Acquired prothrombin deficiency, which is also referred to as acquired factor II deficiency (AFIID), is a rare coagulation disorder of autoimmune origin. It is most frequently diagnosed in the presence of lupus anticoagulants, then constituting the so-called lupus anticoagulant-hypoprothrombinemia syndrome (LAHS). Isolated AFIID is increasingly rare but has been described. AFIID therapy is based on the compensation for blood loss, immunosuppression, and treatment of any underlying disorder.
The clinical presentation of AFIID depends on the extent of the deficiency. While minor deficiencies of prothrombin may go unnoticed, the near-complete inactivation of this coagulation factor may lead to extensive hemorrhages .
The formation of hematoma after minor trauma is most commonly observed. Hematoma may form in subcutaneous tissues, muscles, or joints . In the long term, recurrent hemarthrosis may induce degenerative changes of joint structures and disabling hemophilic arthropathy . Furthermore, AFIID patients tend to bleed for prolonged periods of time after sustaining a penetrating injury, and they may report a propensity to gum bleeding, epistaxis, and other forms of mucosal hemorrhages. Women in fertile age may suffer from menorrhagia . Fortunately, AFIID isn't typically associated with life-threatening hemorrhages of the gastrointestinal tract or central nervous system . Hematuria is rather common, though .
It should be noted that AFIID is generally diagnosed in pediatric patients suffering from systemic lupus erythematosus or viral infections . Thus, their general condition may be determined by the primary disorder or by acquired hemophilia. The primary disorder may be associated with a prothrombotic state that may be restored upon the resolution of AFIID  .
If anamnestic and clinical data suggest hemophilia, coagulation studies have to be carried out. These include the assessment of platelet count, plasma fibrinogen concentration, activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT). While APTT reflects the integrity of the intrinsic cascade and common pathway of coagulation, PT depends on the extrinsic cascade and common pathway. In order to measure TT, thrombin is added to the plasma sample, so the result doesn't depend on the conversion of factor II to factor IIa. Hence, prolonged APTT and PT would be expected in AFIID patients, whereas their TT should be in the reference range  . Platelet count and plasma fibrinogen concentration are not altered by AFIID.
Prolonged APTT and PT may also be obtained in those who suffer from a deficiency of factors I, V, or X, or vitamin K, from liver disease or disseminated intravascular coagulation, so all these conditions should be ruled out  . Similarly, therapy with anticoagulants like warfarin may induce a prolongation of APTT and PT. The patient's medical history, hemogram, and blood chemistry should implicate a coagulation disorder, and this suspicion is most easily confirmed by the detection of an endogenous inhibitor. Therefor, the patient's plasma is mixed with normal plasma . In case of an antibody-mediated inactivation of AFIID, this procedure will not correct prolonged bleeding times and thereby confirm the presence of an inhibitor, namely lupus anticoagulant or an inhibitor of factorsor prothrombin. The presence of AFIID antibodies that accelerate the factor's clearance but don't interfere with its activation may result in a normalization of PT upon mixing .
Testing for lupus anticoagulant is the next step and carried out as the dilute Russell’s Viper Venom Test or Staclot LA. Its results depend on the etiology of AFIID in the index case. In LAHS patients, lupus anticoagulant is present; in the rare cases of isolated AFIID, it cannot be detected. Lupus anticoagulant is typically related to venous and arterial thrombosis, so its association with a tendency to bleed should raise suspicion as to LAHS and warrants the assessment of factor II activity . If the test for lupus anticoagulant yields negative results, the activities of coagulation factors I, V, and X, should also be measured. In AFIID, the activity of prothrombin is below the reference range, and a determination of the factor II inhibitor titer becomes necessary .
The diagnosis of AFIID may be followed by studies aiming at the identification of the underlying disorder if it hasn't been defined until this point. Laboratory analyses of blood samples may yield valuable hints at a primary autoimmune disease, so the presence of anti-beta-2-glycoprotein, anticardiolipin, anti-double-stranded DNA, antinuclear, antimitochondrial, and antineutrophil cytoplasmic antibodies should be reviewed . Due to a possible link to malignancy, patients should undergo a general cancer screening.
Because of the rarity of AFIID, there are no standardized recommendations for treatment . According to the general condition of the patient and their particular needs, either of the strategies listed below may be followed.
AFIID is a potentially curable disease, and even spontaneous resolution has been described. The latter is likely to occur in patients developing AFIID due to the transient formation of lupus anticoagulants, e.g., in the scope of a viral infection. If the underlying disorder persists, relapses are to be expected. AFIID-related hemorrhages may be life-threatening, and fatal cases have been reported  . Death may also occur from the primary disorder .
AFIID is provoked by autoantibodies directed against coagulation factor II. These antibodies may partially or completely neutralize the function or activation of prothrombin, or accelerate its clearance . Similar to other autoimmune disorders, the precise triggers of the immune response against prothrombin remain unknown. Certain pathological conditions, however, seem to predispose to AFIID. There is a high prevalence of systemic lupus erythematosus and viral infections among AFIID patients, and a causal relation is very likely. AFIID has also been related to lymphoma and other types of malignancy  . In some cases, though, no primary disease can be identified, and AFIID is deemed idiopathic .
AFIID is a rare disorder affecting two groups of patients:
The conversion of prothrombin to thrombin constitutes the first step of the common pathway of coagulation. It is preceded by the intrinsic and extrinsic cascades, so irrespective of whether endothelial lesions or tissue damage trigger clotting, it always relies on the presence of factor II and its activation to factor IIa . Thus, AFIID may cause extensive, potentially life-threatening hemorrhages.
An interesting phenomenon can be observed in LAHS patients. These patients' blood contains autoantibodies binding to plasma proteins that have an affinity for phospholipid surfaces, such as prothrombin. The antibody-prothrombin complexes are rapidly cleared, thereby decreasing factor II levels and causing a hemorrhagic diathesis - which is in contrast to the more common prothrombotic phenotype of patients with antiphospholipid syndrome. The hepatic clearance of the antibody-prothrombin complexes is even faster in pediatric patients, which may explain why LAHS is preferentially observed in the young. Somewhat surprisingly, antibody binding doesn't interfere with the activiation of prothrombin, so PT may normalize after mixing the patient's plasma with normal plasma. As implied above, antiphospholipid antibodies may also bind to anticoagulative components of the coagulation system, thereby inducing a prothrombotic state . This is the pathogenesis of antiphospholipid syndrome, a frequent complication of systemic lupus erythematosus. The antibodies' affinity to prothrombin seems to determine whether a patient develops LAHS or antiphospholipid syndrome .
Few recommendations can be given to prevent the onset of AFIID. The precise triggers of the disease remain elusive, and effective measures to prevent the primary disorders predisposing to AFIID have not been described. However, regular follow-ups may allow for the early identification of high-risk patients, e.g., those suffering from systemic lupus erythematosus who test positive for antiphospholipid antibodies. These individuals may subsequently be informed about the symptoms of a coagulation disorder, so that they can react faster in case of hemorrhages or thromboembolism . In general, patients should stay up to date with screenings for cancer, so malignancies can be diagnosed and treated in a timely manner.
AFIID is a rare coagulation disorder. The deficiency of factor II interrupts the coagulation cascade in the common pathway, so neither the intrinsic nor the extrinsic activation of coagulation are successful. The severity of the disease varies largely, but AFIID patients may experience life-threatening hemorrhages. Disease onset is triggered by an autoimmune reaction leading to the generation of antibodies against prothrombin. The causes of this autoimmune reaction remain unknown, but patients suffering from systemic lupus erythematosus, viral infections, or lymphoma seem to be predisposed. Still, many cases of AFIID are deemed idiopathic because no primary disorder can be identified.
The diagnosis of AFIID relies on standard coagulation studies. Common findings are prolonged APTT and PT, which may or may not normalize when the patient's plasma is mixed with normal plasma. Depending on the etiology of AFIID, lupus anticoagulant may yield positive or negative results: AFIID may occur as a complication of systemic lupus erythematosus and be associated with the formation of lupus anticoagulants, and the patient is then diagnosed with LAHS. On the other hand, AFIID may develop in the absence of lupus anticoagulant, resulting in the rare entity of isolated AFIID.
AFIID treatment is based on the rapid compensation for blood loss, the suppression of the causative autoimmune reaction, and, if feasible, therapy of the primary disease. If cure of the underlying disorder can be achieved, chances are the patient will also recover from AFIID.
The formation of blood clots is tightly regulated by a complex network of factors favoring or inhibiting coagulation. Prothrombin is one of these factors and is also called factor II. It is required for one of the final steps of the coagulation cascade, and patients with a factor II deficiency have a propensity to bleed. Such a deficiency may be congenital, when certain mutations are inherited, or acquired. Acquired prothrombin deficiency manifests if the patient's body generates antibodies that bind to factor II and accelerate its degradation. But why are those antibodies produced?
This question could not yet be answered satisfactorily. Acquired prothrombin deficiency is most commonly diagnosed in children and adolescents who suffer from systemic lupus erythematosus. Individuals who recently recovered or are still suffering from a viral infection are at increased risks, too. Deficiency of factor II may occasionally affect the elderly, and while the disease may be related to cancer in this age group, no cause is identified in the majority of patients. Indeed, studies aiming at the identification of an underlying disorder are an integral part of the diagnosis, which is otherwise based in standard coagulation tests.
Treatment relies on three pillars: the transfusion of blood products to immediately compensate for possibly life-threatening blood loss, the administration of immunosuppressive drugs to inhibit the production of autoantibodies, and an adequate therapy of the primary disease if it can be identified. Unless the underlying disorder is associated with a poor outcome, patients diagnosed with acquired prothrombin deficiency have a favorable prognosis. In the majority of individuals, especially in children, spontaneous resolution occurs.