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Disseminated Intravascular Coagulation. Robert R. Zaid D.O. Genesys Regional Medical Center PGY-I. Barcelona - Gaudi. - Background - Pathophysiology -Etiology -Clinical Manifestations -Diagnosis -Treatment -Xigris. Primarily a thrombotic process

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Disseminated intravascular coagulation

Disseminated Intravascular Coagulation

Robert R. Zaid D.O.

Genesys Regional Medical Center

PGY-I



Disseminated intravascular coagulation1

-Background

-Pathophysiology

-Etiology

-Clinical Manifestations

-Diagnosis

-Treatment

-Xigris

Primarily a thrombotic process

Systemic process producing both thrombosis and hemorrhage

Also called consumption coagulopathy and defibrination syndrome1

Its clinical manifestation may be widespread hemorrhage in acute, fulminant cases2.

Disseminated Intravascular Coagulation

1. Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179,

HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY2. Uptodote, 2005, www.utdol.com, Clinical feadures, diagnosis and teratment of disseminated intravascular coagulation


Disseminated intravascular coagulation2

-Background

-Pathophysiology

-Etiology

-Clinical Manifestations

-Diagnosis

-Treatment

-Xigris

Basic pathophysiology

Entry into the circulation of procoagulant substances

Trigger systemic activation of the coagulation system and platelets

Lead to the disseminated deposition of fibrin-platelet thrombi.

Procoagulant stimulus is tissue factor (most cases)

Lipoprotein

Not normally exposed to blood.

Tissue factor gains access to blood by

Tissue injury,

Malignant cells,

Expression on the surfaces of monocytes and endothelial cells by inflammatory mediators.

Disseminated Intravascular Coagulation

Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179,

HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY


Stein B, Fuster V, Israel DH, et al. Platelet inhibitor agents in cardiovascular disease: an update. J Am Coll Cardiol. 1989;14:813–836.


Disseminated intravascular coagulation3

- agents in cardiovascular disease: an update. Background

-Pathophysiology

-Etiology

-Clinical Manifestations

-Diagnosis

-Treatment

-Xigris

Tissue factor triggers

Thrombin

Protease

Induces fibrin formation and platelet activation

Other procoagulants

Cysteine protease

Mucin

Trypsin

Disseminated Intravascular Coagulation

Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179,

HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY


Disseminated intravascular coagulation4

- agents in cardiovascular disease: an update. Background

-Pathophysiology

-Etiology

-Clinical Manifestations

-Diagnosis

-Treatment

-Xigris

Acute DIC

Coagulation factors are consumed at a rate in excess of the capacity of the liver to synthesize them,

Platelets are consumed in excess of the capacity of bone marrow megakaryocytes to release them.

Disseminated Intravascular Coagulation

Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179,

HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY


Disseminated intravascular coagulation5

- agents in cardiovascular disease: an update. Background

-Pathophysiology

-Etiology

-Clinical Manifestations

-Diagnosis

-Treatment

-Xigris

Laboratory manifestations

Prolonged prothrombin time (PT)

Prolonged Activated partial thromboplastin time (aPTT)

Thrombocytopenia.

Increased fibrin formation

Stimulates compensatory process of secondary fibrinolysis,

Plasminogen activators generate plasmin to digest fibrin (and fibrinogen) into fibrin(ogen) degradation products (FDPs).

FDPs are potent circulating anticoagulants that contribute further to the bleeding manifestations of DIC.

Intravascular fibrin deposition can cause fragmentation of red blood cells and lead to the appearance of schistocytes in blood smears

Hemolytic anemia is unusual in DIC.

Microvascular thrombosis in DIC can compromise the blood supply to some organs and lead to multiorgan failure

Disseminated Intravascular Coagulation

Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179,

HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY


Disseminated intravascular coagulation6
Disseminated Intravascular Coagulation agents in cardiovascular disease: an update.

-Background

-Pathophysiology

-Etiology

-Clinical Manifestations

-Diagnosis

-Treatment

-Xigris


Citadel park
Citadel Park agents in cardiovascular disease: an update.


Disseminated intravascular coagulation7

- agents in cardiovascular disease: an update. Background

-Pathophysiology

-Etiology

-Clinical Manifestations

-Diagnosis

-Treatment

-Xigris

DIC always has an underlying etiology

Must be identified and eliminated to treat the coagulopathy successfully.

The development of DIC in many of these disorders is associated with an unfavorable outcome1.

Occurs in 1% of hospitalized patients2

Mortality rate approaches 40-80%

Disseminated Intravascular Coagulation

1. Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179,

HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY2. Uptodote, 2005, www.utdol.com, Clinical feadures, diagnosis and teratment of disseminated intravascular coagulation


Disseminated intravascular coagulation8

- agents in cardiovascular disease: an update. Background

-Pathophysiology

-Etiology

-Clinical Manifestations

-Diagnosis

-Treatment

-Xigris

Causes

Infection

Most common cause of DIC.

The syndrome particularly is associated with gram-negative or gram-positive sepsis

Can be triggered by a variety of other

Bacterial

Fungal

Viral

Rickettsial, and protozoal microorganisms.

Disseminated Intravascular Coagulation

Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179,

HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY


Disseminated intravascular coagulation9

- agents in cardiovascular disease: an update. Background

-Pathophysiology

-Etiology

-Clinical Manifestations

-Diagnosis

-Treatment

-Xigris

Obstetrics

The placenta and uterine contents are rich sources of

Tissue factor

Other procoagulants that normally are excluded from the maternal circulation

Disseminated Intravascular Coagulation

Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179,

HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY


La familia
La Familia agents in cardiovascular disease: an update.


Disseminated intravascular coagulation10

- agents in cardiovascular disease: an update. Background

-Pathophysiology

-Etiology

-Clinical Manifestations

-Diagnosis

-Treatment

-Xigris

Clinical manifestations of DIC may accompany obstetric complications, especially in the third trimester.

These syndromes range from

Acute, fulminant, and often fatal DIC in amniotic fluid embolism

Blood is exposed to large amounts of tissue factor in a short period of time creating large amounts of thrombin

Multiorgan failure

Chronic or subacute DIC with a retained dead fetus.

Exposure to small amounts of tissue factor

Disseminated Intravascular Coagulation

Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179,

HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY


Disseminated intravascular coagulation11

- agents in cardiovascular disease: an update. Background

-Pathophysiology

-Etiology

-Clinical Manifestations

-Diagnosis

-Treatment

-Xigris

Other obstetric problems associated with DIC include

Abruptio placentae

Toxemia

Septic abortion.

Disseminated Intravascular Coagulation

Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179,

HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY


Disseminated intravascular coagulation12

- agents in cardiovascular disease: an update. Background

-Pathophysiology

-Etiology

-Clinical Manifestations

-Diagnosis

-Treatment

-Xigris

Clinical manifestations

Determined by

Nature

Intensity

Duration of the underlying stimulus.

Chronicity

Low-grade DIC is often asymptomatic

Diagnosed only by laboratory abnormalities.

Bleeding is most common clinical finding

Generalized or widespread ecchymoses

Chronic disease

Thrombotic complications

Trousseau's syndrome in cancer

Gangrene of the digits or extremities

Hemorrhagic necrosis of the skin

Purpura fulminans

Enhanced by

Coexistence of liver disease

Disseminated Intravascular Coagulation

Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179,

HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY


Candy factory
Candy Factory agents in cardiovascular disease: an update.


Disseminated intravascular coagulation13

- agents in cardiovascular disease: an update. Background

-Pathophysiology

-Etiology

-Clinical Manifestations

-Diagnosis

-Treatment

-Xigris

Diagnosis of severe, acute (easy)

Prolongation of PT, aPTT and Thrombin time

Due to consumption and inhibitiion of clotting factors

Thrombocytopenia

Fibrin degradatin products

Increased due to secondary fibrinolysis

Measured by latex agglutination or D-dimer assays.

Schistocytes may be seen in the peripheral blood smear

Neither sensitive nor specific for DIC.

Disseminated Intravascular Coagulation

Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179,

HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY


Disseminated intravascular coagulation14

- agents in cardiovascular disease: an update. Background

-Pathophysiology

-Etiology

-Clinical Manifestations

-Diagnosis

-Treatment

-Xigris

Chronic or compensated forms of DIC

Highly variable patterns of abnormalities in "DIC screen" coagulation tests.

Increased FDPs and prolonged PT are generally more sensitive measures than are abnormalities of the aPTT and platelet count.

Overcompensated synthesis of consumed clotting factors and platelets in some chronic forms

Cause shortening of the PT and aPTT and/or thrombocytosis

Though, elevated levels of FDPs indicate secondary fibrinolysis in such cases.

Disseminated Intravascular Coagulation

Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179,

HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY


Street entertainers
Street entertainers agents in cardiovascular disease: an update.


Disseminated intravascular coagulation15

- agents in cardiovascular disease: an update. Background

-Pathophysiology

-Etiology

-Clinical Manifestations

-Diagnosis

-Treatment

-Xigris

Treatment

Identify underlying cause and treat

All other therapies are temporizing

Disseminated Intravascular Coagulation

Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179,

HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY


Disseminated intravascular coagulation16

- agents in cardiovascular disease: an update. Background

-Pathophysiology

-Etiology

-Clinical Manifestations

-Diagnosis

-Treatment

-Xigris

Asymptomatic patients with self-limited DIC

Have only laboratory manifestations of the coagulopathy

No treatment may be necessary.

Disseminated Intravascular Coagulation

Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179,

HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY


Disseminated intravascular coagulation17

- agents in cardiovascular disease: an update. Background

-Pathophysiology

-Etiology

-Clinical Manifestations

-Diagnosis

-Treatment

-Xigris

Actively bleeding or who are at high risk of bleeding,

Blood component treatments of choice

Transfusions of platelets

Improve the thrombocytopenia

Fresh-frozen plasma (FFP)

Replace all consumed coagulation factors and correct the prolonged PT and aPTT.

Large volumes of plasma in severe cases

The theoretical concern that these blood products may "fuel the fire" and exacerbate the DIC has not been supported by clinical experience

Disseminated Intravascular Coagulation

Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179,

HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY


Disseminated intravascular coagulation18

- agents in cardiovascular disease: an update. Background

-Pathophysiology

-Etiology

-Clinical Manifestations

-Diagnosis

-Treatment

-Xigris

Special cases

Profound hypofibrinogenemia

Additional transfusion of cryoprecipitate,

Plasma concentrate enriched in fibrinogen

Sepsis

Infusion of antithrombin III concentrate may be considered as an adjunctive measure

Disseminated Intravascular Coagulation

Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179,

HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY


Disseminated intravascular coagulation19

- agents in cardiovascular disease: an update. Background

-Pathophysiology

-Etiology

-Clinical Manifestations

-Diagnosis

-Treatment

-Xigris

Pharmacologic inhibitors of coagulation and fibrinolysis

Heparin

Theoretical benefit

It blocks thrombin and the secondary fibrinolysis.

Might exacerbate the bleeding tendency

Usually reserved for

Forms manifested by

Thrombosis

Acrocyanosis

Cancer

Vascular malformations

Retained dead fetus

Acute promyelocytic leukemia.

Disseminated Intravascular Coagulation


Disseminated intravascular coagulation20

- agents in cardiovascular disease: an update. Background

-Pathophysiology

-Etiology

-Clinical Manifestations

-Diagnosis

-Treatment

-Xigris

Antifibrinolytic agents,

ε-aminocaproic acid and tranexamic acid

Generally are contraindicated

May precipitate thrombosis

May be effective in decreasing life-threatening bleeding

Disseminated Intravascular Coagulation


Festivals
Festivals agents in cardiovascular disease: an update.


Disseminated intravascular coagulation21

- agents in cardiovascular disease: an update. Background

-Pathophysiology

-Etiology

-Clinical Manifestations

-Diagnosis

-Treatment

-Xigris

XIGRIS® (Lilly)Drotrecogin alfa (activated)

Recombinant form of human Activated Protein C

Disseminated Intravascular Coagulation


Disseminated intravascular coagulation22

- agents in cardiovascular disease: an update. Background

-Pathophysiology

-Etiology

-Clinical Manifestations

-Diagnosis

-Treatment

-Xigris

General Pharmacology

Activated Protein C

Antithrombotic effect

Inhibits Factors Va and VIIIa.

Indirect profibrinolytic activity through its ability to inhibit plasminogen activator inhibitor-1 (PAI-1)

Limits generation of activated thrombin-activatable-fibrinolysis-inhibitor.

In vitro data indicate that Activated Protein C may exert an anti-inflammatory effect by inhibiting human tumor necrosis factor production by monocytes

Blocks leukocyte adhesion to selectins

Limits the thrombin-induced inflammatory responses within the microvascular endothelium.

Disseminated Intravascular Coagulation


Disseminated intravascular coagulation23

- agents in cardiovascular disease: an update. Background

-Pathophysiology

-Etiology

-Clinical Manifestations

-Diagnosis

-Treatment

-Xigris

Clinical study (PROWESS)

1690 patients with severe sepsis

Entry criteria included a systemic inflammatory response presumed due to infection and at least one associated acute organ dysfunction

The study was terminated after a planned interim analysis due to significantly lower mortality in patients on Xigris than in patients on placebo

(210/850, 25% vs. 259/840, 31% p=0.005).

Disseminated Intravascular Coagulation


Disseminated intravascular coagulation24

- agents in cardiovascular disease: an update. Background

-Pathophysiology

-Etiology

-Clinical Manifestations

-Diagnosis

-Treatment

-Xigris

INDICATIONS AND USAGE

Xigris is indicated for the reduction of mortality in adult patients with severe sepsis (sepsis associated with acute organ dysfunction) who have a high risk of death (APACHE II)

Disseminated Intravascular Coagulation


Disseminated intravascular coagulation25

- agents in cardiovascular disease: an update. Background

-Pathophysiology

-Etiology

-Clinical Manifestations

-Diagnosis

-Treatment

-Xigris

Contraindications

Active internal bleeding

Recent (within 3 months) hemorrhagic stroke

Recent (within 2 months) intracranial or intraspinal surgery, or severe head trauma

Trauma with an increased risk of life-threatening bleeding

Presence of an epidural catheter

Intracranial neoplasm or mass lesion or evidence of cerebral herniation

Disseminated Intravascular Coagulation


Disseminated intravascular coagulation26

- agents in cardiovascular disease: an update. Background

-Pathophysiology

-Etiology

-Clinical Manifestations

-Diagnosis

-Treatment

-Xigris

Warnings

Concurrent therapeutic dosing of heparin to treat an active thrombotic or embolic event

Platelet count <30,000 × 10 6 /L, even if the platelet count is increased after transfusions

Prothrombin time-INR >3.0

Recent (within 6 weeks) gastrointestinal bleeding

Recent administration (within 3 days) of thrombolytic therapy

Recent administration (within 7 days) of oral anticoagulants or glycoprotein IIb/IIIa inhibitors

Recent administration (within 7 days) of aspirin >650 mg per day or other platelet inhibitors

Recent (within 3 months) ischemic stroke

Intracranial arteriovenous malformation or aneurysm

Known bleeding diathesis

Chronic severe hepatic disease

Any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location .

Disseminated Intravascular Coagulation


Disseminated intravascular coagulation27

- agents in cardiovascular disease: an update. Background

-Pathophysiology

-Etiology

-Clinical Manifestations

-Diagnosis

-Treatment

-Xigris

DOSAGE AND ADMINISTRATION

Xigris should be administered intravenously at an infusion rate of 24 µg/kg/hr for a total duration of infusion of 96 hours.

Disseminated Intravascular Coagulation


Any questions
Any questions? agents in cardiovascular disease: an update.


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