Current Drug Targets, Volume 6, No. 5, 2005
Contents
Coagulopathies
and Abnormal Pregnancies
Guest
Editor: Takao Kobayashi
Editor’s Note Pp.531-531
Francis J. Castellino
Editorial Pp.533-533
Takao Kobayashi
Maternal Fibrinogen is Necessary for
Embryonic Development
Pp.535-539
Takayuki Iwaki and
Francis J. Castellino
Congenital Blood Coagulation Factor XIII
Deficiency and Perinatal Management Pp.541-549
Akitada Ichinose,
Toshihiko Asahina and Takao Kobayashi
Factor XII, Kininogen and Plasma
Prekallikrein in Abnormal Pregnancies Pp.551-557
T. Sugi and T. Makino
Antithrombin Abnormalities and Perinatal
Management Pp.559-566
Takao Kobayashi
The Role of Factor V Leiden in Maternal Health
and the Outcome of Pregnancy
Pp.567-576
C.J. Calderwood and
I.A. Greer
Pregnancy and Delivery in Protein C-Deficiency Pp.577-583
Mayumi Sugiura
Protein S and Congenital Protein S
Deficiency: The Most Frequent Congenital Thrombophilia in Japanese Pp.100%-592
Tomoko Adachi
Antiphospholipid Syndrome: Characteristics
and Obstetrical Management
Pp.593-605
Tomizo Nishiguchi and
Takao Kobayashi
General Articles
The Role of Newer Antiglutamatergic Agents as
Mood-Stabilizers in Bipolar Disorder Pp.607-614
Marianna Abelli,
Claudia Martini, Stefano Pini, Camilla Gesi and Giovanni B. Cassano
Phenothiazinium Based Photosensitisers –
Photodynamic Agents with a Multiplicity of Cellular Targets and Clinical Applications Pp.615-627
F. Harris, L.K.
Chatfield and D.A. Phoenix
Abstracts
[Back
to top] Editor’s Note
Francis J. Castellino
“Current Drug Targets” has achieved notable growth during the last few years as evidenced by its favorable initial impact factor rating. An effort is now being made to best structure the journal in a unique niche. It has been decided that each issue will be focused on a particular topic related to drug targets in its broadest interpretation, introduced by a guest editor. Such issues have become very popular and examples of this approach have appeared in the current year.
Many such topics are invited by the editorial board, but we also strongly encourage interested potential guest editors to submit ideas to the editor-in-chief. An abstract of the proposal, along with possible subtopics to be covered and authors to be solicted, should accompany the submission. Decisions will be reached promptly and schedules will be suggested after acceptance.
Individual reviews are still encouraged and will be published in a topical issue that best fits the review.
It is our hope that this new approach will serve the journal in the desire to become a focal point as an outlet for rigorous reviews on all scientific approaches for discovery and utilization of drug targets.
[Back
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Takao Kobayashi
Inherited thrombophilias are the leading causes of maternal thromboembolism and are associated with increased risks of certain adverse pregnancy outcomes, including second- and third-trimester fetal loss, abruptions, severe intrauterine growth restriction, and early-onset severe preeclampsia. Current information suggests that all patients with a history of prior venous thrombotic events, and those with these characteristic adverse pregnancy events, should be evaluated for thrombophilias.
Among thrombophilias, Antithrombin (AT) deficiencies have long been associated with a significant thrombotic tendencies throughout gestation and the puerperium. AT is an important regulator of the coagulation cascade because of its ability to efficiently inhibit proteases such as factor (F) Xa and thrombin. Protein C and protein S (PS) are vitamin K-dependent anticoagulant proteins. Activated protein C (APC) is a strong inhibitor of coagulation, inactivating coagulation FVa and FVIIIa upon binding to PS in the presence of thrombin and thrombomodulin. A major function of PS is a cofactor to facilitate the action of APC. The factor V Leiden mutation is a heritable thrombophilia present in 5-8% of Caucasian populations. In its heterozygous form it is associated with a 4 to 8 fold increase in thrombotic risk. Homozygous inheritance, however, confers around an 80 fold increase in relative risk of thrombosis. Treatments for these disorders include antithrombotic therapy with unfractionated heparin or low molecular weight heparin, followed by an oral vitamin K antagonist, such as warfarin. FXII, plasma prekallikrein and high molecular weight kininogen were first identified as coagulation proteins in the intrinsic pathway because patients deficient in these proteins had marked prolongation of in vitro surface-activated coagulation time. Paradoxically, studies suggest that these proteins have anticoagulant and profibrinolytic activities. Since contact proteins or kallikrein-kininogen-kinin system may play important roles in pregnancy especially in the fetoplacental unit, deficiencies of these proteins and/or auto-antibodies to these proteins may be associated with pregnancy losses. Antiphospholipid syndrome (APS) is characterized by a combination of clinical features consisting of thrombotic or pregnancy-related events and autoimmune antiphospholipid antibodies. Recurrent pregnancy losses or fetal death, and increased rates of preeclampsia and placental insufficiency are the clinical features in the APS. It is now accepted that unfractionated or low-molecular-weight heparin in combination with low-dose aspirin represents the current standard treatment.
Fibrinogen (Fg) is a precursor of fibrin, which is one of the main components of blood clots generated during the hemostatic response. FXIII is a plasma transglutaminase circulating in blood as a heterotetramer and consisting of two catalytic A subunits and two non-catalytic B subunits. It is a proenzyme activated by thrombin in the blood coagulation cascade. Both Fg and FXIII play important roles in hemostasis, wound healing, and maintenance of pregnancy. Accordingly, a lifelong bleeding tendency as well as abnormal wound healing and recurrent spontaneous miscarriage are common symptoms of these deficiencies. Supplemental therapies with Fg and FXIIIA concentrates allow the patients to sustain the pregnancy.
This special issue of ‘Coagulopathies and abnormal pregnancies’ consists of 8 articles which review recent advances on this topic.
[Back
to top] Maternal Fibrinogen is Necessary for Embryonic Development
Takayuki Iwaki and
Francis J. Castellino
Fibrinogen (Fg) is a precursor of fibrin, which is one of the main components of blood clots generated during the hemostatic response. Beyond its important role in hemostasis, Fg is involving in several physiologic and pathophysiologic states, such as infection, wound healing, the progression of certain types of tumors, and the severity of atherosclerosis. In addition, Fg has a critical role in maintaining pregnancy. Ovulation, fertilization, and implantation of the fertilized egg to the uterine wall can occur in afibrinogenemic women. However, all pregnancies in these patients resulted in spontaneous miscarriage. Fg supplemental therapy allows the patients to sustain the pregnancy. Mice with a total fibrinogen deficiency (FG-/-) reproduce the human experience. Despite of successes with fibrinogen supplementation, “paradoxical thrombosis” sometimes occurs, wherein supplemental therapies cause catastrophic thrombosis, such as pulmonary and mesenteric venous thrombosis. In these therapies, syncytial knots, hyaline membrane, and multiple recent infarctions with abruptio placenta were also observed. These findings indicate that the dosage regimen of Fg in afibrinogenemia-related pregnancies needs to be optimized according to other coagulation markers, such as thrombin-antithrombin complex (TAT) concentration, which represents the extent of thrombin formation. In addition, baseline thrombin assays would be helpful to predict the potential for paradoxical thrombosis during the supplemental therapy offered during pregnancy.
[Back
to top] Congenital
Blood Coagulation Factor XIII Deficiency and Perinatal Management
Akitada Ichinose,
Toshihiko Asahina and Takao Kobayashi
Transglutaminases are at least 9 enzymes which cross-link a number of proteins. This type of reaction not only enhances the original functions of substrate proteins, but also adds new functions to them. Factor XIII (FXIII) is a plasma transglutaminase circulating in blood as a heterotetramer and consisting of two catalytic A subunits and two non-catalytic B subunits. It is a proenzyme activated by thrombin in the blood coagulation cascade. It plays an important role(s) in hemostasis, wound healing, and maintenance of pregnancy. Accordingly, a lifelong bleeding tendency as well as abnormal wound healing and recurrent spontaneous miscarriage are common symptoms of FXIII deficiency. Genetic and molecular mechanisms of congenital deficiencies have been analyzed in vitro. The mechanisms of these defects have also been studied in detail by using FXIII gene knock-out mice in vivo.
We analyzed eight successful outcomes of pregnancy in patients with congenital deficiency of FXIIIA, in which the plasmatic level of maternal FXIIIA and/or the precise substitute therapies were mentioned. Then we propose the following guidelines for the perinatal management: (i) decidual bleeding usually begins from 5 weeks of gestation and spontaneous abortion always occurs subsequently without substitute therapy; (ii) the plasma level of FXIIIA must be at least 2~3%, however, if possible, higher than 10% to prevent bleeding and miscarriage; (iii) the administration of 250 IU of FXIIIA concentrate each 7 days is enough to keep the level of plasma FXIIIA more than 10% in the early gestation, however 500 IU each 7 days is adequate in the later period to keep that level; (iv) during labor, the desired level is higher than 20%, if possible, higher than 30% to avoid any risk of strong obstetrical bleeding.
[Back
to top] Factor
XII, Kininogen and Plasma Prekallikrein in Abnormal Pregnancies
T. Sugi and T. Makino
Factor XII, plasma prekallikrein and high molecular weight kininogen were first identified as coagulation proteins in the intrinsic pathway because patients deficient in these proteins had marked prolongation of in vitro surface-activated coagulation time. However, deficiencies of these proteins are not associated with clinical bleeding. Paradoxically, studies suggest that these proteins have anticoagulant and profibrinolytic activities. In fact, association between deficiencies of these proteins and thrombosis has been reported. Also, deficiencies of these proteins, auto-antibodies to these proteins and anti-phospholipid antibodies are frequent hemostatis-related abnormalities found in unexplained recurrent aborters. Recently, evidence has accumulated for the presence of the kallikrein-kininogen-kinin system in the fetoplacental unit. Since contact proteins or kallikrein-kininogen-kinin system may play an important role in pregnancy especially in the fetoplacental unit, deficiencies of these proteins and/or auto-antibodies to these proteins may be associated with pregnancy losses. These possibilities will be reviewed, the functions of the individual components will be summarized, and their role in blood coagulation and pregnancy discussed.
[Back
to top] Antithrombin
Abnormalities and Perinatal Management
Takao Kobayashi
Antithrombin (AT) is an important regulator of the coagulation cascade because of its ability to efficiently inhibit proteases such as Factor (F) Xa and thrombin. Type I hereditary AT deficiency is characterized by a quantitative deficiency in the antigen and activity of AT to about 50% of normal. Type II hereditary AT deficiency is characterized by a normal antigenic level of AT, with a low level of activity due to a dysfunctional protein. Impaired synthesis, consumptive coagulopathy including pregnancy-induced AT deficiency in multiple pregnancies, and urinary protein loss are associated with acquired AT deficiencies.
Inherited thrombophilias are the leading cause of maternal thromboembolism and are associated with increased risk of second- and third-trimester fetal loss, abruptions, severe intrauterine growth restriction, and early-onset severe preeclampsia. Among thrombophilias, AT deficiency has long been associated with a significant thrombotic tendency throughout gestation and the puerperium. Treatment for this disorder includes antithrombotic therapy with unfractionated heparin or low molecular weight heparin, followed by an oral vitamin K antagonist, such as warfarin. Some patients with very low AT levels may be resistant to heparin therapy and may require increased doses of heparin or AT concentrates. In addition, an acquired decrease of AT plasma levels is a common finding in patients with preeclampsia. It is suggested that the administration of AT concentrates improves uteroplacental circulation and influence the pathophysiology of preeclampsia. Furthermore, it has been demonstrated that hereditary AT deficiency is associated with fetal loss. In women with a severe thrombotic tendency and recurrent fetal loss, thromboprophylaxis may offer more benefits.
[Back
to top] The
Role of Factor V Leiden in Maternal Health and the Outcome of Pregnancy
C.J. Calderwood and
I.A. Greer
There is growing evidence that women with thrombophilia are at increased risk of pregnancy related venous thromboembolism and of adverse pregnancy outcome including pregnancy loss, pre-eclampsia, intrauterine growth retardation and placental abruption. The factor V Leiden mutation is a heritable thrombophilia present in 5-8% of Caucasian populations. In its heterozygous form it is associated with a 4-to 8-fold increase in thrombotic risk. Homozygous inheritance, however, confers around an 80-fold increase in relative risk of thrombosis. The relationship between factor V Leiden and adverse pregnancy outcome has been studied in the recent literature, however the size of the estimated risks varies between individual studies due to heterogeneity of study design and small sample size in many cases. The management of women with factor V Leiden in pregnancy with low molecular weight heparin has been shown to be both safe and effective in preventing venous thromboembolism and improving pregnancy loss. Large scale, randomised controlled studies are required to confirm these findings.
Selective screening for factor V Leiden based on prior venous thromboembolism has been shown to be marginally more cost-effective than universal screening in pregnancy and a recent consensus statement has recommended screening for thrombophilia based on a strong personal or family history of venous thromboembolism.
There is now some evidence that placental problems may be associated with factor V Leiden in the fetus. There has also been an observed association between maternal factor V Leiden and fetal or neonatal stroke. These areas require further study and at present there is no evidence-based approach to investigation, prevention or management.
[Back
to top] Pregnancy
and Delivery in Protein C-Deficiency
Mayumi Sugiura
Activated protein C (APC) is a strong inhibitor of coagulation, inactivating coagulation factors Va and VIIIa upon binding to protein S (PS) in the presence of thrombin and thrombomodulin. The normal concentration of PC in the plasma is approximately 4 mg/ml. Throughout pregnancy, PC activity and antigenic levels show no significant trend and remain within the normal reference range. Several PC point mutations have been documented, including those characterized as type I and II PC deficiencies. These, as well as mutations in Protein S (PS), factors Va and VIIIa, and thrombomodulin, can result in venous thromboses of various degrees of severity. The relative risk of thrombosis with PC deficiency is 7.3%. In pregnancy, the risk is 3-10% antepartum and 7-19% postpartum. PC deficiency has also been reported to be associated with both non-recurrent and recurrent first, second and third trimester miscarriages, intrauterine fetal death, intrauterine growth retardation, placental abruption and preeclampsia. However, prior to 10 weeks of gestation, no significant relationship between PC deficiency and pregnancy loss has been established.
[Back
to top] Protein
S and Congenital Protein S Deficiency: The Most Frequent Congenital
Thrombophilia in Japanese
Tomoko
Adachi
Protein S is a natural anticoagulant. Congenital protein S (PS) deficiency is a confirmed risk factor of venous thromboembolism (DVT) which though occurs infrequently yet is a leading cause of maternal mortality and morbidity. Congenital PS deficiency may also be responsible for obstetric complications such as preeclampsia/eclampsia, recurrent fetal loss and intrauterine fetal restriction. Congenital PS deficiency has been identified in 1-7.5 % of patients with DVT and in 0.03-0.13 % general Caucasian population. However, Japanese people have higher prevalence both in VTE patients (12.7 %) and general population (0.48-0.63 %). Because PS deficiency is the most frequent congenital thrombophilia in Japanese people, Japanese obstetricians must understand this thrombophilia and also that women with PS deficiency have an increased risk of VTE and a necessity of prophylactic use of anticoagulant against recurrent VTE during pregnancy and puerperium. This article reviews the literature to understand PS and congenital PS deficiency, especially the association of this thrombophilia with pregnancy.
[Back
to top] Antiphospholipid
Syndrome: Characteristics and Obstetrical Management
Tomizo Nishiguchi and
Takao Kobayashi
Antiphospholipid syndrome (APS) is characterized by a combination of clinical features consisted of thrombotic or pregnancy-related events and autoimmune antiphospholipid antibodies. In the 1998 International Consensus Preliminary Criteria, APS is defined by the concomitant presence of these clinical features and laboratory tests, including solid immunoassay and lupus anticoagulant (LAC). Current concept of antiphospholipid antibodies directed against plasma proteins with affinity for negatively charged phospholipids, mainly beta2-glyoprotein 1 (beta2GP1) and prothrombin, that is, anti-beta2GP1 and anti-prothrombin antibodies have been shown as a key antibody in the APS, while the pathophysiological mechanisms remain still uncertain. In the recent investigations potential mechanisms, such as endothelial activation induced by bivalent-formed antiphospholipid antibodies and complement activation, have emerged. Recurrent pregnancy losses or fetal death, and increased rates of preeclampsia and placental insufficiency are the clinical features in the APS. It is now accepted that unfractionated or low-molecular-weight heparin in combination with low-dose aspirin represents the current standard treatment for pregnant women with anti-phospholipid antibodies, and high-dose immunoglobulin is considered as a salvage therapy for refractory APS. This review highlights the characteristics of APS and the recent consensus for obstetrical managements in APS.
[Back
to top] The
Role of Newer Antiglutamatergic Agents as Mood-Stabilizers in Bipolar Disorder
Marianna Abelli,
Claudia Martini, Stefano Pini, Camilla Gesi and Giovanni B. Cassano
In bipolar patients, maintenance treatment with anticonvulsive agents is a valid alternative to lithium. These agents have widely varying mechanisms of action. Some of these medications focus on the current understanding of antiglutamatergic mechanisms of action and their treatment implications for bipolar disorders.
[Back
to top] Phenothiazinium
Based Photosensitisers – Photodynamic Agents with a Multiplicity of Cellular
Targets and Clinical Applications
F. Harris, L.K.
Chatfield and D.A. Phoenix
Phenothiazinium based photosensitisers (PhBPs) possess planar heteroaromatic ring structures that give the parent molecules photosensitising properties. PhBPs show potential application in photodynamic therapy (PDT) as antitumour agents, and in photodynamic chemotherapy (PACT) as antimicrobial compounds.
PhBPs show selectivity for tumour and microbial cells, which appears to be based on electrostatic interactions between the positive charge generally carried by these molecules and the negative charge found on the outer surface of these target cells. In some cases, a site of action for photoactivated PhBPs is the outer membrane / envelope of the target cell. Such action can involve the modification of membrane lipid and / or lipopolysaccharide, and the inactivation of essential proteins and enzymes, with these effects usually leading to cell lysis and death. However, more often, PhBPs are internalised by target cells, promoted by a variety of factors, including low pH and enzymatic reduction, and upon photoactivation, internalised, PhBPs are able to inflict damage on a number of intracellular targets. In tumour cells, PhBPs can photodamage DNA and the membranes of organelles, thereby inducing necrosis and / or apoptosis. In bacterial cells, whilst DNA is generally a primary target of PhBPs, these compounds can exhibit multiple sites of action within a given cell and show different sites of action between different bacterial species. This variable targeting makes PhBPs attractive propositions as alternatives to conventional antibiotics in that the emergence of bacterial strains with acquired resistance to these compounds appears to be highly unlikely.
For a long time it has been known that obesity (adiposity) is linked to insulin resistance. Recently, many investigators have reported that adipocytes secrete a variety of bioactive molecules, termed adipokines (adipocytokines), including TNFa, IL-6, leptin, adiponectin, resistin and so on. These adipokines play pivotal roles in energy homeostasis by affecting insulin sensitivity, glucose and lipid metabolisms, food intake, the coagulation system and inflammation. This review provides a summary of these adipose tissue-secreting biomolecules and discusses their feasibilities as drug targets for the treatment of metabolic syndrome.