Bleeding in the antiphospholipid syndrome

Abstract

Antiphospholipid syndrome (APS) is an autoimmune disease characterized clinically by the occurrence of venous or arterial thrombosis, and/or pregnancy morbidity. The detection of persistently elevated levels of antiphospholipid antibodies (aPL) is a requisite laboratory feature for the diagnosis of APS. The positivity for at least one aPL test: lupus anticoagulant and/or IgG/IgM anticardiolipin and/ or IgG/IgM anti-β2glycoprotein I antibodies must be detected. Sometimes aPL coagulopathy may start with a hemorrhagic syndrome when a severe thrombocytopenia, or an acquired thrombocytopathy, or an acquired fator VIII inhibitor, or an acquired prothrombin deficiency is present. aPL-associated thrombocytopenia is usually moderate without clinical manifestations. Except in the occasional situations in which thrombocytopenia is associated with thrombotic microangiopathy, such as catastrophic APS, bleeding is uncommon in APS patients. When platelet counts are less than 30×109/L and there are symptoms of bleeding, the treatments used are the same for idiopathic thrombocytopenic purpura. In rare occasions a hemorrhagic diathesis due to the occurrence of non-neutralizing anti-prothrombin antibodies causing severe hypoprothrombinemia (HPT) can be observed. Levels of prothrombin in plasma are less than 10-20% in cases with HPT-related bleeding requiring transfusion and/or corticosteroid treatment. The APS mainly causes thrombosis, and pregnancy losses. However, other clinical manifestations are also associated with the presence of persistent autoimmune aPL. Bleeding is uncommon but can be the first clinical manifestation in patients having severe thrombocytopenia or prothrombin deficiency.

Keywords:

• Antiphospholipid syndrome
• Antiprothrombin antibodies
• Bleeding
• Thrombocytopenia
• Thrombosis

Background

The antiphospholipid syndrome (APS) is an autoimmune disease characterized clinically by the occurrence of either venous or arterial thrombosis in different vascular beds, and/or recurrent miscarriages in the first trimester, or fetal death in the second or third trimesters, or severe pre-eclampsia requiring delivery of a premature infant before 34 weeks of gestation (Table 1).1 Cerebrovascular infarction is the most common event within the arterial circulation, whereas lower limb deep venous thrombosis and pulmonary embolism are the main sites within the venous circulation. The detection of persistently elevated levels of antiphospholipid antibodies (aPL) is a requisite laboratory feature for the diagnosis of APS (Table 2). The positivity for at least one aPL test: lupus anticoagulant (LA) by clotting assays and/or IgG/IgM anticardiolipin (aCL) and/or IgG/IgM anti-beta₂ glycoprotein I antibodies (aβ₂GPI) by enzyme-linked immunosorbent assays must be detected. aPL can occur in isolation or in association with other autoimmune conditions, particularly systemic lupus erythematosus (SLE).2 The catastrophic APS is a rare variant of APS characterized by microthrombi in multiple organs. It is commonly triggered by several factors including infection, trauma, surgery, and the withdrawal of oral anticoagulation. Less than 1% of patients with the APS develop the catastrophic complication but it has a life-threatening clinical course.

Table 1. Revised clinical criteria for the antiphospholipid syndrome

1. Vascular thrombosis: one or more clinical episodes of arterial, venous, or small vessel thrombosis, in any tissue or organ. Thrombosis must be confirmed by objective validated criteria (i.e. unequivocal findings of appropriate imaging studies or histopathology). For histopathologic confirmation, thrombosis should be present without evidence of inflammation in the vessel wall.

2. Pregnancy morbidity:

a. One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, with normal fetal morphology documented by ultrasound or by direct examination of the fetus, or

b. One or more premature births of a morphologically normal neonate before the 34th week of gestation because of

i. eclampsia or severe preeclampsia defined according to standard definitions, or

ii. recognized features of placenta insufficiency [(i) abnormal or non-reassuring fetal surveillance test(s), e.g. a non-reactive non-stress test, suggestive of fetal hypoxemia, (ii) abnormal Doppler flow velocimetry waveform analysis suggestive of fetal hypoxemia, e.g. absent end-diastolic flow in the umbilical artery, (iii) oligohydramnios, e.g. an amniotic fluid index of 5 cm or less, or (iv) a postnatal birth weight less than the 10th percentile for the gestational age], or

c. Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded.

Table 2. Updated laboratory criteria for the antiphospholipid syndrome

1. Lupus anticoagulant present in plasma, on two or more occasions at least 12 weeks apart, detected according to the guidelines of the International Society of Thrombosis and Haemostasis

2. Anticardiolipin antibody of IgG and/or IgM isotype in serum or plasma, present in medium or high titer (i.e. >40 IgG phospholipid units or IgM phospholipid units, or above the 99th percentile), on two or more occasions at least 12 weeks apart, measured by a standardized enzyme-linked immunosorbent assay (ELISA)

3. Anti-beta2 glycoprotein I antibody of IgG and/or IgM isotype in serum or plasma, (titer above the 99th percentile) present on two or more occasions at least 12 weeks apart, measured by a standardized ELISA

It is advised to classify antiphospholipid syndrome patients in studies into one of the following categories: I, more than one laboratory criteria present (any combination); IIa, lupus anticoagulant present alone; IIb, anticardiolipin antibodies present alone; IIc, anti-beta2 glycoprotein I antibodies present alone

Sometimes aPL coagulopathy may start with a hemorrhagic syndrome when a severe thrombocytopenia, or an acquired thrombocytopathy, or an acquired factor VIII inhibitor, or an acquired prothrombin deficiency is present.

Thrombocytopenia

In the 2006 updated APS criteria, there is a subgroup of clinical disorders not included as current APS-related clinical complications.2 Among them, thrombocytopenia is frequently found in patients with aPL. Thus, a patient with aPL and low platelet count without a history of thrombosis or pregnancy morbidity is not classified as having APS. Thrombocytopenia was recognized early as a complication in patients with LA and aCL. Its incidence ranges between 20 and 45% in different clinical studies. Researchers from the Euro-Phospholipid project, which gathered 1000 patients with either primary or secondary APS, reported a prevalence of 29·6% of thrombocytopenia.3 Patients with APS associated with SLE more frequently exhibited thrombocytopenia than patients with primary APS (43 vs 21%).3 However, aPL-associated thrombocytopenia is usually moderate without clinical manifestations. Most of the patients have more than 50×10⁹/l platelets. Except in the occasional situations in which thrombocytopenia is associated with thrombotic microangiopathy such as catastrophic APS, bleeding is uncommon in APS patients. Consequently, thrombocytopenia in APS rarely requires therapy. When platelet counts are less than 30×10⁹/l and there are symptoms of bleeding, the treatments used are the same for idiopathic thrombocytopenic purpura.4 In the Italian Registry of aPL, 25% of 360 APS patients had thrombocytopenia but only four experienced major hemorrhagic events.5

Contradictory results were described concerning clinical association and thrombocytopenia in APS. Some authors found no clinical association between thrombocytopenia and other APS clinical features while others demonstrated significant relationship between thrombocytopenia and livedo reticularis, chorea, cardiac valve dysfunction and skin ulcerations. In the Italian Registry of aPL, severe thrombocytopenia was associated with a significantly lower prevalence of thrombosis (9%) than those with mild (32%) or non-thrombocytopenia (40%).5

In a recent study, 55 patients with aPL and thrombocytopenia, autoimmune hemolytic anemia, or both were followed for a median of 6 years.6 Thirty aPL patients have isolated hematologic manifestations and 25 also fulfill one current clinical criteria for definite APS. Approximately one-half of the aPL patients with thrombocytopenia developed APS, whereas one-half of them remained free of thrombosis and/or pregnancy morbidity. It appears that mainly depending upon their aPL profile (LA and/or aCL and/or aβ₂GPI), patients with hematologic manifestations belong to a subset of patients with APS, some develop thrombosis during follow-up whereas some continue having thrombocytopenia or hemolytic anemia as isolated clinical manifestations.

The pathogenesis of aPL-related thrombocytopenia is heterogeneous and still unclear. It seems that aPL bind to activated platelets via β₂GPI but thrombocytopenia in APS has also been associated with the presence of antibodies directed against specific platelet membrane glycoproteins such as glycoprotein Ib/IX, glycoprotein IIb/IIIa and glycoprotein IV.

Hypoprothrombinemia

Most autoimmune aPL with specificity towards β₂GPI and/or prothrombin are associated with thrombosis, but in rare occasions a hemorrhagic diathesis due to the occurrence of non-neutralizing anti-prothrombin antibodies (aPT) causing severe hypoprothrombinemia (HPT) can be observed. The first description of LA causing bleeding was published in 1960, describing an 11-year-old girl with severe bleeding and SLE.7 Several authors have reported cases in children under age 17 years after viral infections with or without an associated autoimmune disease. Some of these cases with minor hemorrhagic diathesis resolved without therapy, but in other patients severe HPT caused hemorrhagic manifestations that required transfusion and/or corticosteroid treatment. There are few cases in the literature presenting an acute bleeding manifestation in adult patients. The presence of antibodies that bind prothrombin without neutralizing its coagulant activity leads to a rapid clearance of prothrombin antigen–antibody complexes from the circulation.8 For this reason, both prothrombin activity and antigen are depleted in plasma. Levels of prothrombin in plasma are less than 10–20% in cases with HPT-related bleeding. The main hemorrhagic symptoms are brain hemorrhage, gastrointestinal bleeding, epistaxis, gum bleeding, and diffuse muscular hemorrhage. Corticosteroids impair macrophage phagocytic activity and thus retard the clearance of these complexes. aPT are found not only in patients with acquired HPT but also in plasma from patients with LA and normal prothrombin levels. In most reported cases, the corticosteroid therapy reduces LA activity and aPT titers but aCL and aβ₂GPI titers remain unchanged. Levels of prothrombin measured by clotting, chromogenic and immunologic methods progressively increase while aPT titers decrease.9 Only few reports needed an additional immunosuppressive drug such as cyclophosphamide or azathioprine.

There are also some reports10 describing bleeding in aPL patients related to the acquired deficiency of other clotting factors such as factor VII, factor X, and factor XI.

Conclusions

The APS mainly causes venous and arterial thrombosis, and pregnancy losses. However, other clinical manifestations are also associated with the presence of persistent autoimmune aPL. Bleeding is uncommon but can be the first clinical manifestation in patients having severe thrombocytopenia or prothrombin deficiency.