Pathology SeminarPathology SeminarOctober 2010October 2010

Year 4 MedicineYear 4 MedicineGroup 1 UST Sana’aGroup 1 UST Sana’a

DIC stands for Disseminated intravascular

coagulation. It is the disturbance of the blood clotting

mechanism. Several clots in some vessels increase

consumption of the blood clotting factors and platelets deficiency, lack or destruction of those factors in other body parts Several bleedings in other areas of the body.

Introduction

During vascular injury hemostasis normally

occurs on the affected site. The hemostasis has four phases:

1. Vasoconstriction then, 2. Primary phase, 3. Secondary phase, 4. Tertiary phase,

Normal Hemostasis

After vascular injury occurs there are certain factors of neurohumoral type released causing transient vasoconstriction to the affected site.

VASOCONSTRICTION

Platelets adhere (via GpIb receptors) to exposed extracellular matrix by binding to von Willebrand factor and are activated, undergoing a shape change and granule release. Released adenosine diphosphate and thromboxane A2 lead to further platelet aggregation (via binding of fibrinogen to platelet GpIIb-IIIa receptors), to form the primary hemostatic plug.

PRIMARY HEMOSTASIS

Local activation of the coagulation cascade (involving tissue factor and platelet phospholipids) results in fibrin polymerization, "cementing" the platelets into a definitive secondary hemostatic plug.

SECONDARY HEMOSTASIS

Counter-regulatory mechanisms, such as release of t-PA (Tissue plasminogen activator, a fibrinolytic product) and thrombomodulin (interfering with the coagulation cascade), limit the hemostatic process to the site of injury.

TERTIARY HEMOSTASIS

1)1) Generation of a hyperthrombinemic stateGeneration of a hyperthrombinemic state2)2) Alteration of the physiological Alteration of the physiological

anticoagulants levelsanticoagulants levels3)3) Impaired fibrinolysis at the onset of the DIC:Impaired fibrinolysis at the onset of the DIC:4)4) Activation and liberation of inflammatory Activation and liberation of inflammatory

cytokines in the pathogenesis of DICcytokines in the pathogenesis of DIC

The exposing of the tissue factors thromboplastin

and factor III during injury causes a cascade activation of a factor pathway that has a dominant role in the hyperthrombinemic state in DIC.

Cytokines and bacterial endotoxin are all triggers to the formation of endothelial cell tissue factor.

In severe trauma also tissue phospholipids initiates the clotting cascade.

1) Generation of a hyperthrombinemic state

cont.: The cascade goes here as follows

cont.: The Thrombin in turn activates

There are 3 most common Anticoagulants in

the body: Antithrombin, Active Protein C Tissue factor pathway inhibitor (TFPI).

In DIC: ↓Antithrombin ↓Active Protein C

2) Alteration of the physiological anticoagulants levels

cont.: The cause of the decrease

Protein C function

Normally In DIC

cont.: Protein C’s Importance

Plasminogen activator inhibitor 1 (PAI-1) is a

neurohumoral compound released by the endothelial cells at the effected site.

PAI-1 suppresses the normal fibrinolysis activity.

Some DIC individuals have shown a mutation in the PAI-1 gene, leading to an increased plasma PAI-1 levels.

3) Impaired fibrinolysis at the onset of the DIC:

Activation of Clotting sys. Inflammatory

cascade activation Induced pro-inflammatory cytokines (thrombin and other serine proteases).

Pro-inflammatory cytokines + Protease-activated receptors (of the cell surface of the endothelial cells) Inducing an inflammatory and clotting reaction.

4) Activation and liberation of inflammatory cytokines

Renal failure. Cough Confusion. Decreased platelets. Blood clots. Drop in blood pressure. Sudden bruising. Bleeding, possibly from multiple sites in the

body. Fever

Signs & symptoms of DIC

Site in decreasing order of frequency

Brain

Heart

Kidney

Adrenals

Spleen

Lungs

Liver

Sites of Thrombosis

DICDIC Is most likely to occur after sepsis, Is most likely to occur after sepsis, obstetric complications, malignancy, obstetric complications, malignancy,

and major trauma (especially trauma to and major trauma (especially trauma to the brain)the brain)

Abruption placentae Retained dead fetus Septic abortion Amniotic fluid embolism Toxemia

Obstetric complications

Sepsis (gram negative and gram positive) Meningococcemia Rocky Mountain spotted fever Histoplasmosis Aspergillosis Malaria

Infections

Carcinomas of pancreas, prostate, lung, and

stomach Acute promyelocytic leukemia

Neoplasms

Trauma Burns Extensive surgery

Massive Tissue Injury

Acute intravascular hemolysis, Snakebite, Giant hemangioma Shock Heat stroke Vasculitis Aortic aneurysm, Liver disease Rejection of graft

Miscellaneous

1.1. CBCCBC2.2. Clotting times:Clotting times:3.3. Fibrin related markers important for the Fibrin related markers important for the

diagnosis of DIC:diagnosis of DIC:4.4. Coagulation factors:Coagulation factors:

CBCthrombocytopenia is usually present

Clotting times:Prothrombin time (PT) – prolonged (may be normal in early or chronic DIC)Partial thromboplastin time (PTT) – prolonged (may be normal in early or chronic DIC)Thrombin time (TT) – may be increased due to consumption of fibrinogen

Fibrin related markers important for the diagnosis of DIC:D-dimer – increased in acute and chronic DIC (best single test)A normal d-dimer essentially rules out DICElevated d-dimer levels are seen in a number of conditions in addition to DIC (eg, pregnancy, acute thrombosis)

Coagulation factors:Fibrinogen is usually decreased (in an acute phase of DIC, the fibrinogen may not be decreased, only until DIC is severe)

Labinvestigations of DIC

International Society on Thrombosis and Haemostasis Scoring System for Diagnosis of DIC

A score below 5 is suggestive as a diagnosis but not definite; hence the test must be repeated.

1.1. Underlying causeUnderlying cause

2.2. Supportive therapySupportive therapy

3.3. Heparin therapyHeparin therapy

The most important fact in the management of

DIC, is the treatment of the underlying cause. Supportive therapy may be given to patients with

excessive bleeding:1) Fluid2) Blood transfusion3) Fresh frozen plasma4) Platelet concentrates5) Fibrinogen

Patients with chronic DIC and thrombosis may need heparin therapy.

Treatment