Transcript slide 20

Thrombotic Disorders
Janna M. Journeycake, MD, MSCS
UT Southwestern Medical Center Dallas,
Children’s Health
Disclosures
• No relevant disclosures to this topic
• Will discuss off label use of anticoagulant
medications
Lecture Outline
•
•
•
•
•
•
Introduction
Coagulation and Regulation of Coagulation
Thrombophilia
Diagnosis of thrombotic events
Treatment of thrombotic events
Outline of content specifications and
corresponding slides
– End of Slides and Handout
Scope of Problem of Venous Thromboembolic
Events (VTE) in Pediatrics
• Incidence on upswing
• Original estimate 5.3/10,000 hospitalized
(1995)
• Health Care Cost and Utilization Project Kids'
Inpatient Database 2003 data: 42/10,000
hospitalized
• PHIS data: Increasing from 32/10,000 in 2000
to 57/10,000 in 2007
– Dramatic 70% increase between 2001-2007
Vu J Pediatr Surg 2008; Raffini Pediatrics 2009
Scope of Problem: Some Basics
• Bimodal age distribution
– Neonates and adolescents
• Highly associated with other medical issues
• Potential impact of thrombosis
– Embolization
– Risk of recurrent events
– Post-thrombotic syndrome
– Loss of venous access
Setty Pediatr Blood Cancer 2012 , Takemoto J Pediatr 2014
Review of Coagulation and
Regulation of Coagulation
• Dr. Young reviewed yesterday and I borrowed
a few of his slides
Natural Coagulation Inhibitors
Inhibits (
)
Thrombin (IIa)
VII
Ca++
XI
XIa
Tissue factor pathway
inhibitor (TFPI)
TF
Ca++
IX
X
Thrombin (IIa)
V
Ca++
Ca++
VIII
VIII
VIIa
IXa
Xa
X
Antithrombin
Xa
Va
XIII
Protein S
Protein S
Prothrombin (II)
Protein Ca
Ca++
Thrombin (IIa)
Fibrinogen (I)
Thrombin (IIa)
Fibrin
XIIIa
Protein C
Cross-linked fibrin
Borrowed from Dr. Young
Endothelial cell’s antithrombotic effects
PS
--Protein S
HS
--heparan sulfate
PC
APC (PS)
Thrombin
TPA --tissue plasminogen activator
TM --thrombomodulin
PAI-1 --plasminogen activator inhibitor type 1
PC—protein C
APC—activated protein C
Va and VIIIa
AT
Thrombin
TM
fibrinolysis
PS
Borrowed from Dr. Young
TPA
HS
PAI-1
Properties of Anticoagulant Factors
• Natural Anticoagulant proteins are reduced at
birth
– Interpret results in first year of life based on
published age associated normal ranges
• Liver produces coagulation proteins
– Liver disease leads to deficiency and/or decreased
clearance of activated factors
• Increasing risk of coagulopathy/thrombosis
• Inflammation increases FVIII activity
Properties of Anticoagulant Factors
Factor
Site of synthesis
Levels in
infancy
Vitamin K- Other
dependent
Fibrinogen (I)
Liver
Normal
No
Acute phase reactant
Factor VIII
Liver
Endothelial Cells
Normal/
High
No
Acute phase reactant
Factor IX
Liver
Low
Yes
VWF
Endothelial cells
Megakaryocytes
Normal/
High
No
Acute phase reactant
Protein C
Liver
Low
Yes
Normalizes in adolescence
Protein S
Liver
Endothelial cells
Megakaryocytes
Brain tissue
Low
Yes
Inflammation increases C4b
binding protein and
reduces free Protein S
Normalized by 6-12 months
of age
Antithrombin (AT)
Liver
Low
No
Normalized by 6-12 months
of age
Thrombophilia
• Definition- a predisposition to develop
thrombosis
– Venous thrombotic events (VTE)
•
•
•
•
•
•
Deep vein thrombosis (DVT)
Pulmonary embolism (PE)
Cerebral sinovenous thrombosis (CSVT)
Renal vein thrombosis
Portal vein thrombosis
Mesenteric
– Arterial events
• Arterial ischemic stroke
• Catheter-related
Thrombophilia

Inherited







Antithrombin deficiency
Protein C deficiency
Protein S deficiency
Factor V Leiden
mutation
Prothrombin G20210A
mutation
Dysfibrinogenemia
Hyperhomocysteinemia





MTHFR
homocysteinuria
Elevated FVIII
Elevated Lipoprotein a
PAI-1
polymorphisms/Elevated
PAI-1

Acquired


Antiphospholipid antibody
syndrome (APS)
 Anticardiolipin
 Anti-β2 glycoprotein
 Lupus anticoagulant
Major medical conditions
 Activate coagulation



inflammation
Loss or Consumption of
inhibitors of coagulation
Invasive procedures
Antithrombin (AT)
• Properties
– Made in liver
– Neutralizes thrombin
(IIa), Xa, and IXa
– Heparin potentiates
activity
– Two binding sites
• Heparin binding site
• Reactive center
• Acquired Causes
–
–
–
–
–
DIC
Sepsis
Burns
Trauma
Liver disease (decreased
synthesis)
– Nephrotic syndrome
(protein loss)
– Heparin (accelerated
clearance)
AT Deficiency
• Thrombotic events
– Venous events more common
• DVT
• PE
• Mesenteric
•
•
•
•
40% of events spontaneous
High rate of PE
Very high rate of recurrence
Homozygous state- fetal demise
AT Deficiency Diagnosis
• Autosomal dominant inheritance
• Type 2 Heparin Binding defects less likely to
have thrombosis
Antigen
Heparin Cofactor
activity
Progressive
Antithrombin
Activity
Low
Low
Low
Active site
defect
Normal
Low
Low
Heparin Binding
site defect
Normal
Low
Normal
Type 1
Type 2
Protein C (PC)
• Vitamin K dependent protein produced in liver
• Needs to be activated by
thrombin/thrombomodulin complex
• Autosomal dominant inheritance
– Rare auto recessive cases
Protein C deficiency
• Varies with age
– 20-40% as neonate
– Does not normalize until adolescence
• Acquired Causes
– Liver disease (decreased production)
– DIC (consumption)
– Sepsis (meningococcemia)
– Uremia (decreased activity)
PC deficiency
• Majority venous events
– Ileofemoral veins
– Mesenteric veins
– PE
– CSVT
– Superficial thrombophlebitis
• Possible association with arterial stroke
• 70% spontaneous thrombosis
• High risk of recurrence
PC Deficiency
Amidolytic activity
Coagulant activity
Type 1
Low
Low
Low
Type 2
Normal
Low
Low
Normal
Normal
Low
Antigen Tests: Immunologic based ELISA, Radioimmunoassays or electroimmunoassays
Functional Tests:
Snake venom activated Protein C and activity of APC is measured by clotting assay (higher
sensitivity) or chromogenic substrate
Severe PC deficiency in Neonate
• Homozygous
deficiency or Double
Heterozygous States
• Symptoms
– Purpura fulminans
– Ophthalmologic
injury
– Renal injury
– Neural
• Treatment
– Aggressive Protein C
replacement
– Anticoagulation life
long
– Case reports of liver
transplant
Protein S (PS)
• Vitamin K dependent protein
• Produced in liver, endothelial cells, platelets,
brain cells
• 40% free protein which is active
• C4b-binding protein carries inactive protein S
– Increased during inflammatory states
PS Deficiency
• Acquired Causes
– Estrogen
• OCPs
• Pregnancy
– DIC
– Liver disease
– Acute thrombosis
– Inflammatory states
• Reduced Free PS
PS Deficiency
• Majority events are venous
– DVT
– PE
– Superficial Thrombophlebitis
– Mesenteric Veins
– CSVT
– Axillary vein
• >50% spontaneous events
• High risk of recurrence
PS deficiency
• Phenotypic variability
Total Protein
Free
Activity
Type 1
low
low
low
Type 2
normal
normal
low
Type 3
normal
low
low
ELISA tests for Total and Free Protein S Antigens
Indirect functional assays based on generation of APC.
People with Factor V Leiden may have artificially low PC/PS activity
Screening for Natural
Anticoagulant Proteins
• Levels change with age
– AT and PS reach adult levels by 6-12 months of age
– PC low until adolescence
• Medications that alter levels
– Heparin reduces AT levels
– Warfarin reduces PC and PS levels
– Oral contraceptive pills (OCPs) can reduce Protein S and
increase activated Protein C resistance (APCR)
• Confirm inherited thombophilia
– In steady state, off medications and at correct age
Factor V Leiden (Factor V Arg506Gln)
• Activated Protein Resistance (APCR)
– Factor V Leiden (FVL) accounts for majority of
APCR
– Slow inactivation by activated Protein C
– Diagnosed with clot based assay based on APTT
• FVL diagnosed by PCR
• Symptoms
– Primarily venous disease
– Pregnancy complications and arterial
complications debated
• Low risk of recurrence in heterozygous state
Prothrombin G20210A
•
•
•
•
Increased prothrombin biosynthesis
Diagnosed by PCR
Increased risk of venous thrombotic events
Possible increased risk of arterial stroke in
children (Kenet et al Circulation 2010)
• Possible increased risk of recurrence in
children (Young et al Circulation 2008)
Association of Inherited Thrombophilia and
First Thrombosis During Childhood
Genetic Trait
Patients/Controls
OR (95% CI)
Protein C deficiency
1079/1979
7.75 (4.48-13.38)*
Protein S deficiency
1075/1979
5.77 ( 3.07-10.85)*
Antithrombin deficiency
1072/1979
8.73 (3.12- 24.2)*
Factor V Leiden
1430/2623
3.56 (2.57-4.93)*
Prothrombin gene
mutation
916/1673
2.63 (1.61-4.29)*
Lipoprotein (a)
586/1441
4.5 (3.19-6.35)**
≥2 genetic traits
965/1625
8.89 (3.43-23.06)*
* P< 0.0001
Young et al. Circulation 2008; 118: 1373-1382
** P< 0.001
Association of Thrombophilia and
Recurrent Thrombosis
Genetic Trait
Patients/Controls
OR (95% CI)
Protein C deficiency
152/1296
2.53 (1.3-4.92 )
P= 0.006
Protein S deficiency
132/857
3.76 (1.76-8.04)
P= 0.0006
Antithrombin deficiency
150/969
3.37 (1.57-7.2)
P=0.001
Factor V Leiden
112/1160
0.77 (0.40-1.45)
P=0.42
Prothrombin gene
mutation
171/1397
2.15 (1.12-4.10)
P=0.02
Lipoprotein (a)
135/1020
0.84 (0.50-1.40)
P=0.50
≥2 genetic traits
144/1127
4.91 (3.12-7.74)
P=0.0001
Young et al. Circulation 2008; 118: 1373-1382
Inherited Thrombophilia Frequency in Population
Risk of Thrombosis
AT deficiency
Heterozygous: 0.2-0.5/1000
Homozygous : fetal demise
50% risk of prior to age 40
60% risk of recurrence
Protein C deficiency
Heterozygous: 1/500
Homozygous 1 in 500,000 to
1,000,000
24 X increased risk prior to
age 55
Increased risk of recurrence
(40-60% in 5 years)
Protein S deficiency
Heterozygous 1/800
31 X increased risk prior to
age 55
Increased risk of recurrence
(44% in 5 years)
Factor V Leiden
Heterozygous : 3-8% of
Caucasians; 1.2% African
American; Rare in Asian
Heterozygous 3-5 X risk
Minimal risk of recurrence
Homozygous 18 X risk
Combined with prothrombin
gene 30-50 X risk
Prothrombin G20210A
Heterozygous state: 2% of US
Caucasians; 0.5% African
Americans
Heterozygous 3 X risk
Possible increased risk of
recurrent events in children
Homozygous increased risk.
but unclear magnitude
Medical Conditions Associated with
Thrombosis
•
•
•
•
•
•
Cancer
Cardiac Disease
Renal disease
Liver disease
Rheumatologic disease
Inflammatory Bowel
disease
• Infection
– Sepsis/DIC
• Diabetes
• APS
• Surgery
• Trauma/Immobility
– Venous stasis
•
•
•
•
Obesity
Use of estrogens
Dehydration
Any condition that
requires central venous
catheter
APS
• Defined as the persistent presence of
antiphospholipid antibodies (ELISA based test) or
lupus anticoagulant (clot based assay) for ≥ 12 weeks
in context with an acute thrombotic event
– Venous or arterial thrombosis
– Recurrent pregnancy loss < 10 week gestation
– Premature delivery or fetal demise >10 week gestation
• Catastrophic APS
– 3 or more new thrombotic events in a week
Impact of Acquired Thrombophilia
• Which has greater impact? Inherited or
Acquired risk factors?
– Prevalence of inherited thrombophilia in children with
thrombosis is 13-79%
• Depends on which tests were performed and timing
• Close to 90% of children with thrombosis have
underlying medical condition
• 75-85% also have central venous catheters
– Thrombophilia plays a stronger role in spontaneous
thrombosis in neonates and adolescents
Revel-Vilk Thromb Res 2006
Thrombophilia Testing
• During acute event transient abnormalities?
– Consumption of Protein C and S
– Elevated FVIII and D-Dimers
– Transient antiphospholipid antibodies/lupus
anticoagulant (LA)
• Any non-genetic abnormality should be
confirmed by repeat testing in stable state
– Off warfarin for Protein C and S
– Off anticoagulation for clot based assays of LA
Thrombophilia Testing
• Guidelines
– screen patients with thrombosis <50 yrs, unusual
sites, recurrent events, first event and family
history
• Factor V Leiden
Protein C
AT
Homocysteine (arterial)
Prothrombin Gene
Protein S
Lipoprotein a
Antiphospholipids/LA
Presentation of DVT
Diagnosis
• Symptoms
• Imaging
• Lab tests
– No specific test that makes diagnosis
– If suspicious for thrombosis, do the imaging
Venous Thrombosis
• Superficial
Thrombophlebitis
– Painful
– Palpable cord
– Often from intravenous
stick or PICC line
– Varicose veins
• Deep Vein Thrombosis
(DVT)
– Acute swelling of
extremity
– Pain
– Discoloration (red to
purple)
– Heat
Specific Syndromes
• Lower Extremity
– Associated with
•
•
•
•
•
•
Trauma,
Immobilization,
Bed rest,
Post-operative state
Long-haul travel
Central venous
catheter
• Anatomic
abnormalities
• Upper Extremity
– Associated with
• Central catheters
• PICC
• Anatomic
abnormalities
Specific Syndromes
• May Thurner
– Left-sided ileofemoral
thrombosis
• Narrowed left iliac vein
due to chronic
compression from right
iliac artery
• More likely in adolescent
girls
• Axillary/Subclavian vein
thrombosis
– Paget-Schroetter,
Thoracic Outlet
Syndrome, Exertional or
Effort-induced
Thrombosis
• More likely in adolescents
• Associated with repetitive
activity
• Compression of veins by
extra rib, muscle group
Neutral arm position vs raised arm position
Catheter-related DVT
• Most common cause of DVT in children
– 90% of DVT in neonates and 60% of DVT in
children are catheter-related
Catheter-related DVT
• Acute (10-15%)
–
–
–
–
Extremity Swelling
Extremity Pain
Discoloration
Line not working well
• Chronic ”asymptomatic”
– Catheter occlusion
– Prominent chest wall
veins
– Arm swelling
– Arm pain
– Recurrent bacteremia?
Imaging for Diagnosis for DVT
• Contrast Venography
–
–
–
–
Requires IV contrast
“gold standard”
Sensitivity lower up to 90%
Sensitivity upper 79 to 94%
• Improve images of contrast in central veins by elevating extremity
and using tourniquet
• Reduces “washout” phenomenon of influx of blood without
contrast into jugular vein
– Reduced ability to identify jugular vein thrombosis
Ultrasonography
• Non-invasive
• Diagnosis
– Lack of compressability
of vessels,
– Visualization of
echogenecity in lumen,
– Lack of wave form
response with
respirations
• Lower extremity
• 95% sensitive for
proximal, 50% for isolated
calf
• Limited ability to see iliac
veins
• Upper extremity
• Sensitivity 54 to 100%,
Specificity 94 to 100%
• Technically difficult in
upper extremity- no
compressibility through
ribs and clavicles
Imaging for Diagnosis of DVT
• CT venography
– High dose radiation, risk of contrast
– High rate of false positives and false negatives
– 3-D reconstruction may help increase reliability
• Detected 100% of thrombi in central and jugular veins
vs 82% by sono
– Farinasso et al. Leukemia 2007; 21:552-556
Imaging for Diagnosis of DVT
• MR Venography
– No radiation
– Requires cooperation and prone to motion artifact
– 100% sensitivity for proximal DVT, 92% for distal in
adults
• Not yet replicated in children
– Baskin et al. Lancet 2009; 374: 159-169
Pulmonary Embolism
• Signs and Symptoms (20% have classic triad)
– Chest pain (splinting)
– SOB
– Hypoxia
– Fever
– Hemoptysis
– History or presence of extremity swelling/ pain OR
known DVT
Imaging for Diagnosis of PE
• CXR
– May be initially normal in patient with PE and
hypoxia
– Knuckle sign and enlarged right heart
• V/Q scan
– Use as initial study if CT scan not available
Imaging for Diagnosis of PE
• CT
– Spiral CT/CT angiography
• Central PE 100% sensitivity
• Sometimes difficult to diagnose sub-segmental PE
• 8-10% of scans will be sub-optimal
• Contrast pulmonary angiography
– “gold standard”
– Invasive
Additional Studies to Evaluate
Severity of PE
• Laboratory
– Troponin- right ventricular overload
– Brain Natriuretic Protein- evidence of heart stress
• ECHO
– Enlarged right ventricle and evidence of
pulmonary hypertension
• EKG
– Tachycardia, atrial fibrillation, ST-T wave
abnormality
Cerebral Sinovenous Thrombosis (CSVT)
• Presentation
– Headache
– Evidence of increased
intracranial pressure
– Seizures
– Cranial nerve palsies
– Papilledema
– Focal neurologic signs
(cortical vein
thrombosis)
– Eyelid swelling, proptosis
(cavernous thrombosis)
• History
– Ear infection progressing
to mastoiditis
– Lymphadenitis
– Dehydration
– Jugular vein
catheterization
– Neonate
Imaging for Diagnosis of CSVT
• Conventional CT scan
– Before and after contrast
• Delta sign in non-contrast
CT and reverse delta with
contrast
– Cerebral edema, venous
infarction
– May need CT
venography in increase
sensitivity
• MRI/MR venography
– Best non-invasive test
for diagnosis
– Direct visualization of
thrombosis
– 2D Time of flight or
phase contrast MRV
• Occlusion of vessel
Portal Vein Thrombosis
• Presentation
– Often slowly evolves
• Discovered with first GI
bleed from varices
• Asymptomatic
hepatomegaly and
splenomegaly
• Ascites
– Acute presentation
• Abdominal pain
• May be masked by
underlying pathology
(pancreatitis)
• History
– UVC
– Intra-abdominal tumor
– Intra-abdominal
infection
– Thrombophilia
– OCP/Pregnancy
Portal Vein Thrombosis Imaging
• Doppler Ultrasonography with Color Flow
– Best initial method
• CT
– CT angiography with helical CT
– Visualize collaterals
• MRI
– 99% sensitivity and 96% specificity for main portal
vein thrombosis
– False positive with noncontrast MRI
Renal Vein Thrombosis
• Presentation
– Generally in first month
of life
– Flank mass
– Hematuria
• History
– Maternal gestational
diabetes
– Dehydration
– Perinatal asphyxia
– IVC catheters
– Nephrotic syndrome
Imaging for Renal Vein Thrombosis
• Doppler Ultrasound and MR Venography
– Equal ability to diagnose obstructed flow and do
not require radiation or contrast media of CT
– If inconclusive, perform angiography/IVC imaging
• Radionuclide renography
– Identify poor perfusion to kidneys
Cautionary Interpretation of Laboratory
Testing in Diagnosing Thrombosis
• D-Dimer as a tool for diagnosis
– Not well studied in children
– Type of D-Dimer important
• Latex agglutination test less sensitive than ELISA
– Not specific
• Can be positive in patients with cancer, infection, trauma
• Can be normal with subacute thrombus (CVL thrombosis)
– Negative test in person with low pretest
probability is reliable
– Le Gal, et al Ann Intern Med. Feb 7 2006;144(3):165-71
Laboratory Testing AT Diagnosis
(not FOR diagnosis)
• CBC
– Thrombocytopenia
• Coagulation Studies
– PT/PTT, fibrinogen, D-Dimer and FVIII
• Baseline prior to initiating anticoagulation
• Elevated D-Dimer and FVIII prognostic
• Creatinine needed prior to initiating low molecular
weight heparin
• Thrombophilia evaluation
– Not necessary urgently
• False results in very acute phase
Probability Scales for PE?
• Canadian (Wells) Prediction Score
•
•
•
•
•
•
•
Previous pulmonary embolism or deep vein thrombosis
Heart rate >100 beats per minute
Recent surgery or immobilization (within the last 30 d)
Clinical signs of deep vein thrombosis
Alternative diagnosis less likely than pulmonary embolism
Hemoptysis
Cancer (treated within the last 6 mo)
High risk ≥7
Intermediate risk 2-6
Low risk ≤1
+ 1.5
+ 1.5
+ 1.5
+3
+3
+1
+1
Probability of Pulmonary Embolism
in Children
• Biss et al. 2009 J Thromb Haemost; 7: 16331638
– Modified Well’s Score applied in retrospective
case-control study
• Probability score and D-Dimer estimation not useful in
children in current form
–
–
–
–
PE likely + above normal D-dimer
PE likely + normal D-dimer
PE unlikely + above normal D-dimer
PE unlikely + normal D-dimer
59 % PE vs 33% no PE
7% vs 17%
26% vs 42%
7% vs 8%
Treatment
Anticoagulants
Vitamin K Antagonists
Block II, FVII, IX, X, PC and PS
Argatroban
Lepirudin
Bivalrudin
Anticoagulation
• Purpose of
anticoagulation
– Prevent new clot
formation
– Allow body’s fibrinolytic
system to dissolve clot
• Anticoagulants
– Unfractionated heparin
(UFH)
– LMWHs (enoxaparin)
– Fondaparinux
– Vitamin K antagonists
(warfarin)
– Direct Thrombin
Inhibitors
• Indications
– Treatment of venous
thrombotic events
– Prevention of
thrombotic events in
high risk individuals
• Strong thrombophilia,
history of prior event,
obese adolescents?
• Prevention of embolic
stroke in CHD
Anticoagulation: Heparin
• Primary action
– Binds to antithrombin
(cofactor)
– After binding, increases
antithrombin’s inhibition
of thrombin (factor IIa)
and factors IXa, Xa, XIa,
XIIa, and kallikrein
– Binds non-specifically to
other plasma proteins
and platelet derived
proteins
– Disaccharides of heparin
(30%) and heparin
sulfate (70%)
– Pentasaccharides
• High affinity for AT
– Must be long enough at
C terminal region to bind
both AT and thrombin
• Both anti-Xa and anti-IIa
activity
Heparin
• Properties
– Short half-life
– Reversible with protamine sulfate
– Excreted by kidney
– Risk of heparin induced thrombocytopenia (HIT)
– aPTT very sensitive to heparin contamination
• Blood drawn through catheters
• Heparinase can detect presence of heparin
Monitoring Heparin
• PTT (Target range 65-80 seconds or 1.5-2.5X baseline)
– Sensitive to improper collection, anemia, thrombocytopenia,
factor deficiencies, lupus anticoagulant, age
• ACT (target range depends on clinical use e.g. ECMO,
cardiac catheterization)
– Sensitive to platelet counts and function, factor deficiencies,
ambient temperature, hypothermia, lupus anticoagulant
• Anti-Xa most consistent result (Target 0.3-0.7 units/ml)
– Affected by hemolysis, high bilirubin, high triglycerides
– Not affected by age or coagulopathy
– Monitor every 4 hours after dose change and daily
Heparin Resistance
• Defined as the need for greater than average
doses to achieve a therapeutic goal
• Possible reasons for heparin resistance:
– AT deficiency
• AT levels <60% - higher likelihood of heparin resistance,
– Increased heparin clearance
• Lasix , CVVH
– Elevation in level of heparin-binding proteins
• Transfusion of plasma products
– High levels of factor VIII or fibrinogen
– DIC
Heparin Induced
Thrombocytopenia (HIT)
• Occurs in 1 to 3% of adult cardiac surgeries
• 6 studies in children
–
–
–
–
Prospective study in neonates: 1.5%
Prospective study after open heart surgery: 0.5%
Retrospective case series of heart surgery: 1.2%
Retrospective ICU: 2.3%
• Bimodal peak (as with all of thrombosis in kids)
– Infants and adolescents
HIT IS CAUSED BY ANTIBODIES AGAINST A HEPARINPLATELET FACTOR 4 COMPLEX
4
binds
3 Antibody
heparin-PF4
complex
Fab
Antibody
binding to
platelet FC
receptor
activates
platelet
2 PF4 binds heparin
PF4
FC
Activated platelet
secretes PF4
FC receptor
Platelet membrane
1
Diagnosis - pretest probability: the 4 T’s
Points: Score 0, 1 or 2 for each of 4 categories:
2
A
B
C
D
1
Thrombocytopenia
> 50% platelet
30-50% platelet
count fall to nadir ≥ count fall to nadir
20
10-19
Timing of fall in
platelet count or
other sequelae
Onset d 5-10 or < 1
d (if heparin
exposure within 30
d)
New thrombosis;
skin necrosis; postheparin bolus acute
Thrombosis or other
systemic reaction
sequelae
OTher cause for
thrombocytopenia
No other cause for
platelet count fall is
evident
> d 10, or timing
unclear, or < d 1
with recent heparin
31-100 d
Progressive or
recurrent
thrombosis;
erythematous skin
lesions; suspected
thrombosis – not
confirmed
0
<30% platelet count
fall to nadir ≤ 10
Platelet count fall <
d 4 (without recent
heparin exposure)
None
Possible other cause Definite other cause
is evident
is present
Diagnosis - pretest probability
Interpretation of 4 T’s score
• Score 0-3:
very unlikely to be HIT (<5%)
• Score 4 - 5:
a minority have HIT (10-30%)
• Score 6 – 8:
20 to >80% have HIT, depending on the clinical
setting and scorer´s experience: these patients
usually require an alternative, non-heparin
anticoagulant in therapeutic doses
Laboratory Testing for HIT
Test
Advantages
Disadvantages
Sensitivity: high
Specificity: high
(false positives rare)
Technically demanding
(radioisotopes)
Not readily available
Platelet (HIPA)
aggregation
Specificity: high
Sensitivity: low
Technique-dependent
Immunoassay
(ELISA)
Sensitivity: high
Technically easy
Rapid turnaround time
Specificity: low (false
positives common for
some populations)
PIFA®
Sensitivity: high
Specificity: high
Technically easy
Rapid turnaround time
Limited clinical history
Positive & Negative
controls not provided
with assay
SRA
HIT Requires a Clinical Diagnosis
SRA=serotonin-release assay; ELISA=enzyme-linked immunosorbent assay.
Fabris et al. Arch Pathol Lab Med. 2000;124:1657-1666; Kelton. Semin Hematol. 1999;36(suppl 1):17-21.
PIFA® Heparin/Platelet Factor 4 Rapid Assay [package insert]. Thorofare, NJ: Akers Biosciences, Inc.; 2005.
Management of HIT – treatment
When HIT is strongly-suspected (score ≥ 4):
• Stop heparin (UFH/LMWH), even in patients without
thrombosis because thrombosis risk is VERY high
• Initiate alternative non-heparin anticoagulant
(DTIs)because of high risk of symptomatic
thrombosis
• Test for HIT antibodies/Confirm
– Send 24 hours after discontinuing heparin
• Duplex ultrasonography for lower-limb DVT
screening
– Adult data
• Do not give platelet transfusions unless needed to
manage serious hemorrhage
Direct Thrombin Inhibitors
Argatroban
Lepirudin
Synthetic
L-arginine
derivative
Recombinant
hirudin
Semi-synthetic
hirulog
39-51 min
1.3 hours
25 minutes
Hepatic
Renal
80% Enzymatic
20% Renal
Monitoring needed
aPTT, ACT
aPTT
aPTT, ACT
Thrombin binding
Reversible
Irreversible
Partially
reversible
None
None
None
Half-life in healthy
subjects
Elimination
Antidote
Bivalirudin
.
Adapted from Chen JL. Heart Dis. 2001;3:189-198. Warkentin, TE, Greinacher A. Heparin-Induced Thrombocytopenia. 3rd ed.
Revised and Expanded. 2004;:339-479.Warkentin TE, Greinacher A. Chest 2004;126:311s–337s.
Anticoagulation
• Alternatives to heparin for initial treatment
– LMWH
– Direct Xa inhibitor- (fondaparinux)
LMWH
• AT mediated Xa and and partial IIa inhibition
• <50% molecular weight (MW) of UFH
– Reduced anti-IIa activity due to small MW
• Less risk of HIT, but still a risk
• Partially reversible with protamine
• Renally cleared
– Contraindicated in renal failure
– Dose reduction in renal insufficiency
Enoxaparin
• Most clinical data for LMWH use in children is
based on studies of enoxaparin
• Peak anti-Xa level is 2 to 6 hours after
administration
– Obtain level 4 to 6 hours after
– Goal 0.5 to 1.0 U/ml for treatment
• 0.1-0.3 for prophylaxis
– Half life 4.5 to 7 hours
• Infants <3 months or 5 kg need higher doses
– Larger volume of distribution
Enoxaparin
• Monitoring in children recommended
– Wide interpatient variability
– Weight based; obesity and neonate concerns
– Age; infants need higher dose
– Decreased renal function increases risk of
accumulation
• Additional monitoring
– Bleeding reported in 0 to 10% of patients
• Primarily neonates
Anticoagulation
• UFH
– Continuous IV infusion
– Monitored with PTT to
correspond to an anti-factor
Xa activity of 0.3 to 0.7
units
– Good first choice in
unstable patient or need
procedure
• Reversible with protamine
and short half-life
– Starting dose
• 75 units/kg bolus***
• 20 units/kg/hr
• 28 units/kg/hr- neonate
• LMWH
– Subcutaneous injection
– Monitor with anti-factor Xa
activity (goal 0.5 to 1.0
units)
– Easier to use in stable
patient
– More predictable
pharmacokinetics
– Requires good renal
function
– Incomplete reversal with
protamine
– enoxaparin 1 mg/kg SQ
BID
– Neonates 1.5 mg/kg
Fondaparinux
•
•
•
•
•
•
•
AT mediated selected inhibition of Xa
Renal clearance
Peak level reached at 3-4 hours
Elimination half life 17-21 hours
Dose in kids 0.1mg/kg SQ daily
Target therapeutic range 0.5- 1 mg/L
Not reversible
– Hemodialysis reduces level by 20%
– rFVIIa has treated bleeding
Anticoagulation
• Hard to use heparin for all of therapy
• May use LMWH for duration of therapy
• Transition to warfarin or other Vitamin K
antagonist
– Must bridge with a heparin/LWMH/DTI
– Acquired hypercoagulability for first 5 days of
warfarin therapy
• Protein C levels reduced before the Factor X levels
• Potential for clot extension
• Potential for warfarin skin necrosis
Vitamin K Antagonists (VKA)
• Difficulty with VKA
– Slow onset of action
• HEPARIN BRIDGE
– Multiple food and drug
interactions
• FREQUENT MONITORING
of PT/INR
– Narrow therapeutic
index
• FREQUENT MONITORING
of PT/INR
– Genetic polymorphisms
• INCONSISTENT DOSING
• Reversible
– Vitamin K 2-5 mg PO, SQ
or IV
• IV slow infusion due to
anaphylaxis
– FFP
• Stop bleeding but not
completely reverse
– Prothrombin Complex
Concentrates
• Contain many Vit K
dependent proteins at
high concentration
Vitamin K antagaonists
• Warfarin- most common
– Monitor with PT/INR
• Target range INR 2-3 for most DVT/PE
• 2.5-3.5 for mechanical valves and some APS patients
• INR is a calculation made to standardize prothrombin
time. INR is based on the ratio of the patient's
prothrombin time and the normal mean prothrombin
time
• Check pregnancy status prior to initiation in
teen girls and change medication in pregnancy
– Warfarin embryopathy
Monitoring Warfarin Therapy
• INR can be altered by:
–
–
–
–
–
–
–
–
Initiation and discontinuation of medications (antibiotics)
Febrile illnesses
Gastroenteritis- diarrhea
Liver disease
Growth
Changes in nutrition
Alcohol
“Coumadin diet”- feeding tube issues
• Alterations can place kids at risk for recurrent clot or for
bleeding
• Check at least once a month when stable, and when
changes suspected
Side Effects
• Osteopenia with longterm use- UFH and
LMWH
• Black Box warning with
LMWH and
fondaparinux
– Spinal anesthesia and
spinal taps
• Tracheal calcificationwarfarin
• Hair loss- heparin,
LMWH, warfarin
• Bleeding
– Increased risk with use
of NSAIDS, aspirin
– Hold for invasive
procedures
– Appropriate activity
guidance
Novel oral anticoagulant agents
(NOAC)/Target Specific Oral Anticoagulant
Agents (TSOAC)
• Not currently indicated as first line therapy in
children
– Studies ongoing
– Dosing and monitoring not established
Additional Treatment
Considerations
Surgical Intervention
• May-Thurner
– Thrombolysis
• Mechanical local and
possibly systemic
– Angioplasty and Stent
placement
– Anticoagulation
• Paget-Schroetter
– Thrombolysis within first
week
– Anticoagulation
– Possible stent placement
subclavian vein
– Surgery (removal first rib
or part of clavicle OR
bypass)
• Recurrent thrombosis
• Anatomic defect
identified on CXR or MRI
IVC interruption
• Indications
– Large ileofemoral thrombosis when
anticoagulation contraindicated
• Temporary
– Recurrent ileofemoral thrombosis and PE despite
anticoagulation
Thrombolytic Agents
• Indications
– Arterial thrombosis- limb
threatening
– Intracardiac thrombus
– Pulmonary embolusmassive and submassive
– Extensive deep venous
thrombosis
• SVC syndrome
• Occlusive IVC thrombosis
• Bilateral renal vein
thrombosis with renal
compromise
• Large iliofemoral clot
• Contraindications
– Active major bleeding
including intracranial,
retroperitoneal or
gastrointestinal
hemorrhage
– Significant potential for
uncontrolled local bleeding
– Surgery within the
preceding 10 days
– Neurosurgery, including
spinal surgery, within
preceding 3 weeks
– New stroke
Thrombolytic Therapy
• Need to determine if systemic or catheter-directed
– Catheter-directed less bleeding risk
• Systemic dosing
– Arterial Thrombosis: tPA 0.3-0.6 mg/kg/h for 6-12 hours
– Venous Thrombosis: tPA 0.1-0.5 mg/kg/h for 6 to 12
hours
• Newer data suggests that lower doses for longer duration (12 to 24
hours) may also be effective for venous thrombosis. Consider
0.03-0.06 mg/kg/h.
Thrombolytic Therapy
• Monitoring/Therapeutic Goals
– PTT/Fibrinogen/D-dimer every 6 hours
– CBC every 12 hours, unless sudden drop in blood
pressure or extensive active bleeding
– Goals
• Fibrinogen 100-200 (expect to decrease by 20-50%
with adequate therapy)
• D-dimers
elevated
• PTT
50-70 (prophylactic heparin)
• Hb
stable (major bleeding if >2 g/dl drop)
• Plt
>100K (transfuse to maintain)
Thrombolytic Therapy
• Expect oozing from line/puncture sites, this is an
indication that thrombolysis is occurring and NOT an
indication to stop the TPA infusion.
– Major bleeding
• Drop of Hemoglobin by 2g/dl
• ICH, retroperitoneal, Intraspinal, intramuscular with compartment
syndrome, intraarticular, etc
• Neonates and infants may need FFP
empirically prior to thrombolysis secondary to
naturally low levels of plasminogen.
• Continue Prophylactic heparin during tPA infusion
Duration of Anticoagulant Therapy
• Standard therapy
– DVT/venous thrombosis
at unusual sites: 3-6
months
– PE: 6-12 months
• Long term
anticoagulaiton
– Antiphospholipid
antibody syndrome
– Protein C, Protein S and
AT deficiency- long
term/indefinite
– Combined inherited
traits
– Persistence of D-Dimer
or FVIII elevation may
lengthen course
Goldeberg and Bernard Hematol Oncol Clin N Amer 2010; 151-166
Hypercoagulable Thrombotic States ABP Content Specifications
(1) GENERAL
a. Know the important antithrombotic properties of vascular
endothelium (SLIDE 8)
b. Know the removal of the activated coagulation factors by the liver is
important in preventing thrombosis (SLIDE 9)
c. Know that estrogen containing contraceptives are associated with an
increased risk of venous thromboembolism, stroke, MI (SLIDE 22, 31)
(1) Diagnosis
a. Know how to evaluate a hypercoagulable state (SLIDE 15, 19, 24-27)
b. For each of the known hereditary thrombotic states, know how to diagnose
the defect in infants and older children (SLIDE 10, 17, 25)
c. Understand the clinical manifestations of antithrombin III and protein C and
S deficiencies (heterozygous and homozygous) (SLIDE 14, 18, 20, 23)
d. Know how to evaluate child with established deep vein thrombosis of
unknown cause (laboratory tests, imaging) (SLIDE 37-65)
e. Know how the normal concentrations of hemostatic factors in neonate
complicates the diagnosis of hypercoagulable states (SLIDE 20)
f. Know the predisposing causes of DVT in infants children and adolescents
(SLIDE 12, 30-33)
g. Know the acquired conditions that have been associated with venous and
arterial thromboembolism (SLIDE 12, 13, 17, 22, 31-33)
h. Know the clinical signs and symptoms of venous thrombosis in children
(SLIDE 38, 39, 43, 51, 56, 58, 60,)
a. Know the clinical signs and symptoms of pulmonary embolism
in children (SLIDE 49)
b. Know the laboratory measures important in evaluating children
with venous thrombosis and pulmonary embolism (SLIDE
37,62-65)
c. Know the clinical presentation, laboratory features and
epidemiology of activated Protein C resistance (Factor V Leiden)
(SLIDE 26)
d. Know the problems inherent in diagnosing hypercoagulable
states in patients receiving Coumadin therapy (SLIDE 25)
e. Know the clinical presentation and lab diagnosis of patient with
prothrombin mutation (SLIDE 27)
(1) Treatment
a. General Considerations
i. Know the treatment of a hypercoagulable state in newborn infant (SLIDE
20,99)
ii. Know the action of anticoagulant drugs used in thrombotic states or in
patients with thrombophilia (SLIDE 67, 69, 79, 81,85)
iii.Know the indications for and treatment of acquired hypercoagulable states
(SLIDE 20, 68, 93, 94, 99,)
b. Warfarin
i. Recognize the embryopathic potential of warfarin therapy (SLIDE 88)
ii. Know the mechanism of action of warfarin and other Vit K antagonists used
as anticoagulant for therapeutic purposes (SLIDE 67)
iii.Recognize the association of skin necrosis with warfarin therapy in patients
with protein C or S deficiency (SLIDE 86)
iv.Know the indications for use of Vit K antagonists (SLIDE 20, 68, 86)
v. Know the importance of INR and its use in monitoring Vita K antagonists
(SLIDE 87,88)
vi.The Recognize the many dietary, and drugs that can interact with VIt k
antagonists (SLIDE 89)
a. Heparin
i. Recognize the clinical and lab correlates or iatrogenic bleeding secondary
to heparin administration (SLIDE 84, 90)
ii. Know how to screen blood samples for presence of heparin (SLIDE 70)
iii.Understand the structure and mechanism of action of heparin and heparin
like substances (SLIDE 68, 69)
iv.Know the causes of heparin resistance (SLIDE 72)
v. Recognize the effect of heparin on coagulation assays in specimens from
plasma, including those drawn from catheters (slide 69)
vi.Know the syndrome and treatment of heparin induced thrombocytopenia
(HIT) including association with thrombosis (SLIDE 73-79)
vii.Know the relative advantages and disadvantaged of standard heparin vs
low molecular weight heparin (SLIDE 81, 84)
b. Direct Thrombin Inhibitors
i. Know the benefits , pharmacokinetics, monitoring of direct anti-thrombin
inhibitors (SLIDE 79)
ii. Know the various means to reverse Vit K antagonists (SLIDE 87)
c. Fibrinolytic drugs
i. Know the indications and risk for using fibrinolytic therapy (SLIDE 95)
ii. Know how to monitor fibrinolytic therapy (SLIDE 96-98)
Questions?
• If your eyes are like mine and you need a word
document of the tables, email me.
• If you need the updated content
specifications, email me
• [email protected]