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Bleeding in the antiphospholipid syndrome

Ricardo Forastiero

To cite this article: Ricardo Forastiero (2012) Bleeding in the antiphospholipid syndrome,
Hematology, 17:sup1, s153-s155, DOI: 10.1179/102453312X13336169156654

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Bleeding in the antiphospholipid syndrome
Ricardo Forastiero
Department of Physiology, Favaloro University, Division of Hematology, Thrombosis and Haemostasis,
University Hospital, Favaloro Foundation, Buenos Aires, Argentina

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-
b2glycoprotein 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 306109/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 erythematosus (SLE).2 The catastrophic APS is a rare

The antiphospholipid syndrome (APS) is an auto-
immune disease characterized clinically by the occur-
rence 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 (ab2GPI) by enzyme-
linked immunosorbent assays must be detected. aPL
can occur in isolation or in association with other
autoimmune conditions, particularly systemic lupus
Correspondence to: Ricardo Forastiero, Hematologia, Universidad
Favaloro, Solis 453, (C1078AAI) Buenos Aires, Argentina. Email:
rforastiero@favaloro.edu.ar
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.
Sometimes aPL coagulopathy may start with a
hemorrhagic syndrome when a severe thrombocyto-
penia, or an acquired thrombocytopathy, or an
acquired factor VIII inhibitor, or an acquired pro-
thrombin 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, throm-
bocytopenia is frequently found in patients with aPL.
Thus, a patient with aPL and low platelet count
without a history of thrombosis or pregnancy morbid-
ity 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

ß W. S. Maney & Son Ltd 2012

DOI 10.1179/102453312X13336169156654 Hematology 2012 VOL . 17 SUPPL . 1 S 153
Forastiero Bleeding in the APS

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.

patients with either primary or secondary APS, report-
ed a prevalence of 29.6% of thrombocytopenia.3
Patients with APS associated with SLE more fre-
quently 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 506109/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 306109/l and there are symptoms of bleeding, the
treatments used are the same for idiopathic thrombo-
cytopenic 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 ulcera-
tions. In the Italian Registry of aPL, severe throm-
bocytopenia 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 ab2GPI), patients with hemato-
logic 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 thrombocytope-
nia is heterogeneous and still unclear. It seems that
aPL bind to activated platelets via b2GPI 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 glyco-
protein IV.
Hypoprothrombinemia
Most autoimmune aPL with specificity towards
b2GPI 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 pub-
lished 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

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

S154 Hematology 2012 VOL . 17 SUPPL . 1


viral infections with or without an associated auto-
immune 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 prothrom-
bin in plasma are less than 10–20% in cases with
HPT-related bleeding. The main hemorrhagic symp-
toms are brain hemorrhage, gastrointestinal bleeding,
epistaxis, gum bleeding, and diffuse muscular hemor-
rhage. Corticosteroids impair macrophage phagocy-
tic 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 ab2GPI titers remain unchanged.
Levels of prothrombin measured by clotting, chromo-
genic and immunologic methods progressively increase
while aPT titers decrease.9 Only few reports needed an
additional immunosuppressive drug such as cyclopho-
sphamide 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 throm-
bosis, and pregnancy losses. However, other clinical
Forastiero Bleeding in the APS
manifestations are also associated with the presence
of persistent autoimmune aPL. Bleeding is uncom-
mon but can be the first clinical manifestation in
patients having severe thrombocytopenia or pro-
thrombin deficiency.
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