thrombophilia(hanan)

8/8/2019 thrombophilia(hanan)

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Hanan Fathy

Pediatric nephrology


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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 morefrequently and may be classified as inherited

or acquired.


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Dr. Rudolph Virchow

1821-1902

Abnormal

Blood Flow

Abnormal

Vessel Wall

Abnormal

Blood

The Hypercoagulable State

(thrombophilia)


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Pathophysiology

Virchows Triad Endothelial Injury

Indwelling catheters

Abnormal Blood Flow

Immobilization Dehydration

Inflammation

Nephrosis

Cancer therapy Hyperviscosity

Hypercoagulability


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Anti-thrombin (AT) Thrombin

IXa

Xa

XIa

XIIa

Plasmin

Kallikrein Heparin co-factor II

Thrombin

E-antitrypsin

XIa

E2-antiplasmin

Plasmin E2-macroglobulin

Thrombin

Plasmin

Kallikrein

ZPI inhibits Xa mediatedthrombin formation

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


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4

majorantithrombotic

pathways

Antithrombin

Protein C

Protein S

TissueFactor

Pathway

Inhibitor

Fibrinolytic System


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Sites of action

of the major

antithrombotic

pathways


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Anticoagulation and fibrinolytic mechanism

PlasminogenActivator Inhibitor

Kallekrein

(intrinsic)

t-PA,u-PA PAI(extrinsic)

2-PI

plasmin

fibrinogen(fibrin) FDP


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D-Dimer

fibrin

D D

D D

D D

fibrinolytic

system


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Seligsohn U and Lubetsky A. N Engl J Med 2001;344:1222-1231

Major Mechanisms Involved in the Normal Control of Coagulation and InheritedThrombophilias

In inherited thrombophilias, thrombosis is most often

caused by impaired neutralization of thrombin or failure to

control the generation of thrombin

Seligsohn U and Lubetsky A. N Engl JMed 2001;344:1222-1231


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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)


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Hemostasis BalanceHemostasis Balance

Coagulation Fibrinolysis

Thrombin Generation

(ie, Factors II XII, cells)

Thrombin Regulation

(ie, PC/PS, AT, TFPI, cells)

Plasmin Regulation

(ie, PAI-1, cells)

Healing

Plasmin Generation

(ie, tPA, uPA, cells)

Cellular contribution: platelets, endothelium, monocytes


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Alteration of BalanceAlteration of Balance

Factor deficienciesFactor deficiencies

Acquired inhibitorsAcquired inhibitors

Anticoagulant therapyAnticoagulant therapy

Consumption (DIC)Consumption (DIC)

DysfibrinogenemiaDysfibrinogenemia

Platelet defectsPlatelet defects

von Willebrandsvon Willebrandsdiseasedisease

DIC, Disseminated intravascular coagulation


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Alteration of BalanceAlteration of Balance

Inhibitor deficienciesInhibitor deficiencies

Acquired inhibitorsAcquired inhibitors

((eg,eg, lupus anticoagulant)lupus anticoagulant)

DICDIC

Heparin induced thrombocytopeniaHeparin induced thrombocytopenia


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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


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Arterial Thrombosis

High speed blood flow

High shear and turbulence

Thrombus primarily composed of plateletswith smaller amounts of fibrin and other cells

Thrombus associated with vascular

abnormalities (atherosclerosis) most often.


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Arterial Thrombosis

Cerebral artery thrombosis =

Stroke

Mesenteric artery thrombosis =

Bowel Infarction

Coronary artery thrombosis =

Myocardial Infarction


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Venous Thrombosis

Slow blood flow

Low shear

Thrombus primarily composed of fibrin withlayers of platelets and RBCs

Most often occurs in cases of stasis

(inadequate flow) or biochemical

abnormalities


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Venous Thrombosis

Venous thrombi form most

often near valves in the leg

veins. As the thrombusgrows larger it can occlude

the vessel.


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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


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Epidemiology

Highest incidence of thrombosis in

children

Neonates Adolescents


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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 thromboticcomplication


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Neonatal Risk

Intimal Injury: Catheters

Polycythemia

Shock

Perinatal Asphyxia

Abnormal Blood Flow: Catheters

Congenital HeartD

isease

Developmentally

Prothrombotic:

Decreased levels of

Natural Anti-coagulants: Protein C, Protein S,

AntiThrombin III

Decreased levels of

Fibrinolytic Proteins:

Esp. Plasminogen


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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.


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Inherited ThrombophiliasInherited 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 forthrombosis

History of objectively confirmed idiopathic thrombosis in first-degreerelative

Thrombosis in an unusual site

Mesenteric veins, dural sinus

Neonatal thromobosis or stroke


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Thrombophilia : causes

Inherited: Protein C deficiency

Protein S deficiency

Antithrombin deficiency

FactorV leiden

Prothrombin gene mutation

Elevated Lipoprotein a, homocysteine


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Potentially inherited but firm evidence lacking.

Plasminogen deficiency

heparin co-factorII deficiency.

Plasminogen activator deficiency.

Elevated plasminogen activator inhibitor


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Inherited

Arterial and venousVenous

HomocystinuriaFactor V Leiden mutation

HyperhomocystinemiaProthrombin G20210A

DysfibrinogenemiaProtein C & Protein S

deficiency

Antithrombin deficiency

Elevated Factor VIII

activity


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Factor V LeidenFactor V Leiden

FactorV 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 betweenclotting and bleeding.


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This autosomal dominant disorder results from

single mutation in the factorV gene which

results in replacement of arginine amino acid

506 with glutamine.

This renders the abnormal protein factorV

Leiden resistant to inactivation by activated

protein C.


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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 theheterozygous state.

FactorV Leiden doesnt appear to be a risk

factor for stroke or M.I.


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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.

Prothromin gene mutation


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Defects in the natural anticoagulantsDefects in the natural anticoagulants

Protein C (PC).

Protein S (PS).

Antithrombin (AT).


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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 thefatty areas).

Treatment includes stopping warfarin, administer vitamin K

and plasma to replete levels, and using an alternative

anticoagulant.


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Congenital antithrombin III deficiencyCongenital 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% byage 50yrs

Homozygous deficiency is almost always incompatible withlife

60% will have recurrent thrombosis.


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Inheritance - usually autosomal dominant.

There are two types ofhereditary ATdeficiency:

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

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

Type 2 - The level of AT produced is normal, but theprotein is dysfunctional.

Type 3 - The quantity and quality of AT is normal but itlacks the receptor for heparin; therefore, it cannot beacclerated.


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HomocysteineHomocysteine

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 mol/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).


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Homocysteine Metabolism

Homocysteine

Cysteine

+CH3

Methionine

-CH3

Tetrahydrofolate

Methylene

Tetrahydrofolate

CBS

B12 MTHFR

If MTHFR or CBS enzymes are missing, or folate or B12 are low

Homocysteine levels rise in the blood

Folate


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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 methioninesynthetase (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).

bl h h h h


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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 .

Possible mechanisms are that hyperhomocysteinemia

may be:


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Patients with enzymatic deficiency especially cystathionine-synthetase with marked elevations of homocysteine

plasma level (> 100 mol/L) suffer from premature

atherosclerosis, arterial and venous thrombosis.

Homocysteinuria (homozygous Cs deficiency) is very rare

and manifested by mental retardation, skeletal anomalies

and ectopia lenses.


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HOMOCYSTINURIA (cbs def)

Mental retardation

Ectopia lentis

Skeletal abnormalities

Thromboembolism


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Homocysteinemia

These patients may present with vascular thromboticevents, with or without the traditional risk factors for a

stroke.

This group of patients may already have a history ofstrokes and myocardial infarctions in the third or fourth

decade of life.


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Therapy

Therapy includes folate therapy

(400ug:2mg/day).

Second line therapy 10 : 25 mg/day of

pyridoxine (Vit. B6) with or without 400 g of

vit. B12/day (if there is vit. B12 deficiency).


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New inherited thrombophilic risk factors

Protein Z-dependent protease inhibitor (ZPI) is a serpin that inhibits theactivated coagulation factors X and XI.

As for antithrombin, deficiency of ZPI could have relevant thromboticconsequences. 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 ofthrombosis and a familial history of thrombosis.

Recently, the frequency of a polymorphism offactor VII-activatingprotease (MarburgIpolymorphism) was shown to be significantlyincreased in patients with VTE and the variant acted as an independentrisk factor, although it has been shown to be only a mild risk factor forrecurrent VTE.


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Acquired hypercoagulable state

1. Vascular disordersAtherosclerosis

Diabetes

Prosthetic materials (grafts, valves,indwelling

vascular catheters)

2. Abnormal rheologyStasis (immobilization, surgery, congestive

heart

failure)

Hyperviscosity (polycythemia vera,

macroglobulinemia, acute leukemia, sicklecell disease)

3.Other disorders associated

with hypercoagubilityCancer (Trousseau syndrome)

Cancer chemotherapeutic agents,thalidomide

Oral contraceptive, estrogen therapy,selective

estrogen receptor modulators

Pregnancy

Infusion of prothrombin complexconcentrates

Nephrotic syndrome

Myeloproliferative disorders

Paroxysmal nocturnal hemoglobinuria

Inflammatory bowel diseaseThrombotic thrombocytopenic purpura

Disseminated intravascular coagulation

Antiphospholipid antibody syndrome

Heparin-inducedthrombocytopenia/thrombosis


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Hypercoagulability in sickle cell disease and beta-

thalassemia.

Patients with both diseases exhibit increased platelet andcoagulation activation, as well as decreased levels of naturalanticoagulant 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.


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Consequences of nitric oxide depletion during intravascular


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

Consequences of nitric oxide depletion during intravascular

hemolysis


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Copyright 2008 Ferrata Storti Foundation

Hemolysis-associated hemostatic activation

S h i i f h h i l i l h i l di


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Copyright 2009 Ferrata Storti Foundation

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

Schematic representation of pathophysiological mechanisms leading to

coagulation activation in sickle cell disease and other hemolytic anemias


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

Mechanisms of Thrombosis in CancerPatients

1

2

3

4

5

6

3

78

9


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Thrombotic Microangiopathies

1. Thrombotic thrombocytopenic Purpura (TTP)

2. Hemolytic-Uremic syndrome (HUS)



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common for both disorders

Mechanism = plateletsthrombi in the

microcirculation Pathogenesis = Systemic endothelial cell damage

Clinically = Fever, Thrombocytopenia, Renal

failure, Hemolytic anemia


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HUS TTP

Absent Neurological

symptoms

Prominent

Prominent Acute Renal Failure Less prominent

Children Age Adults

Infection

( E.coli O157 : H7)

Cause Genetic

(vWF metalloprotease-

ADAMTS 13)

deficiency

Supportive Rx. Plasma Exchange

Good in children

Bad in adults

Prognosis Better with plasma

exchange

Feature

K ki di


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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

E d th li l i j i KD


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Endothelial injury in KD:

Circulating endothelial cells and endothelial

progenitor cells, prostacyclin production,

Cytotoxic antiendothelial cell Ab

(IVIG in KD-> improved PC production)

Platelet adhesion to the subendothelial matrix at

the site of endothelial injury

Ab l Pl t l t ti ti


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Serum levels of -thromboglobulin and other platelet-specific

proteins produced by activated platelets are elevated duringthe first 3 weeks of KD.

Elevated serum -thromboglobulin : marker for those patientswho are likely to develop CAL

platelet production of thromboxane A2, a metabolite ofarachidonic acid : potent vasoconstrictor and promoter of

platelet aggregation, during the acute phase of KD

Thrombocytosis (platelet >500K/mm3)

Thrombocytopenia: risk factor for the development ofcoronary artery aneurysms and myocardial infarction

Abnormal Platelet activation

Ab l fib i l i


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Abnormal fibrinolysis

KD :PAI-1

Low ratio of tPA to PAI-1:predictive of

development of coronary arteries abnormalities

Ab l fl d i


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Abnormal flow dynamics

Within the aneurysm itself, blood flow is sluggish andstagnant with decreased shear stress.

Vascular remodeling during the chronic phase of KD,Markedly intimal hyperplasia -> coronary a stenosis.

Blood flow through the stenotic areas : shear stress andsubsequent platelet activation and aggregation

-> inhibited by antiplatelet dose aspirin

Abnormal coronary artery flow dynamics and coagulationabnormalities in patients with persistent coronary arteryabnormalities : high risk for arterial thrombotic complications


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i l l d i l i l i


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Antiplatelet agents used in long-term anticoagulation

therapy in patients with Kawasaki disease

Abciximab


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Human -murine monoclonal antibody fragment that binds to the plateletglycoprotein IIb/IIIa receptor

- inhibition of platelet aggregation with a long platelet-bound half-life (safeand effective)

- binds to the 3 receptor, or vitronectin receptor, expressed on endothelialand smooth muscle cells, which is an important mediator of cell migrationand proliferation and intimal hyperplasia

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

- anti-inflammatory action, anticoagulation property

- Abciximab + tPA:sucessful resolution of an intracoronarythrombus(Chandwaney 2001)

Abciximab

American Heart Association guidelines for long-term therapy


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in Kawasaki disease based on risk level


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Heparin induced thrombocytopeniaHeparin induced thrombocytopenia (HIT)(HIT)

Two distinct types ofHITare known:

The more common form, which may occur in up to

15% of patients receiving therapeutic doses ofheparin is a benign and self limiting side effect.

This type is non immune mediated, rarely causessevere thrombocytopenia and usually doesn't

require heparin discontinuation.


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In contrast the immune type ofHITmay cause serious arterialas well as venous thrombosis.

Its pathogenesis involves the formation of antibodies (usually

I

gG

) 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):


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Heparin Induced Thrombocytopenia (HIT):

Pathophysiology

Formation of

PF4-heparin

complexes

IgG antibody

Formation of

immune complexes

(PF4-heparin-IgG)

EC injury

PF4

release

Platelet

activation*

Microparticle

release

Fc receptor

Platelet

Heparin-like

molecules

Blood vessel

PF4 Heparin

Pathophysiology


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PFPF--4 binds to surface of4 binds to surface of

platelet following activationplatelet following activation

Pathophysiology

Complexes of heparin (GAG)Complexes of heparin (GAG)

and PFand PF--44 molecules formmolecules formIgG binds to the PFIgG binds to the PF--44//

heparin complexheparin complex

IgG/PFIgG/PF--4/heparin complex activates4/heparin complex activates

via the Fc receptorvia the Fc receptor

Fc stimulation leads to the generation ofFc stimulation leads to the generation of

procoagulantprocoagulant--rich microparticlesrich microparticles

alpha granulealpha granule PFPF--4/heparin4/heparin

complexcomplex

IgGIgG

FcFc

receptorreceptor

microparticlesmicroparticles

PlateletPlatelet

Courtesy ofDr John G. Kelton, McMaster UniversityCourtesy ofDr John G. Kelton, McMaster University..Hirsh et al.Hirsh et al.Arch Intern MedArch Intern Med. 2004;164:361. 2004;164:361--369369..


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The incidence ofHIT is about 3-5% in patientsexposed 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.


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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 thrombosisthat may be arterial (Stroke, MI, PAD) or

venous in nature.


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Other manifestation include hypotension fromadrenal 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.


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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.


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Platelet transfusion should be avoided if possible as it mayworsen 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 1stmonth.


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Antiphospholipid Antibodies SyndromeAntiphospholipid 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.


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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.


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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 factorII and

factor X level of 20% to 30 %.


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Stepwise Approach For Management of

Thrombophilias

(A) When to suspect ?!


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(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 ofVTE.


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(C) Treatment


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(C) Treatment

There are no specific therapies to reverse most

hypercoagulablestates.

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


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Therapeutic Goals

Prevent thrombus propagation and/or

embolization

Restore blood flow (rapidly, when necessary)

Minimize long-term sequelae

Risk Stratification*

(f i t )


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(for persistence or recurrence)

Low Risk Thrombus post surgery, trauma, CVL

Resolves within 6 weeks

Standard Risk FVIII 500ng/mL >3 thrombophilic factors

Occlusive thrombus

Manco-Johnson, Blood 2006

*Studies in progress


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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


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LMWH inhibits factor Xa and minimally affects factorIIa; thus aPTT is not used

to measure its anticoagulant activity.


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Protocol for Heparin Administration

and Adjustment in Children


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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

Age > 1 year

28 units/ Kg hour

20 units/Kg/ hour

__ __ __

III. A PTT adjustment*

< 50

50-59

60-85

86-95

96-120

> 120

50 units/Kg

-

-

-

-

-

0

0

0

0

30

40

+10%

+10%

0

-10%

-10%

-15%

4 hours

4 hours

Next day

4 hours

4 hours

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*Heparin adjusted to maintain aPTT at 60 to 85 seconds, assuming that this reflects an antifactor Xa level of 0.35 to 0.70.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.aPTT = activated prothrombin time. This table adapted from Michelson et al. and the experience of the writing group.

and Adjustment in Children


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Warfarin Anticoagulation Protocol for

Children


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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



>3.5 Hold dosing until INR is 3.5 Hold dosing until INR is


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New Anticoagulant Drugs

1.Anti-Xa Rivaroxaban

Synthetic pentasaccharide

2. Thrombin inhibitors

Lepirudin

Dabigatran

Possible standard therapy within 2-5 years

No laboratory monitoring required

No specific antidotes to treat bleeding

Antiplatelet Drugs


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p g


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Direct Thrombin Inhibitors (DTI)


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Available Agents

Refludan (lepirudin)

Argatroban

Angiomax (bivalirudin)

Exanta (ximelagatran)**Awaiting FDA approval

Newer antiplatelet agents:


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Ticlopine, clopidogrel

- inhibit platelet aggregation via the adenosine diphosphatepathway

Ticlopidine

- Antiplatelet agent with fibrinolytic and thrombolyticactions

- 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


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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 individualizedbased on underlying co-morbidities

Patients should be followed closely for recurrentdisease and/or post-phlebitic syndrome

Summary


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All thrombosis patients should be screened for

treatable molecular thrombophilias

Some patients may benefit from additionalscreening

Asymptomatic patients and family members not at

increased risk for thrombosis should not routinelybe screened


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thrombophilia(hanan)

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