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Thrombin Generation
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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)
Hypercoaguable States
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)
Hypercoaguable States
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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Pathophysiology of DIC
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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Pathophysiology of DIC
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