Transcript Hemostasis and thrombosis

Bleeding and Thrombosis
Disorders in the ICU
Division of Critical Care Medicine
University of Alberta
Outline

Normal hemostasis
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Coagulopathies
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Coagulation pathways
Initial investigations
Pathogenesis of coagulopathies
Specific causes
Thrombosis
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Pathogenesis
Diagnosis
Treatment
Prevention
Normal hemostatic mechanism
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There are four phases
to the normal
coagulation cascade:
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Blood vessel
constriction
Platelet aggregation
Fibrin generation
Vessel repair and fibrin
degradation
Constriction of vessels
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There are 2 mechanisms for vessel
constriction:
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Local smooth muscle contractile response
Thromboxane A2 release from endothelium
Formation of the unstable
platelet plug
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Exposure of the subendothelial layers cause
platelets to adhere.
They release ADP and TxA2, inducing further
platelet aggregation and activation
Binding and activation of
platelets

Binding of vWf to
platelet receptor
induces the release of
ADP and thromboxane
Adhesion requires von
Willebrand factor (vWf)
from the subendothelial
layers.
Generation of fibrin
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Aggregated platelets provide a surface on which blood
coagulation occurs through the generation of thrombin
and cleavage of fibrinogen.
Stabilization of platelet plug
with fibrin
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A platelet plug is inherently unstable and
needs to be buttressed with support beams.
This function is supplied by fibrin strands.
Blood coagulation
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Fibrin generation can be
activated by two
pathways that lead into a
common pathway.
The central feature is the
sequential activation of a
series of pro-enzymes in
a stepwise manner that
causes amplification at
each step.
Intrinsic clotting system
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The intrinsic clotting
pathway requires at
least four coagulation
proteins and two cofactors.
Tested using the
aPTT.
Activation of intrinsic pathway
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The intrinsic pathway
is initiated by the
exposure of blood to
a negatively charged
surface.
Extrinsic clotting system
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The extrinsic
system, in contrast,
requires only one
coagulation protein
and two co-factors
which allows for
rapid activation.
Tested using the
INR.
Activation of extrinsic pathway
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Tissue thromboplastin
(also known as tissue
factor) is present in the
endothelial but is only
exposed to blood flow
during injury.
Thromboplastin, in the
presence of calcium,
binds to Factor VII to
cause the activation of
Factor X.
The two pathways feed into …
… the common pathway
The Common Pathway
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Both the extrinsic and intrinsic pathway
converge on the activation of Factor X (this also
facilitates amplification).
Factor Xa converts prothrombin to thrombin, the
final enzyme in the clotting cascade.
Thrombin converts fibrinogen from a soluble
plasma protein into an insoluble fibrin clot.
Thrombin also is an important feedback protein
on the rest of the clotting cascade and platelets.
Role of thrombin
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Thrombin induces
platelets to release
ADP and endothelial
cells to release PGI2
Only small amounts
of thrombin are
generated by the
extrinsic pathway,
but amplification
occurs through
intrinsic pathway
feedback loop
stabilizes
Fibrinolysis
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The restore vessel patency, the clot must be
organized and removed by plasmin while wound
healing and tissue remodeling occur.
Fibrinolysis and repair
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Plasminogen binds fibrin and tissue plasminogen
activator (tPA).
This complex then converts the plasminogen to plasmin.
Plasmin cleaves fibrin in addition to fibrinogen and a
variety of plasma proteins and clotting factors.
tPA is an endothelial cell enzyme that is released in
response to thrombin, serotonin, bradykinin, cytokines
and epinephrine.
When fibrin is degraded by plasmin it exposes new lysine
terminals on the clot that act as further binding sites for
plasminogen creating a positive feedback loop.
Investigations
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The basic investigations into any
coagulation problem are:
1.
2.
3.
4.
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INR
aPTT
Platelet count
Fibrinogen
Three patterns of defects can be seen.
Elevated INR, Normal aPTT
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Isolated elevated INR indicate factor VII
deficiency.
Causes include:
1.
2.
3.
4.
5.
Congenital factor VII deficiency
Vitamin K deficiency
Warfarin
Sepsis
DIC (occasionally)
Normal INR, Elevated aPTT
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Causes include:
1.
2.
3.
4.
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Isolated factor deficiency (VIII, IX, XI, XII)
Specific factor inhibitor
Heparin
Lupus inhibitor
Mixing study can help narrow the
differential diagnosis.
Elevated aPTT, Elevated INR
Usually due to multiple factors.
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1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Multiple coagulation factor deficiencies
Dilutional effect
Liver disease
DIC
Isolated factor X, V, II deficiency
Factor V inhibitors
High hematocrit
High heparin levels
Severe vitamin K deficiency
Low fibrinogen
Dysfibrinogemia
Investigations
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When a low platelet count, a blood smear should
be sent to rule out clumping and
microangiopathic process.
Low fibrinogen levels reflect either severe liver
disease, consumptive coagulopathy, or massive
transfusion (dilution effect).
Other bleeding defects are harder to diagnosis
on routine testing and are usually platelet
function defects or increases in fibrinolysis.
Transfusion Therapy
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Replacement therapy should be based on the lab
results and the patient’s clinical situation.
The transfusion trigger for platelets can be less
than 10,000/uL if the patient is not bleeding, is
not on platelet inhibitors, has preserved renal
function, and does not have DIC.
The usual dose of platelets is one
plateletpheresis unit.
For a fibrinogen level < 1 g/L, transfusion of 10
units of cryoprecipitate should increase the
fibrinogen level by 1.0 g/L.
Transfusion Therapy
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In patients with an INR of >1.6 and an
abnormal aPTT, FFP is given dependent on
the aPTT.
aPTT >1.5 times normal – 2-4 units of FFP
aPTT >2 times normal – 15-30 ml/kg of
FFP
Repeat laboratory tests should be sent
frequently to reassess adequacy of
treatment.
Abnormal hemostatic
mechanisms
Coagulopathies
Pathogenesis of Coagulopathies
1.
2.
3.
4.
5.
·
Vascular defects
Thrombocytopenia
Platelet function defects
Coagulation defects
Excessive fibrinolysis
Often these conditions will overlap.
Vascular disorders
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Characteristics:
1.
2.
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Easy bruising
Spontaneous bleeding
Clinical manifestations
1.
2.
3.
Bleeding often not severe
Mainly bleeding into skin
Bleeding occurs
immediately after trauma
Types of vascular disorders
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Inherited
1.
2.
3.
4.
Hemorrhagic
telangiectasis
Ehlers-Danlos
Osteogenesis
imperfecta
Pseudoxanthoma
elasticum
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Acquired
1.
2.
3.
4.
5.
6.
7.
Simple easy bruising
Senile purpura
Corticosteroids
Henoch-Sclonlein
purpura
Cushing’s disease
Amyloidosis
Scurvy
Thrombocytopenia
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Three general mechanisms:
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Decreased production
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Increased destruction
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Causes include thrombopoietin underproduction in liver
disease, bone marrow suppression by viral, drugs, toxins,
nutritional deficiency, congenital or acquired disorders of
hematopoiesis.
Caused by immune or nonimmune processes.
Dilution or distribution
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Caused by massive transfusion or splenic sequestration in
splenomegaly.
Causes of Increased Platelet
Destruction
Disorder
Mechanism
Idiopathic ITP
Immune
Alloimmune (posttransfusion, neonatal)
Immune
Drug induced (especially heparin)
Either
Infection associated
Either
HELLP syndrome
Either
DIC
Nonimmune
TTP-HUS
Nonimmune
Antiphospholipid antibody syndrome
Nonimmune
Physical destruction (bypass,hemangiomas)
Nonimmune
Specific Causes of
Thrombocytopenia - HIT
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Antibodies form against the heparin/platelet
factor IV (PF4) complex.
Despite the low platelets, thrombosis is the
major clinical problem.
Occurs 1-5% when unfractionated heparin is
used, <1% if LMWH is used.
Suspect if platelet count drops 50% from
previous level or if count < 100,000/uL.
Usually occurs in 4 days from heparin start.
Specific Causes of
Thrombocytopenia - HIT
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First step in treatment is to stop all heparin.
Do not use warfarin alone because of the
hypercoagulable period and only after the
platelet count has recovered.
Argatroban is a thrombin inhibitor with a half life
of 40-50 minutes but is not reversible.
Hepatic, not renally cleared.
Dose 2 ug/kg/min, adjusted to keep aPTT 1.5-3
times normal.
Argatroban will prolong the INR.
Specific Causes of
Thrombocytopenia - HIT
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Danaparoid is a heparinoid which can be
used as an alternative to heparin in HIT.
There is a 10% cross reactivity with the
antibody responsible for HIT but clinical
significance is unknown.
It has a long half life of 25 hours and is
not reversible.
Monitor using anti-factor Xa levels.
Specific Causes of
Thrombocytopenia - TTP
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Caused by an inhibitor against an enzyme responsible for
cleaving vWF causing spontaneous platelet aggregation.
Often spontaneous but can be induced by drugs such as
cyclosporin, tacrolimus, and ticlopidine.
Suspect in patients presenting with fever,
thrombocytopenia, hemolysis, neurological symptoms,
and renal dysfunction.
Plasma exchange is gold standard followed by steroids.
Exchanges should be 1.5 plasma volume/day until LDH
normalizes and platelets rebound.
Specific Causes of
Thrombocytopenia - HELLP
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Presents as part of the spectrum of preeclampsia, generally > 28 weeks.
Pre-eclampsia need not be severe.
First sign is a fall in platelets, then abnormal
liver function tests, and hemolysis.
Can progress to liver failure and death from
hepatic rupture.
Delivery usually resolves the condition.
May require steroids or plasma exchange if
condition worsens.
Specific Causes of
Thrombocytopenia – CAPS
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Catastrophic antiphospholipid antibody
syndrome (CAPS) is caused by widespread
microthrombi in multiple vascular fields.
Patients generally have a known
autoimmune condition with anticardiolipin
antibodies.
Treatment is with plasmaphreresis and
immunosuppression.
Platelet Dysfunction – Uremia and
Drugs
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Renal failure can cause bleeding from platelet
dysfunction.
Best treatment is aggressive dialysis to control
the uremia and DDAVP (20 ug IV) for acute
bleeding or pre-procedure.
ASA irreversibly inhibits platelet function and so
platelets must be replaced if bleeding occurs.
Other drugs such as ketorolac and hydroxyethyl
starch reversible inhibit and platelet function will
recover as the drug clears.
Coagulation Defects - DIC
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Syndrome of inappropriate thrombin activation
leading to:
1.
2.
3.
4.
5.
6.
Fibrinogen conversion to fibrin
Platelet activation and consumption
Activation of factors V and VIII
Protein C activation (and degradation of factors Va
and VIIIa)
Endothelial cell activation
Fibrinolysis
Coagulation Defects – DIC Causes
Sepsis
Crush
Cancer
AML
Amniotic
Abruptio
HELLP
Pre-
Dead
Septic
Amphetamine
Giant
AAA
Peritoneovenous
Acute
Paroxysmal
Snake
Fulminant
Reperfusion
Heat
Burns
Severe
fluid emboli
abortion
transfusion
reaction
stroke
injury
placentae
overdose
Severe
injury
head
eclampsia
hemangioma
nocturnal
venoms
hemoglobinuria
and viper
meningococcemia
hepatic
failure
(M3)
fetus
shunt
after
liver transplant
Coagulation Defects - DIC
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1.
2.
3.
4.
Patients can present in one of four ways:
Asymptomatic - Laboratory evidence only but no
bleeding or thrombosis.
Bleeding – Caused by factor and platelet depletion,
platelet dysfunction and fibrinolysis. Present with
diffuse bleeding from multiple sites.
Thrombosis – Despite the microthrombi,
macrothrombi are unusual but can occur in cancer
patients.
Purpura fulminans – Described in more detail later.
Coagulation Defects – DIC
Diagnosis
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Diagnosis established by the history and
presence of thrombocytopenia, microangiopathic
changes on the smear.
FDP or D-dimers are always elevated due to the
marked fibrinolysis.
Both the INR and aPTT are elevated.
Fibrinogen is low.
Liver failure can mimic DIC but factor VIII levels
are low in DIC (consumed) and normal in liver
failure (produced by the endothelium not the
liver).
Coagulation defects – DIC
Treatment
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First, treat the underlying condition.
Initiate other supportive measures as necessary
(i.e. intubation, vasopressors).
Low levels of evidence suggest that low doses of
heparin in non-bleeding patients may be helpful.
Both factor and platelet replacement in bleeding
patients and those at risk for major bleeding can
be life-saving but only supportive until the
underlying condition can be treated.
Coagulation Defects – Purpura
fulminans
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DIC in association with limb ecchymosis and skin
necrosis.
Often associated with meningococcemia and
post-splenectomy sepsis.
Optimum therapy has not been established but
includes:
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rhAPC infusion
Blood products to keep INR < 2, aPTT < 1.8 normal,
and platelets >50000/uL
Coagulation Defects – Vitamin K
Deficiency
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Body stores are normally low and require
40-80 ug/day.
Once depleted, production of factors II,
VII, IX, and X fall and INR rapidly rises.
The diagnosis should be suspected when
there is a history of prolonged antibiotic
use, biliary obstruction, and pre-existing
malnutrition.
Coagulation Defects – Massive
Transfusion
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Defined as requiring more than one blood
volume in 24 hours or less.
Coagulation defects occur from dilution of the
plasma volume by fluid resuscitation or red cell
transfusions and consumption from the
underlying disorder.
It is difficult to predict the degree of
coagulopathy from the amount of blood
transfused. Therefore, monitoring the patient’s
coagulation status during massive transfusion is
critical.
Coagulation Defects – Massive
Transfusion
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Platelets < 50,000/uL
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Fibrinogen < 1 g/L
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give 10 units of cryoprecipitate
Hematocrit < 30%
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give 6-8 units of random donor platelets
give red cells
INR > 1.6 and aPTT abnormal
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give 2-4 units of FFP
Coagulation Defects – Use of Factor
VIIa
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Recently released, recombinant factor VIIa is a very
effective hemostatic agent.
Has been used for the treatment of congenital FVII, XI,
or V deficiency, liver failure coagulopathy, reversal of
warfarin overdose, thrombocytopenia due to antiplatelet
glycoprotein antibodies, and intracerebral hemorrhage.
rFVIIa enhances platelet-surface thrombin generation
independent of tissue factor.
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A platelet dependant mechanism explains why rFVIIa localizes to
sites of endothelial injury.
Dosing varies based on the indication

40 ug/kg for ICH
Thrombosis
Thrombosis - Incidence
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Most ICU patients have one or more risk
factors for thrombosis.
The true incidence is unknown but
estimates run up to 33%.
15% of DVT are in the upper limbs and
are associated with central lines.
Thrombosis - Pathophysiology
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Virchow triad – endothelial damage, abnormal
blood flow, altered blood composition.
Trauma and surgical patients inevidently have
endothelial damage triggering coagulation.
Inflammation and stress response causes
thrombocytosis, hyperfibrinogenemia, altered
coagulation factors, and elevated levels of PAI-1
which tips the balance toward thrombosis.
Patients are immobilized, ventilated and sedated
which alters blood flow causing stasis.
Thrombosis - Pathophysiology
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There are many inherited hypercoagable
states.
These increase the relative risk by 10 fold
on top of the acquired risks.
The most important risk factors for DVT
are a previous episode of thrombosis and
a family history of DVT.
Genetic Risk Factors for Thrombosis
Risk Factor
Prevalence in
the General
Population
Prevalence in
Patients with DVT
Elevated factor VIII level
11%
25%
Factor V Leiden
5%
20%
Hyperhomocysteinemia
5-10%
10%
Prothrombin gene variant
2%
6%
Protein S deficiency
1%
3%
Protein C deficiency
0.2%
3%
Antithrombin deficiency
0.18%
1%
Thrombosis – PE Pathophysiology
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Pulmonary artery obstruction causes a rise in pulmonary
artery pressure that leads to right ventricular failure.
RV failure leads to a rise in central venous pressures and
fall in cardiac output.
RV oxygen demands is higher in the presence of
hypoxia, hypotension, and reduced coronary perfusion
causing infarction.
Infarction leads to worsening RV function and output
perpetuating the vicious cycle.
Patients with a PFO can also develop paradoxical
embolism.
A PE with PFO can lead to greater hypoxia due to an
intracardiac right-to-left shunt.
Thrombosis - Diagnosis

Clinical symptoms and signs are fraught with poor
sensitivity and specificity.
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Acute onset dyspnea
Pleuritic chest pain
Cough
Hemoptysis
Tachypnea
Sinus tachycardia
Syncope
Although the gold standard test is pulmonary angiogram,
the most practical in the critically ill patient is CT chest
angiogram.
V/Q scan is likewise impractical because of the long
image acquisition time.
Thrombosis – Use of echo in PE
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Sensitivity and specificity of TEE in the diagnosis
of proximal PE is 84%.
RV volume and pressure overload following
massive PE is readily identified.
Echo findings includes dilated right atrium and
ventricle, increased ratio of RV to LV chamber
size, paradoxical septal bulging and a reduction
in RV function.
In severe cases of RV volume and pressure
overload, an under filled and hyperdynamic left
ventricle will be evident.
Thrombosis – DVT/PE Treatment
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Once detected, both DVT and PE require full
anticoagulation with heparin.
LMWH is a therapeutic option but can be
contraindication by it long half life and renal
clearance.
Coumadin is best avoided in the critical care
phase because of the number of interactions
with other medications and difficult reversibility.
Thrombosis – PE and tPA

While most of the treatment for PE is supportive
(oxygen, vasopressors etc.), intravenous tPA for
clot lysis is indicated for the following conditions:
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Persistent hypotension
Severe hypoxemia
Large perfusion defect
RV dysfunction
Free floating RV thrombus
PFO
Maybe – RV dilation and/or hypokinesis without
systemic hypotension.
Thrombosis – DVT Prevention
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Preventative strategies fall into two groups –
pharmacological (UFH and LMWH) and
mechanical (stockings and compression
devices).
Heparin – either UFH or LMWH – in the mainstay
of prophylaxis. Reduces incidence by over 50%.
LMWH is as effective as UFH but is superior in
trauma and spinal cord injury.
Thrombosis – DVT Prevention
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
The incidence of hemorrhagic complications is
no different in treated and control patients.
Only contraindications to prophylaxis heparin is:



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Intracranial bleeding
Spinal cord injury associated with hematoma
Uncontrolled ongoing bleeding
Uncorrected coagulopathy


Warning: Liver failure patients may be thrombotic despite an
elevated INR.
Those at high risk for bleeding should receive a
pneumatic compression devices until able to be
converted to heparin.
Summary

Normal hemostasis



Coagulopathies



Coagulation pathways
Initial investigations
Pathogenesis of coagulopathies
Specific causes
Thrombosis




Pathogenesis
Diagnosis
Treatment
Prevention