Disseminated intravascular coagulAtion (DIC) (BSH 2009)

 

ISTH DIC Score: Score ≥5 compatible with overt DIC. Predicts mortality.

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Intro

 

DIC is the loss of localization or compensated control of intravascular activation of coagulation

 

The loss of the regulated balance between procoagulant/anticoagulant and profibrinolytic/antifibrinolytic processes —> simultaneous bleeding and microvascular thrombosis at different vascular sites.

 

Pathophysiology

 

1. Excess Thrombin Generation

 

Excess thrombin generation results from an increased presence of tissue factor (TF), and the reason for this depends on the underlying pathology:

  • Infection: Increased TF expression on monocytes

  • Trauma: Thromboplastin-like substances released from injured tissues, e.g. brain

  • Obstetrics: Amniotic fluid is a rich source of TF + Phospholipid

  • Malignancy: TF-like proteins produced by malignant cells

 

Excess thrombin results in:

  • Clotting factor and platelet consumption --> Bleeding

  • Hyperfibrinolysis – Increased D-dimers and thrombin-antithrombin complexes --> bleeding

  • Anticoagulant consumption – reduced protein C/S, Anti-thrombin --> Thrombosis

  • Excess Antifibrinolysis – increased thrombin activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor (PAI) --> Thrombosis

 

2. Mechanisms that fuel and perpetuate thrombin generation become pathogenic

 

3. Parallel activation of inflammatory cascade further promotes thrombin generation, e.g.

  • TNF activates coagulation

  • Thrombin activates PAR receptors and converts C5 —> C5a promoting inflammation

 

4. Complicated role of endothelial microvasculature in the above processes.

 

Clinical Features

 

Excess Bleeding

  • Depletion of coagulation factors & platelets

  • Abnormal platelet function in uraemia

  • Reduced factor production in liver impairment

 

Microvascular thrombosis --> Organ failure

  • Reduced levels of anticoagulants

  • Loss of thrombomodulin receptors on the damaged endothelium

  • Endothelial dysfunction --> reduced nitrous oxide --> uninhibited platelet activation

 

Treatment

 

1. Reverse underlying pathology

 

2a. If not bleeding:

  • No blood products unless to prepare for invasive procedure

  • Prophylactic LMWH should be given

(Side note: ?Recombinant activated protein C (continuous infusion for 4 days) ?fallen out of favour. 2001 trial showed increased survival in severe sepsis but with increased rate of severe bleeding. Contraindicated if platelet count <30. Stop 20 minutes prior to invasive procedures.)

 

2b. If bleeding:

  • Aim to maintain, plt >50, FGN >1.5, PT/APTT <1.5x ULN

  • There is no evidence that administration of FFP stimulates the ongoing activation of coagulation

  • Consider PCC if FFP contraindicated, but will provide only partial correction of global deficiencies.

  • Use cryo / FGN concentrate if FGN <1.0g/l

In general avoid tranexamic acid. Consider if hyperfibrinolytic state and severe bleeding

 

2c. If thrombosis predominates:

Therapeutic dose heparin infusion if significant thrombosis occurs

 

Differential Diagnosis for DIC

dic ddx.png

 

Chronic DIC

 

Usually thrombotic > haemorrhagic

Adenocarcinoma – thrombophlebitis migrans & recurrent VTE (Trousseau’s Syndrome)

Retained dead fetus syndrome – starts low grade, will become fulminant DIC if not evacuated

Liver disease – DIC may play a part in the coagulopathy of liver disease

Localised lesions  - aneurysms, haemangiomata, empyema

 

 

Notes on Fibrinolysis

 

Pro-Fibrinolysis Elements

 

Tissue Plasminogen Activator (tPA)

  • Serine protease produced in endothelial cells

  • Under normal circumstances tPA has a half-life of 2-3 min, due to inhibition by PAI-1

  • In the presence of fibrin clot, tPA’s affinity for plasminogen is greatly increased

 

Plasminogen

  • Inactive zymogen that is cleaved by t-PA or u-PA —> Active Plasmin serine protease

  • Plasminogen deficiency very rare —> causes haemorrhagic conjunctivitis

 

Anti-Fibrinolysis Elements

 

Plasminogen Activator Inhibitor 1 (PAI-1)

  • A member of the serine protease inhibitor (SERPIN) family, produced in endothelial cells

  • t-PA:PAI-1 complexes are removed by the liver

 

a2-Plasmin inhibitor (a2-AP)

  • Major inhibitor of plasmin

  • Member of SERPIN family, it becomes cross-linked into fibrin clot, rendering the clot resistant to fibrinolysis.

 

Tissue Activatable Fibrinolytic Inhibitor (TAFI)

  • Removes the t-PA binding site from plasminogen, preventing its conversion to plasmin