Warfarin syndrome

Other Names: Warfarin embryopathy; Fetal anticoagulant syndrome; DiSala syndrome; Congenital warfarin syndrome; Coumarin syndrome; Vitamin K antagonists embryofetopathy; Coumarin embryopathy; Embryofetopathy due to oral anticoagulant therapy; Fetal warfarin syndrome; di Sala syndrome; Vitamin K-antagonist embryofetopathy; Vitamin K-antagonist embryopathy; Warfarin embryofetopathy

Vitamin K antagonist embryofetopathy is characterized by a group of symptoms that may be observed in a fetus or newborn when the mother has taken oral vitamin K antagonists, such as warfarin during pregnancy. Vitamin K antagonists are anticoagulant drugs that provide efficient thromboprophylaxis and that can cross the placenta.

Cause

Fetal warfarin syndrome appears in greater than 6% of children whose mothers took warfarin during pregnancy. Warfarin has a low molecular weight so can pass from the maternal to fetal bloodstream through the tight filter-like junctions of the placental barrier.

As the teratogenic effects of warfarin are well known, the medication is rarely prescribed to pregnant women. However, for some patients, the risks associated with discontinuing warfarin use may outweigh the risk of embryopathy. Patients with prosthetic heart valves carry a particularly high risk of thrombus formation due to the inorganic surface and turbulent blood flow generated by a mechanical prosthesis. The risk of blood clotting is further increased by generalized hypercoagulability as concentrations of clotting factors rise during pregnancy.

This increased chance of blood clots leads to an increased risk of potentially fatal pulmonary or systemic emboli cutting of blood flow and oxygen to critical organs. Thus, some patients may continue taking warfarin throughout the pregnancy despite the risks to the developing child.

Mechanism

Warfarin’s ability to cause fetal warfarin syndrome in utero stems from its ability to limit vitamin K activation. Warfarin binds to and blocks the enzyme Vitamin K epoxide reductase which is usually responsible for activating vitamin K during vitamin K recycling. Vitamin K, once activated, is able to add a carboxylic acid group to glutamate residues of certain proteins which assists in correct protein folding. Without active vitamin K, a fetus exposed to warfarin is unable to produce large quantities of clotting and bone growth factors.

Without vitamin K, clotting factors II, VII, IX and X are unable to be produced. Without these vital parts of the coagulation cascade a durable fibrin plug cannot form to block fluid escaping from damaged or permeable vasculature. Anemia is common in fetuses exposed to warfarin as blood constantly seeps into the interstitial fluid or amniotic cavity .High doses of warfarin and heavy bleeding lead to abortion and stillbirth.

Osteocalcin is another protein dependent on vitamin K for correct folding and function. Osteocalcin is normally secreted by osteoblast cells and plays a role in aiding correct bone mineralization and bone maturation. In the presence of warfarin and subsequent absence of vitamin K and active osteocalcin, bone mineralization and growth are stunted.

Signs and symptoms

5-12 % of infants exposed to warfarin between 6-9 weeks gestation present nasal hypoplasia and skeletal abnormalities, including short limbs and digits (brachydactyly), and stippled epiphyses. Warfarin fetopathy with central nervous system abnormalities (hydrocephalus, intellectual disability, spasticity, and hypotonia) or ocular abnormalities (microphthalmia, cataract, optic atrophy), fetal loss, and stillbirth, occurs in infants exposed at later gestations. Additional features that have been reported after in utero warfarin exposure include facial dysmorphism (cleft lip and/or palate, malformed ears), choanal atresia or stenosis, aorta coarctation, situs inversus totalis, bilobed lungs, and ventral midline dysplasia.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Anteverted nares(Nasal tip, upturned)
• Depressed nasal bridge(Depressed bridge of nose)
• Epiphyseal stippling(Speckled calcifications in end part of bone)
• Punctate vertebral calcifications
• Short nose(Decreased length of nose)

30%-79% of people have these symptoms

• Brachydactyly(Short fingers or toes)
• Intellectual disability(Mental deficiency)
• Intrauterine growth retardation(Prenatal growth deficiency)
• Respiratory insufficiency(Respiratory impairment)
• Short distal phalanx of finger(Short outermost finger bone)
• Short neck(Decreased length of neck)

5%-29% of people have these symptoms

• Abnormality of cardiovascular system morphology
• Aplasia/Hypoplasia affecting the eye(Absent/small eye)
• Cataract(Clouding of the lens of the eye)
• Choanal atresia(Blockage of the rear opening of the nasal cavity)
• Hearing impairment(Deafness)
• HydrocephalusToo much cerebrospinal fluid in the brain
• Hypertelorism(Wide-set eyes)
• Macroglossia(Abnormally large tongue)
• Microtia(Small ears)
• Muscular hypotonia(Low or weak muscle tone)
• Myelomeningocele
• Optic atrophy
• Proptosis(Bulging eye)
• Seizure
• Visual impairment(Impaired vision)

Prevention

Fetal warfarin syndrome is prevented by withholding prescription to pregnant women or those trying to conceive. As warfarin can remain in the mother’s body for up to five days, warfarin should not be administered in the days leading up to conception. Doctors must take care to ensure women of reproductive age are aware of the risks to the baby should they get pregnant, before prescribing warfarin.

For some women, such as those with prosthetic heart valves, anticoagulation medication cannot be suspended during pregnancy as the risk of thrombus and emboli is too high. In such cases an alternate anticoagulant, which cannot pass through the placental barrier to the fetus, is proscribed in place of warfarin. Heparin is one such anticoagulant medication, although its efficacy in patients with prosthetic heart valves is not well established. New anticoagulant medications, which are efficacious and non-teratogenic such as ximelagatran continue to be developed.

Treatment

Medication As well as the routine dose of vitamin K given to newborns after birth, babies born with fetal warfarin syndrome are given additional doses intramuscularly to overcome any remaining warfarin in the circulation and prevent further bleeding. Fresh frozen plasma is also administered to raise concentrations of active blood clotting factors. If the child is anemic from extensive bleeding in-utero, red blood cell concentrate is given to restore oxygen carrying capacity.

Surgical correction Surgical interventions can be given to improve functionality and correct cosmetic abnormalities. Osteotomy (bone cutting) and zetaplasty surgeries are used to cut away abnormal tissue growths at the piriform aperture around and pharynx to reduce airway obstruction.

Rhinoplasty surgery is used to restore normal appearance and function of the nose.Heart surgery may also be required to close a patent ductus arteriosus.

NIH genetic and rare disease info

• NIH info on Warfarin syndrome

Warfarin syndrome is a rare disease.

Warfarin syndrome Resources
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