Hemostatic Factors In Pregnancy

Normal pregnancy is associated with changes in the hemostasis mechanisms that tend to create a prothrombotic milieu. Thromboembolic disease is a leading cause of maternal morbidity and mortality during pregnancy and the puerperium. There is an increase in several of the coagulation factors that have been shown to be risk factors for thrombosis.

GenPath Pregnancy Thrombophilia Profile:

Anti-beta-2 glycoprotein (IgG, IgA, IgM) Anti-cardiolipin antibodies (IgG, IgA, IgM) P.T.T. (LA sensitive)
CBC with differential DRVVT complete Factor V mutation (Leiden)
Hexagonal phase (lupus anticoagulant) Homocysteine Protein S activity
Protein S antigen, total Protein S antigen, free Prothrombin gene mutation (G20210A)
Prothrombin time (PT) Protein Z antigen Partial Thromboplastin Time (PTT)

The natural anticoagulant system is compromised by lower levels of protein S and increased resistance to activated protein C (APC). The fibrinolytic process is decreased as manifest by increased levels of plasminogen activator inhibitor –1&2 (PAI-1 & PAI-2) and increased levels of thrombin activatable fibrinolysis inhibitor (TAFI). The markers of activated coagulation, such as prothrombin fragment 1.2 (PF1.2), thrombin antithrombin complex (TAT) and D.dimer (DD) are increased with the progression of pregnancy to levels as seen in those patients with active thrombosis. The risk for deep vein thrombosis (DVT) in pregnancy is 0.05-1.8% and there is a recurrence rate of 1 per 71 women with a previous history of DVT or venous thromboembolism (VTE). Women on heparin therapy during pregnancy often require upward adjustment in the dose to maintain the therapeutic level.

Table 1 Changes in hemostatic factors in pregnancy compared to non-pregnant state
Modified from M. Franchini, Thromb Haemost 2006;95:401-13
Parameters Changes*
Platelet count
Fibrinogen, vWF
Factors VII, VIII, IX, X, XII
Factor XI = / ↓
Factor V, XIII ↑ / ↓
Antithrombin, protein C =
Protein S (see table 2 below)
TPA
PAI-1, TAFI
PAI+2, TAT, d.Dimer, FPA
Resistance to activated protein C
Protein Z**

* ↑ Represents increase, ↓ represents decrease, = represents no change
** D-H Ku, YS Arkel, et al. J Thromb Haemost 2005; 3:497

Table 2 Free protein S levels 1st to 3rd trimenster of normal gestation (D-H Ku, YS Arkel)
1st 2nd 3rd Non-Pregnant
N 82 64 78 50
Mean % 38.8 35.9 27.9 88
STD % 10.5 8.3 7.0 19

With these findings and described issues, it is not at all surprising that thrombosis is one of the major causes for maternal morbidity and mortality in pregnancy. Thrombophilia (TP) is a term used to denote the increased tendency to develop pathological clotting or thrombotic disorders. There are inherited and acquired conditions that have been associated with thrombosis. The acquired issues, in addition to pregnancy, might be immune related as seen with the antiphospholipid antibodies (APLA), or other conditions such as malignancy, use of oral contraceptive hormones, surgery, travel, trauma, immobilization and serious medical illness. Women with inherited and acquired TP abnormalities have a significantly higher risk for adverse pregnancy outcomes (APO), such as fetal demise (FD), pregnancy loss (PL), intra-uterine growth restriction (IUGR), preeclampsia (PEE) and/or thrombosis during the pregnancy or in the puerperium. There have been many studies that have implicated TP in relation to adverse pregnancy outcomes and thrombosis during pregnancy and the postpartum.

Thrombophilia and Pregnancy Outcome Studies

There have been many studies that have addressed the relationship of inherited and acquired TP with adverse pregnancy outcomes (APO) and thrombosis during gestation and postpartum. FV Leiden and PGMG20210A as risk factors for miscarriage during a 1st intended pregnancy. The two mutations increased risk for PL between the 10th to 19th weeks of gestation and FVLeiden increased risk from the 20th through the 39th week of gestation. It is recommended that patients with prior single PL should be tested for these mutations and that low molecular weight heparin be used to increase the chance for successful pregnancy.

Protein Z (PZ) is a co-factor for a protease that inhibits factor Xa. Deficiency of PZ has been reported in association with stroke, venous thrombosis and other thrombotic disorders. In addition PZ has been associated with APO by several authors. The mean 1st trimester levels were lower in the APO group when compared to matched normal pregnancies. Also noted was a trend to lower levels in women with TP and APO compared to those with normal pregnancies. In addition we reported a lower level of protein S (PS free antigen) in the 2nd and 3rd trimesters in women with APO compared to those with normal pregnancies. The conclusions included that PZ and PS are additive risk factors for APO.