Hereditary antithrombin deficiency type 2, in literature generally referred to as type 2 antithrombin III deficiency (AT3D2), is a major risk factor for thromboembolic disease. It is caused by mutations of the SERPINC1 gene that lead to the production of dysfunctional antithrombin III. By contrast, hereditary deficiency of antithrombin III type 1 is associated with quantitative deficiencies of antithrombin III. AT3D2 is less frequently reported than type 1 disease but seems to be more prevalent in the general population. This apparent contradiction is explained by the fact that AT3D2 is less thrombogenic than its counterpart.
Thrombophilia is the clinical hallmark of AT3D2, and it may manifest in different ways. Most patients present with symptoms of venous thrombosis, arterial thrombosis and/or thromboembolism. Deep vein thrombosis, possibly complicated by pulmonary embolism, is the presenting symptom in about one-third of AT3D2 patients. Erythema, edema, and pain, which are classical symptoms of deep vein thrombosis, more commonly affect the lower limbs than the upper ones. Visceral vein thrombosis is reported in <5% of all cases, and cerebral vein thrombosis affects about 1% of patients only. One in ten patients experiences arterial thromboembolism, either in the form of stroke, myocardial infarction, intracardial thrombus, mechanical heart valve thrombosis, or mesenteric ischemia. The proportions described are different from those known for hereditary deficiency of antithrombin III type 1: Here, deep-vein thrombosis affects the majority of patients, but arterial thromboembolism is rare .
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 III deficiency, both the activity of antithrombin III and its plasma level have to be measured. The activity of antithrombin III 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 .
AT3D2 is associated with normal concentrations of the antigen but reduced anticoagulant activity, while quantitative deficiencies reflect in low activity levels and decreased plasma concentrations of antithrombin III . Accordingly, the cause of thrombophilia may be overlooked if only antigen levels are assessed. Reduced antithrombin III activity may also be found in case of liver disease or disseminated intravascular coagulation, so findings have to be interpreted in context. The recent formation of thrombi and the administration of heparin may also account for false-positive results .
Finally, genetic studies should be realized to identify the underlying mutation of the SERPINC1 gene. In patients with a family history of AT3D2, 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 III 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 .
Long-term thromboprophylaxis isn't recommended for asymptomatic AT3D2 patients because the risk of potentially life-threatening hemorrhages outweighs the benefits of such treatment. This applies to all subtypes of the disease. However, the decision against thromboprophylaxis may 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 III, and antithrombin III concentrates may constitute another option .
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 III. As implied above, AT3D2 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 .
Thromboembolic events are major causes of morbidity and mortality in AT3D2 patients, with pregnant women being at particularly high risks of suffering from thrombosis and thromboembolism. Pregnancy losses are also common  . A patient's individual prognosis depends on a variety of factors, such as their family history, the severity and subtype of the disease (see Etiology). Half of all patients diagnosed with AT3D2 of subtype HBS don't experience venous thromboembolism until the age of 50, but this applies to only 40 and 30% of those with subtypes RS and PE, respectively. By contrast, arterial thromboembolism is almost exclusively seen in those with subtype HBS .
AT3D2 is caused by mutations of the SERPINC1 gene, which encodes for member C1 of the serine proteinase inhibitor superfamily, better known as antithrombin III. 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 III 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 III . AT3D2 is due to qualitative deficiencies and has mainly been related to missense mutations, which may affect the heparin-binding domain and/or the reactive site . Accordingly, subtypes of AT3D2 may be defined: Subtype 2a corresponds to mutations interfering with both domains, subtype 2b to those compromising the reactive site, and subtype 2c to those impairing heparin binding. These subtypes may also be referred to as type 2-PE (pleiotropic effects), type 2-RS (reactive site), or type 2-HBS (heparin binding site). Noteworthy, mutation c.1246G>T results in the synthesis of an antithrombin III variant that is inhibited by heparin, but whose anticoagulant activity remains impaired in the absence of this glycosaminoglycan . This form of AT3D2 may not be classified as either of the aforementioned subtypes and suggests an even greater variability in the molecular background of antithrombin III-related thrombophilia .
AT3D2 is generally inherited in an autosomal dominant manner, with the majority of patients being heterozygous for pathogenic mutations of SERPINC1. However, homozygosity has been described. Affected individuals usually suffer from severe thrombophilia manifesting early in life and are typically diagnosed with AT3D2 of subtype HBS  .
The overall prevalence of antithrombin III deficiency has been estimated at 1-8 in 5,000 inhabitants . AT3D2 may account for almost 90% of all cases but is less frequently seen in clinical practice. This is due to the fact that hereditary deficiency of antithrombin III type 1 is associated with a higher risk of thrombotic complications .
Despite AT3D2 being a congenital condition, it isn't usually diagnosed until adulthood. Severe AT3D2 has been hypothesized to cause intrauterine death, so intermediate and mild forms only may be compatible with life. In AT3D2 patients, venous thromboembolism occurs at a mean age of 39 years, entailing a diagnostic workup for thrombophilia. Arterial thromboembolism tends to occur a few years earlier . Man and women are affected equally, and no ethnic predisposition has been described .
Antithrombin III 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 III 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 III, but this process is largely disturbed if the heparin binding site is altered due to pathogenic mutations of the SERPINC1 gene. Notwithstanding, heparin binding remains without effect if antithrombin isn't capable of forming complexes with thrombin or any of the other coagulation factors mentioned above. This is the case in patients suffering from AT3D2 of subtype RS .
Interestingly, antithrombin III 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 III to heparan sulfate on endothelial cells induces the production of anti-inflammatory cytokines like prostacyclin  . Therefore, antithrombin III has been ascribed a potent anti-inflammatory action. For AT3D2 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 III make it an interesting candidate for the management of inflammatory conditions .
Families affected by AT3D2 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 .
On the other hand, women diagnosed with AT3D2 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, especially if information regarding risk-adopted therapies based on the disease' subtype is sought . In general, pregnant women may be provided antithrombotic medication like antithrombin III concentrates, low-molecular-weight heparin, and warfarin, among others   .
AT3D2 is a rare cause of thrombophilia. The disease is generally inherited in an autosomal dominant manner and is associated with the production of dysfunctional antithrombin III. Thus, AT3D2 may also be referred to as qualitative deficiency of antithrombin III. The diagnosis of AT3D2 requires functional assays revealing a reduction of antithrombin III activities; antigen levels alone are insufficient to rule out this condition. 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 of AT3D2. Thromboprophylaxis and symptomatic therapy are the cornerstones of AT3D2 management, but permanent medication is not required.
Antithrombin III 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 III is an anticoagulant, those suffering from antithrombin III 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 deficiency of antithrombin III is caused by mutations of the SERPINC1 gene. These mutations may cause the body to produce dysfunctional antithrombin III, i.e., the amount of antithrombin III remains unaltered, but it cannot fulfill its function, or mutations may be associated with a quantitative deficiency of the anticoagulant. Hereditary deficiency of antithrombin III type 2 refers to the former. Thus, if the concentration of antithrombin III in the patient's blood is assessed, it will be in the normal range. However, functional assays will reveal reduced activity of antithrombin III.
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.