Hemostasis and Thrombosis in Gynecology and Obstetrics, Aging, Malignancy, and Medical Patients

In this issue of Seminars in Thrombosis and Hemostasis, various problems related to thrombosis and hemostasis as complications of pregnancy are discussed, especially preeclampsia and the hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome. The bleeding disorder of newborns, related to vitamin K deficiency, is also addressed. In addition, the topic of aging and thrombosis is expertly reviewed, and, finally, the problems of thrombosis during surgery for malignancies and in medical patients are discussed.

In the first article, Kobayashi and coworkers describe a coagulation index that allows the differentiation between preeclamptic patients and healthy pregnant women with a high degree of certainty. Antithrombin activity, thrombin-antithrombin (TAT) complex, D-dimer, and changes in platelet counts appear to be important discriminators. TAT levels and changes in platelet counts were found to be the most sensitive indicators. The optimal time for termination of pregnancy, in cases of preeclampsia, could be determined using this index.

In the following article, Kobashi and colleagues investigated risk factors for hypertension in pregnancy. There are genetic and acquired factors, and the authors examined their interactions. They demonstrated that a given angiotensinogen genotype varies depending on the lifestyle during pregnancy. Nonobese women who carry the TT genotype of angiotensinogen and who are on a healthy diet should avoid mental stress. Obese patients with the genotype require dietary considerations in order to prevent hypertension during pregnancy. Based on these data, preventive measures can be recommended.

The next contribution by Kobashi and associates examines the relationship between smoking and preeclampsia in Japanese patients. Some studies on Caucasian women have revealed that smoking during pregnancy is actually associated with a reduced risk of preeclampsia. Only very limited information exists concerning women of different racial heritage. Although the authors found, in general, no differences between smokers and nonsmokers, they did find an association in patients with a high prepregnancy body mass, and smoking women had a higher incidence of preeclampsia. It is suggested that lifestyle modification could prevent preeclampsia in this group of patients.

In the next article, Kobayashi and coworkers report two patients with preeclampsia who developed eclamptic seizures following the administration of scopolamine butylbromide. One patient died of a massive cerebral hemorrhage. The authors describe the potential mechanisms involved in the development of these complications and caution on the use of anticholinergics in patients with severe preeclampsia.

In their article, Minakami et al review the relationship among gestational thrombocytopenia, pregnancy-induced antithrombin (AT) deficiency, and the development of the HELLP syndrome and fatty liver. Both the HELLP syndrome and acute fatty liver of pregnancy (AFLP) can occur without preceding preeclampsia, and many investigators have expressed the view that both syndromes develop abruptly and that decreased AT levels and thrombocytopenia are consequences of the developing syndromes. The authors confirm that thrombocytopenia can occur during pregnancy without preeclampsia or other complications but that it may also be a progenitor of the HELLP syndrome. AT activity, in contrast, is relatively stable during normal pregnancy. Decreased AT levels were correlated with elevations in aspartate aminotransferase (AST) levels and were thus more indicative of complications. The authors also found that twin pregnancies are more prone to be associated with the HELLP syndrome and with AFLP. AT determinations during pregnancy appear to be useful in identifying women at risk for the HELLP and AFLP syndromes.

The next article by Watanabe et al describes changes in AT and in platelet counts during gynecologic surgeries and their relationship to other risk factors. It has been reported that both AT levels and platelet counts decrease during general surgery and that these changes could be linked to the development of postoperative thromboembolism. The authors found similar changes during gynecologic surgeries. Levels were lower in patients subjected to long operative times and to increased blood loss. Interestingly, patients with a high body mass index had the fewest declines in AT levels and in platelet counts. No correlations to underlying disease states that necessitated the surgeries, to heparin use for thromboprophylaxis, to age or estrogen use were found. Although none of the patients studied developed venous thromboembolism, the authors suggest measurements of plasma AT levels and platelet counts in patients with above-normal blood loss and in those subjected to long surgical procedures.

Adachi and colleagues present a patient with a history of paradoxical brain embolism who became pregnant. The pathophysiology of paradoxical brain embolism is reviewed and details of the management of this complicated case are given. These patients, although rare, require special attention.

The influence of low-molecular-weight and high-molecular-weight plasminogen activators, t-PA and u-PA, on the onset of labor and on the hemostatic system is described by Moriyama and coworkers. Because fibrin plays an important role in maintaining the integrity of the uteroplacental circulation, the authors investigated certain fibrinolytic parameters during pregnancy and at the onset of labor. Plasma of pregnant patients contained immunologic assays of both high-molecular-weight and low-molecular-weight t-PA and u-PA. Low-molecular-weight t-PA was elevated during pregnancy but decreased at onset of labor. No such changes were seen in the high-molecular-weight forms of t-PA and u-PA. Euglobulin lysis times were prolonged during pregnancy but shortened at onset of labor. This coincided with a decrease in prekallikrein levels at onset of labor.

Nishiguchi and associates discuss the vitamin K status of breastfed infants with or without maternal vitamin K supplementation. Because the intramuscular administration of vitamin K to infants may be linked to childhood cancer, different routes of administration to mothers postpartum have been considered in order to avoid the potential development of the hemorrhagic disorder of infants. All infants studied by the authors did receive their routine vitamin K orally (twice in the first week), but after that, the mothers of one half of the infants received oral vitamin K, the other half not. PIVKA-II levels and the Hepaplastin test were performed to study the effects. Although no significant differences were found between the groups, the authors suggest that maternal vitamin K supplementation can maintain the vitamin K status of infants and thus avoid the hemorrhagic disorder.

Fukushima and coworkers report on prothrombin levels in newborn infants. They employed a procedure in which prothrombin is converted to thrombin by carinactivase-1, an extract from the venom of Echis carinatus. In contrast to previously employed methods in a similar setting, this procedure measures γ-carboxylated prothrombin or "fully functional" prothrombin. About half normal prothrombin levels were detected. They did not differ significantly for low-birth-weight or normal-birth-weight infants or whether the children had concomitant diseases. Prothrombin levels did correlate with gestational age, especially when the infants were of normal weight. Vitamin K administration did not alter prothrombin levels significantly. This seems to suggest that low levels of prothrombin are not the result of a vitamin K deficiency but rather a reflection of a low rate of synthesis in the still immature liver.

The effect of aging on the fibrinolytic system and its possible link to the increased thrombotic risk of elderly is the subject of the article by Takeshita and associates. The study used the murine model of aging, the klotho (kl/kl) mouse. Emphasis was placed on plasminogen activator inhibitor 1 (PAI-1). PAI-1 antigen levels were much higher in the kl/kl mice than in wild-type mice, and several organ systems expressed considerably higher PAI-1 mRNA levels than their healthy counterparts did. Most notably, this expression was found in the kidneys. This coincided with considerable fibrin depositions in the glomeruli. Although the mechanisms underlying these changes are not yet understood, the authors discuss the role of PAI-1 in aging and its related thromboembolic complications.

In the next article, Wilkerson and Sane comprehensively review the topic of aging and thrombosis. It is well-known that the risk for thromboembolic events increases with age. Aging is associated with a number of changes in the clotting system, in platelet function, and in the fibrinolytic system that make the blood in many respects more hypercoagulable. In addition, there are alterations in the vascular wall that make the endothelial surface procoagulatory. This combination of changes is likely responsible for the increased thromboembolic risk of the elderly. Their review is comprehensive in scope and should serve as an excellent basis for additional research on this important topic.

Khushal and coworkers review the topic of prolonged thrombosis prophylaxis in cancer patients undergoing surgery. Cancer patients have a priori a high risk for venous thromboembolism, and so does surgery. Cancer patients undergoing surgery thus have a high incidence of deep venous thrombosis and pulmonary embolism, both in the first few postoperative days and following discharge. Studies on general and orthopedic surgery patients have clearly demonstrated that extended prophylaxis (up to 3 to 4 weeks post discharge) greatly reduces the incidence of postoperative venous thromboembolic complications. Low-molecular-weight heparins appear to be especially suitable, and several calculations have demonstrated that extended thromboprophylaxis is economically viable. The authors stress that cancer patients undergoing surgery should receive extended thromboprophylaxis.

In the last article, Haas reviews the issue of thromboprophylaxis in medical patients. Although in many countries, thrombosis prophylaxis is well-established for surgical patients, medical patients appear to be undertreated. Depending on the type of the underlying medical condition, medical patients are at equal risk of developing venous thrombosis and pulmonary embolism as surgical patients. Risk profiling is a very important aspect of medical patients in order to reduce the potential of thromboembolism. Data on the therapeutic modalities for thromboprophylaxis in medical patients are extensively reviewed, and low-molecular-weight heparins seem to be especially effective in this patient population. Clear recommendations are given. Unclear at this time is how long prophylaxis should last. This comprehensive review should be of great value in selecting the proper medical patients for thromboprophylaxis and for initiating appropriate treatments.

Thanks and appreciation are expressed to all authors for their valuable contributions; special gratitude is extended to the two guest editors who assembled this issue.