coagulation system fibrinolytic system
activation of tissue factor/factor VIIa pathway and impaired
function of physiological anticoagulant pathway (e.g. reduction of
Cytokine
antithrombin levels, depression of the protein C pathway,
production
Thrombosis
Bleeding
inhibition of tissue factor pathway inhibitor);
• impaired fibrinolysis mediated by release of plasminogen
Consumption of
activators from endothelial cells immediately followed by an
clotting factors
increase in the plasma levels of PAI-1; and
• activation of the inflammatory pathway mediated by activated
Table 1: Laboratory Tests in Diagnostics of Disseminated
Intravascular Coagulation
coagulation proteins and depression of the protein C pathway.
2
Global Haemostatic Tests
While cytokines and inflammatory mediators can induce coagulation,
Prolongation of prothrombin time (PT), activated partial thromboplastin time
thrombin and other serine proteases interact with protease-
(APTT) and thrombin time (TT)
activated receptors on cell surfaces to boost inflammation.
Hypofibrinogenaemia Furthermore, since activated protein C has an anti-inflammatory
Thrombocytopenia effect through its inhibition of endotoxin-induced production of
Elevated fibrin/fibrinogen degradation products (FDP, D-dimer)
tumour necrosis factor-α (TNF-α), interleukin (IL)-β, IL-6 and IL-8,
Abnormalities on the peripheral smear (schistocytes, large platelets)
depression of the protein C system may also result in a pro-
Presence of biphasic waveform
inflammatory state.
2
Taken together, this biological evidence is
Specific Tests Suggestive of Hypercoagulability
consistent with the hypothesis that septic DIC should be considered
Elevated prothrombin fragment 1 + 2 (F1+2)
as a unique pathophysiological, biochemical and clinical entity in
Elevated fibrinopeptide A (FPA) and B (FPB)
which inflammatory and coagulation pathways interplay in a sort of
Elevated thrombin–antithrombin complexes (TAT)
vicious circle (see Figure 1).
Elevated soluble fibrin monomer (sFM)
Specific Tests Suggestive of Natural Inhibitor Consumption
Decreased antithrombin
Laboratory Diagnostics in Septic Disseminated
Decreased antiplasmin
Intravascular Coagulation
Decreased protein C and S
The diagnosis of septic DIC is possible using a combination of
Elevated plasmin–antiplasmin (PAP) complexes
laboratory tests for which simple diagnostic algorithms have now
Inflammatory Biomarkers
become available. However, these tests can be used for diagnosing
C-reactive protein (CRP) and monitoring DIC only when at least two main requisites are fulfilled:
Procalcitinin (PCT) identification of DIC at the earliest possible phase and availability in
Interleukins 1, 6 and 8
routine and, especially, urgent clinical settings.
12
Patients with DIC have
Tumour necrosis factor-α (TNF-α)
a low or rapidly decreasing platelet count, prolonged coagulation tests,
LPS-binding protein (LBP)
low plasma levels of coagulation factors and inhibitors and increased
White blood cell and differential counting
markers of fibrin formation and/or degradation, such as D-dimer or
fibrin degradation products (see Table 1). Therefore, a reliable
A second important mechanism triggering sepsis-related DIC is thought approach to the diagnosis of DIC is the use of a simple scoring system
to be the translocation of cell membrane aminophospholipids from the based on the combination of routinely available coagulation tests.
inner to the outer leaflet, or their release into the bloodstream as a
consequence of cell breakdown. This is commonplace in several forms Scoring Cards for Disseminated
of sepsis, since host cells may be injured or broken directly by the Intravascular Coagulation
microrganisms, whereas bacterial cells may be destroyed by heat, The SSC on DIC of the ISTH has developed a four-parameter scoring
antibodies or antibiotics;
8
as such, it can be concluded that ‘all bugs bite card for DIC for ‘overt’ and ‘non-overt’ DIC. The scoring for overt DIC
equally’. In fact, although there is a widespread perception that septic is as follows:
DIC is most commonly associated with Gram-negative bacteria
infection, Gram-positive bacteria – as well as other micro-organisms, • platelet count: >100x10
9
/l = 0, <100x10
9
/l = 1, <50x10
9
/l = 2;
including viruses and parasites (such as malaria) – may cause dramatic • elevated fibrin degradation products: no increase = 0, moderate
activation of blood coagulation, causing severe forms of DIC.
9
increase = 2, strong increase = 3;
• prothrombin time (PT) upper limit of reference range: <3 seconds =
Overall, the pathogenesis of DIC is characterised by simultaneous 0, >3 seconds = 1, >6 seconds = 2; and
activation of haemostasis and fibrinolysis, resulting in extensive and • fibrinogen level: >100mg/dl = 0, <100mg/dl = 1.
20 EUROPEAN HAEMATOLOGY
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