block lecture 13

7/30/2019 Block Lecture 13

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13

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Thrombin Generation


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1000 1 . , ,

40-

40%

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Inherited (Primary)

Hypercoaguable States

Activated Protein C Resistance: Factor V

Leiden

Prothrombin Gene Mutation 20210 (G-A)

Antithrombin III deficiency

Protein C deficiency

Protein S deficiency

Dysfibrinogenemias (rare)

Hyperhomocystenemia


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Acquired(Secondary)


Immobilization

Trauma

Surgery (postoperative state)

Obesity Pregnancy (especially postpartum period)

Estrogen use (oral contraceptives, estrogen

replacement therapy) Prolonged Air Travel

Antiphospholipid Antibody Syndrome/LupusAnticoagulant


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Acquired (Secondary)


Nephrotic Syndrome

Paroxysmal Nocturnal Hemoglobinuria

Myeloproliferative Syndromes (especiallyPolycythermia Vera & Essential

Thrombocythemia)

Heparin-induced thrombocytopenia (HIT) Disseminated Intravascular Coagulation

(DIC)

Malignancy


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Disseminated intravascular

coagulation

(DIC)


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Characteristics of DIC

Arterial

thrombosis

Venous

thrombosisDIC


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Hemostatic Balance

ATIIIClotting Factors

Tissue factor

PAI-1

AntiplasminTFPI

Prot. CProt. S

Procoagulant Anticoagulant

Fibrinolytic System


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Introduction

Thrombotic microangiopathy (TMA) anddisseminated intravascular coagulation (DIC)

are disorders causing obstruction of the

microvascular circulation

Trombotic

microangiopathyIncreased platelet aggregation

DIC

Increased fibrin formation


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Thrombotic microangiopathy

Trombotic

microangiopathy

Increased platelet aggregation

TTP HELLP HUS

TTP: Thrombotic Thrombocytopenic Purpura

HELLP: Haemolysis, Elevated Liver enzymes, Low Platelets

HUS: Haemolytic Uremic Syndrome


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Causes of DICTissue damage (release of tissue factor) e.g. trauma

(esp brain or crush injury), thermal injury (burns,hyperthermia, hypothermia), surgery, shock,

asphyxia/hypoxia, ischaemia/infarction, rhabdomyolysis,

fat embolism.

Complications of pregnancy (release of tissue factor)e.g. amniotic fluid embolism, abruptio placentae,

eclampsia and pre-eclampsia, retained dead fetus, uterine

rupture, septic abortion.

Neoplasia (release of tissue factor, TNF, proteases)e.g. solid tumours, leukaemias (esp. acute

promyelocytic).


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Infection (endotoxin release, endothelial cell damage) e.g.Gram ve bacteria (e.g. meningococcus), Gram +ve bacteria

(e.g. pneumococcus), anaerobes, M tuberculosis, toxic shock

syndrome, viruses (e.g. Lassa fever), protozoa (e.g. malaria),

fungi (e.g. candidiasis).

Vascular disorders (abnormal endothelium, plateletactivation) e.g. giant hemangioma (KasabachMerritt

syndrome), vascular tumours, aortic aneurysm, vascular

surgery, cardiac surgery, malignant hypertension, pulmonary

embolism, acute MI, stroke, subarachnoid hemorrhage.

Immunological (complement activation, release of tissuefactor) anaphylaxis, acute hemolytic transfusion reaction,

heparin-associated thrombocytopenia, renal allograft rejection,

acute vasculitis, drug reactions (quinine).


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Proteolytic activation of coagulation factorse.g. pancreatitis, snake venom, insect bites.

Neonatal disorders e.g. infection, aspirationsyndromes, small-for-dates infant, respiratorydistress syndrome, purpura fulminans.

Other disorders e.g. fulminant hepatic failure,cirrhosis, Reyes syndrome, acute fatty liver of

pregnancy, ARDS, therapy with fibrinolytic

agents, therapy with factor IX concentrates,

massive transfusion, acute intravascular hemolysisfamilial, ATIII deficiency, homozygous protein C

or S deficiency.


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Conditions Associated With

DIC

Malignancy

Leukemia

Metastatic disease

Cardiovascular

Post cardiac arrest

Acute MI

Prosthetic devices

Hypothermia/Hyperthermia

Pulmonary

ARDS/RDS

Pulmonary

embolism

Severe acidosis

Severe anoxia

Collagen vasculardisease

Anaphylaxis


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Conditions Associated With

DIC Infectious/Septicemia

Bacterial

Gm - / Gm +

Viral CMV

Varicella

Hepatitis

Fungal Intravascular

hemolysis

Acute Liver Disease

Tissue Injury

trauma

extensive surgery

tissue necrosis head trauma

Obstetric

Amniotic fluid emboli

Placental abruption

Eclampsia

Missed abortion


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Haemostatic

mechanisms

SYSTEMIC INFLAMMATION

TF

TF

TF

MonocyteActivation of monocytes

TF

TF

Cytokines

Intravascular

clot formation

NORMAL HAEMOSTASIS

Activated

monocyte


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Progression of SEPSIS

MonocytesEndothelial

cells

Cytokines

Endothelial

cells

Tissue

factor

Activation of coagulation Thrombin Fibrin

Platelets

Leuko-cytes

Non-adhesive

surface

Adhesivesurface

Accelerates

coagulation


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Progression of DIC

TimeOnset of DIC

Systemic fibrinformationSystemicinflammation

Multiple organdysfunctionSystemicbleeding


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PathophysiologyDIC may be initiated by

Exposure of blood to tissue factor (e.g. after trauma).Endothelial cell damage (e.g. by endotoxin

or cytokines).

Release of proteolytic enzymes into the blood(e.g. pancreas, snake venom).

Infusion or release of activated clotting factors(factor IX concentrate).

Massive thrombosis Severe hypoxia and acidosis.


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Pathophysiology of DIC

Activation of Blood Coagulation

Suppression of Physiologic

Anticoagulant Pathways

Impaired Fibrinolysis

Cytokines


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Suppression of Physiologic

Anticoagulant Pathways

reduced antithrombin III levels reduced activity of the protein C-protein S

system

Insufficient regulation of tissue factoractivity by tissue factor pathway inhibitor

(TFPI)

inhibits TF/FVIIa/Fxa complex activity


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Impaired Fibrinolysis

relatively suppressed at time of

maximal activation of coagulation dueto increased plasminogen activator

inhibitor type 1


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Pathophysiology of DIC -

Cytokines Cytokines

IL-6, and IL-1 mediates coagulation activation in

DIC

TNF- mediates dysregulation of physiologic

anticoagulant pathways and fibrinolysis

modulates IL-6 activity

IL-10 may modulate the activation of coagulation

CoagulationInflamation


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Clinical Manifestations of DIC

ORGAN ISCHEMIC HEMOR.

Skin Pur. FulminansGangrene

Acral cyanosis

Petechiae

Echymosis

Oozing

CNS Delirium/ComaInfarcts

Intracranial

bleeding

Renal Oliguria/AzotemiaCortical Necrosis

Hematuria

Cardiovascular MyocardialDysfxn

Pulmonary Dyspnea/HypoxiaInfarct

Hemorrhagiclung

GI

Endocrine

Ulcers, Infarcts

Adrenal infarcts

Massive

hemorrhage.

Ischemic Findingsare earliest!

Bleeding is the most

obvious

clinical finding


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Clinical Manifestations of DIC


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Microscopic findings in DIC

Fragments Schistocytes

Paucity of platelets


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Laboratory Tests Used in DIC

D-dimer*

Antithrombin III*

F. 1+2*

Fibrinopeptide A*

Platelet factor 4*

Fibrin Degradation

Prod Platelet count

Protamine test

Thrombin time

Fibrinogen

Prothrombin time

Activated PTT

Protamine test

Reptilase time

Coagulation factorlevels

*Most reliable test


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Laboratory diagnosis Thrombocytopenia

plat count


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Scoring system for overt DIC

Platelet count (>100=0,


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Scoring system for overt DIC

Platelet count (>100=0,


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Differential Diagnosis

Severe liver failure

Vitamin K deficiency

Liver disease

Thrombotic thrombocytopenic purpura

Congenital abnormalities of fibrinogen

HELLP syndrome


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Treatment of DICdirected against etiological factors

Infections

Trauma

Obstetriccomplications

Antibiotics

Removal of damaged tissue

stabilisation of fractures

Evacuation of the uterus


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Treatment of DIC

Stop the triggering process .

The only proven treatment!

Supportive therapy

No specific treatments

Plasma and platelet substitution therapy

Anticoagulants

Physiologic coagulation inhibitors


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Plasma therapy

Indications

Active bleeding

Patient requiring invasive procedures

Patient at high risk for bleeding complications Fresh frozen plasma(FFP):

provides clotting factors, fibrinogen, inhibitors, and

platelets in balanced amounts.

Usual dose is 10-15 ml/kg


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Platelet therapy

Indications

Active bleeding

Patient requiring invasive procedures Patient at high risk for bleeding

complications

Platelets approximate dose 1 unit/10kg


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Blood

Replaced as needed to maintain

adequate oxygen delivery.

Blood loss due to bleeding RBC destruction (hemolysis)


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Coagulation Inhibitor Therapy

Antithrombin III

Protein C concentrate

Tissue Factor Pathway Inhibitor (TFPI)

Heparin


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Tissue Factor Pathway

Inhibitor Tissue factor is expressed on endothelial

cells and macrophages

TFPI complexes with TF, Factor VIIa,andFactor Xa to inhibit generation of thrombin

from prothrombin

TF inhibition may also have antiinflammatory

effects

Clinical studies using recombinant TFPI are

promising.


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Heparin

Use is very controversial. Data is mixed. May be indicated in patients with clinical

evidence of fibrin deposition or significant

thrombosis.

Generally contraindicated in patients with

significant bleeding and CNS insults.

Dosing and route of administration varies. Requires normal levels of ATIII.


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Antifibrinolytic Therapy

Rarely indicated in DIC Fibrinolysis is needed to clear thrombi from the micro

circulation.

Use can lead to fatal disseminated thrombosis.

May be indicated for life threatening bleeding

under the following conditions:

bleeding has not responded to other therapies and:

laboratory evidence of overwhelming fibrinolysis. evidence that the intravascular coagulation has

ceased.

Agents: tranexamic acid, EACA

block lecture 13

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