Thrombophilia is the clinical hallmark of ATD1, and it may manifest in different ways. Most patients present with symptoms of venous thrombosis, arterial thrombosis and/or thromboembolism. Deep vein thrombosis is the presenting symptom in about two-thirds of ATD1 patients, and it is complicated by pulmonary embolism in up to 40% of these cases. Erythema, edema, and pain, which are classical symptoms of deep vein thrombosis, much more commonly affect the lower limbs than the upper ones. Visceral vein thrombosis is reported in approximately 6% of all cases, and cerebral vein thrombosis affects about 1% of patients only. One in twenty patients experiences arterial thromboembolism, either in the form of stroke, myocardial infarction, intracardial thrombus, mechanical heart valve thrombosis, or mesenteric ischemia [1].

• HELLP Syndrome

  On the other hand, women diagnosed with ATD1 deserve special attention during pregnancy; they are at risk of thromboembolic events, deteriorated placental circulation placental abruption, preeclampsia, HELLP syndrome, intrauterine growth restriction, [symptoma.com]

  HELLP syndrome associated with factor V R506Q mutation. Br J Haematol 1996 ; 92 : 999 –1001. De Vries JIP, Dekker GA, Huijgens PC, et al. Hyperhomocysteinaemia and protein S deficiency in complicated pregnancies. [jcp.bmj.com]

• Long Arm

  The gene is located on the long arm of chromosome 1; it spans 13.5 kb and contains 7 exons. The gene product consists of a heparin-binding domain at the N-terminus and a reactive site at the C-terminus. [symptoma.com]

• Cognitive Disorder

  F06.7 경도인식 장애(Mild cognitive disorder) 장애는 기억의 손상, 학습곤란에 의해서 특징이 나타나고 장기 직무에 대한 집중능력을 감소시킨다. 정신적인 직무를 시도할 때는 현저한 정신적 피로감이 나타나고 새로운 학습은 객관적으로 성공했을 때 조차도 주관적으로 어려움을 발견하게 된다. 이러한 징후는 치매(F00-F03) 또는 섬망(F05.-)의 진단을 받을 만큼 심하지는 않다. [dic.impact.pe.kr]

• Cognitive Disorder

  F06.7 경도인식 장애(Mild cognitive disorder) 장애는 기억의 손상, 학습곤란에 의해서 특징이 나타나고 장기 직무에 대한 집중능력을 감소시킨다. 정신적인 직무를 시도할 때는 현저한 정신적 피로감이 나타나고 새로운 학습은 객관적으로 성공했을 때 조차도 주관적으로 어려움을 발견하게 된다. 이러한 징후는 치매(F00-F03) 또는 섬망(F05.-)의 진단을 받을 만큼 심하지는 않다. [dic.impact.pe.kr]

Standard analyses of blood samples, comprising hemogram, blood biochemistry, and bleeding times, yield normal results, and specific assays have to be carried out to determine the functionality of anticoagulant factors. In order to reliably detect antithrombin deficiency, both the activity of antithrombin and its plasma level have to be measured. The activity of antithrombin corresponds to its inhibitory action on activated serine proteases like thrombin or factor Xa in the presence of heparin, while the plasma concentration of the anticoagulant is assessed in immunoassays [2].

ATD1 is associated with decreased concentrations of the antigen and reduced anticoagulant activity, while qualitative deficiencies reflect in low activity levels despite normal plasma concentrations of antithrombin [3]. Symptomatic disease may be expected if antithrombin levels are <70% of the physiological range, which is about 112-140 µg/ml in patients aged more than six months [4]. Still, antithrombin concentrations below the reference range don't necessarily indicate a genetic defect. They may also be found in case of liver disease, protein-losing enteropathy or nephropathy, or disseminated intravascular coagulation, so findings have to be interpreted in context. The recent formation of thrombi and the administration of heparin may similarly account for false-positive results, and minor reductions in antithrombin levels may be attributed to hormonal contraception or hormone replacement therapy [2].

Finally, genetic studies should be realized to identify the underlying mutation of the SERPINC1 gene. In patients with a family history of ATD1, a straight-forward approach may be chosen to identify carriers and non-carriers. Still, genotype-phenotype correlations remain unclear, so the distinction between types 1 and 2 of antithrombin deficiency should be made in at least one member of the family. Family members with the same genotype have been reported to present the same phenotype [5].

Long-term thromboprophylaxis isn't recommended for asymptomatic ATD1 patients because the risk of potentially life-threatening hemorrhages outweighs the benefits of such treatment. The decision against thromboprophylaxis may, however, be reconsidered in moments of risk, e.g., during surgery, immobilization, or pregnancy. In this context, heparin may be applied, but higher-than-conventional doses may be required. Fondaparinux may be effective despite its dependence on antithrombin, and antithrombin concentrates may constitute another option [4].

Treatment strategies in case of thrombosis, venous or arterial thromboembolism don't differ from those pursued if these conditions arise in a patient with normal activity of antithrombin. As implied above, ATD1 patients may prove resistant to conventional doses of heparin, and higher doses may be needed. Titration against clinical response is generally recommended to this end [4].

The prediction of thrombotic events is a major challenge:

• While ATD1 is generally attributed a reduced secretion of qualitatively normal antithrombin into the blood, the precise correlation between the plasma concentration of antithrombin and the severity of the disease has not yet been investigated [2] [4].
• Carriers of null mutations and missense mutations show similar rates of thrombotic disease, although the former favor an earlier onset of symptomatic disease [1].
• Furthermore, patients with a family history of thrombotic disease due to ATD1 are more likely to have complications [4].
• Pregnant women are at particularly high risks of suffering from thrombosis and thromboembolism, and pregnancy losses may occur [6] [7].
• The presence of multiple risk factors, e.g., personal and family history of thrombosis plus pregnancy, further augments the likelihood of complications [4].

ATD1 is caused by mutations of the SERPINC1 gene, which encodes for member C1 of the serine proteinase inhibitor superfamily, better known as antithrombin. The gene is located on the long arm of chromosome 1; it spans 13.5 kb and contains 7 exons. The gene product consists of a heparin-binding domain at the N-terminus and a reactive site at the C-terminus. Heparin binding enhances the activity of antithrombin but is not an absolute requirement for its inhibitory actions.

More than 300 pathogenic mutations of SERPINC1 have been identified to date, and they may induce a quantitative or qualitative deficiency of antithrombin [1]. ATD1 is due to quantitative deficiencies and has been related to missense and null mutations resulting from mostly short deletions, insertions, frameshift, nonsense, and splice-site mutations. Null mutations have been ascribed particularly high risks of venous thromboembolism [1].

ATD1 is generally inherited in an autosomal dominant manner, with the majority of patients being heterozygous for pathogenic mutations of SERPINC1. However, compound heterozygosity resulting in ATD1 has been described [8]. Compound heterozygosity may combine mutations predisposing for the same or different types of antithrombin deficiency, and the phenotype may vary. Complete quantitative deficiency is thought to be incompatible with life and has been shown to induce embryonic lethality in mice [2].

The overall prevalence of antithrombin deficiency has been estimated at 1-8 in 5,000 inhabitants [2]. ATD1 is assumed to account for only about 12% of all cases but is more commonly seen in clinical practice. This is due to the facts that ATD1 has a high penetrance and is associated with a higher risk of thrombotic complications than hereditary antithrombin deficiency type 2 [4]. The mean age at the first diagnosis of venous thromboembolism is 39 years for carriers of missense mutations and 25 years for those with null mutations [1]. By the age of 40, almost 80% of individuals affected by ATD1 have been diagnosed with thrombotic disease. Men and women are affected equally, and no ethnic predisposition has been described [4].

Antithrombin is the major physiological inhibitor of coagulation. It inhibits thrombin as well as factors Xa, IXa, XIa, and XIIa, which are activated in reactions upstream of the conversion of prothrombin to thrombin, in the intrinsic pathway of coagulation. Antithrombin circulates in a form with low inhibitory activity, though. Its actions may be accelerated by heparin or heparin-like glycosaminoglycans. Since there's no free heparin under physiological conditions, it is thought that heparan sulfate on endothelial cells may fulfill this function. Binding of heparin or heparin-like compounds induces a conformational change that boosts the inhibitory activity of antithrombin.

Regardless of the presence of heparin, antithrombin acts as a suicide inhibitor and is consumed upon binding to the aforementioned serinproteases. Thus, the antithrombotic capacity of an individual with ATD1 is severely limited. What's more, the administration of heparin may have no effect because the inhibitor itself is lacking [4].

Interestingly, antithrombin is also part of the complex network of pro- and anti-inflammatory factors. On the one hand, the inhibition of thrombin and coagulation factor Xa hinders the release of proinflammatory cytokines like interleukin 6 and interleukin 8. On the other hand, binding of antithrombin to heparan sulfate on endothelial cells induces the production of anti-inflammatory cytokines like prostacyclin [4] [9]. Therefore, antithrombin has been ascribed a potent anti-inflammatory action. For ATD1 patients, this may be translated into a propensity to inflammation, but it has not yet been clarified whether or not this condition is of clinical significance. Beyond that, the new insights regarding the anti-inflammatory potential of antithrombin make it an interesting candidate for the management of inflammatory conditions [10].

Families affected by ATD1 may benefit from genetic counseling. Precise knowledge regarding the underlying mutation of SERPINC1 largely facilitates the prenatal diagnosis of the disease. However, the results of prenatal diagnosis don't usually affect prenatal or perinatal decisions so that testing may be postponed until after birth. The one exception from this rule are children who are assumed to be homozygous or compound heterozygous for pathogenic SERPINC1 mutations [4].

On the other hand, women diagnosed with ATD1 deserve special attention during pregnancy; they are at risk of thromboembolic events, deteriorated placental circulation placental abruption, preeclampsia, HELLP syndrome, intrauterine growth restriction, fetal loss, and stillbirth. But literature regarding therapeutic strategies for pregnant women is scarce [11]. In general, pregnant women may be provided antithrombotic medication like antithrombin concentrates, low-molecular-weight heparin, and warfarin, among others [4] [11].

ATD1 is a rare cause of thrombophilia. The disease is generally inherited in an autosomal dominant manner and is associated with a reduced secretion of functional antithrombin into the bloodstream. Thus, ATD may also be referred to as quantitative deficiency of antithrombin. The production of dysfunctional antithrombin is characteristic of type 2 disease. Because the latter is much more prevalent, the appropriate first test to carry out when evaluating for antithrombin deficiency is a functional assay that would demonstrate any possible reduction of antithrombin activity. Antigen levels are determined in a second step and allow for the confirmation of the type of the disease. The diagnostic workup is usually complemented by molecular biological studies aiming at the identification of the causative mutation. According to current knowledge, there is no cure for ATD1. Thromboprophylaxis and symptomatic therapy are the cornerstones of ATD1 management, but permanent medication is not required.

Antithrombin plays an essential role in the complex network of factors favoring and inhibiting the formation of blood clots. If the physiological equilibrium cannot be maintained, patients may be prone to bleed or develop thrombosis. Since antithrombin is an anticoagulant, those suffering from antithrombin deficiency are at risk of thrombosis and thromboembolism. The latter term describes the severe consequences of a blood clot detaching from its site of origin and being moved to another vessel, which is obstructed by the thrombus. This may result in a stroke or myocardial infarction. It is very difficult to predict when this will occur, but patients in determined conditions may receive thromboprophylaxis. This applies to those about to undergo surgery, individuals who are immobilized, and pregnant women. Long-term thromboprophylaxis is not recommended because of the inherent risk of severe hemorrhages.

Hereditary antithrombin deficiency is caused by mutations of the SERPINC1 gene. These mutations may cause the body to produce dysfunctional antithrombin, i.e., the amount of antithrombin remains unaltered, but it cannot fulfill its function, or mutations may be associated with a quantitative deficiency of the anticoagulant. Hereditary antithrombin deficiency type 1 refers to the latter. Thus, if the concentration of antithrombin in the patient's blood is assessed, it will be below the normal range, and functional assays will reveal reduced activity of antithrombin.

The disease is inherited in an autosomal dominant manner. Thus, the chance that a child inherits the disease from their mother or father is 50%. If the underlying mutation has been identified in the parents, it can easily be tested whether or not the child carries the pathogenic mutation of SERPINC1.

1. Luxembourg B, Pavlova A, Geisen C, et al. Impact of the type of SERPINC1 mutation and subtype of antithrombin deficiency on the thrombotic phenotype in hereditary antithrombin deficiency. Thromb Haemost. 2014; 111(2):249-257.
2. Cooper PC, Coath F, Daly ME, Makris M. The phenotypic and genetic assessment of antithrombin deficiency. Int J Lab Hematol. 2011; 33(3):227-237.
3. Mulder R, Croles FN, Mulder AB, Huntington JA, Meijer K, Lukens MV. SERPINC1 gene mutations in antithrombin deficiency. Br J Haematol. 2017; 178(2):279-285.
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