Babies “R” Us

October 11, 2007

Dr. Alexander DuncanLucienne Ide

Ken SuthasinekulScott Robinson

Little Tots need no Clots

“Pregnancy is the only controlled hypercoaguable state we know”

I know it’s your first time, but I promise it won’t hurt!

We came all this way for nothing ?

Anybody got a flashlight?

What do you mean it’s all about fibrinolysis !

Pregnancy is a risky business !

1 woman in 16 in Sub-Saharan Africa faces the risk of maternal death in the course of her lifetime, compared with 1 in 2,800 in developed regions.

Peripartum hemorrhage

Uterine blood flow increases 50-fold

CO doubles & 40% rise in blood volume

At term, uterine flow rate = 750 mL/min

Gabbe: Obstetrics - Normal and Problem Pregnancies, 4th ed.

What’s wrong with being sticky?

Good/Normal

Bad/Abnormal

“Ugly”

Virchow’s Triad

1. Alterations in blood flow (stasis)

1. Injury to the vascular endothelium

2. Alterations in the blood components (hypercoaguability)

Factor V Leiden

Prothrombin

Normal Coagulation Changes in Pregnancy

Changes start at end of first trimester.

Increases in Fibrinogen, Factors VII &VIII

Increases in PAI-1 & PAI-2

Increased Thrombin generation (MOCHA)

Increased von Willebrands factor

Decreased fibrinolysis

Increased platelet activation

High Lipoprotein (a)

Duncan’s Bad Signs

Any increase in activity in first trimester.

F VII increases faster than F VIII.

Supra normal values in activities.

Rapid increases in MOCHAs

Rapid increases in PAI-1

Early evidence of Pre- eclampsia.

Early IUGR.

Multiple recurrent losses.

MOCHA

What we know about thrombin generation can help us make diagnostic and therapeutic decisions.

Thrombin is locally controlled by various functions including anticoagulants such as antithrombin and the Protein C pathway

Functioning endothelial cells provide the bulk of thrombin downregulation to control in vivo clot extension.

Markers Of Coagulation andHemostasis Activation.

An assessment of thrombin generation and control.

Prothrombin Fragment 1.2

Thrombin: Antithrombin Complexes

Quantitative D-Dimer

Quantitative Fibrin Monomer

Underlying Issues

What about the impact (or not) of underlying thrombophilia ?

Should F V Leiden & PT gene patients be prophylaxed with LMWH if they have had no problems ( NO !!)

What about 1st degree relatives with losses ? ( harder question)

More Issues

What about the patient with 2 losses and no identifiable thrombophilia, desperate to stay pregnant !

What about high Lp(a) ?

What about MTHFR mutations, homozygous/double heterozygotes

Is it true that 70% of first trimester losses are genetic?

Even More Issues

What to do when science and emotion conflict ?

Only 70% of patients with VTE, currently have a diagnostic etiology determined.

What about new analytes !! ( EPCR, TFPI, PZI, TM)

What about safety of therapy!

Gestational Vascular Complications (GVC)

Severe pregnancy complications associated with deficient uteroplacental circulation possibly due to microthrombi of the placental vasculature

• Placental abruption

• Pre-eclampsia

• Intrauterine growth retardation (IUGR)

• Intrauterine fetal death (IUFD)

Serious complications occur in 1-5% of pregnancies

Who is at risk?

Women with primary or secondary thrombophilia.

Five fold increased risk of above complications!

SEMINARS IN REPRODUCTIVE MEDICINE/VOLUME 24, NUMBER 1 2006

RPL and Thrombophilia

Pre-eclampsia10-20% of maternal deathsTreatment is delivery of the fetus and placenta

Placental abruption20% maternal deathsCan lead to hemorrhagic shock & fulminant DICTreatment is delivery of the fetus and placenta

Intrauterine growth retardation (IUGR)Below 10th percentileNutrient and oxygen supply compromised (4x decrease in flow)Treatment is frequently delivery of the fetus

Intrauterine fetal death (IUFD) (>500g, ~20wks)1/4th of cases unexplainedInfections, chromosomal abnormalities, fetal hydrops

Consequences of GVC

IUFD

Also associated with:

• Antithrombin deficiency

• Protein S and C deficiencies

• Other inherited thrombophilias

• Antiphospholipid Syndrome

How to Treat PRL / GVC ?Aspirin

Inhibits cyclooxygenase activityDecrease in TXA2 inhibits platelet aggregation

Low molecular weight heparin (LMWH)Causes conformational change in antithrombin.Increases enzymatic inactivation by 1000-fold (factor Xa>IIa)Stimulates expression of TFPI by endothelial cells

40 mg LMWH v 100mg ASA daily:86% LMWH treated pregnancies vs 29% ASA only treated pregnancies resulted in normal births

LMWH vs UFH

UFH has NO place in prophylaxis anymore.!!!!!

Poor bio-availability, HIT risk, osteoporosis, variable blood levels.

Is good for IV use if monitored properly. Can NOT use the APTT in a term patient to monitor UFH ( high factors, sensitivity)

Shorter half life in pregnancy.

LMWeight Heparins

None approved for use in pregnancy

All have been used with minimal issues.

Minimal to no HIT risk

Almost no osteoporosis ( < 3% average)

More LMWH

FDA state no monitoring of these drugs is needed.

They do need monitoring !!

Many woman are undertreated.

In vivo drug half lives vary by molecular weight. (Fragmin > Lovenox)

Little published on Arixtra, but works well in my experience.

Controversies !!

Some people would argue there is almost NO evidence based medicine to support the use of LMWH in pregnancy.

LOVENOX trial is only major peer reviewed publication

Even less to support it’s use in fertility patients.

More Controversies.

What is the rationale in infertility patients?

Are they hypercoagulable ?

Do they really have hypofibrinolysis ?

What has Lp(a) to do with anything (a lot)

Is it even ethical to treat patients with LMWH just because anecdotal evidence says it works.