2. dr. sarma - hellp complication peb

7/29/2019 2. Dr. Sarma - Hellp Complication Peb

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CURRICULUM VITAE

Nama : dr. SarmaLumbanraja, SpOG(K)

Tpt/tgl. Lahir : Pakpahan, 30 Juli 1959

Agama : Kristen

JenisKelamin : Perempuan

Pendidikan : SpesialisObstetridanGinekologi FK USU (1998)

Jabatan : StafObstetridanGinekologi FK USU

Alamat : PabrikTenun 35A, Medan 20118

No. Telp : (061) 4523-085

No. HP : 08126536472


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HELLP SYNDROME AS

COMPLICATION OF PREECLAMPSIA

Sarma LUMBANRAJA

Department of Obstetrics and Gynecology

Faculty of Medicine, Universitas Sumatera Utara


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Introduction

Pregnancy Induced Hypertension:BP > 140/90 mmHg after 20 weeks of gestation

Preeclampsia:+ Proteinuria> 300 mg/24 h


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Introduction

HELLP Syndrome:

0.2-0.6 % in all pregnancy

Severe preeclampsia 4-12 % HELLP

Hemolysis

Elevated liver enzymes

Low platelet


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Abnormal Plasentation

Placenta-derived agents : ???

Hypoxia

Microvascular endothelial damage

Intravascular platelet activation and deposition

Stimulates secretion of Thromboxane A2 & serotonin

Vasoconstriction & more platelet deposition/agregation &

damage to the blood vessel wall


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Vasoconstriction & more platelet deposition/agregation &

damage to the blood vessel wall

Further vessel narrowingHypertension

Circulating

(serum) platelets

Actual

platelet count

RBC

damage

Hepatocellular

hypoxia

Hepatocellular&

periportal

necrosis

Microangiopathiche

molysis

Liver enzyme LDH

HemoglobinLiver rupture


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Preeclampsia is an endothelial disease

Hipertenson EclampsiaProteinuria HELLP

?


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Preeclampsia is an endothelial disease

Normal Glomerulus Glomerulusw/ Endotheliosis


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Placenta, the Origin of this disease

Vascular Defect Placental ischemia


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Production and secretion of a substance, toxic to

mother


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What is the problem?

Preeclampsia is a disease of theories


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Copyright 2005 American Heart Association

Roberts, J. M. et al. Hypertension 2005;46:1243-1249

Used with permission

Two-stage model of the pathophysiology ofpreeclampsia

Stage 2 develops in

some, but not all

women with stage 1


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DEVELOPMENT OF STAGE 1

Poor placentation


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Normal Placental Development

From 9-12 weeks gestation

the uterine spiral

arteriesare transformed

from thick-walled, muscular

vessels, to more flaccidtubes to accommodate a

10-fold increase in uterine

blood flow to support the

pregnancy.C. W. Redman et al., Science 308, 1592 -1594 (2005)

Used with permission

National Institute of Health (NIH) National High Blood Pressure Education

Program Working Group on High Blood Pressure in Pregnancy, (2000)

Uterine spiral

arteriesUterine spiral

arteries


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Normal Placental Development

Uterine spiral artery remodeling takes place by

the invasion oftrophoblastcells into the

uterine lining.

These trophoblasts enter the arterial walls and

replace parts of the vascular endothelium so

that smooth muscle is lost and the artery

dilates.


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Placental Pathophysiology in

Stage 1

Trophoblasts fail to completely remodel the

uterine spiral arteries.

Remodeling either absentor

Remodeling limited to the superficial portion of

the artery located in the decidua, rather than

extending into the inner third of the myometrium.

Redman, C.W., Sargent, I.L. (2005)


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Theoretical basis for incomplete

remodeling:

Production failure of endothelial adhesion

molecules from trophoblasts

or

Failure of/ or weak signaling of immune cells by

trophoblasts prevents deep invasion necessary for

normal artery remodeling.

Redman, C.W., Sargent, I.L .(2005)

(NIH 2000)


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C. W. Redman et al., Science 308, 1592 -1594 (2005)Used with permission

Poor placentation and preeclampsia

Uterine spiral artery

unwinds and becomes

a wider, flaccid tube to

accommodate increased

blood flow.

Uterine spiral artery

remains tightly coiled,

diminishing placental

blood flow


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THE RESULT:

Poor placentation, or a decreased capacity of

the uteroplacental circulation. This causes

placental hypoxia, resulting in oxidative stress. Pathophysiology is generally established before 20

weeks.

(NIH, 2000)


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The beginnings of the maternal

disease process:

Stage 2 begins when maternal clinical features

appear.

Cause is most likely related to the hypoxic anddysfunctional placenta releasing factors into the

maternal circulation resulting from cell death.

These factors target the maternal endothelium,

causing vascular damage.

Roberts, J.M., Gammill H.S. (2005)


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Stage 2:

Multisystemic, maternal syndrome

Perfusion isreduced to

virtually every

organ

Reduced

Placental

perfusion

Release of

Toxins-

Maternal

Endothelial

damage

Reduced uterine

blood flow



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Normal function of endothelial cells

Line all blood vessels providing vessel wall

integrity

Prevent intravascular coagulation

Regulate smooth muscle contractility

Mediate immuneand inflammatory responses

Gilbert E.S., & Harmon J.S. (2003). Hypertensive Disorders. In Manual of High Risk Pregnancy and

Delivery (p. 451). St Louis, MO: Mosby.


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Toxic factors released by the placenta are

believed to cause maternal endothelial

dysfunction by one or more of followingmechanisms:

1. The factors are directly toxic to endothelial

cells

2. The factors stimulate maternal oxidative stress

3. The factors stimulate/activate inflammatory

cytokines

Gilbert & Harmon (2003) p. 451



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With maternal endothelial damage:

Decreased production

of vasodilators

(prostacyclin and nitric

oxide)

Inactivation of

circulating nitric oxide

(vasodilator).

Poor tissue perfusion

to all maternal organs

Increases total

peripheral resistanceresulting in

elevated blood pressure

VASOSPASM

Gilbert & Harmon (2003) pp. 451-452


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Maternal vasospasm also causes:

Increases endothelial cell permeability, (leaky

capillaries) fluid shifts from intravascular to

intracellular space resulting in:

Decreased plasma volume, increased hematocrit

Generalized tissue and organ edema



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Additionally, damage to the vascular

endothelium causes:

Increased production ofthromboxanewhich

leads to clot formation through increasing

platelet adhesion.

Activation of the clotting cascade

Decreased production of platelets



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Identification of circulating factor

Increased endothelial cell permeability

Lipid peroxidation

Oxidative stress

Platelet activation

Increased circulating fibronectin, factor VII antigen,thrombomodulin

Diminished production of endothelial-derived-vasodilators such asprostacyclins and increased vascular sensitivity to angiotensin II andnorepinephrine-mediated vascular constriction

Increased placental production and maternal serum level of sFlt-1

and sEng Etc.


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Stage 1 Stage 2

Maternal

Endothelial

Damage

VASOSPASM

Reduced PlacentalPerfusion

Abnormal vascular

remodeling of spiral

arteries

Release of toxic

factors

Hypertriglyceridemia

Reduced HDL

Predominance of small, dense LDLcholesterol

Insulin resistance

Hyperinsulinemia

Hypertriglyceridemia

Inflammatory cytokines +

endothelial damage

Increasedproduction of free

radicals and lipid

peroxides

+endothelial cell

damage

Maternal

Disease

Fetal

Effects


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Role of angiogenic factors in

Preeclampsia and HELLP syndrome


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2002 Phase 2 study of the use of

bevacisumab (VEGF neutralizing antibody) in

colorectal cancer

Tumor progression is slower

Better survival

BUT

HYPERTENSION (19/68) AND PROTEINURIA (17/68) WAS

FOUND


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Hypertension

VEGF interaction with VEGF-R on endothelial

cells induces the production NO and PG


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Proteinuria

VEGF is critically involved in the maintenance

of GBM barrier

Excision of one VEGF A allele in the podocyte

of mice causes endotheliosis and proteinuria

(Eremina, 2003)


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Was the same process happened in PE??


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Relevant protein

Soluble

Small enough to cross placental barrier

Able to target endothelium


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Soluble Vascular Endothelial Growth

Factor receptor -1 (sVEGFR-1 a.k.a sFlt-1)


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Excess placental soluble fms-like tyrosine

kinase 1 (sFlt1) may contribute to endothelial

dysfunction, hypertension, and proteinuria in

preeclampsia.

Sharon E. Maynard, Jiang-Yong Min,JaimeMerchan,Kee-Hak Lim, Jianyi Li,

SusantaMondal,Towia A. Libermann,James P. Morgan,Frank W. Sellke, Isaac E. Stillman,

Franklin H. Epstein, Vikas P. Sukhatme, and S. AnanthKarumanchi

J Clin Invest 2003; 111: 649-658


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PIGF

VEGFSfLT1

PROANGIOGENIC vs ANTIANGIOGENIC

PROANGIOGENIC (Normal) ANTIANGIOGENIC (PE)


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Normal pregnancy: very few of molecules are caught by soluble receptor


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In Preeclampsia, the soluble receptor sFlt catches many VEGF and PLGF molecules


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HYPOTHESIS


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Could sFlt-1 lead to maternal

syndrome of PE?

i.e to:

Hypertension?

Proteinuria/GlomerularEndotheliosis?

In severe form (HELLP): Liver disorder?


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Histopathological analysis of renal tissue from one representative Fc-treated pregnant

rat (upper panel), one sFlt1treated pregnant rat (middle panel). H&E stain shows

capillary occlusion in the sFlt1 treated animal with enlarged glomeruli and swollen

endothelial cells compared to Fc control animal.


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IN NORMAL PREGNANCY

Increased of sFlt-1

Strevens (2003): in kidney biopsy of normal

pregnant women 1 month beforedelivery,

glomerularendotheliosis is found in 5/12

patients.


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Yoshimatsu J, Eur J

ObstGyn 2006;

128:204-8


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Preeclampsia could be the occurrence

of a PHYSIOLOGICAL process during

which the maternal endothelium isimpaired because of presence of

circulating placental factor


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sFlt-1 doesnt explain everything


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Soluble endoglin contributes to thepathogenesis of preeclampsia

ShivalingappaVenkatesha, MouradToporsian, Chun Lam, Jun-ichiHanai, Tadanori

Mammoto, Yeon M Kim, Yuval Bdolah, Kee-Hak Lim, Hai-Tao Yuan, Towia A

Libermann, Isaac E Stillman, Drucilla Roberts, Patricia A DAmore, Franklin H

Epstein, Frank W Sellke, Roberto Romero, Vikas P Sukhatme, Michelle Letarte&

S AnanthKarumanchi

Nature med Jun 2006 12(6): 642-689


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Endoglin

Accessory receptor for TGF-

TGF-


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TGF

Signaling by TGF-b family members, which includes TGF-bs, activins and BMPs, occurs via specific cell surface type I and type II receptors that are

endowed with serine/threoninekinase activity. Accessory receptors endoglin and betaglycan modulate TGF-b family signaling via type I and type IIreceptors. Soluble endoglin and betaglycan can sequester ligand and thereby inhibit receptor binding. In most cells TGF-b signals via TbRII and ALK5.

In endothelial cells (depicted here) it signals also via another type I receptor ALK1. Activins signal via ActRII and ALK4. BMPs signal via BMPRII and

ActRII and type I receptors ALK1, ALK2, ALK3 and ALK6. The type I receptors act downstream of type II receptor and determine the signaling

specificity of the receptor complex. Activated type I receptors initiate intracellular signaling by phosphorylatingspecific R-Smads. Activation of ALK1,

ALK23, ALK3 and ALK6 leads to phosphorylation of Smad1, Smad5 and Smad8, and Smad2 and Smad3 are phosphorylated by ALK4, ALK5 and ALK7.

Activated R- Smads assemble with Smad4 in heteromeric complexes that accu- mulate in the nucleus. There these complexes regulate specific gene

expression responses by binding to DNA together with other DNA binding transcription factors. Abbreviatons: ActR, activin receptor; BMP, bone

morphogenetic protein; BMPR, BMP receptor; sEnd, soluble endoglin; transforming growth factor-b; TbR, TGF-brecep- tor; TF, transcription factor

TGF


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TGF-

TGF-1 induces vasorelaxation through

activation of eNOS

TGF-1 stimulate production of PGI2


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sEng joins the sFlt-1 receptor as a preeclampsia molecule


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Infection of gestant rats with a virus encoding :

sFlt-1: preeclampsia

Soluble endoglins: HT and modest proteinuria


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Infection of gestant rats with a virus encoding :

sFlt-1: preeclampsia

Soluble endoglins: HT + modest Proteinuria

sFlt-1 + sEng: PE + Liver disorder


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Glomerular disorder

sFlt1-injected rats showed moderate to severe endotheliosis with complete occlusion of

capillary lumens. sFlt1+sEng-treated rats showed extremely swollen glomeruli and markedendotheliosis with protein resorption droplets in the podocytes.


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Liver disorder

Liver histology in the control, sEng, sFlt1 and sFlt1+sEng groups. Ischemic changes

with multifocal necrosis were noted in the sFlt1+sEng group. Control group and rats

given sEng or sFlt1 showed no changes.


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Peripheral blood smear

Peripheral blood smear (Wright stain) of control, sEng, sFlt1 and sFlt1+sEng groups. Arepresentative smear in the sFlt1+sEng group showed active schistocytes

(arrowheads) and reticulocytosis (arrows). No hemolysis was seen in the other

groups.


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Recombinant VEGF-121 was shown to

suppress the maternal syndrome of

preeclampsia in rats.

Tobacco smoke (?) was found to suppress thesecretion of sFlt-1 by syncytiotrophoblasts

The role of endoglin in HELLP syndrome has

not been confirmed

Preeclampsia remains the disease of


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Preeclampsia remains the disease of

theories

?


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Take Home Points

The maternal syndrome of PE is consecutive to

excessive concentrations of anti-angiogenic

factors

These factors are produced by an ischemicplacenta

The cause for this disease remains

unelucidated


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2. dr. sarma - hellp complication peb

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