Title: Thrombotic Disorders
1Thrombotic Disorders
- Janna M. Journeycake, MD, MSCS
- UT Southwestern Medical Center Dallas, Childrens
Health
2Disclosures
- No relevant disclosures to this topic
- Will discuss off label use of anticoagulant
medications
3Lecture 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
4Scope 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
5Scope 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
6Review of Coagulation and Regulation of
Coagulation
- Dr. Young reviewed yesterday and I borrowed a few
of his slides
7Natural Coagulation Inhibitors
Inhibits ( )
Thrombin (IIa)
VII
Ca
Tissue factor pathway inhibitor (TFPI)
XI
XIa
TF
Ca
VIIa
IX
IXa
Ca
Ca
VIII
VIII
Antithrombin
Xa
X
X
Xa
Thrombin (IIa)
V
Va
XIII
Ca
Prothrombin (II)
Thrombin (IIa)
Protein S
Protein S
Fibrinogen (I)
Fibrin
Thrombin (IIa)
XIIIa
Protein Ca
Protein C
Cross-linked fibrin
Borrowed from Dr. Young
8Endothelial cells antithrombotic effects
--Protein S
--tissue plasminogen activator
PS
PCprotein C APCactivated protein C
TPA
TM
--thrombomodulin
--heparan sulfate
HS
--plasminogen activator inhibitor type 1
PAI-1
PC
APC (PS)
Va and VIIIa
Thrombin
AT
Thrombin
HS
TM
fibrinolysis
PS
TPA
PAI-1
Borrowed from Dr. Young
9Properties 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
10Properties of Anticoagulant Factors
Factor Site of synthesis Levels in infancy Vitamin K-dependent Other
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
11Thrombophilia
- 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
12Thrombophilia
- Acquired
- Antiphospholipid antibody syndrome (APS)
- Anticardiolipin
- Anti-ß2 glycoprotein
- Lupus anticoagulant
- Major medical conditions
- Activate coagulation
- inflammation
- Loss or Consumption of inhibitors of coagulation
- Invasive procedures
- 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
13Antithrombin (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)
14AT 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
15AT Deficiency Diagnosis
- Autosomal dominant inheritance
- Type 2 Heparin Binding defects less likely to
have thrombosis
Antigen Heparin Cofactor activity Progressive Antithrombin Activity
Type 1 Low Low Low
Type 2 Active site defect Normal Low Low
Heparin Binding site defect Normal Low Normal
16Protein C (PC)
- Vitamin K dependent protein produced in liver
- Needs to be activated by thrombin/thrombomodulin
complex - Autosomal dominant inheritance
- Rare auto recessive cases
17Protein 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)
18PC deficiency
- Majority venous events
- Ileofemoral veins
- Mesenteric veins
- PE
- CSVT
- Superficial thrombophlebitis
- Possible association with arterial stroke
- 70 spontaneous thrombosis
- High risk of recurrence
19PC 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 Functiona
l Tests Snake venom activated Protein C and
activity of APC is measured by clotting assay
(higher sensitivity) or chromogenic substrate
20Severe PC deficiency in Neonate
- Treatment
- Aggressive Protein C replacement
- Anticoagulation life long
- Case reports of liver transplant
- Homozygous deficiency or Double Heterozygous
States - Symptoms
- Purpura fulminans
- Ophthalmologic injury
- Renal injury
- Neural
21Protein 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
22PS Deficiency
- Acquired Causes
- Estrogen
- OCPs
- Pregnancy
- DIC
- Liver disease
- Acute thrombosis
- Inflammatory states
- Reduced Free PS
23PS Deficiency
- Majority events are venous
- DVT
- PE
- Superficial Thrombophlebitis
- Mesenteric Veins
- CSVT
- Axillary vein
- gt50 spontaneous events
- High risk of recurrence
24PS deficiency
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
25Screening 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
26Factor 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
27Prothrombin 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)
28Association 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)
Plt 0.0001
Plt 0.001
Young et al. Circulation 2008 118 1373-1382
29Association 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) P0.001
Factor V Leiden 112/1160 0.77 (0.40-1.45) P0.42
Prothrombin gene mutation 171/1397 2.15 (1.12-4.10) P0.02
Lipoprotein (a) 135/1020 0.84 (0.50-1.40) P0.50
2 genetic traits 144/1127 4.91 (3.12-7.74) P0.0001
Young et al. Circulation 2008 118 1373-1382
30Inherited 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
31Medical 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
32APS
- 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 lt 10 week gestation
- Premature delivery or fetal demise gt10 week
gestation - Catastrophic APS
- 3 or more new thrombotic events in a week
33Impact 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
34Thrombophilia 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
35Thrombophilia Testing
- Guidelines
- screen patients with thrombosis lt50 yrs, unusual
sites, recurrent events, first event and family
history - Factor V Leiden Prothrombin Gene
- Protein C Protein S
- AT Lipoprotein a
- Homocysteine (arterial) Antiphospholipids/LA
36Presentation of DVT
37Diagnosis
- Symptoms
- Imaging
- Lab tests
- No specific test that makes diagnosis
- If suspicious for thrombosis, do the imaging
38Venous 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
39Specific 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
40Specific 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
41Neutral arm position vs raised arm position
42Catheter-related DVT
- Most common cause of DVT in children
- 90 of DVT in neonates and 60 of DVT in children
are catheter-related
43Catheter-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?
44Imaging 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
45Ultrasonography
- 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
- Non-invasive
- Diagnosis
- Lack of compressability of vessels,
- Visualization of echogenecity in lumen,
- Lack of wave form response with respirations
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48Imaging 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 21552-556
49Imaging 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
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51Pulmonary 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
52Imaging 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
53Imaging 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
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55Additional 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
56Cerebral Sinovenous Thrombosis (CSVT)
- History
- Ear infection progressing to mastoiditis
- Lymphadenitis
- Dehydration
- Jugular vein catheterization
- Neonate
- Presentation
- Headache
- Evidence of increased intracranial pressure
- Seizures
- Cranial nerve palsies
- Papilledema
- Focal neurologic signs (cortical vein thrombosis)
- Eyelid swelling, proptosis (cavernous thrombosis)
57Imaging 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
58Portal 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
59Portal 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
60Renal Vein Thrombosis
- Presentation
- Generally in first month of life
- Flank mass
- Hematuria
- History
- Maternal gestational diabetes
- Dehydration
- Perinatal asphyxia
- IVC catheters
- Nephrotic syndrome
61Imaging 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
62Cautionary 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 2006144(3)165-71
63Laboratory 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
64Probability Scales for PE?
- Canadian (Wells) Prediction Score
- Previous pulmonary embolism or deep vein
thrombosis 1.5 - Heart rate gt100 beats per minute 1.5
- Recent surgery or immobilization (within the last
30 d) 1.5 - Clinical signs of deep vein thrombosis 3
- Alternative diagnosis less likely than pulmonary
embolism 3 - Hemoptysis 1
- Cancer (treated within the last 6 mo) 1
- High risk 7
- Intermediate risk 2-6
- Low risk 1
65Probability of Pulmonary Embolism in Children
- Biss et al. 2009 J Thromb Haemost 7 1633-1638
- Modified Wells 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 59 PE vs
33 no PE - PE likely normal D-dimer 7 vs 17
- PE unlikely above normal D-dimer 26 vs 42
- PE unlikely normal D-dimer 7 vs 8
66Treatment
67Anticoagulants
Vitamin K Antagonists Block II, FVII, IX, X, PC
and PS
Argatroban Lepirudin Bivalrudin
68Anticoagulation
- Purpose of anticoagulation
- Prevent new clot formation
- Allow bodys 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
69Anticoagulation Heparin
- 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
- Primary action
- Binds to antithrombin (cofactor)
- After binding, increases antithrombins
inhibition of thrombin (factor IIa) and factors
IXa, Xa, XIa, XIIa, and kallikrein - Binds non-specifically to other plasma proteins
and platelet derived proteins
70Heparin
- 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
71Monitoring 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
72Heparin Resistance
- Defined as the need for greater than average
doses to achieve a therapeutic goal - Possible reasons for heparin resistance
- AT deficiency
- AT levels lt60 - 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
73Heparin 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
74HIT IS CAUSED BY ANTIBODIES AGAINST A
HEPARIN-PLATELET FACTOR 4 COMPLEX
FC receptor
Platelet membrane
75Diagnosis - pretest probability the 4 Ts
Points Score 0, 1 or 2 for each of 4 categories
2 1 0
Thrombocytopenia gt 50 platelet count fall to nadir 20 30-50 platelet count fall to nadir 10-19 lt30 platelet count fall to nadir 10
Timing of fall in platelet count or other sequelae Onset d 5-10 or lt 1 d (if heparin exposure within 30 d) gt d 10, or timing unclear, or lt d 1 with recent heparin 31-100 d Platelet count fall lt d 4 (without recent heparin exposure)
Thrombosis or other sequelae New thrombosis skin necrosis post-heparin bolus acute systemic reaction Progressive or recurrent thrombosis erythematous skin lesions suspected thrombosis not confirmed None
OTher cause for thrombocytopenia No other cause for platelet count fall is evident Possible other cause is evident Definite other cause is present
A
B
C
D
76Diagnosis - pretest probabilityInterpretation of
4 Ts score
- Score 0-3 very unlikely to be HIT (lt5)
- Score 4 - 5 a minority have HIT (10-30)
- Score 6 8 20 to gt80 have HIT, depending on
the clinical setting and scorers experience
these patients usually require an alternative,
non-heparin anticoagulant in therapeutic doses
77Laboratory Testing for HIT
Test Advantages Disadvantages
SRA Sensitivity high Technically
demanding Specificity high (radioisotopes)
(false positives rare) Not readily
available Platelet (HIPA) Specificity high
Sensitivity low aggregation Technique-dependen
t Immunoassay Sensitivity high Specificity low
(false (ELISA) Technically easy positives
common for Rapid turnaround time some
populations) PIFA Sensitivity high Limited
clinical history
Specificity high Positive Negative
Technically easy controls not provided
Rapid turnaround time with assay
HIT Requires a Clinical Diagnosis
SRAserotonin-release assay ELISAenzyme-linked
immunosorbent assay. Fabris et al. Arch Pathol
Lab Med. 20001241657-1666 Kelton. Semin
Hematol. 199936(suppl 1)17-21. PIFA
Heparin/Platelet Factor 4 Rapid Assay package
insert. Thorofare, NJ Akers Biosciences, Inc.
2005.
78Management 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
79Direct Thrombin Inhibitors
Argatroban
Lepirudin
Bivalirudin
Synthetic L-arginine derivative Recombinant hirudin Semi-synthetic hirulog
Half-life in healthy subjects 39-51 min 1.3 hours 25 minutes
Elimination Hepatic Renal 80 Enzymatic 20 Renal
Monitoring needed aPTT, ACT aPTT aPTT, ACT
Thrombin binding Reversible Irreversible Partially reversible
Antidote None None None
. Adapted from Chen JL. Heart Dis.
20013189-198. Warkentin, TE, Greinacher A.
Heparin-Induced Thrombocytopenia. 3rd ed. Revised
and Expanded. 2004339-479.Warkentin TE,
Greinacher A. Chest 2004126311s337s.
80Anticoagulation
- Alternatives to heparin for initial treatment
- LMWH
- Direct Xa inhibitor- (fondaparinux)
81LMWH
- AT mediated Xa and and partial IIa inhibition
- lt50 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
82Enoxaparin
- 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 lt3 months or 5 kg need higher doses
- Larger volume of distribution
83Enoxaparin
- 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
84Anticoagulation
- 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
85Fondaparinux
- 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
86Anticoagulation
- 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
87Vitamin 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
88Vitamin 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
89Monitoring 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
90Side Effects
- Osteopenia with long-term use- UFH and LMWH
- Black Box warning with LMWH and fondaparinux
- Spinal anesthesia and spinal taps
- Tracheal calcification-warfarin
- Hair loss- heparin, LMWH, warfarin
- Bleeding
- Increased risk with use of NSAIDS, aspirin
- Hold for invasive procedures
- Appropriate activity guidance
91Novel 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
92Additional Treatment Considerations
93Surgical 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
94IVC interruption
- Indications
- Large ileofemoral thrombosis when anticoagulation
contraindicated - Temporary
- Recurrent ileofemoral thrombosis and PE despite
anticoagulation
95Thrombolytic Agents
- Indications
- Arterial thrombosis- limb threatening
- Intracardiac thrombus
- Pulmonary embolus- massive 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
96Thrombolytic 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.
97Thrombolytic 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 gt2 g/dl drop)
- Plt gt100K (transfuse to maintain)
-
98Thrombolytic 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
99Duration of Anticoagulant Therapy
- 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
- Standard therapy
- DVT/venous thrombosis at unusual sites 3-6
months - PE 6-12 months
Goldeberg and Bernard Hematol Oncol Clin N Amer
2010 151-166
100- Hypercoagulable Thrombotic States ABP Content
Specifications - GENERAL
- Know the important antithrombotic properties of
vascular endothelium (SLIDE 8) - Know the removal of the activated coagulation
factors by the liver is important in preventing
thrombosis (SLIDE 9) - Know that estrogen containing contraceptives are
associated with an increased risk of venous
thromboembolism, stroke, MI (SLIDE 22, 31)
101- Diagnosis
- Know how to evaluate a hypercoagulable state
(SLIDE 15, 19, 24-27) - For each of the known hereditary thrombotic
states, know how to diagnose the defect in
infants and older children (SLIDE 10, 17, 25) - Understand the clinical manifestations of
antithrombin III and protein C and S deficiencies
(heterozygous and homozygous) (SLIDE 14, 18, 20,
23) - Know how to evaluate child with established deep
vein thrombosis of unknown cause (laboratory
tests, imaging) (SLIDE 37-65) - Know how the normal concentrations of hemostatic
factors in neonate complicates the diagnosis of
hypercoagulable states (SLIDE 20) - Know the predisposing causes of DVT in infants
children and adolescents (SLIDE 12, 30-33) - Know the acquired conditions that have been
associated with venous and arterial
thromboembolism (SLIDE 12, 13, 17, 22, 31-33) - Know the clinical signs and symptoms of venous
thrombosis in children (SLIDE 38, 39, 43, 51,
56, 58, 60,)
102- Know the clinical signs and symptoms of pulmonary
embolism in children (SLIDE 49) - Know the laboratory measures important in
evaluating children with venous thrombosis and
pulmonary embolism (SLIDE 37,62-65) - Know the clinical presentation, laboratory
features and epidemiology of activated Protein C
resistance (Factor V Leiden) (SLIDE 26) - Know the problems inherent in diagnosing
hypercoagulable states in patients receiving
Coumadin therapy (SLIDE 25) - Know the clinical presentation and lab diagnosis
of patient with prothrombin mutation (SLIDE 27)
103- Treatment
- General Considerations
- Know the treatment of a hypercoagulable state in
newborn infant (SLIDE 20,99) - Know the action of anticoagulant drugs used in
thrombotic states or in patients with
thrombophilia (SLIDE 67, 69, 79, 81,85) - Know the indications for and treatment of
acquired hypercoagulable states (SLIDE 20, 68,
93, 94, 99,) - Warfarin
- Recognize the embryopathic potential of warfarin
therapy (SLIDE 88) - Know the mechanism of action of warfarin and
other Vit K antagonists used as anticoagulant for
therapeutic purposes (SLIDE 67) - Recognize the association of skin necrosis with
warfarin therapy in patients with protein C or S
deficiency (SLIDE 86) - Know the indications for use of Vit K antagonists
(SLIDE 20, 68, 86) - Know the importance of INR and its use in
monitoring Vita K antagonists (SLIDE 87,88) - The Recognize the many dietary, and drugs that
can interact with VIt k antagonists (SLIDE 89)
104- Heparin
- Recognize the clinical and lab correlates or
iatrogenic bleeding secondary to heparin
administration (SLIDE 84, 90) - Know how to screen blood samples for presence of
heparin (SLIDE 70) - Understand the structure and mechanism of action
of heparin and heparin like substances (SLIDE 68,
69) - Know the causes of heparin resistance (SLIDE 72)
- Recognize the effect of heparin on coagulation
assays in specimens from plasma, including those
drawn from catheters (slide 69) - Know the syndrome and treatment of heparin
induced thrombocytopenia (HIT) including
association with thrombosis (SLIDE 73-79) - Know the relative advantages and disadvantaged of
standard heparin vs low molecular weight heparin
(SLIDE 81, 84) - Direct Thrombin Inhibitors
- Know the benefits , pharmacokinetics, monitoring
of direct anti-thrombin inhibitors (SLIDE 79) - Know the various means to reverse Vit K
antagonists (SLIDE 87) - Fibrinolytic drugs
- Know the indications and risk for using
fibrinolytic therapy (SLIDE 95) - Know how to monitor fibrinolytic therapy (SLIDE
96-98)
105Questions?
- 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 - Janna.journeycake_at_childrens.com