Hematological

Manifestations of
Collagen Vascular
Diseases
Mona Al Deeb
1033

Systemic Lupus Erythematosus

Hematological abnormalities are common in SLE. All the cellular
elements of the blood & coagulation pathway can be affected in SLE
patients.
The major hematological manifestations of SLE are anemia,
leucopenia, thrombocytopenia, and antiphospholipid syndrome (APS)

Anemia
Anemia of chronic disease
A frequent cause of anemia in SLE is suppressed erythropoiesis from
chronic inflammation (anemia of chronic disease or anemia of chronic
inflammation), being the most common form. this type of anemia is
normocytic and normochromic with a relatively low reticulocyte count.

Renal Insufficiency
An inappropriately low level of erythropoietin is a hallmark of anemia
due to renal insufficiency. The primary cause of anemia in this setting
is typically deficient production of erythropoietin by the diseased
kidneys

Iron Deficiency Anemia

Anemia may reflect acute or chronic blood loss from the
gastrointestinal tract, usually secondary to medications (nonsteroidal
antiinflammatory drugs or steroids), or may be due to excessive
menstrual bleeding. Iron deficiency anemia is not uncommon,
especially among teenagers or young women. Long-term anemia of
chronic inflammation can also lead to iron deficiency, since, hepcidin,
the key inducer of the anemia of chronic inflammation, inhibits iron

absorption from the gastrointestinal tract. Pulmonary hemorrhage is a

rare cause of anemia in SLE. Not all patients have hemoptysis.

Red Cell Aplasia

Red cell aplasia, probably due to antibodies directed against either
erythropoietin or bone marrow erythroblasts, has been observed,
although it is rare

AutoImmune Hemolytic anemia

Overt autoimmune hemolytic anemia (AIHA), 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 percent of patients with SLE. The presence of
hemolytic anemia may be associated with other manifestations of
severe disease such as renal disease, seizures, and serositis .
Other patients have a positive Coombs' test without evidence of 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

Leukopenia
Leukopenia is common in SLE and 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

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,

Lymphocytopenia
Lymphocytopenia (lymphocytes less than 1500/microL), especially
involving suppressor T cells, has been observed in 20 to 75 percent of
patients, particularly during active disease. This finding is strongly
associated with IgM, cold reactive, complement fixing, and presumably
cytotoxic antilymphocyte antibodies.

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.

Thrombocytopenia
Mild thrombocytopenia (platelet counts between 100,000 and
150,000/microL) has been noted in 25 to 50 percent of patients; There
are several potential causes of thrombocytopenia in patients with SLE.
Immune mediated platelet destruction is most often the cause or could
be due to impaired platelet production as a result of the use of
cytotoxic, immunosuppressive, or other drugs.
Thrombocytosis is a less frequent finding in patients

Pancytopenia
Although peripheral destruction of red cells, leukocytes, and platelets
may occur together and lead to clinically significant pancytopenia,
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 include drugs and coincidental 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.

AntiPhospholipid Syndrome
About 5% of the general population, but 50% of patients with systemic
lupus erythematosus, have an antiphospholipid antibody, such as the
lupus anticoagulant, anticardiolipin antibody, or anti-2 glycoprotein-1.
Because phospholipids are integral parts of the control of coagulation,
these antibodies can lead to a hypercoagulable state, antiphospholipid
antibody syndrome (APS).

Systemic Vasculitis
Systemic vasculitis occurs in a heterogeneous group of primary
disorders or can be a manifestation of infection, an adverse drug
reaction, malignancy or a collagen vascular diseases like SLE, RA,
Scleroderma and Sjorgens syndrome.
Several classification systems for vasculitis are available; some are
based on the size of the vessels involved and others are based on the
extent of the disease
Dominant Vessel
Large vessels

Medium sized and small vessels

Small vessels

Type of Vasculitis
Giant cell arteritis
Takayasus arteritis
Primary angiitis of the central
nervous system
Polyarteritis nodosa
Kawasaki disease
Wegeners granulomatosis
Churg-Strauss syndrome
Microscopic polyangiitis
Henoch-Schnlein purpura
Cryoglobulinemia
Leukocytoclastic vasculitis

Takayasus arteritis
Laboratory findings include anemia and thrombocytosis. ESR and CRP
could be elevated, but these markers are often normal and do not
directly correlate with disease activity.
Polyarteritis Nodosa
Laboratory results may reflect leukocytosis and thrombocytosis, and
the ESR and CRP are usually high. PAN is not associated with ANCA.

Wegeners Granulomatosis
Laboratory tests show normocytic normochromic anemia, leukocytosis,
thrombocytosis, and elevated ESR and CRP. ANCA, especially c-ANCA,
is associated with WG. It has high specificity (~98%) yet lower
sensitivity. Elevated titers usually reflect active disease; however cANCA titer itself does not strongly correlate with disease activity. Five
percent of patients can be p-ANCA positive.
Cryoglobulinemic Vasculitis
Cryoglobulins are circulating immunoglobulins that precipitate at low
temperatures. Type 1 cryoglobulinemia is composed of single
monoclonal IgG or IgM. Type 2 is composed of a monoclonal
component with activity toward polyclonal immunoglobulins. Type 3 is
composed of two or more polyclonal immunoglobulins. Mixed (type 2
and 3) cryoglobulinemia leads to immune complex disease by
depositing in the vessels and activating complement, which results in
inflammation.

Table 371. Types of Cryoglobulinemia

Subtype

Rheumatoid
Factor Positivity

Type I

No

Type II Yes

Monoclonality

Yes (lgG or lgM)

Associated Diseases

Hematopoietic malignancy (multiple

myeloma, Waldenstrm
macroglobulinemia)

Yes (polyclonal lgG, Hepatitis C (other infection, Sjgren

monoclonal lgM)
syndrome, systemic lupus
erythematosus)

Subtype

Rheumatoid
Factor Positivity

Type III Yes

Monoclonality

No (polyclonal lgG
and lgM)

Associated Diseases

Hepatitis C (other infection, Sjgren

syndrome, systemic lupus
erythematosus)

Table 372. Laboratory and Radiologic Evaluation in Possible Mixed Cryoglobulinemia

(MC)

Test

Typical Results

Complete blood cell count

Mild anemia common. Thrombocytopenia may be

present if liver disease is advanced.

Erythrocyte sedimentation
rate/C-reactive protein

Moderate to severe elevations common, generally

reflecting disease activity when very high.

ANA

Positive in the majority of cases.

Rheumatoid factor

Positive in types II and III.

Test

Typical Results

C3, C4

Low, particularly C4 levels.

ANCA

Negative.

ANA, antinuclear antibody; ANCA, antineutrophil cytopiasmic antibody.

Cryoglobulins
Assays for cryoglobulins are associated with a high false-negative rate, caused principally
by insufficient care in handling. After phlebotomy, the blood sample must be transported
to the laboratory at 37C and allowed to clot at that same temperature. Specimens are
then centrifuged at 37C and stored at 4C for up to 1 week.
Cryocrit
The percentage of serum comprised by cryoglobulins may be determined by the
centrifugation of serum at 4C. The cryocrit may then be measured in precisely the same
fashion as a hematocrit. As with other laboratory indicators, the cryocrit correlates poorly
with clinical status and treatment. Cryocrit levels should not dictate therapeutic decisions,
which are driven more appropriately by the clinical condition of the patient.
Hypocomplementemia
Because complement proteins are involved in the formation of immune complexes, C3
and C1q are often found on specific immunofluorescence testing of biopsy specimens.
Serum complement levelsC3, C4, and CH50are also low in MC. The finding of a
very low serum C4 level in the setting of a normal or only moderately reduced level of
C3 is a strong clue to the presence of MC.
Rheumatoid Factor Positivity
Eighty percent of the monoclonal IgMs found in HCV-associated MC share a major
complementarity region termed "WA." ("WA" refers to the initials of the patient in whom
it was initially reported.) This cross idiotype has a high degree of RF activity. Virtually all
patients with type II MC are RF positive.

References

Brighams and Womens Experts Approach to Rheumatology

Current Rheumatology Diagnosis and Treatment
Review of Rheumatology
http://cdn.intechopen.com/pdfs/33017/InTechHaematological_manifestations_in_systemic_lupus_erythematosus.pdf