Hanan Fathy

Pediatric nephrology
Hypercoagulable states
(Thrombophilias) :

► Definition:
• Conditions that predispose to an increased
risk for thrombosis either venous (most
common), arterial or both.

• These conditions are being identified more

frequently and may be classified as inherited
or acquired.
 Abnormal
Blood Flow

Abnormal Abnormal
Vessel Wall Blood

The Hypercoagulable State

(thrombophilia)

Dr. Rudolph Virchow

1821-1902
Pathophysiology

• Virchow’s Triad • Endothelial Injury

– Indwelling catheters
• Abnormal Blood Flow
– Immobilization
– Dehydration
– Inflammation
– Nephrosis
– Cancer therapy
– Hyperviscosity
• Hypercoagulability
• Anti-thrombin (AT)
– Thrombin
– IXa
– Xa
– XIa
– XIIa
– Plasmin
– Kallikrein
• Heparin co-factor II
– Thrombin
 -antitrypsin
– XIa
 2-antiplasmin
– Plasmin
 2-macroglobulin
– Thrombin
– Plasmin
– Kallikrein
• ZPI – inhibits Xa mediated thrombin
formation

Graphic accessed at URL http://ecc-book.com/assets/images/autogen/a_Hep_Action_Mode02.jpg, 2008.

 Antithrombin

Tissue 4
Factor major Protein C
antithrombotic Protein S
Pathway pathways
Inhibitor

Fibrinolytic System
Sites of action
of the major
antithrombotic
pathways
Anticoagulation and fibrinolytic mechanism
Plasminogen
Activator Inhibitor
Kallekrein
(intrinsic)
t-PA,u-PA PAI
(extrinsic)
α2-PI
plasmin

fibrinogen(fibrin) FDP
 D-Dimer

fibrin
fibrinolytic
system

D D

D D

D D
 Major Mechanisms Involved in the Normal Control of Coagulation and Inherited
Thrombophilias

Seligsohn U and Lubetsky A. N Engl J

In inherited thrombophilias, thrombosis
Seligsohn U and Lubetsky is most
A. N Engl J Medoften
2001;344:1222-1231 Med 2001;344:1222-1231

caused by impaired neutralization of thrombin or failure to

control the generation of thrombin
Non-physiologic inhibitors of coagulation

• Vitamin K antagonists (in vivo only)

• Ca chelators (in vitro only)
– EDTA
– Citrate
– Oxalate
* Heparin (in vivo and in vitro)
Hemostasis Balance

Thrombin Generation Plasmin Generation

(ie, Factors II – XII, cells) (ie, tPA, uPA, cells)

Healing
Coagulation Fibrinolysis

Thrombin Regulation Plasmin Regulation

(ie, PC/PS, AT, TFPI, cells) (ie, PAI-1, cells)

Cellular contribution: platelets, endothelium, monocytes

Alteration of Balance

• Factor deficiencies
• Acquired inhibitors
• Anticoagulant therapy
• Consumption (DIC)
• Dysfibrinogenemia
• Platelet defects
o mbo s is
• von Willebrand’s Thr
disease l ee d i ng
B

DIC, Disseminated intravascular coagulation

Alteration of Balance

Inhibitor deficiencies
Acquired inhibitors
(eg, lupus anticoagulant)
DIC
Heparin induced thrombocytopenia

Bleed
in g
Throm
bosis
 Types of Thrombosis

Arterial: platelet-based (white) thrombus

Platelet-VWF interactions critical

Associated with end-stage atherosclerosis

Venous: Fibrin-based (red) thrombus

Coagulation factors critical

Venous stasis
Arterial Thrombosis

• High speed blood flow

• High shear and turbulence
• Thrombus primarily composed of platelets
with smaller amounts of fibrin and other cells
• Thrombus associated with vascular
abnormalities (atherosclerosis) most often.
Arterial Thrombosis

Cerebral artery thrombosis =

Stroke

Mesenteric artery thrombosis =

Bowel Infarction

Coronary artery thrombosis =

Myocardial Infarction
Venous Thrombosis

• Slow blood flow

• Low shear
• Thrombus primarily composed of fibrin with
layers of platelets and RBCs
• Most often occurs in cases of stasis
(inadequate flow) or biochemical
abnormalities
Venous Thrombosis

Venous thrombi form most

often near valves in the leg
veins. As the thrombus
grows larger it can occlude
the vessel.
Thrombosis in Children

• On average children have fewer spontaneous

thromboses than adults
• Children and young adults may require 3 or 4
risk factors before thrombosis occurs:
– Central Venous Catheters
– Disease (cancer, heart disease, infection etc)
– Hereditary deficiencies
Epidemiology

• Highest incidence of thrombosis in

children
– Neonates
– Adolescents
Neonatal Epidemiology

• Highest risk group in the pediatric population

• Thrombosis Incidence
– 2.4/1000 NICU Admissions
• Catheters associated with:
– 80+% of Venous Thrombi
– 90% of Arterial Thrombotic Complications
• Renal Vein Thrombosis
– Most common non-catheter related thrombotic
complication
Neonatal Risk

• Intimal Injury: • Developmentally

– Catheters Prothrombotic:
– Polycythemia
– Decreased levels of
– Shock
– Natural Anti-coagulants:
Perinatal Asphyxia
• Protein C, Protein S,
• Abnormal Blood Flow: AntiThrombin III
– Catheters – Decreased levels of
– Congenital Heart
Disease Fibrinolytic Proteins:
• Esp. Plasminogen
Neonatal Presentation

• Typically in-utero or within first 48hrs of life.

• Catheter thrombosis.
• Renal vein thrombosis
– Flank mass on exam
– Thrombocytopenia, HTN, hematuria.
• Seizures.
• Neonatal Purpura Fulminans
– Homozygous Protein C or S def.
Inherited Thrombophilias

• Inherited hypercoaguable states

• A genetic tendency for venous thromboembolism

• Should be suspected in anyone who:

– Presents with an unprovoked venous or arterial thromboembolic disease
– 2 or more thrombotic episodes in the absence of a risk factor for
thrombosis
– History of objectively confirmed idiopathic thrombosis in first-degree
relative
– Thrombosis in an unusual site
• Mesenteric veins, dural sinus
– Neonatal thromobosis or stroke
Thrombophilia : causes

• Inherited:
– Protein C deficiency
– Protein S deficiency
– Antithrombin deficiency
– Factor V leiden
– Prothrombin gene mutation
– Elevated Lipoprotein a, homocysteine
Potentially inherited but firm evidence lacking.

• Plasminogen deficiency
• heparin co-factor II deficiency.
• Plasminogen activator deficiency.
• Elevated plasminogen activator inhibitor
• Inherited

Venous Arterial and venous

Factor V Leiden mutation Homocystinuria

Prothrombin G20210A Hyperhomocystinemia

Protein C & Protein S Dysfibrinogenemia

deficiency
Antithrombin deficiency
Elevated Factor VIII
activity
Factor V Leiden

• Factor V Leiden mutation is the most common

inherited thrombophilia.

• Normally, Activated protein C inactivates

factors Va and VIIa and is one of the
mechanisms that maintains a balance between
clotting and bleeding.
• This autosomal dominant disorder results from
single mutation in the factor V gene which
results in replacement of arginine amino acid
506 with glutamine.

• This renders the abnormal protein factor V

Leiden resistant to inactivation by activated
protein C.
• Both homozygous and heterozygous states are
at an increased risk for venous thrombosis with
a 50- to 100-fold increase in the homozygous
state and a 3- to 7-fold increase in the
heterozygous state.

• Factor V Leiden doesn’t appear to be a risk

factor for stroke or M.I.
Prothromin gene mutation

• The prothromin gene mutation is inherited as an

autosomal dominant mutation and leads to a
higher plasma level of prothrombin probably by
increase in mRNA and confers a 2.8-fold
increased risk for venous thrombosis.
Defects in the natural anticoagulants

• Protein C (PC).
• Protein S (PS).
• Antithrombin (AT).
• Deficiency of any of the three natural
anticoagulants is associated with an increased
risk for venous thrombosis.

• They are inherited as AD defects.

• PS is bound to C4 binding protein in the plasma

and acts as a cofactor in the inactivation of
factors Va and VIIIa by activated PC.
• Levels of PC & PS are lowered by warfarin therapy So,
initiation of warfarin therapy without concomitant
anticoagulant therapy may lead to warfarin induced skin
necrosis (manifested by painful skin necrosis primarily in the
fatty areas).

• Treatment includes stopping warfarin, administer vitamin K

and plasma to replete levels, and using an alternative
anticoagulant.
Congenital antithrombin III deficiency

• A vitamin K-independent protein that works inhibit thrombin

• Prevalence: 1:2000-1:5000 persons

• 30% of heterozygotes develop a thrombosis by 30yrs, 65% by

age 50yrs

• Homozygous deficiency is almost always incompatible with

life

• 60% will have recurrent thrombosis.

• Inheritance - usually autosomal dominant. 

• There are two types of hereditary AT deficiency:

• Type 1 - Classic - There is reduced synthesis of the AT

molecule. A gene deletion or frameshift mutation results in
a truncated protein which is unstable.

• Type 2 - The level of AT produced is normal, but the

protein is dysfunctional.

• Type 3 - The quantity and quality of AT is normal but it

lacks the receptor for heparin; therefore, it cannot be
acclerated.
Homocysteine

• It is derived from sulfur containing amino acid

methionine and metabolized through pathways
associated with folic acid, vitamin B6 and B12 as
cofactors.

• Elevated plasma homocysteine levels > 15 μmol/L

confer an independent risk factor for vascular
disease (the relative risk for stroke and M.I. is
double normal & for PVD is triple normal).
Homocysteine Metabolism

Cysteine
CBS Methylene
Homocysteine Tetrahydrofolate

B12 MTHFR
-CH3 +CH3

Tetrahydrofolate
Methionine
Folate
If MTHFR or CBS enzymes are missing, or folate or B12 are low
Homocysteine levels rise in the blood
• Causes of Hyperhomocystenemia :
1. Deficiencies in the cofactors for its metabolism.

2. Defects in the genes for 5,10-methylene tetrahydrofolate

reductase (MTHFR) (rare), cystathionine B-synthetase
(0.5%), homocysteine methyl transferase and methionine
synthetase (rare).

3. Secondary causes: age, male sex, menopause, liver and

renal impairment, hypothyroidism, smoking and drugs
(e.g. niacin, oral CCP, phenytoin, methotrexate and
theophyllin).
Possible mechanisms are that hyperhomocysteinemia
may be:

 Impair release of NO from endothelial cells,

 Stimulates proliferation of atherogenic smooth muscle
cells and contribute to thrombogenesis through activation
of protein C kinase and  expression of vascular adhesion
molecule .
 endothelial cell damage.
 lipid peroxidation.
 Up-regulation of prothrombotic factors (XII and V).
 Down-regulation of antithrombotic factors .
• Patients with enzymatic deficiency especially cystathionine
β-synthetase with marked elevations of homocysteine
plasma level (> 100 μmol/L) suffer from premature
atherosclerosis, arterial and venous thrombosis.

• Homocysteinuria (homozygous Cβs deficiency) is very rare

and manifested by mental retardation, skeletal anomalies
and ectopia lenses.
HOMOCYSTINURIA (cbs def)

• Mental retardation
• Ectopia lentis
• Skeletal abnormalities
• Thromboembolism
Homocystinuria

– Patients with classic homocystinuria may first

be recognized because of downward dislocation of the
lens (ectopia lentis), marfanoid habitus, mental
retardation , and/or seizures.

– Patients with defective methylcobalamin synthesis

may have all of these features, along with symptoms
of methylmalonic acidemia. Acute stroke symptoms
may occur in these patients.

– Traditional risk factors—hypertension, smoking, and

diabetes—may or may not be present.
 Homocysteinemia

– These patients may present with vascular thrombotic

events, with or without the traditional risk factors for a
stroke.

– This group of patients may already have a history of

strokes and myocardial infarctions in the third or fourth
decade of life.
Therapy

• Therapy includes folate therapy

(400ug:2mg/day).

• Second line therapy 10 : 25 mg/day of

pyridoxine (Vit. B6) with or without 400 µg of
vit. B12/day (if there is vit. B12 deficiency).
New inherited thrombophilic risk factors

• Protein Z-dependent protease inhibitor (ZPI) is a serpin that inhibits the

activated coagulation factors X and XI.

• As for antithrombin, deficiency of ZPI could have relevant thrombotic

consequences. Results of studies analysing mutations in the ZPI gene
suggest an association between ZPI deficiency and venous thrombosis,
with carriers of a particular polymorphism having a threefold risk of
thrombosis and a familial history of thrombosis.

• Recently, the frequency of a polymorphism of factor VII-activating

protease (Marburg I polymorphism) was shown to be significantly
increased in patients with VTE and the variant acted as an independent
risk factor, although it has been shown to be only a mild risk factor for
recurrent VTE.
Acquired hypercoagulable state
3.Other disorders associated
1. Vascular disorders with hypercoagubility
Atherosclerosis Cancer (Trousseau syndrome)
Diabetes Cancer chemotherapeutic agents,
Prosthetic materials (grafts, valves, thalidomide
indwelling Oral contraceptive, estrogen therapy,
vascular catheters) selective
estrogen receptor modulators
2. Abnormal rheology Pregnancy
Stasis (immobilization, surgery, congestive
heart Infusion of prothrombin complex
concentrates
failure)
Nephrotic syndrome
Hyperviscosity (polycythemia vera,
Myeloproliferative disorders
macroglobulinemia, acute leukemia, sickle
cell disease) Paroxysmal nocturnal hemoglobinuria
Inflammatory bowel disease
Thrombotic thrombocytopenic purpura
Disseminated intravascular coagulation
Antiphospholipid antibody syndrome
Heparin-induced
thrombocytopenia/thrombosis
Hypercoagulability in sickle cell disease and beta-
thalassemia.

• Patients with both diseases exhibit increased platelet and

coagulation activation, as well as decreased levels of natural
anticoagulant proteins.

• The pathogenesis of hypercoagulability is likely multifactorial,

with contributions from
• The abnormal red blood cell (RBC) phospholipid membrane
asymmetry (with resultant phosphatidylserine exposure),
• Ischemia -reperfusion injury,
• And chronic hemolysis with resultant nitric oxide depletion.
Consequences of nitric oxide depletion during intravascular
hemolysis

Copyright ©2007 American Society of Hematology. Copyright restrictions may apply.

 Hemolysis-associated hemostatic activation

Copyright ©2008 Ferrata Storti Foundation

 Schematic representation of pathophysiological mechanisms leading to
coagulation activation in sickle cell disease and other hemolytic anemias

Ataga, K. I. Haematologica 2009;94:1481-1484

Copyright ©2009 Ferrata Storti Foundation

HYPERCOAGULABILITY SYNDROME ASSOCIATED WITH CANCER
" TROUSSEAU SYNDROME"

- Occult cancer in 0.5 – 5% of VTE pts

- 19% of cancer pts have a VTE

- Necrotic areas produce thromboplastin like material and endotoxins in the

circulation.
- Activates procoagulant proteins.
- Stimulates circulating blood cell release a protease that activates coagulation
cascade.

- Chemotherapy increases risk of VTE because it increases tissue factor and

expression of E-selectin, thereby increasing thrombus potential
Mechanisms of Thrombosis in Cancer Patients

9 5

4
6

2 3
7
8

Bick, R. L. N Engl J Med 2003;349:109-111

Thrombosis in Paroxysmal Nocturnal Hemoglobinuria

• Usually venous thromboses occur at unusual sites (abdominal and cerebral veins) and
arterial thromboses have been reported in a minority of patients.

• Several failures of the fibrinolytic system have been observed, such as a deficiency of
urokinase type plasminogen activator receptor on leucocytes.

• Another explanation is complement-mediated attack on CD55 and CD59 deficient platelets

which results in a phospholipid- rich milieu and the generation of factors Va, Xa and
prothrombin complex.

• On the other hand, complement mediated damage may lead to increased leukocyte–
derived tissue factor levels in plasma, which activates the coagulation pathway .

• Venous endothelium in PNH may also be deficient in DAF and susceptible to complement
mediated damage .

• In patients with PNH, thromboembolic events have also been linked to hemolysis,
potentially through the build-up of cell-free plasma haemoglobin . The effect of free
hemoglobin on platelet function and hypercoagulability and the recognized increase in
thrombotic tendency in PNH may be largely due to its ability to scavenge nitric oxide .

• Propensity towards thrombosis appears roughly proportional to the size of the PNH clone
 Thrombotic Microangiopathies

1. Thrombotic thrombocytopenic Purpura (TTP)

2. Hemolytic-Uremic syndrome (HUS)
 Thrombotic Microangiopathies
common for both disorders

• Mechanism = plateletsthrombi in the

microcirculation
• Pathogenesis = Systemic endothelial cell damage
• Clinically = Fever, Thrombocytopenia, Renal
failure, Hemolytic anemia
 Thrombotic Microangiopathies
HUS Feature TTP

Absent Neurological Prominent

symptoms

Prominent Acute Renal Failure Less prominent

Children Age Adults
Infection Cause Genetic
( E.coli O157 : H7) (vWF metalloprotease-
ADAMTS 13)
deficiency
Supportive Rx. Plasma Exchange

Good in children Prognosis Better with plasma

Bad in adults exchange
Kawasaki disease

1. Abnormal endothelial function

2. Abnormal Platelet activation
3. Abnormal fibrinolysis
4. Abnormal blood flow dynamics
-> Coronary artery thrombosis
myocardial infarction
=> anticoagulation: important part of acute and long-
term management
• Giant (>8 mm in diameter) aneurysms require long-
term anticoagulation
: antiplatelet dose aspirin, warfarin

• Heparin :short-term management until oral

anticoagulant therapy
Antiplatelet agents used in long-term
anticoagulation therapy in patients with
Kawasaki disease
 Abciximab
• Human -murine monoclonal antibody fragment that binds to the platelet
glycoprotein IIb/IIIa receptor

- inhibition of platelet aggregation with a long platelet-bound half-life (safe

and effective)

- binds to the ανβ3 receptor, or vitronectin receptor, expressed on endothelial

and smooth muscle cells, which is an important mediator of cell migration
and proliferation and intimal hyperplasia

- ↓ circulating markers of inflammation(CRP, IL-6)

- anti-inflammatory action, anticoagulation property

- Abciximab + tPA:sucessful resolution of an intracoronary

thrombus(Chandwaney 2001)
American Heart Association guidelines for long-term therapy
in Kawasaki disease based on risk level
Heparin induced thrombocytopenia (HIT)

• Two distinct types of HIT are known:

The more common form, which may occur in up to
15% of patients receiving therapeutic doses of
heparin is a benign and self limiting side effect.

This type is non immune mediated, rarely causes

severe thrombocytopenia and usually doesn't
require heparin discontinuation.
In contrast the immune type of HIT may cause serious arterial
as well as venous thrombosis.
 Its pathogenesis involves the formation of antibodies (usually
IgG) against the heparin-platelet factor 4 (PF 4) complex.

 The HIT Abs trigger procoagulant effect through platelets

and endothelial cell activation, as well as thrombin generation
leading to both micro- and macrovascular thrombosis.
Heparin-Induced Thrombocytopenia (HIT):
Pathophysiology
IgG antibody
PF4 Heparin
Formation of
immune complexes
(PF4-heparin-IgG)

Formation of
PF4-heparin
complexes
Microparticle
release

EC injury
Platelet PF4
release

Platelet
activation*

Heparin-
Fc receptor like
molecules

Blood vessel
 Pathophysiology
Platelet

alpha granule PF-4/heparin IgG

complex
PF-4 binds to surface of Complexes of heparin (GAG) IgG binds to the PF-4/
platelet following activation and PF-4 molecules form heparin complex

microparticles Fc
receptor
Fc stimulation leads to the generation of IgG/PF-4/heparin complex activates
procoagulant-rich microparticles via the Fc receptor
Courtesy of Dr John G. Kelton, McMaster University.Hirsh et al. Arch Intern Med. 2004;164:361-369.
• The incidence of HIT is about 3-5% in patients
exposed to UFH, the incidence is much lower
with the use of LMWH.

• In patients with de novo exposure to heparin a

fall in the platelet count in those with HIT
occurs between day 5 and 14.
• The clinical diagnosis requires a fall in platelet
count by 50% following heparin exposure or a
fall by 30% in a setting of new thrombosis on
heparin use.

• The clinical spectrum ranges from isolated HIT

to HIT (T), where there is associated thrombosis
that may be arterial (Stroke, MI, PAD) or
venous in nature.
• Other manifestation include hypotension from
adrenal hemorrhage secondary to adrenal
infarction, skin necrosis or venous limb
gangrene.

• Lab diagnosis includes functional assays of

such as heparin induced platelet aggregation,
serotonin release assay, immunoassays such as
antibodies to heparin-PF 4 complexes.
• The serotonin release assay has the highest
sensitivity and specificity for the diagnosis of
HIT.

• Therapy includes stopping Heparin and starting

an alternative anticoagulant unless C.I.
• Direct thrombin inhibitors including Lepirudin
and Argatorban are approved for the use in
therapy of HIT (N.B. There are no available
agents that reverse the effects of these drugs).

• As argatorban falsely  INR, it should not be

discontinued until the INR is > 4.
• Platelet transfusion should be avoided if possible as it may
worsen the situation.

• Once the platelet count is > 100.000/CC warfarin may be

started at low dose.

• It is reasonable to continue anticoagulation for at least a

month in the absence of contraindications because the
highest incidence of thrombosis occurs within the 1st
month.
Antiphospholipid Antibodies Syndrome

• They are heterogeneous group of

autoantibodies that in clinical practice can
be divided into two large groups :
(a) Anticardiolipin antibodies.
(b) Lupus anticoagulants.
• They are either not associated with an autoimmune disorder
(1ry APS) or very often associated with autoimmune
conditions (e.g. SLE) (2ry APS) and can cause recurrent
pregnancy loss, as well as arterial or venous thrombosis.

• APA have also been reported in conjunction with idiopathic

autoimmune hemolytic anemia, malaria, Q fever, infections
by mycobacteria, Pneumocystis carinii, cytomegalovirus, and
human immunodeficiency virus (HIV), and after exposure to
drugs such as neuroleptics, quinidine, and procainamide.
•
• Once a thrombotic event occurs, long-term therapy with
warfarin must be considered (Recurrence rate of thrombosis
up to 70%).

• A higher target INR is used (approximately 3.0) as this may

be superior to normal target INR of 2.0 to 3.0 in preventing
recurrent events.

• Another strategy is to correlate the INR to a factor II and

factor X level of 20% to 30 %.
Stepwise Approach For Management of
Thrombophilias
(A) When to suspect ?!

• Idiopathic (i.e., spontaneous) VTE.

• VTE at young age.
• Recurrent VTE.
• VTE in unusual sites (e.g. U.L.)
• VTE in the setting of a strong family history of
VTE.
 Recommended Laboratory Evaluation for Patients
Suspected of Having an Underlying Hypercoagulable State
Screening Tests Confirmatory Tests
Activated protein C resistance. Factor V Leiden PCR

Prothrombin G20210A mutation testing by Antigenic assays for

PCR. antithrombin, protein C, and/or
Antithrombin, protein C, and protein S protein S
activity (functional) levels.
Factor VIII activity level.

Screening tests for lupus anticoagulants Confirmatory tests for lupus

(sensititve aPTT, aPTT mixing studies,
dilute Russell viper venom time)
Anticardiolipin antibody testing by ELISA.
Fasting total plasma homocysteine level.
Anticoagulants (Include at least
one of the following: platelet
neutralization procedure, hexagonal
phase phospholipids, Textarin /
Ecarin test, platelet vesicles, DVV
Confirm.)
 (C) Treatment

• There are no specific therapies to reverse most

hypercoagulable states.

• Recombinant factor concentrates of antithrombin and APC exist.

• Gene transfer to correct a particular genetic defect is theoretically

feasible but likely cost prohibitive at this time. Attempts to eliminate
APA by plasmapheresis or immunosuppressive therapy have not
been very successful.
Therapeutic Goals

• Prevent thrombus propagation and/or

embolization

• Restore blood flow (rapidly, when necessary)

• Minimize long-term sequelae

Risk Stratification*
(for persistence or recurrence)

• Low Risk
– Thrombus post surgery, trauma, CVL
– Resolves within 6 weeks
• Standard Risk
– FVIII <150U/dL
– D-dimer <500ng/mL
– < 3 thrombophilic factors
– Non-occlusive thrombus
• High Risk
– FVIII >150u/dL
– D-dimer >500ng/mL
– >3 thrombophilic factors
– Occlusive thrombus

Manco-Johnson, Blood 2006

*Studies in progress
• Initiation of oral anticoagulation for primary
VTE prophylaxis in asymptomatic carriers of any
hypercoagulable state has not been advised,
mainly because the annual absolute risk of
idiopathic VTE is either low or not high enough
to be favorably balanced against the annual risk
of oral anticoagulation- related major and fatal
hemorrhage.
UFH inactivate factor IIa through formation of a tertiary complex (unlike
LMWH).
UFH binds more to plasma proteins, endothelium and macrophages:
reduced bioavailability & greater patient variability to a given dose.
UFH inactivates factors IIa and Xa & affects the aPTT
LMWH inhibits factor Xa and minimally affects factor IIa; thus aPTT is not used
to measure its anticoagulant activity.
Benefits of Low Molecular Weight Heparins
(LMWH)

•LMWHs have a higher affinity for antithrombin-factor Xa.

•Longer plasma half-life.

•Safe and effective for venous thromboembolism, and with

unstable angina or acute thrombotic stroke.

•Convenient, given subcutaneously without laboratory assay

monitoring (allowing for patient and home care options).

GENERAL Heparin Targets

-Thrombin
-IXa, Xa, XIa, XIIa
-Measure efficacy with APTT
warfarin
 Protocol for Heparin Administration
and Adjustment in Children
Stage Description aPTT Bolus (units/Kg) Hold (min) Change rate Repeat aPTT
(%)

I. Loading dose 75 IV over 10 minutes __ __ __

II. Begin maintenance

Age < 1 year 28 units/ Kg hour __ __ __
Age > 1 year 20 units/Kg/ hour

III. A PTT adjustment*

< 50 50 units/Kg 0 +10% 4 hours
50-59 - 0 +10% 4 hours
60-85 - 0 0 Next day
86-95 - 0 -10% 4 hours
96-120 - 30 -10% 4 hours
> 120 - 40 -15% 4 hours

IV. Obtain aPTT 4 hours after heparin load and 4 hours after any infusion rate change

V. When aPTT values are in therapeutic range, measure daily CBC and aPTT

*Heparin adjusted to maintain aPTT at 60 to 85 seconds, assuming that this reflects an anti–factor Xa level of 0.35 to 0.70.
aPTT = activated prothrombin time. This table adapted from Michelson et al. and the experience of the writing group.
Protocol for Using Low-Molecular-Weight
Heparin in Children
Initial Initial
Treatment Prophylactic
Preparation Dose Dose
Reviparin
Body weight–dependent dose (Units/kg per12 hours)
<5 kg 150 50
>5 kg 100 30

Enoxaparin
Age-dependent dose (mg/kg per 12 hours)
<2 mo 1.5 0.75
>2 mo 1.0 0.5

Dalteparin
All-age pediatric dose (Units/kg per 24 hours) 129 ± 43 92 ± 52

Tinzaparin
Age-dependent dose (Units/kg)
0-2 mo 275
2-12 mo 250
1-5 years 240
5-10 years 200
10-16 years 275

Adapted from Monagle et al. and the experience of the writing group.
 Warfarin Anticoagulation Protocol for
Children
Stage INR Action
Day 1 1.0-1.3 0.2 mg/kg orally

Days 2-4 1.1 –1.3 Repeat day 1 loading dose

1.4 –1.9 50% of day 1 loading dose
2.0 –3.0 50% of day 1 loading dose
3.1 –3.5 25% of day 1 loading dose
>3.5 Hold dosing until INR is <3.5
then restart according to stage
III guidelines
Maintenance
1.1 –1.4 Increase by 20% of dose
1.5 –1.9 Increase by 10% of dose
1.0–3.0 No change
3.1 –3.5 Decrease by 10% of dose

>3.5 Hold dosing until INR is <3.5 then restart at 20% less than last
dose
INR indicates international normalized ratio.
*The protocol is designed to maintain an INR between 2 and 3 with warfarin.
Adapted from Michelson et al and the experience of the writing group .
 New Anticoagulant Drugs
Possible standard therapy within 2-5 years

1. Anti-Xa Rivaroxaban
Synthetic pentasaccharide
2. Thrombin inhibitors
Lepirudin
Dabigatran

No laboratory monitoring required

No specific antidotes to treat bleeding
Antiplatelet Drugs
Schematic diagram of platelet
pathway with site of action of
antiplatelet and other agents.
Parenteral antiplatelet drugs

• Glycoprotein IIb/IIIa Inhibitors

– Abciximab (Reopro®), eptifibatide (Integrilin®),
tirofiban (Aggrastat®)
– Prevent fibrinogen binding to Gly IIb/IIIa receptor
and block platelet aggregation producing
profound platelet inhibition.
– Used in conjunction with percutaneous coronary
interventions (PCI).
Direct Thrombin Inhibitors (DTI)

Available Agents
• Refludan® (lepirudin)
• Argatroban
• Angiomax® (bivalirudin)
• Exanta® (ximelagatran)*
*Awaiting FDA approval
Newer antiplatelet agents:
• Ticlopine, clopidogrel
- inhibit platelet aggregation via the adenosine diphosphate
pathway

• Ticlopidine
- Antiplatelet agent with fibrinolytic and thrombolytic
actions
- Mediated via endothelial release of prostacyclin and t- PA
- ASA+Ticlopidine : beneficial unstable angina
- No reports of use of ticlopidine in the long –term Mx in
KD
Summary
• Initial treatment should be standard or low
molecular weight heparinization

• Short courses may be completed with heparin,

longer courses may benefit from transition to
Warfarin

• Duration of anticoagulant therapy is individualized

based on underlying co-morbidities

• Patients should be followed closely for recurrent

disease and/or post-phlebitic syndrome
Summary

• All thrombosis patients should be screened for

treatable molecular thrombophilias

• Some patients may benefit from additional

screening

• Asymptomatic patients and family members not at

increased risk for thrombosis should not routinely be
screened