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Antithrombin deficiency
People with antithrombin deficiency have an increased risk of developing abnormal blood clots, particularly in the veins. The condition typically presents in adulthood and affects approximately 1 in 2,000 to 5,000 individuals.
Overview
Antithrombin deficiency is a hereditary thrombophilia - a group of conditions that predispose individuals to forming blood clots inappropriately. Antithrombin is a naturally occurring protein in the bloodstream that acts as an important brake on the clotting system, preventing excessive or unnecessary clot formation. When antithrombin levels are reduced or the protein does not work properly, the balance tips towards increased clotting.
This condition is one of the more significant inherited thrombophilias, conferring a notably elevated risk of venous thromboembolism compared to the general population. Most affected individuals remain well for many years, but the condition becomes clinically relevant when blood clots develop, often triggered by situations that temporarily further increase clotting risk, such as surgery, prolonged immobility, pregnancy, or use of oestrogen-containing medications.
Symptoms & clinical features
Many people with antithrombin deficiency have no symptoms until they experience their first thrombotic event, which most commonly occurs in adulthood, typically between the ages of 20 and 50 years. The hallmark clinical feature is venous thromboembolism - the formation of blood clots within veins. Deep vein thrombosis, where clots form in the deep veins of the legs, is the most frequent presentation, causing leg pain, swelling, warmth, and redness. If a clot breaks free and travels to the lungs, it can cause pulmonary embolism, which may present with sudden breathlessness, chest pain, coughing up blood, or collapse.
Unlike some other thrombophilias, antithrombin deficiency can occasionally be associated with clots in unusual sites, such as the veins draining the brain or the vessels supplying the intestines or liver. Arterial clots are far less common than venous ones but have been reported in some individuals. The severity and frequency of clotting episodes can vary considerably between affected individuals, even within the same family.
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Affected organs
The condition primarily affects the venous circulation - the network of blood vessels that returns blood to the heart. The deep veins of the legs and pelvis are most commonly involved, but clots can develop in the upper limbs, particularly in association with central venous catheters or similar medical devices. The pulmonary arteries in the lungs are affected when clots embolise from elsewhere in the venous system.
In some cases, unusual venous sites may be affected, including cerebral venous sinuses in the brain, mesenteric veins in the abdomen, portal and hepatic veins serving the liver, and retinal veins in the eye. The underlying clotting tendency is systemic, meaning it affects the entire circulation, though venous thrombosis remains far more characteristic than arterial disease.
Risks & severity
The lifetime risk of developing a blood clot is substantially elevated in individuals with antithrombin deficiency compared to the general population. Research suggests that people with this condition face a markedly increased cumulative risk of experiencing at least one venous thromboembolism during their lifetime, though the precise magnitude varies across studies. The risk is not uniform throughout life - it increases considerably during high-risk situations such as surgery, pregnancy and the postpartum period, prolonged immobilisation, trauma, or use of hormonal contraceptives or hormone replacement therapy.
The severity of antithrombin deficiency varies depending on whether the deficiency is quantitative (reduced amount of normal protein) or qualitative (normal amount but impaired function), and the extent of the deficiency. Individuals with very low antithrombin levels or complete absence may experience more severe or recurrent thrombotic events, sometimes from childhood. However, many affected individuals have mild deficiency and may never experience a clot, or only develop one late in life or in association with a clear provoking factor. Family history often provides useful prognostic information.
Genetic causes
Antithrombin deficiency arises from pathogenic variants in SERPINC1, which encodes the antithrombin protein. Antithrombin acts as a critical regulator within the coagulation cascade, blocking the activity of multiple clotting factors - most notably thrombin and factor Xa - to prevent runaway clot formation and keep blood flowing normally. The SERPINC1 gene is located on chromosome 1.
Pathogenic changes in SERPINC1 may either diminish the quantity of antithrombin produced (referred to as type I deficiency) or lead to a structurally abnormal protein unable to inhibit clotting factors effectively (type II deficiency). When circulating antithrombin drops below levels needed to adequately restrain the clotting cascade, the system shifts towards a prothrombotic state, raising the likelihood that clots will form inappropriately. The particular variant and its position within the gene can influence how severely antithrombin function is compromised and the resulting clinical picture.
- SERPINC1 serpin family C member 1
Inheritance pattern
Antithrombin deficiency follows an autosomal dominant pattern of inheritance. This means that inheriting just one altered copy of SERPINC1 from either parent is sufficient to cause the condition. Each child of an affected parent has a 50% chance of inheriting the pathogenic variant and therefore being at increased risk of blood clots.
Because the condition is autosomal dominant, it typically affects multiple generations within a family, with both males and females equally likely to inherit and be affected by the condition. However, not everyone who carries a pathogenic SERPINC1 variant will necessarily experience blood clots - a phenomenon known as incomplete penetrance. Family members who inherit the variant may remain asymptomatic throughout life or only develop problems in high-risk circumstances. Very rarely, individuals may inherit pathogenic variants from both parents, which typically results in severe deficiency presenting in infancy.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Antithrombin deficiency is typically diagnosed through specialised blood tests that measure both the quantity and function of antithrombin protein in the plasma. These tests are usually requested by haematologists or other specialists after an individual has experienced a venous thromboembolism, particularly if it occurred at a young age, in an unusual location, without obvious provocation, or if there is a family history of blood clots. Testing may also be offered to relatives of someone known to have the condition.
It is important that antithrombin testing is performed when the individual is not acutely unwell and is not taking anticoagulant medication, as these factors can temporarily affect antithrombin levels and lead to misleading results. Once biochemical evidence of deficiency is established, genetic testing of SERPINC1 can be performed to identify the specific pathogenic variant, which confirms the diagnosis and enables predictive testing of at-risk family members. Within the NHS Genomic Medicine Service, testing for hereditary thrombophilia may be accessed through haematology services, with relevant PanelApp panels including genes associated with increased clotting risk.
Management & lifestyle
Management of antithrombin deficiency focuses on preventing initial and recurrent blood clots, particularly during high-risk situations. For individuals who have never had a clot, the approach is typically preventive, involving counselling about risk factors and prophylactic anticoagulation during temporary high-risk periods such as surgery, hospitalisation, long-haul flights, or pregnancy. Women with antithrombin deficiency are generally advised to avoid oestrogen-containing contraceptives and hormone replacement therapy, as these significantly increase thrombotic risk.
For those who have experienced a blood clot, longer-term anticoagulation is usually recommended, though the duration and intensity are individualised based on multiple factors including severity of deficiency, circumstances of the thrombotic event, and bleeding risk. During pregnancy, specialist management is essential, often involving prophylactic low-molecular-weight heparin and careful monitoring throughout pregnancy and the postpartum period. Individuals with antithrombin deficiency should be under the care of a haematologist experienced in thrombophilia management. Genetic counselling is valuable for discussing inheritance, family testing, and reproductive options.
UK care pathway
Within the UK NHS, individuals with suspected or confirmed antithrombin deficiency are typically managed through haematology services. Referral may come from general practitioners, emergency departments, obstetric services, or other specialties following a thrombotic event or based on family history. The NHS Genomic Medicine Service provides access to genetic testing for hereditary thrombophilia through appropriate clinical pathways, with testing coordinated by haematology or clinical genetics services.
Genetic counselling is available through regional genetics centres and can help individuals and families understand the inheritance pattern, discuss testing for at-risk relatives, and explore reproductive options. Specialist haematology clinics provide ongoing monitoring and management, with particular attention to pregnancy planning and management in women of childbearing age. Multidisciplinary care may involve obstetricians, vascular specialists, and other healthcare professionals depending on individual circumstances.
Frequently asked questions
If I have antithrombin deficiency, will I definitely have a blood clot?
Not necessarily. While antithrombin deficiency increases your risk of blood clots compared to the general population, many people with the condition never experience a clot, or only develop one in high-risk situations such as surgery or pregnancy. Your individual risk depends on several factors including the severity of your deficiency and other risk factors.
Can I take the contraceptive pill if I have antithrombin deficiency?
Oestrogen-containing contraceptives are generally not recommended for women with antithrombin deficiency, as they significantly increase the already elevated risk of blood clots. Your GP or haematologist can discuss alternative contraceptive options that do not carry this risk, such as progesterone-only methods or non-hormonal approaches.
Should my children be tested for antithrombin deficiency?
This decision should be made in consultation with your haematologist or genetic counsellor. Testing may be considered for adult relatives who can use the information for medical decision-making, particularly around surgery, contraception, or pregnancy. Testing children who have not had clots is often deferred until they are old enough to participate in the decision, unless there are specific clinical reasons for earlier testing.
How will antithrombin deficiency affect a pregnancy?
Pregnancy naturally increases clotting risk, and this is further elevated in women with antithrombin deficiency. With specialist management - typically involving prophylactic anticoagulation and close monitoring - most women with antithrombin deficiency can have successful pregnancies. Early referral to a specialist obstetric haematology service is essential for pregnancy planning and management.
Is antithrombin deficiency the same as taking warfarin or other blood thinners?
No, they are different. Antithrombin deficiency is an inherited condition where your body does not produce enough antithrombin protein or produces protein that does not work properly. Blood thinners like warfarin are medications given to reduce clotting risk. People with antithrombin deficiency may be prescribed anticoagulant medications to help prevent clots, but the underlying genetic condition remains.
References
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- Hart C, Rott H, Heimerl S. Management of Antithrombin Deficiency in Pregnancy. Hamostaseologie. 2022. PMID: 36323279
- Kozak M, Cosmi B, Gerotziafas G. Venous thromboembolism in pregnancy: recent advances. Polish archives of internal medicine. 2025. PMID: 40792350
- Phillippe HM, Hornsby LB, Treadway S. Inherited Thrombophilia. Journal of pharmacy practice. 2014. PMID: 24739277
- Salvagno GL, Pavan C, Lippi G. Rare thrombophilic conditions. Annals of translational medicine. 2018. PMID: 30306081
- Nowak-Göttl U, Kosch A, Schlegel N. Neonatal thromboembolism. Seminars in thrombosis and hemostasis. 2003. PMID: 12709927
- Kovac M, Ignjatovic V, Orlando C. The use of direct oral anticoagulants in the secondary prevention of venous thromboembolism in patients with severe thrombophilia: communication from the ISTH SSC Subcommittee on Physiological Anticoagulants and Thrombophilia. Journal of thrombosis and haemostasis : JTH. 2024. PMID: 39233011
- Bianchini EP. Antithrombin deficiency: no sugar, no diagnosis! Blood. 2022. PMID: 35834281