• Nathan Riley, MD

Obgyno Wino Podcast Episode 28 - Inherited Thrombophilias in Pregnancy

"A man who has not passed through the inferno of his passions has never overcome them. As far as we can discern, the sole purpose of human existence is to kindle a light in the darkness of mere being. Everything that irritates us about others can lead us to an understanding of ourselves." - Carl Jung

2015 Tempranillo from Las Almenas

PB#197 - Published July 2018

Five Pearls

  1. Normal pregnancy physiology: ↑ fibrinogen, ↑ clotting factors, ↓ protein S, and ↑ venous stasis

  2. VTE risk is relatively higher in pregnancy than outside of pregnancy

  3. Inherited thrombophilias, especially homozygous carries, are at an increased risk of VTE in and out of pregnancy (still low absolute risk). This risk is augmented in patients with history of prior VTE personally and those who have an affected 1st degree relative

  4. There's insufficient evidence to suggest that stillbirth, preeclampsia, placental abruption, or fetal growth restriction are more likely due to inherited thrombophilias. As such, empiric therapy to prevent these conditions is not recommended.

  5. For high risk patients, heparin products can be started in pregnancy or postpartum to reduce VTE risk.

Recall: how does blood clot?

- Interruptions to endothelium activates platelets --> platelet plug --> reinforced through fibrin (Ia)

- fibrin (Ia) is the activated form of fibrinogen (I), a reaction catalyzed by thrombin (IIa)

- thrombin is activated by means of the extrinsic pathway, which starts with the release of tissue factor (III) from the site of endothelial injury

- thrombin activates factors V, VII, VIII, IX, and XIII, meaning the intrinsic pathway is triggered secondarily as means of quickly mass producing a crap ton of fibrin

- heparin: activates antithrombin, which deactivates factor X and thrombin

- coumadin: inactivates factors II, VII, IX, and X, by interfering with Vitamin K metabolism

- the amplification process consumes fibrinogen

- Proteins S and C, antithrombin, and tissue factor pathway inhibitor (TFPI) prevent inappropriate activation of this system

- normal pregnancy physiology: ↑ fibrinogen, ↑ clotting factors, ↓ protein S, and ↑ venous stasis

- these factors prevent subchorionic and postpartum hemorrhages

Recall: Virchow's triad, a) hypercoagulability, b) venous stasis, and c) endothelial injury

VTE risk in pregnancy and primer on inherited thrombophilias

- 11-132/ 100,000 is annual incidence in general population

- pregnant women at 4-5x increased risk of VTE

- recurrence rate 11% (3-4 x increased)

Factor V leiden: mutation in gene that codes for clotting Factor V. Deficiency in Factor V leads to impaired proteolysis by activated Protein C. Prothrombin G20210A mutation is a point mutation. Heterozygous prothrombin mutations + Factor V leiden mutations = 4-5% VTE risk, even without personal or family history. Both are most commonly seen in Caucasians. Protein C deficiency has been linked to >150 single mutations; as such, there's a highly variable phenotype. Protein S deficiency, likewise, is highly variable and not much is known about prevalence and severity. Due to normal fluctuations binding proteins in pregnancy, screening for either needs to take place outside of pregnancy. Antithrombin deficiency has been linked to >250 mutations, also highly variable phenotype.

No evidence to support screening for methylene tetrahydrofolate reductase deficiency (MTHFR). This deficiency leads to elevated serum homocysteine, though this elevation hasn't been found to significantly elevate VTE risk.

Dangers of inherited thrombophilias to mom and baby

- "a definitive causal link cannot be made between inherited thrombophilias and adverse pregnancy outcomes" --> including fetal loss, preeclampsia, fetal growth restriction, or placental abruption

- available evidence is derived from small case control and cohort studies; larger prospective cohort studies have no found strong evidence to support causality and therefore universal screening for thrombophilias is not recommended

- furthermore, anticoagulation in patients diagnoses with inherited thrombophilias should not be initiated for the purpose of preventing poor pregnancy outcomes

Who should I screen anybody? Yes, two populations:

a) personal history of VTE

b) 1st degree relative diagnosed with high-risk inherited thrombophilia

- here's how it's done:

- as mentioned before, Protein S and C deficiencies are generally better screened for outside of pregnancy; levels are artificially decreased in pregnancy due to increased protein binding

- note that screening for hyperhomocysteinemia or MTHFR mutation are not all...ever...for the purpose of preventing VTE (if treatment isn't helpful, why screen?)

In which patients is anticoagulation recommended?

- full clinical picture must be considered: severity of thrombophilia, history of personal VTE or VTE in a 1st degree relative, and postpartum considerations like immobility, c-section, and other VTE risks factors like postpartum hemorrhage and obesity

- risks and benefits should always be provided in counseling patients on the need for thromboprophylaxis

- patients deemed to require thromboprophylaxis should typically be treated for at least 6 weeks postpartum

- some of the highest risk patients may use thromboprophylaxis even outside of pregnancy; in pregnancy, they should be upgraded to weight-adjusted dosing; postpartum, they should be transitioned back to their pre-pregnancy regimen

A few points on safety of these medications in pregnancy

LMWH and unfractionated heparin

- don't cross placenta, reasonably safe in pregnancy

- LMWH has a longer half-life, making it a better agent earlier pregnancy when delivery is remote

- Unfractionated heparin has a shorter half-life and can be reversed with protamine sulfate, so it's best as delivery approaches

- For women requiring weight-based dosing ("therapeutic"), dosing can be initially started based on weight, then adjusted with goal of achieving a serum anti-Xa level of 0.6-1.0 uhits/mL drawn four hours after injection

- If using unfractionated heparin, you could consider mid-interval aPTT to ensure therapeutic serum levels

- LMWH should be held 24 hrs prior to IOL to facilitate a safe epidural/spinal

- wait 12 hrs for unfractionated heparin

- patients should withhold injections at onset of labor

- postpartum: either medication shouldn't be restarted earlier than 4-6 hrs after a vaginal delivery or 6-12 hrs after c-section

- neither med crosses into breastmilk

Vitamin K antagonists like Coumadin

- cross placenta, potentially teratogenic (pregnancy category D), avoid in pregnancy except maybe in the presence of mechanical heart valves

- totally safe postpartum for mom and baby (doesn't cross into breastmilk)

- should be started concurrently with heparin products postpartum to bridge

- start at 5 mg daily, then up-titrating no more frequently than every 2 days with goal INR of 2-3 achieved for 2 consecutive days

What contraception do you recommend for these women given their increased VTE risk?

- we have little data for relative VTE risk in inherited thrombophilia homozygotes (would need a GIANT study population due to its low prevalence) with the use of estrogen-containing contraception

- the risk in heterozygotes is increased above baseline, albeit modestly

- I would recommend progestin-only options because there are so many safe options (the benefit of training patients in fertility awareness methods from an early age is also sadly overlooked in OBGYN practice)

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