Hemostasis and Thrombosis in Obstetrics and Gynecology

This issue of Seminars in Thrombosis and Hemostasis encompasses a variety of topics that relate to hemostasis and thrombosis in obstetrics and gynecology.

In the first article, Hirota and Nakabayashi describe the risk of thromboembolic complications during pregnancy, postpartum, and following cesarean section. Thromboprophylaxis with low molecular weight heparins is reviewed in these cases. The authors then report on studies they performed to investigate the usefulness of molecular markers of clotting (thrombin-antithrombin [TAT] complexes) and of fibrinolysis (plasmin-inhibitor complexes [PIC], D-dimer) in patients subjected to cesarean section and prophylactically treated with dalteparin. On the basis of these studies, the authors suggest that D-dimer determinations might be helpful in identifying patients at risk for thromboembolism under these circumstances.

In the next contribution, Morikawa and coworkers describe a patient with a positive personal and family history of thromboembolism who was found to have a deficiency of both protein C and protein S. With each of her previous five pregnancies, the patient experienced a thrombotic event in the lower limbs. During her sixth pregnancy, she again had a deep vein thrombosis and developed a second one in her other leg while being treated with prophylactic doses of danaparoid and low-dose aspirin. This case illustrates that dual congenital deficiencies of protein C and protein S place patients at a very high risk for thrombosis.

Kobashi and coworkers examined the role of mutations in the methylenetetrahydrofolate reductase (MTHFR) gene and the factor V gene in recurrent abortions in Japanese patients. It is well established that these two mutations predispose to thrombosis and other obstetrical complications. The authors identified 38 women with unexplained recurrent abortions. None of the patients had the factor V gene mutation (factor V Leiden), but a trend became apparent that the frequency of the T677 allele and the TT genotype correlated with the number of recurrent abortions. However, these changes did not reach statistical significance. The authors conclude that the factor V gene mutation does not play a role in Japanese women, but that MTHFR mutations require a larger sample size to allow a firm conclusion.

Adachi and colleagues report on the incidence of thromboembolism in Japanese women taking oral contraceptives or hormone replacement therapy. In Japan, hormonal therapy is rather uncommon and oral contraceptives were only introduced to the Japanese market in 1999. The authors used two questionnaires to address this issue. The first one was sent to 1083 institutions with a 71% return rate. This one identified the overall incidence of thromboembolic complications. The second, follow-up questionnaire addressed the issue of the types of thromboses and the types of hormonal therapy used. Although the overall incidence of thromboembolism is considerably lower than what has been reported from Western countries, there were arterial and venous events recorded. In many patients additional risk factors were identified, such as obesity, smoking, age, and lifestyle, which appeared to have influenced the overall occurrence of thromboembolism.

Suzuki and coworkers investigated certain hemorheological and hematological parameters in adult and climacteric women of various age ranges. Blood flow measurements decreased significantly with age, and flow time values of the Thrombostat 4000 were significantly prolonged with age. The authors suggest that decreased blood flow in the elderly women might contribute to the well-known increased incidence of venous thromboembolism.

Kanai and associates describe a patient with blue rubber bleb nevus syndrome (BRBNS) who encountered severe gastrointestinal bleeding during pregnancy. BRBNS is a rare disorder, characterized by hemangiomas at multiple sites throughout the body. Only two other patients with BRBNS and pregnancy have so far been described. Both patients did not experience bleedings. The authors detail diagnostic considerations and management options.

In the next article, Morikawa et al studied antithrombin (AT) levels, platelet counts, and certain chemistry parameters in women with twin and triplicate pregnancies. This investigation was based on the suspicion that women with triplicate pregnancies are more likely to develop pregnancy-induced AT deficiency, gestational thrombocytopenia, and thus also the hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome. Women with triplicate pregnancies were indeed more prone to develop gestational thrombocytopenia and AT deficiency than women with twin pregnancies. Several patients developed abnormal chemistry profiles and signs of an increased activation of the coagulation system, especially when thrombocytopenia became apparent. The authors conclude that women with triplicate pregnancies are at greater risk of developing the HELLP syndrome and acute fatty liver of pregnancy. Women with multifetal pregnancies should be tested routinely and monitored carefully.

In the next article, Kakogawa and coworkers describe preliminary results of measuring oxygenation of the placenta by near-infrared spectroscopy (NIRS). Oxygenation of the placenta has not been measured to date. NIRS has been used for oxygen measurements in several intact organs. By modifying the probe, the authors were able to assess oxygenation in at least parts of the placenta. This work could lead to important technological advances.

Kobashi and coworkers report the results of a study that used an egogram, a psychological analysis tool, in patients with hypertension in pregnancy (HP). Obesity and carriership of the T677 allele of the angiotensinogen gene were also included in the study. The results revealed that in addition to obesity and carriership of the T677 allele, also women of the free child and adapted child types, as measured by the egogram, were at risk for HP. This is the first study that establishes this relationship.

In the next contribution, Murakami and coworkers present results of an animal study in which mice developed preeclampsia-like symptoms when injected with vascular endothelial growth factor (VEGF). This has long been suspected in humans, but was never ascertained experimentally. Changes in systolic blood pressures, AT and TAT levels, platelet counts, and fibrin deposits were identified in the placentas. In addition to the VEGF group of mice, other mice were injected with monoclonal antihuman neutralizing VEGF antibodies. VEGF produced hypertension and hypercoagulability with fibrin deposits in the placentas, and thus appears to be important in the pathogenesis of preeclampsia. Anti-VEGF antibodies protected from these changes.

Omatsu and associates report on the induction of preeclampsia in pregnant mice by the injection of phosphatidylserine/phosphatidylcholine microvesicles. These procoagulant particles activate the hemostasis system. The authors found that not only were fetal and placental weights lower in the injected group than in control animals, but that antithrombin levels and platelet counts decreased, whereas TAT levels increased. Histologically, the placentas contained large quantities of fibrin. Systolic blood pressures were also elevated in the treated mice. The data indicate that a state of hypercoagulability can produce preeclampsia-like changes in a mouse model.

Adachi and colleagues describe a patient with placenta previa totalis who developed pulmonary emboli intraoperatively (cesarean section). Anticoagulant therapy (heparin) resulted in considerable bleeding that necessitated discontinuation of heparin. This was followed by additional pulmonary emboli so that anticoagulation had to be resumed. Fortunately, the patient survived these complications. The authors stress the need to be vigilant in detecting pulmonary emboli during cesarean sections by monitoring these patients carefully.

Matsuda and coworkers report the results of a case-control study that evaluated fetal/neonatal outcome in patients with abruptio placentae during preterm gestation, using ultrasonography and fetal heart rate monitoring. Sixteen percent of their 50 patients experienced stillbirth and 26% experienced adverse outcomes. An obstetrical disseminated intravascular coagulation score was higher in the stillbirth group than in the adverse outcome group or in a group of patients with a satisfactory outcome. There were no ultrasonographic findings or changes in fetal heart rate that would have predicted adverse outcomes.

Yamada and colleagues review the influence of genetic factors on reproduction. A number of genetic abnormalities have been identified that are involved in the pathogenesis of fetal growth retardation; others are involved in the pathogenesis of sporadic and recurrent abortions. These defects may act by themselves or in combination with other environmental factors. Factor V Leiden, for example, is involved in fetal growth retardation, but also improves implantation rate and reduces maternal blood loss during delivery. Another example of this bidirectional effect is the hormone CYP17. On one hand, it makes carriers more susceptible to recurrent miscarriages; on the other it enhances fetal growth. The authors expertly and extensively review all of these complex relationships between gene defects and reproduction.

Kobashi and coworkers review the possible relationship between polymorphism of the angiotensinogen-converting enzyme (ACE) gene and preeclampsia. This study was based on the observation that polymorphisms of the ACE gene are associated with myocardial infarction, coronary artery spasm, and essential hypertension. A possible association with pregnancy-induced hypertension and preeclampsia has also been reported. The authors determined the homozygous deletion (DD) genotypes of the ACE gene in 122 patients with preeclampsia and 291 controls. No differences were found between the two groups. Other contributing factors to preeclampsia were also considered. In a subgroup of the preeclampsia group that had a history of hypertension, a trend toward a higher frequency of polymorphism was found, but this difference lacked statistical significance.

Nishiguchi and coworkers determined des-gamma-carboxyprothrombin (PIVKA-II) in women during their course of pregnancy. PIVKA-II levels in sera are an indication of the relative availability of vitamin K (i.e., high PIVKA-II levels suggest a vitamin K deficiency). The authors found gradually increasing levels as pregnancy progressed. Very high levels were found in patients with preeclampsia. These levels correlated with the concentration of TAT complexes. Except for patients with hyperemesis, who also had high levels, patients with other pregnancy complications had normal PIVKA-II levels.

In the last article, Takahashi and associates examine the role of components of the fibrinolytic system, especially plasminogen activator inhibitors (PAIs), in tumor cell adhesion. The relationship between PAI-1, urokinase-type plasminogen activator (u-PA), and prognosis for cancer patients is well known. The authors found that PAI-1 inhibited fibrosarcoma cell adhesion to vitronectin via α_vβ₅ integrin, and that PAI-1 stimulated cell migration from vitronectin to collagen. The relationship to the tumor-promoting effect of PAI-1 and u-PA is discussed.

I would like to thank all authors and coauthors for their contributions, and Professor Suzuki for assembling this issue.