HEMATOLOGICAL MANIFESTATIONS OF

CONNECTIVE TISSUE DISORDERS

AYMEN OMER
Systemic lupus erythematosus (SLE) is the most common multisystem
connective tissue disease.

Hematological abnormalities are common in SLE. All the cellular elements of the
blood & coagulation pathway can be affected in SLE patients.

Haematological manifestations of systemic lupus erythematosus (SLE):

1. Anemia
2. Leucopenia.
3. Lymphopenia.
4. Thrombocytopenia.
5. Thrombotic thrombocytopenic purpura (TTP).
6. Antiphospholipid syndrome (APS).
7. Myelofibrosis.
ACR hematologic criteria in Systemic Lupus Erythematosus

In the updated 1982 ACR criteria, the presence of one or more of the four
following elements is now considered as a single hematologic disorder:

I. Hemolytic anemia (with reticulocytosis).

II. Leukopenia (<4000/µL on two or more occasions).
III. Lymphopenia (< 1500/µL on two or more occasions).
IV. Thrombocytopenia (< 100,000/microL in the absence of offending drugs).
Red Cell Changes
Anemia
 According to the World Health Organization (WHO), anemia is defined as hemoglobin
(Hb) levels <12.0 g/dL in women and <13.0 g/dL in men. It is about 50% in SLE & (33 -
60)% in R.A.

 Anemia, the most common extra-articular manifestation of rheumatoid arthritis (RA), is

associated with a negative impact on both patient symptoms and quality of life. anemic
patients were reported to show more severe disease than nonanemics.

 Anemia emerged as a hematologic manifestation strongly associated with disease activity

and with early and late damage during the SLE course, being also identified as a disease
flare and mortality predictor.

 Anemia has been reported to be a predictor of unfavourable prognosis in systemic

sclerosis (SSc) (scleroderma).
Pathogenesis of anemia in connective tissue diseases:
A. Nonautoimmune
• Anemia of chronic disease
• Iron deficiency anemia
• Anemia of chronic renal failure
• Sideroblastic anemia
• Marrow erythroid hypoplasia
• Drug toxicity
B. Autoimmune
• Autoimmune hemolytic anemia
• Pure red cell aplasia
• Aplastic anemia
• Pernicious anemia
• Autoimmune dyserythropoiesis
• Drug-induced hemolytic anemia
A. Anemia of chronic disease:

• ACD and IDA are widely reported as the most common variants in RA.

• In RA of recent onset, mild anemia was found to develop in 64% of patients, mainly
within the first year, and was classified as ACD in 77%, and as iron deficiency
anemia (IDA) in 23%, with frequent overlap.

• Anemia in SLE is suppressed erythropoiesis from chronic inflammation (anemia of

chronic disease or anemia of chronic inflammation), being the most common form
(60 to 80 %) . This type of anemia is normocytic and normochromic with a
relatively low reticulocyte count. Although serum iron levels may be reduced, bone
marrow iron stores are adequate and the serum ferritin concentration is elevated.

• In the absence of either symptoms or renal insufficiency, anemia of chronic

inflammation does not require specific treatment.
Pathogenesis of Anemia of chronic disease (ACD):

I. Iron Dysregulation/Reticulo-Endothelial Iron Block.

II. Hypoferraemia.
III.Reduced Erythropoiesis and Reduced Erythrocyte Survival.
IV.Diminished Response to Erythropoietin.
 In normal individuals, serum erythropoietin ranges between 4 and 24
mU/mL, with mean values between 8 and 10 mU/mL.

 Patients with mild anemia usually have an erythropoietin level within the
normal range.

 Only in cases of severe anemia elevated erythropoietin will be observed in

patients with RA. The marked elevation in serum erythropoietin that is seen
in iron-deficiency anemia is never observed in the anemia of chronic disease.
• Erythropoietin production is regulated by cytokine levels, tissue oxygenation
and tissue iron reserves.

• In anemia of chronic disease, tissue iron reserves are increased and the degree
of tissue hypoxia is not severe. Hence, serum erythropoietin production is not
increased according to the degree of anemia.

• In patients with anemia of RA, there are usually adequate iron stores,
however, much of that iron is unavailable for use due to hepcidin, and excess
intracellular iron actually suppresses erythropoietin production.

• In iron deficiency, tissue iron reserves are low or absent and erythropoietin
production is significantly increased.
• Functional iron deficiency in which there are adequate quantities of tissue
iron, but these iron reserves cannot be mobilized for red cell production
quickly enough by erythropoietin. This is due to the small protein produced
by the liver called hepcidin, which regulates iron absorption and turnover.

• In inflammation, IL-6 levels increase in response to the inflammatory

stimuli. Elevated IL-6 levels increase the levels of acute-phase proteins such
as C-reactive protein, fibrinogen, and hepcidin.
• Hepcidin blocks the ability of gastrointestinal cells to absorb iron and also the
ability of macrophages to release iron.

• When red blood cells die and are ingested by macrophages, iron from the
digested red cells is typically released by the macrophages and recycled in the
circulation bound to transferrin for use in red cell production.

• When hepcidin levels are elevated, iron remains sequestered in the

macrophages. Both these effects are mediated by the ability of hepcidin to
bind to ferroportin-1, which is present on macrophages and enterocytes and
is responsible for transporting iron out of cells. Binding to hepcidin targets
ferroportin for lysosomal degradation.
• Ability of IL-1 and TNF to induce hepcidin production is likely related to
their ability to promote IL-6 production.

• IL-6 stimulates hepcidin production is related to its activation of the JAK-

STAT pathway, which is associated with increased upregulation of hepcidin
mRNA. Once hepcidin levels increase, iron absorption ceases.
 Patients with symptoms due to anemia of chronic inflammation, who have no
other definite indication for glucocorticoid or other immunosuppressive
therapy, may be given a trial of an agent that promotes erythropoiesis:
1. Epoetin alfa (recombinant human erythropoietin).
2. Darbepoetin alfa, a unique molecule that stimulates erythropoiesis with a
longer half life than recombinant human erythropoietin.
 Symptomatically anemic patient, having signs of active inflammations, and
do not respond to erythropoiesis stimulating agents, often improve with
glucocorticoids if are used in high doses(1 mg/kg per day of prednisone or its
equivalent in divided doses). After approximately one month of treatment,
the response is unsatisfactory (eg, hemoglobin still <11 g/dL) the dose of
glucocorticoids should be rapidly reduced, and discontinued if there is no
other indication for their use. If there is a response, the dose should be
tapered as rapidly as possible to the lowest dose that maintains the
improvement.

 Immunosuppressive agents also may help, but carry a risk of further bone
marrow suppression.
 The effects of IL-6 in contributing to anemia are 2-fold:
1. First, it increases the plasma volume.
2. Second, it stimulates the inappropriate production of hepcidin:
which prevents iron absorption and iron transport from macrophages.
 Tocilizumab (Actemra ®) is humanized monoclonal antibody against the
interleukin-6 receptor (IL-6R).
 Mean changes in Hb in patients with anemia were also higher in patients
receiving infliximab compared with placebo.
 Patients treated with TCZ demonstrated a mean and adjusted increase in Hb
and Hct levels of 0.23 g/dL and 0.96%, respectively, at 24 months.
 Patients with anemia treated with TCZ demonstrated increases in Hb and
Hct by 0.72 g/dL and 2.06%, respectively.
 Other biologic disease-modifying antirheumatic drugs (DMARDs) and the
small-molecule Janus kinase inhibitor, tofacitinib, were not as effective in
improving anemia markers.
B. iron deficiency anemia (IDA):

less frequently, microcytic hypochromic anemia, defined by:

I. Hypoferremia.
II. normal or decreased transferrin levels.
III. reduced transferrin saturation.
IV. normal/elevated serum ferritin.
V. normal or reduced reticulocytes.
VI. adequate/increased reticuloendothelia system (RES) iron stores.
VII. iron-restricted erythropoiesis, in the presence of normal (BM M/E ratio).
C. Renal insufficiency
 Low level of erythropoietin is a hallmark of anemia due to renal
insufficiency, due to deficient production of erythropoietin by the
diseased kidneys.

 In SLE, anemia, and renal insufficiency who does not have other
evidence of active inflammation, administration of erythropoiesis-
stimulating agents may be indicated when the anemia is
symptomatic or the hemoglobin concentration is <11 gm/dL.
D. Red cell aplasia
• May be due to antibodies directed against either erythropoietin or
erythroblasts. it is rare.

• Responds to steroids, cyclophosphamide and cyclosporine

successfully.

• Rare to be presented as aplastic anemia, mediated by auto

antibodies against bone marrow precursors. Immunosuppressive
therapy may be effective.

• Bone marrow suppression can also be induced by medications such

as immunosuppressive drugs.
E. Autoimmune hemolytic anemia
 Characterized by an elevated reticulocyte count, low haptoglobin levels, increased indirect
bilirubin concentration, and a positive direct Coombs' test, has been noted in up to 10 % of
patients with SLE.

 Warm-type IgG, Underexpression of CD55 and CD59 serve as protection against complement-
induced cell lysis.

 The presence of hemolytic anemia may be associated with other manifestations of severe
disease such as renal disease, seizures, and serositis .

 Some patients have a positive Coombs' test without overt hemolysis. The presence of both
immunoglobulin and complement on the red cell is usually associated with some degree of
hemolysis, while the presence of complement alone (eg, C3 and/or C4) is often not
associated with hemolysis.
 Treatment of AIHA:

 AIHA responds to steroids (1 mg/kg per day of prednisone or its equivalent in

divided doses).

 Once the hematocrit begins to rise and the reticulocyte count falls, steroids can
be rapidly tapered. If there is no response, we can consider pulse steroids
(eg,1000 mg methylprednisolone intravenously daily for three days),
azathioprine, cyclophosphamide , or splenectomy. Success rates is high as 60%.

 Drugs to patients with refractory AIHA :

IVIG, danazol, mycophenolate mofetil , and rituximab.
• IVIG 400 mg/kg for five consecutive days and then monthly for 1 year, most
patients respond for treatment in day 5.

• IVIG demonstrates the short-term efficacy of IVIG but no long-term response.

F. Microangiopathic hemolytic anemia
 manifested by a peripheral blood smear showing schistocytes and elevated serum
levels of lactate dehydrogenase (LDH) and bilirubin.

 Many affected patients also have thrombocytopenia, kidney involvement, fever, and
neurologic symptoms. This pentad of features is compatible with a diagnosis of TTP.

 Whether the occurrence of both SLE and TTP in an individual patient is a coincidence or
represents a true association is an unsettled question.

 The presence of aPL in SLE patients with severe hemolytic anemia, renal dysfunction, and
central nervous system involvement has also been reported.
 patients, those treated with plasma infusions or plasmapheresis,
glucocorticoids alone, or no therapy had mortality rates of 25, 50, and 100
percent, respectively.

 Patients with SLE, severe microangiopathic hemolytic anemia, and other major
organ dysfunction should be treated with plasmapheresis and plasma infusion
as in other cases of thrombotic thrombocytopenic purpura or the hemolytic-
uremic syndrome.

 Less severe disease treated with high-dose glucocorticoids and observed

carefully with the addition of plasmapheresis should they deteriorate or fail to
improve with steroid treatment alone.
An approach to lupus patient with anaemia
• After the detailed analysis and discussion of each type of anemia associated with SLE, here is
a simple approach to anemic SLE patient with an easy mechanism to the diagnosis.

 Anaemia can be divided into

I. impaired red cell production (marrow suppression, nutrient deficiency)
II. increased red cell destruction (haemolysis, hypersplenism) or
III. blood loss.

 Measurement of reticulocyte production (reticulocyte index) usually used to make this

distinction and it is the major step for determination of causes of anaemia.

 IDA is defined by serum ferritin level below: 20 μg/dl.

 Pernicious anemia (PA) is defined by serum vitamin B12 of less than: 180 pmol/l
together with one or more of the following: an abnormal Schilling test result or
the presence of anti-intrinsic factor antibody in the blood.

 Peripheral blood smear is a mandatory step in the initial evaluation of all SLE
patients with hematologic disorders.

 The examination of blood films stained with Wright's stain frequently provides
important clues in the diagnosis of anemias and various disorders of leukocytes
and platelets.
 For example, some of the abnormalities suspicious for the presence
of hemolysis in blood smear include the following:
• Spherocytes (microspherocytes and elliptocytes) indicate autoimmune
hemolytic anemia
• Fragmented RBC (schistocytes, helmet cells) indicating the presence of
microangiopathic hemolytic anemia (TTP-HUS).
• Acanthocytes (spur cells) in patients with liver disease.
• Blister or "bite" cells due to the presence of oxidant-induced damage to the
red cell and its membrane (G-6-PD).
• RBCs with inclusions, as in malaria, babesiosis, and Bartonella infections ("
nonimmune hemolytic anemia due to systemic disease", '').
• Teardrop RBCs with circulating nucleated RBC and early white blood cell
forms, indicating the presence of marrow involvement, as in primary
myelofibrosis or tumor infiltration.
 So at a practical level, when you are faced with SLE anaemia, it will be easy to
differentiate among the possible mechanisms with only a few tests. If the
reticulocytes are increased, a haemolytic process or acute bleeding should be
the probable cause. If the reticulocytes are inadequate, you should rule out a
nutritional deficiency of iron, vitamin B12, or folate.

 IF ferritin concentration ˃20 μg/dl, IDA never present and BM examination may
be considered, but we have to mention that ferritin is an acute phase reactant
and it can be elevated in any patients with inflammatory process due to any
cause, although the diagnostic yield may be very low and anaemia of chronic
disease is the most common diagnosis of exclusion.
Leucoytes Changes
Leukopenia in systemic lupus erythematosus
• usually reflects disease activity. A white blood cell count of less than
4500/microL has been noted in approximately 50 percent of patients, especially
those with active disease, while lymphocytopenia occurs in approximately 20
percent.

• In comparison, a white blood cell count below 4000/microL (an American

College of Rheumatology criterion for SLE) occurs in only 15 to 20 percent of
patients.

• Neutropenia, lymphocytopenia, and decreased circulating eosinophils and

basophils may all contribute to leukopenia.
 Neutropenia

 Neutropenia in patients with SLE can result from: immune mechanisms,

medications (eg, cyclophosphamide or azathioprine), bone marrow
dysfunction, or hypersplenism.

 Other clinical features that may be associated with moderate to severe

neutropenia (absolute neutrophils <1000/microL) include infection, anemia,
thrombocytopenia, and a history of neuropsychiatric involvement.
Pathogenesis of Neutropenia:
• Both humoral and cellular immune mechanisms may be involved. Three
potential mechanisms of neutropenia in SLE are
• (1) increased peripheral destruction of granulocytes, due to circulating
antineutrophil antibodies. The IgG neutrophil-binding activity of the patient’s
serum was elevated. complement-activating antineutrophil IgG autoantibodies
existed in SLE and their presence correlated with neutropenia. SLE with anti-Ro
autoantibodies were found to have significantly lower neutrophil counts than
patients with SLE without anti-Ro.
• (2) changes in marginal and splenic pool, or increased margination.
• (3) decreased marrow production.
Treatment of Neutropenia:
• A treatment regimen of recombinant human granulocyte (rhG)-CSF and
methylprednisolone saw a rapid and sustained resolution of the neutropenia,
rhG-CSF (100 μg/day for 5 days) and methylprednisolone pulse therapy (1 g/day
for 3 days). Filgrastim resulted in a rapid rise in neutrophil count within 48 h.
Lymphocytopenia

 Lymphocytopenia (lymphocytes less than 1500/microL),

especially involving suppressor T cells, seen in 20 - 75 % of
patients, particularly during active disease.

 This finding is strongly associated with IgM, cold reactive,

complement fixing, and presumably cytotoxic
antilymphocyte antibodies; such antibodies were noted in
almost all patients with SLE and the antibody titer
correlated directly with the degree of lymphopenia.
• Treatment of Lymphopenia:
• no recommendations for treatment specifically for lymphopenia.

• Use of prophylaxis against P. jiroveci should be considered in patients with

lymphocyte counts ≤0.35×109/L.30

• Belimumab, a monoclonal antibody that impairs B lymphocyte survival by

binding B lymphocyte stimulator (BLyS), is efficacious as add-on therapy in
patients with SLE with uncontrolled disease activity.
Decreased eosinophils and basophils

 Steroid therapy may result in low absolute eosinophil and monocyte

counts.

 The number of basophils may also be decreased in SLE, particularly

during active disease.
Leukopenia:
• In SLE rarely needs treatment.
• Neutropenia and recurrent pyogenic infections, need treatment.
• Prednisone (10 to 60 mg/day) may raise the WBC count but can also
result in an increased risk of infections.
• Immunosuppressive agents such as azathioprine or
cyclophosphamide may worse leukopenia via bone marrow
suppression.
• Cautious use of azathioprine, with monitoring of the white blood cell
count, may be considered in this setting.
 Leukocytosis
• Leukocytosis (mostly granulocytes) can occur in SLE. When present, it is usually
due to infection or the use of high doses of glucocorticoids .but may occur
during acute exacerbations of SLE. A shift of granulocytes to more immature
forms (a "left" shift) suggests infection.
Thrombocytopenia in systemic lupus erythematosus
 Mild thrombocytopenia (platelets 100,000 -150,000/microL) has been noted in 25- 50
% of patients; while counts of ˂ 50,000/microL occur in 10 %.

 Causes of thrombocytopenia:
I. Immune mediated platelet destruction is most often the cause.
II. Platelet consumption may also occur in association with MAHA.
III. Impaired platelet production, as a result of the use of cytotoxic,
immunosuppressive, or other drugs.

 The major mechanism is immunoglobulin binding to platelets followed by

phagocytosis in the spleen, as in ITP .

 Membrane glycoproteins (GP) are most often the target of such antibodies (eg, GP
IIb/IIIa) but anti-HLA specificity also occurs.
 Binding of CD40 on B cells to CD40-ligand on activated T cells. The finding of autoantibodies
to CD40- ligand in patients with SLE, APS, and ITP, suggests that interference with T cell and B
cell interaction may play a role in the development of thrombocytopenia.

• BM. suppression by immunosuppressive drugs (other than corticosteroids), increased

consumption due to a TTP , the antiphospholipid syndrome, or antibodies that block the
thrombopoietin receptor on megakaryocytes or their precursors.

• ITP may be the first sign of SLE, followed by other symptoms as long as many years later. It
has been estimated that 3 to 15 percent of patients with apparently isolated ITP go on to
develop SLE.

• Evans syndrome also may precede the onset of SLE.

• Severe bleeding seen in minority of patients; however, SLE patients with thrombocytopenia
are more likely to have associated significant organ damage, such as heart and kidneys and
the CNS.
• Platelet 50,000- 20,000/microL rarely cause more than a prolonged bleeding time,
˂ 20,000/microL may be associated with petechiae, purpura, ecchymoses, epistaxis, gingival,
and other clinical bleeding.
• Treatment of thrombocytopenia is usually recommended for symptomatic patients with
counts of less than 50,000/microL and for all patients with counts ˂ 20,000/microL.
Treatment of Thrombocytopenia:

• mainstay of treatment is glucocorticoid therapy. Older studies used prednisone

(1 mg/kg per day in divided doses). However, treatment with four to eight
cycles of oral high dose dexamethasone (40 mg per day for four days) at
intervals of two weeks to four weeks may result in similar remission rates and
better long-term responses than those observed in historical controls treated
with daily prednisone.

• Most patients respond to glucocorticoid therapy within one to eight weeks.

• If there is no significant increase in the platelet count within one to three weeks
or side effects are intolerable, the following options may be considered and
used depends upon the severity of the thrombocytopenia and the presence or
absence of other manifestations of SLE:
i. Azathioprine
ii. Cyclophosphamide.
iii. IVIG is very effective and may be preferred to azathioprine or
cyclophosphamide when a rapid rise in platelet count is necessary (as in the
patient who is actively bleeding or requires emergent surgery).
iv. Mycophenolate mofetil less toxic than intravenous cyclophosphamide, may
be useful in the patient refractory to other medical therapy.
v. Rituximab (Anti-B-Cell Therapies) has been used to treat ITP in patients
without SLE who were refractory to other treatments and this B lymphocyte
depleting approach may be beneficial for other manifestations of lupus.
• Eltrombopag is a thrombopoeitin (TPO) receptor agonist that activates TPO
surface receptor on the megakaryocytes which results in increased platelets
production. It is approved for treatment of ITP. This drug is being used
successfully in some patients with SLE who had refractory ITP.
 Splenectomy can raise the platelet count but it does not reliably produce a
durable remission of thrombocytopenia. Relapse following splenectomy may
occur and has been noted at varying times from 1 to 54 months after surgery.

 Patients with persistent thrombocytopenia after splenectomy may respond to

azathioprine, cyclophosphamide, rituximab, intravenous immunoglobulin, or
danazol. If possible, splenectomy should be preceded by immunization with
pneumococcal vaccine to reduce the risk of pneumococcal sepsis.
• Danazol, a weak androgenic steroid, has also been used in the treatment of
thrombocytopenia caused by SLE, although its complete mechanism of action is
In another study, safe and well tolerated and like IVIG can be used in pregnancy

• West and colleagues used danazol (800 mg/day initially for 8 weeks) in six
patients with SLE with severe thrombocytopenia, all of whom had failed
glucocorticoid treatment. Four of the six had failed splenectomy. At 8 weeks, all
had normal platelet counts and were on lower doses of glucocorticoid. Five
were followed for 1 year, and all maintained a normal platelet count on lower
doses of danazol, ranging from 200 to 600 mg/day.still unknown.
• Pancytopenia in systemic lupus erythematosus
 Depression of all three cell lines also suggests bone marrow failure, as in the case in
aplastic anemia. Thus, bone marrow examination is the most important diagnostic
test to perform.

 Causes of marrow failure:

I. Drugs
II. Diseases including: the acute leukemias, large granular lymphocyte leukemia, the
myelodysplastic syndromes, marrow replacement by fibrosis or tumor, severe
megaloblastic anemia, paroxysmal nocturnal hemoglobinuria (PNH), and
overwhelming infection.
III. Unexplained cytopenia can be associated with bone marrow necrosis,
dysplasia,and distortion of the bone marrow architecture.

 Macrophage activation syndrome. The clinical characteristics of 12 patients with SLE-

associated macrophage activation syndrome.
Lymphadenopathy

• Enlargement of lymph nodes occurs in approximately 50 percent of patients

with SLE.
• Lymphadenopathy is more frequently noted at the onset of disease or in
association with an exacerbation.
• Biopsies reveal areas of follicular hyperplasia and necrosis, the appearance of
hematoxylin bodies is highly suggestive of SLE, but it is unusual.
• Tender lymphadenopathy may be due to infection.
• lymphoproliferative disease may also present in SLE.
• Prominent lymphadenopathy may also be a manifestation of
angioimmunoblastic T cell lymphoma.
splenomegaly
• occurs in 10 to 46 % of patients, particularly during active disease±
cytopenia.

• onion skin appearance of the splenic arteries means healing from

vasculitis.

• lymphadenopathy and splenomegaly in SLE, think about

lymphoproliferative malignancy.

• The risk of non-Hodgkin lymphoma appears to be increased four- to five

fold in patients with lupus.
Kikuchi-Fujimoto’s disease (KFD)
Histiocytic Necrotizing Lymphadenitis:
• Benign and self limited.
• Affects mainly young women.
• Cervical lymphadenopathy is the main site, less commonly in axillary &
mesenteric.
• Fever and leucopenia in up to 50% of the cases.
• There is association with systemic lupus erythematosus (SLE), SLE may be
present before, at the same time, or after the clinical appearance of KFD.
• KFD can be a complication of prolonged and multiple immunosuppressant use
in SLE patients.
Antibodies to clotting factors and anti-phospholipids
syndrome in SLE.
• The APS is characterized by venous or arterial thromboses, morbidity
occurring in the setting of pregnancy, and/or aPL-related clinical
manifestations that are not part of the APS Classification Criteria, such as
livedo reticularis thrombocytopenia, cardiac valve disease, or aPL-
nephropathy.

• Antibodies to a number of clotting factors, including VIII, IX, XI, XII, and
XIII have been noted in patients with SLE, that may also cause bleeding.

• associated with a prolongation of (PTT), and an increased risk of arterial and

venous thrombosis, thrombocytopenia, and fetal loss.

• The characteristic pathologic finding in the APS is a bland thrombosis with

minimal vascular or perivascular inflammation.
• Antiphospholipid Syndrome mnemonic:
• It is an autoantibody-mediated acquired thrombophilia characterized by recurrent arterial or venous
• thrombosis and/or pregnancy morbidity.

• The presence of at least one clinical and one laboratory criterion ensures the diagnosis:
• Clinical criteria:
• Vascular thrombosis defined as: One or more clinical episodes of
• - Arterial
• - Venous
• - Small vessel thrombosis
• (In any tissue or organ.)
• Pregnancy morbidity, defined as:
• - One or more unexplained deaths of a morphologically normal fetus at or beyond the tenth week of gestation
• - One or more premature births of a morphologically normal neonate before the thirty-fourth week
• of gestation because of eclampsia, severe preeclampsia, or placental insufficiency
• - Three or more unexplained consecutive spontaneous abortions before the tenth week of gestation.
• Laboratory criteria:
• - Lupus anticoagulant (LA)
• - Anticardiolipin (aCL)
• - Anti-β2GPI antibodies
• Deep vein thrombosis (32%), Thrombocytopenia (22%), Livedo reticularis (20%),
Stroke (13%), Superficial thrombophlebitis (9%), Pulmonary embolism (9%), Fetal
loss (8 %), TIA (7%), Hemolytic anemia (7%).

• Thrombosis: the risk of both venous and arterial thrombosis and/or

thromboembolism is increased in individuals with positive tests for LA activity or
medium or high levels of aCL.

• Catastrophic APS : is a rare presentation with multiorgan thrombi . Precipitants of

catastrophic APS include infection, surgery, pregnancy, exogenous estrogen, and
cessation of anticoagulation.
• The risk of recurrent thrombosis or thromboembolism may be further enhanced
in those with positivity to three aPL activities (LA, aCL, and ß2-glycoprotein-I)
upon repeated testing.
• venous thromboses are more common than arterial thromboses in the APS
• The most common site of DVT is the calf, but the renal veins, the hepatic, axillary,
subclavian, and retinal veins, the cerebral sinuses, and the vena cava may also be
involved.

• Deep venous thrombosis: APL can be detected in approximately 5 to 21% of all

patients with DVT. The incidence of DVT may correlate with the level of aCL.