nemoci-sympt/GYNEKOLOGIE/tehotenstvi-trombofilie

Změny hemostatického a fibrinolytického systému vyvolané normálním těhotenstvím

Prokoagulační faktory

• 20 ­ 200 % nárůst hladin:
• Fibrinogenu
• Faktoru II
• Faktoru VII
• Faktoru VIII
• Faktoru X
• Faktoru XII [2]
• Nezměněné koncentrace:
• Faktoru V
• Faktoru IX [2]

Antikoagulační faktory

• Vzestup koncentrací jen minimální:
• TFPI­ inhibitor zevní cesty tkáňového faktoru
• Alfa2-makroglobulin [2]
• Nezměněné koncentrace:
• ATIII
• Heparin II-kofaktor
• protein C
• Snížené koncentrace:
• protein S [2]

Protrombotické faktory

• 2-3 x vyšší hladiny:
• Aktivní inhibitor aktivátoru plasminogenu typ 1 (PAI 1) [2]

Trombofílie v těhotenství

• Další zvýšení prokoagulační aktivity

Epidemiologie

• EU: vrozené trombofilie cca u 15 % populace [2]

Zvýšená asociovaná rizika při trombofílii a těhotenství obecně

Potraty

• 25% početí končí potratem
• 5% žen má 2 a více potratů
• 1 - 2% žen mají 3 a více potratů
• Acquired and inherited thrombophilias are associated with an increased risk of early (recurrent) fetal loss [1]
• Separation of early (recurrent) loss into recurrent pregnancy loss in the first trimester and single loss in the second trimester častěji u trombofilních stavů [1]
• 5 - 8 x [2]

Doporučení

• Women with recurrent early pregnancy loss (3 a více)
• Screening for APLAs [1]
• Antepartum administration of prophylactic or intermediate-dose UFH or prophylactic LMWH combined with aspirin (Grade 1B) [1]

APLAs

• UFH / LMWH and low-dose aspirin
• Reducing miscarriage rates in women with APLA syndrome with prior recurrent fetal loss. [1]
• Samotný aspirin = více potratů než LMWH, lepší LMWH + aspirin [1]
• Enoxaparin 40 mg/d nebo 80 mg/d - nesignifik. rozdíl [1]

Factor V Leiden, prothrombin gene mutation or protein S deficiency and one previous pregnancy loss after 10 weeks of gestation

• 40 mg of enoxaparin daily
• Significantly higher live birth rate (86%) compared with low-dose aspirin alone (29%) (Gris et al. 2005) [1]
• Difficult to assess the implications of these results (small sample, other study limitations...) [1]
• Treatment that prevents fetal loss may not prevent other complications
• Insufficient data on the effect of antithrombotic interventions in other adverse pregnant outcomes in women with thrombophilia to provide any recommendations [1]

Preeclampsia

• 3-7% of all pregnancies
• Cca 5x častěji u trombofilních stavů [2]
• Associated with microvascular fibrin deposition
• Activation of platelets and coagulation
• Widespread endothelial dysfunction [1]
• Maternal response to abnormal placentation [1]
• Influenced by the maternal phenotype
• Increased risk:
• Essential hypertension
• Underlying angiotensin-converting enzyme insertion/deletion polymorphism [1]
• Many others...
• Diabetes mellitus
• Underlying renal disease
• BMI nad 35 kg/m2
• Věk nad 35
• Prior preeclampsia
• Thrombophilic disorder acquired / heritable [1]
• May contribute to the expression of the disease
• Association with disease severity, rather than disease occurrence [1]
• Magnify activation of coagulation in response to trophoblast dysfunction in preeclampsia [1]

Doporučení

• Women in high risk for preeclampsia:
• Low-dose aspirin throughout pregnancy (Grade 1B) [1]
• Associated with modest reductions in the relative risk of preeclampsia [1]

• Preeklampsie v OA
• UFH and LMWH should not be used as prophylaxis in subsequent pregnancies (Grade 2C). [1]
• Severe or recurrent preeclampsia:
• Screening for APLAs (Grade 2C) [1]

• UFH / LMWH for women at very high risk of preeclampsia
• Reduction in thrombosis formation
• LMWH - antiapoptotic effect on trophoblasts
• Source of the trigger for preeclampsia
• LMWH - lower incidence of preeclampsia, IUGR, resistance indexes of both uterine arteries, were also significantly lower in the treated group [1]
• Interpretace studie a implikace opět problematické [1]

Abrupce placenty

• 0.5% of all gestations
• Cca 5x častěji u trombofilních stavů [2]
• Several studies association
• Heterozygous prothrombin G20210A variant
• Heterozygous factor V Leiden mutation [1]

Trombóza placenty

• The low-pressure uteroplacental system susceptible to thrombotic complications in hypercoagulable states [1]

Zánětlivé reakce

• Trombofilní stavy may also magnify the maternal inflammatory response [1]

Presence of activated coagulation factors

• Cell-type specific changes in trophoblast gene expression [1]

Structural abnormalities placentae of tissue-factor null mice embryos

• Thinning of the layer lining the maternal lacunae
• Reduced number of trophoblast cellular contacts [1]

IUGR

• Cca 5x častější u trombofilních stavů [2]
• Příčinou trombózy v uteroplacentárním a intervilózním prostoru [2]
• Intrauterinní růstové retardaci ev. až úmrtí plodu [2]
• Anticardiolipin antibody positivity controversial [1]

Doporučení

• Screening for APLAs (Grade 2C) [1]

Trombózy - DVT - Trombembolie - VTE

• Přes 50% TE v graviditě [2]
• Incidence of VTE ranges from 0.6 - 1.3 episodes per 1,000 deliveries [1]
• 5-10 x increase in risk compared to those reported for nonpregnant women of comparable age [1]
• 2/3 of DVT occur antepartum
• Relatively equally throughout all three trimesters [1]

Doporučení for pregnant patients with thrombophilia but no prior VTE

• Individualized risk assessment (Grade 1C) [1]
• Remains controversial - limited knowledge of various thrombophilias
• Based only on case-control studies [1]
• Risk of venous thromboembolism appears to begin early in pregnancy
• When antepartum prophylaxis is utilized, it should be commenced in the first trimester [1]

Antithrombin deficiency

• Antepartum and postpartum prophylaxis (Grade 2C) [1]

All other pregnant women with thrombophilia

• Antepartum clinical surveillance or prophylactic LMWH or UFH [1]
• Postpartum anticoagulants (Grade 2C) [1]

Plicní embolie - PE

• Major cause of maternal mortality in the Western world
• Important cause of maternal morbidity
• 43 - 60% of pregnancy-related episodes of PE occur in the 4-6 weeks after delivery [1]
• Daily risk of PE, as well as DVT, is considerably higher following delivery than antepartum [1]

Císařský řez a riziko trombembolismu

DVT

• Incidence of DVT after:
• Cesarean section was reported to be 0.424/1,000
• Following vaginal delivery 0.173/1,000 [1]
• United States
• Frequency of VTE was reported as 0.521/1,000 cesarean sections [1]

• Risk similar to that seen in low-risk surgical patients for whom no routine thromboprophylaxis other than mobilization is recommended
• Frequency of proximal DVT: 0,4% [1]
• Frequency of symptomatic PE: 0,2% [1]

• Routine thromboprophylaxis is not justified and cannot be recommended on the basis of cesarean section alone [1]

PE

• Incidence of PE after cesarean delivery 0.4/1,000 [1]
• Swedish study
• (RR) of PE associated with cesarean section compared to that with vaginal delivery was 6.7 (95% CI, 4.5–10.0) [1]

Emergently cesarean section

• Risk of VTE is approximately double that of an elective procedure [1]

• Age nad 35 years
• Emergency cesarean delivery
• Incidence of DVT of approximately 1.2/1,000 deliveries [1]
• Incidence of PE of 1/1,000 deliveries [1]

• Norwegian cohort study
• 5 / 1,067 women undergoing cesarean section had symptomatic confirmed VTE (0.47%) [1]
• Had risk factors:
• Twin pregnancy
• obesity
• Severe preeclampsia
• Re-operation
• Immobilization
• Placenta previa [1]

Pelvic vein thrombosis po CS

• A recent clinical trial of 15 women considered to be at moderate or high risk of DVT after cesarean section
• Pelvic MRV reported that 46% (95% CI, 21–73%) had evidence of pelvic vein thrombosis !!! [1]
• None had a positive ultrasound assessment of the legs !!! [1]
• None of the affected women were symptomatic [1]
• Clinical significance of these radiologic findings is not clear. [1]
• Natural history of these types of thrombi is unknown [1]
• Že by konečně pádné vysvětlení pro vznik hemeroidů během těhotenství a jejich trvání po porodu ???
• Jak je to pak s tvrzením, že D-dimery mohou být v těhotenství falešně pozitivní ??? Co když jen prostě chybí diagnostika...

Císařský řez + další rizikové faktory DVT

• Quantification of risk when multiple factors are combined is not clearly established
• Place the patient at moderate to high risk of VTE:
• Increased age
• Prior VTE
• obesity
• Thrombophilia
• Lower limb paralysis
• Immobilization
• Extended surgery such as hysterectomy
• Preeclampsia
• Comorbid medical conditions such as heart failure

Thromboprophylaxis Following Cesarean Section

• Individ. thrombosis risk assessment in all women undergoing cesarean section (Grade 2C). [1]
• Guidelines in the UK
• Use of prophylaxis following cesarean section in women with additional risk factors
• Use of thromboprophylaxis with LMWH following cesarean section is now widespread in Europe [1]
• Based on expert opinion and consensus rather than good quality clinical trials [1]

Recommendations

• Increased risk of VTE after CS
• While in hospital following delivery (Grade 2C) prophylactic LMWH or UFH
• Or mechanical prophylaxis
• Graduated compression stockings
• Intermittent pneumatic compression [1]
• Multiple RF for TE and CS
• Pharmacologic prophylaxis combined with the use of graduated compression stockings and/or intermittent pneumatic compression (Grade 2C) [1]
• Selected high-risk patients (významný RF trvá i po porodu)
• Extended prophylaxis (up to 4 - 6 weeks after delivery) following discharge from hospital (Grade 2C) [1]

Literatura:

[1] American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)++ Shannon M. Bates et al., 2009 by the American College of Chest Physicians chestjournal.chestpubs.org/content/133/6_suppl/844S.full.html
[2] Gaillyová Renata MUDr., Genetické příčiny poruch reprodukce Vyšetření párů s opakovanými fetálními ztrátami, Disertační práce, Lékařská fakulta Masarykovy university v Brně, Ústav preventivního lékařství, Oddělení lékařské genetiky Fakultní nemocnice Brno, 2006