Page 2341 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 140 Hypercoagulable States 2083

Hypercoagulability of the blood occurs in pregnancy and reflects the risk of venous thrombosis increases steeply in those over the age
a combination of venous stasis and changes in the hemostatic of 40 years. The risk for venous thromboembolism is highest during
system. The enlarging uterus reduces venous blood flow from the the first 3 months of oral contraceptive use and persists only for the
lower extremities. This is not the only mechanism responsible for duration of use.
venous stasis because blood flow from the lower extremities begins to Case-control studies suggest that the risk for venous thromboem-
decrease by the end of the first trimester, likely reflecting hormonally bolism is 20- to 30-fold higher in women with inherited thrombo-
induced venous dilatation. Systemic factors also contribute to hyper- philia who use oral contraceptives than the risk for non-users with
coagulability. Thus the levels of circulating procoagulant proteins thrombophilia or users without these defects. Despite the increased
increase in the third trimester of pregnancy. These include factor VIII, risk, however, routine screening for thrombophilia is not indicated
fibrinogen, and von Willebrand factor, among others. Coincidentally, in women considering the use of oral contraceptives. Based on the
suppression of natural anticoagulant pathways and decreased fibrino- estimated incidence and case fatality rate of thrombotic events, it is
lytic activity occur. Thus there is an acquired resistance to activated estimated that 400,000 women would need to be screened to detect
protein C that is related, at least in part, to reduced levels of free 20,000 carriers of factor V Leiden . Oral contraceptives would need to
protein S. The net effect of these changes is enhanced thrombin be withheld in all of these women to prevent a single death. For less
generation, in addition to release of tissue factor from the uteropla- prevalent thrombophilic defects, even larger numbers of women
cental circulation, as evidenced by elevated levels of prothrombin would need to be screened. Based on these considerations, routine
fragments and thrombin/antithrombin complexes. Platelet activation screening cannot be recommended.
and increased platelet turnover occur, and mild thrombocytopenia, Oral contraceptive pills may cause prothrombotic side effects by
likely secondary to consumption, occurs in 8.3% of women at term. inducing modest increases in levels of procoagulant factors (such as
The altered levels of hemostatic proteins normalize 4 to 6 weeks after factors VII, VIII, X, prothrombin, and fibrinogen) and decreases in
delivery. the levels of anticoagulant proteins (such as antithrombin and protein
About half of the episodes of venous thromboembolism in preg- S). Acquired APC resistance is an almost universal finding in women
nancy occur in women with thrombophilia. The risk for venous taking oral contraceptives; the clinical significance of this phenomenon
thromboembolism in women with thrombophilic defects depends on is uncertain.
the type of abnormality and the presence of other risk factors. The There is good evidence that oral hormonal replacement therapy
risk appears to be highest in women with a positive family history of with conjugated equine estrogen (with or without a progestogen)
venous thromboembolism who are homozygous for the factor V Leiden increases the risk for myocardial infarction, ischemic stroke, and
or FIIG 20210A mutation. There is also an increased risk in women venous thrombosis. Carriers of the factor V Leiden mutation receiving
with antithrombin, protein C, or protein S deficiency and a positive hormone replacement therapy have a significantly increased risk for
family history and a lower risk in those who are heterozygous for the venous thromboembolism. Data from the Heart and Estrogen
factor V Leiden or FIIG 20210A mutation. The risk of venous throm- Replacement Study (HERS) and the Estrogen Replacement and
boembolism during pregnancy is similar in all three trimesters and Atherosclerosis Trial indicate that heterozygous carriers of the factor
begins in early pregnancy. In general, the daily risk is higher in the V Leiden mutation who were taking hormone replacement therapy had
postpartum period than it is during pregnancy. Therefore, if throm- a 14-fold higher risk for venous thromboembolism compared with
boprophylaxis is given during pregnancy, it must be administered non-carriers receiving placebo. Based on this information, the use of
throughout the pregnancy and continued for at least 6 weeks oral hormone replacement preparations has markedly decreased. Use
postpartum. of transdermal hormone replacement therapy does not appear to
increase the risk of venous thrombosis. 25
Selective estrogen receptor modulators (SERMs) are estrogen-like
Assisted Conception and Ovarian compounds. The prototypical SERM is tamoxifen, which serves as
Hyperstimulation Syndrome an estrogen antagonist in the breast, but has an estrogen agonist effect
in other tissues, such as bone and uterus. Like estrogens, tamoxifen
The overall risk for venous thrombosis in women undergoing ovarian increases the risk for venous thromboembolism three- to four-fold.
hyperstimulation is small (estimated as 0.1% per treatment cycle). The risk is higher in postmenopausal women, particularly when they
Often, thrombosis affects veins of the upper extremities or the jugular are receiving systemic combination chemotherapy.
veins; the explanation for this phenomenon remains unclear. Throm- Aromatase inhibitors are replacing tamoxifen for treatment of
bophilia testing is not routinely recommended in women undergoing estrogen receptor–positive breast cancer. These agents are associated
ovarian stimulation as its predictive value is low. with a lower risk for venous thromboembolism than is tamoxifen.
Raloxifene, a SERM used to prevent osteoporosis, increases the risk
for venous thromboembolism threefold compared with placebo.
Hormonal Therapy Therefore this agent is contraindicated for prevention of osteoporosis
in women with a prior history of venous thromboembolism.
Oral contraceptives, estrogen replacement therapy, and SERM are all
associated with an increased risk for thrombosis. The relatively high
risk for venous thromboembolism associated with early oral contra- Prior History of Venous Thromboembolism
ceptives prompted development of low-dose formulations containing
reduced doses of estrogen and progestin. Currently available low- A history of previous venous thromboembolism places patients at risk
estrogen combination oral contraceptives contain 20 to 50 µg of for recurrence. Those with unprovoked venous thromboembolism
ethinylestradiol and one of several different progestogens. Even these have a particularly high risk for recurrence when anticoagulant treat-
low-dose combination contraceptives are associated with a three- to ment is stopped. 26–28 Their risk for recurrence is about 10% at 1 year
four-fold increased risk for venous thromboembolism compared with and 30% at 5 years. This risk occurs regardless of whether or not
the risk in non-users. In absolute terms, this translates to an incidence there is an underlying thrombophilic defect, such as factor V Leiden or
of 3 to 4 per 10,000. In contrast, progesterone only methods of the FIIG 20210A mutation.
contraception, including pills, cutaneous implants and progesterone- The risk for recurrent venous thromboembolism is lower in
releasing intrauterine devices, are associated with little or no risk of patients whose incident event occurred in association with a well-
thrombosis. 24 recognized and transient risk factor, such as major surgery or pro-
Although smoking increases the risk for myocardial infarction and longed immobilization. These patients have a risk for recurrence of
stroke in women taking oral contraceptives, it is unclear whether about 4% at 1 year and 10% at 5 years. Patients at highest risk for
smoking affects the risk for venous thromboembolism. In contrast, recurrence are those homozygous for factor V Leiden or the FII G20210A
obesity increases the risk for both arterial and venous thrombosis and mutation and those with antiphospholipid syndrome, advanced