296 Vitamin K antagonists

Pharmacology

Coumarin derivatives (4-hydroxycoumarin compounds) are oral anticoagulants (OA) that prevent vitamin K from acting as a cofac-tor in the hepatic synlhesis of the vitamin K-dependcnt coagulation factors II. VII, IX, and X (as well as the anticoagulants, proteins C and S). They arc also called vitamin K antagonists (VKA). Available coumarin derivatives are acenocoumarol, phenprocoumon, and warfarin. Apart from coumarins, the indanediones, fluindione and phenidione, are used as a VKA for the same purpose.

Coumarin derivatives are nearly totally resorbed in the gut and are bound to albumin by more than 95%. Because the action of the drug is based on inhibition of the synthesis of the coagulation factors, it takes 1-3 days before blood concentrations arc effectively lowered and the drug becomes effective. Coumarins are oxidated in the liver and excreted by the kidneys. The elimination half-time is

24 hours for accnocoumarol, 36 hours for warfarin, and 150 hours for phenprocoumon. Interaction with other drugs can occur through competition, oxidating enzymes in the liver as well as binding to plasma proteins.

Toxicology

The embryotoxic properties of coumarins have been established in humans. Coumarins readily cross the placenta and will reach the fetus. Coumarin therapy during pregnancy is implicated in two major adverse effects. Coumarins can produce a characteristic pattern of malformations, coumarin or warfarin embryopathy, central nerve system (CNS) abnormalities, and fetal bleeding. The rate of spontaneous abortion is also increased {Schaefcr 2006, Blickstein 2002, Bates 1997, Pauli 1993, Hall 1980).

To estimate the prevalence of congenital anomalies associated with coumarin exposure during pregnancy, van Driel (2002A) reviewed 17 studies describing a total of 979 pregnancies, of which 449 involved acenocoumarol, 327 warfarin, and 203 an unspecified coumarin). From the 979 pregnancies, 689 children were born alive. Twenty-three children had skeletal anomalies, interpreted as indicative for coumarin embryopathy, of 394 children born alive to mothers using coumarins throughout pregnancy (6%).

Warfarin is by far the most discussed vitamin K antagonist (VKA) in scientific literature with respect to teratogenicity. Considering the pathogenetic mechanisms discussed in the context of warfarin, it can be assumed that all coumarins and indanediones have a similar teratogenic and fetotoxic potential. Van Driel et al. (2002A) summarized 57 reports published since 1955, describing 63 cases of congenital anomalies after exposure to VKAs. Of the 63 cases, 51 (81%) had skeletal anomalies. The most consistent clinical feature was mid-face hypoplasia (n = 47), including a depressed nasal bridge, underdevelopment or absence of the nasal septum, a small, upturned nose with grooves between the tip of the nose and the alac nasi, micrognathia, a prominent forehead, and a flat appearance of the face. Stippling in the epiphyseal regions (chondrodysplasia punctata) was described in 32 of the 63 cases, mostly along the axial skeleton, at the proximal femora and in the calcanei (Hall 1980). The possible mechanisms for this effect arc thought to be the inhibition of the enzyme arylsulfafase and inhibition of the synthesis of vitamin K-dependent (non-coagulant) proteins, thus interfering with normal bone and cartilage development. This radiological finding apparently resolves as the epiphyses calcify. Limb hypoplasia, primarily involving the distal digits, may be seen in up to one-third of children with warfarin embryopathy (Pauli 1993). Other abnormalities that have been associated with the coumarin embryopathy are summarized by van Driel (2002A). Abnormalities described include abnonnalities of the central nervous system, e.g. agenesis of the corpus callosum, schizencephaly, meningocele, Dandy-Walker malformation, and optic atrophy, as welt as microcephaly, cerebral atrophy, hydrocephaly or ventriculomegaly, hearing loss, retardation, or slow development. Furthermore, there were a few cases reporting dysgenesis of the eye, cardiac defects (tetralogy of Fallot, persistent truncus arteriosus, and atrial septal defects), asplenia syndrome, absence of a kidney, cleft lip and palate, hypoplasia of the lungs with absence of the right diaphragm, and situs inversus. In addition, 13 cases of minor physical anomalies were reported, including low-set or poorly developed ears, a high-arched palate, hypertelorism, antimongoloid palpebral fissures, and widely spaced nipples.

Most publications state that the sensitive time for causing teratogenic effects (coumarin embryopathy) is in weeks 6-9, without clearly defining whether this is counted from conception or LMP, or evaluate those case reports exclusively exposed before week 9. A critical review of all published reports, however, does not provide evidence for a highly sensitive period until week 8 after LMP (week 6 postconception). Those five case reports cited in the literature as indicative for an embryopathy risk associated with exposure exclusively at s week 8 were either calculated in weeks after conception (Hall 1989, Balde 1988), or causality was doubtful (Ruthnum 1987, Cox 1977) and/or additional contributing factors were reported (Lapiedra 1986).

CNS abnormalities are thought to result from intracerebral hemorrhages and subsequent scarring, and arc associated with exposure at any time during pregnancy - mostly the second trimester. The sequelae of intracerebral bleeding appear to be more debilitating than those of the coumarin embryopathy; intracranial bleeding during delivery is especially to be feared.

To study long-term effects, van Driel (2003B, 2001) and Wesseling and co-workers (2001, 2000) compared a coumarin exposed cohort of about 300 children aged from 7.6 to 15.1 years with a control group consisting of some 260 non-exposed children, with respect to their neurological, behavioral, and cognitive development. There were only two children in the exposed cohort with signs of coumarin embryopathy. They were normally developed at 9.2 and 13.1 years, respectively (van Driel 2002B). The mean height and overall growth of exposed children did not differ from those of the unexposed children. None of the children was found to be neuro-logically abnormal. 1 lowever, there was a slightly increased risk for minor neurological dysfunction after exposure during the second or third trimester (Wesseling 2001). There were no differences in mean 1Q, but 11 of the exposed children versus 3 unexposed children measured an IQ of < 80, These 11 children were only exposed during the second and third trimesters. There were no differences in clinically relevant problem behavior. However, less favorable task-oriented and social-emotional behavior was observed among the exposed cohort (van Dricl 2001). Three other follow-up studies with a total of 72 children could not find significant differences in physical or mental development (Olthof 1994, Wong 1993, Chong 1984). These data suggest that the risk of a healthy newborn developing late onset teratogenic effects of first-trimester VKA exposure is remote.

The largest controlled, prospective study until now includes 666 pregnancies with 670 exposures to different vitamin K antagonists. In this multicenter study, pregnancies were compared, with respect to their outcome, with 1049 controls. In most cases, treatment occurred from the beginning. This study confirmed the teratogenicity of coumarins, and revealed a three-fold miscarriage rate after firsttrimester treatment. The rate of elective terminations was also higher. Live births occurred in only 53%. Prematurity was more frequent. The rate of major birth defects was significantly increased (OR 3.86; 95% CI 1.86-8.00). There were only two coumarin embryopathies observed among 356 live births (0.6%), and exposure to a vitamin K antagonist in these cases was later than 6 weeks postconception. The risk for coumarin embryopathy seems to be small, however, and the outcomes of this study confirmed that when exposure was limited to the first 6 (postconceptional) weeks, the risk of major malformations did not appear to be substantially increased (Peters 2006, Schaefer 2006).

Adverse outcome was suggested to be dose-dependent (more than 5 mg/day) in a small study of 52 patients with mechanical heart valves who had been exposed to warfarin during 71 pregnancies (Cotrufo 2002).

Several studies indicate that (he choice of anticoagulant regimens for mechanical heart valve thromboprophylaxis during pregnancy should be made by balancing two risks: maternal morbidity and mortality from thromboembolic complications on the one hand, and fetal loss and embryopathy on the other - which means choosing between coumarin therapy throughout pregnancy, or substitution with adjusted-dose heparin between weeks 6 and 12. The dosage necessary to keep satisfactory levels of anticoagulation and thrombotic risks associated with specific valves are parameters to be reckoned with (Bates 2004, Cotrufo 2002, Chan 2000, Vitale 2000): maternal risk should be weighed against a possible fetal risk.

Recommendation, In view of possible fetal embryopathy and other adverse effects, coumarin derivatives are not recommended in the first trimester or at the end of pregnancy, and generally are not recommended for use during pregnancy. Patients on coumarin derivatives who are planning a pregnancy should preferably be put on heparin (UH or LMWH) prior to pregnancy or, at the latest, prior to the sixth week after conception, which warrants adequate pregnancy testing. In high-risk patients with mechanical heart valves, an exception may be necessary because of maternal health requirements; here, oral anticoagulants throughout pregnancy until near term may need to be considered. The risk for coumarin embryopathy is small, in particular when therapy during the first trimester did not take place later than week 8 after the first day of last menstruation; therefore, elective termination of a wanted pregnancy is not recommended if (inadvertent) exposure took place in early pregnancy. Close follow-up by the obstetrician, including level II ultrasound, should be recommended in any case of vitamin K antagonist exposure during pregnancy.

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