Page 2033 - Williams Hematology ( PDFDrive )

2008 Part XII: Hemostasis and Thrombosis Chapter 117: Thrombocytopenia 2009

thrombocytopenia is not severe in patients with secondary ITP, but that these antibodies cause thrombocytopenia. Platelet activation,
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bleeding risk may be enhanced at a particular platelet count because of aggregation, and consumption (APS-associated thrombotic microan-
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the underlying disorder. The treatment strategy should be tailored to the giopathy) may also contribute to thrombocytopenia. Another issue
individual patient. of clinical importance in evaluating thrombocytopenia associated with
APS is the risk for future development of thrombosis. In one study in
which APS patients were divided into three groups according to platelet
IMMUNE THROMBOCYTOPENIA IN PATIENTS counts as normal, moderately thrombocytopenic (50 to 100 × 10 /L), or
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WITH ANTIPHOSPHOLIPID SYNDROME, severely thrombocytopenic (<50 × 10 /L), the rates of future thrombosis
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SYSTEMIC LUPUS ERYTHEMATOSUS AND were 40 percent, 32 percent, and 9 percent, respectively. These data
show that moderate thrombocytopenia does not prevent thrombosis in
OTHER CONNECTIVE TISSUE DISORDERS patients with APS. Antithrombotic prophylaxis should be considered in
Thrombocytopenia in the Antiphospholipid Syndrome these patients whenever it is possible. 257,268
APS is characterized by recurrent arterial and/or venous thrombo- Although thrombocytopenia is a common finding in patients
sis and well-defined morbidity during pregnancy in the presence of with APS, bleeding complications are rare, even with severe throm-
antiphospholipid antibodies (APLAs) (Chap. 132). APS may affect bocytopenia. Bleeding in an APS patient with moderate thrombocy-
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any organ in the body, including the heart, brain, kidney, skin, lung, topenia should trigger evaluation for the presence of antiprothrombin
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and placenta. This syndrome predominantly affects females (female- antibodies and other disorders that may affect hemostasis, such as
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to-male ratio 5:1), especially during the childbearing years. APLAs DIC, liver insufficiency, and uremia. Severe thrombocytopenia may
(lupus anticoagulant; anticardiolipin antibodies; anti–β -GPI anti- require therapy, with treatment strategies similar to those used for
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bodies) represent a heterogeneous family of antibodies that react with patients with ITP. Glucocorticoids are effective in only 15 percent of
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anionic phospholipids and phospholipid–protein complexes. Despite patients. IVIG and immunosuppressive drugs such as azathioprine
overwhelming evidence that APLAs are associated with thrombosis, and cyclophosphamide can be used in patients with severe bleeding
the mechanisms remain uncertain. Many have been proposed, includ- and “catastrophic” APS. In general, splenectomy should be postponed
ing endothelial cell damage and apoptosis, inhibition of prostacyclin as long as possible, and is only preferred in patients with severe bleed-
release from endothelial cells, inhibition of the protein C–protein S ing. Splenectomy may produce sustained remission in approximately
anticoagulant system, induction of tissue factor, activation of platelets two-thirds of patients as in patients with primary ITP. 167,270,271 Because
and the complement system, interference with antithrombin, impair- of their increased risk of thrombosis, patients should be prophylacti-
ment of fibrinolytic activity, and inhibition of annexin V binding to cally anticoagulated in the immediate postoperative period. Rituximab
membrane phospholipids, eliminating the antithrombotic effect of has been used to treat refractory thrombocytopenia in patients with
annexin V. 251–254 APS is considered one of the most common causes of APS, with a wide range of results. 272–274 Although there is no consen-
acquired thrombophilia. 255,256 sus on dosing and schedule with rituximab therapy, it is generally
Thrombocytopenia is reported in approximately 20 to 40 percent administered as in patients with ITP (see ITP therapy in “Therapy and
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of patients with APS, usually is mild (70 to 120 × 10 /L), and does not Course” above). TPO receptor agonists may increase thrombosis risk
require clinical intervention. Severe thrombocytopenia (platelet counts in patients with APS and SLE and these diagnoses in a patient with
<50 × 10 /L) occurs in 5 to 10 percent of patients. 257–259 Although throm- ITP were accepted as exclusion criteria in some randomized controlled
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bocytopenia was a clinical criterion used to define the syndrome in the studies of TPO-receptor agonists. Two case reports described acute
initial classification of APS, it was not included in the most recently renal failure (one was a result of thrombotic microangiopathy) after use
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proposed classification. Because ITP patients who present with of eltrombopag. 275,276
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APLAs are at increased risk for thrombosis, measurement of APLA,
especially lupus anticoagulant, in patients diagnosed with ITP may Thrombocytopenia in Patients with Systemic Lupus
identify a subgroup at high risk for developing APS. The pathogenesis Erythematosus and Other Connective Tissue Disorders
of thrombocytopenia in APS is not clear. Potential mechanisms explain- SLE is a complex autoimmune disease that primarily afflicts women
ing thrombocytopenia in APS patients include APLA-related direct of childbearing age. The autoimmune attack in SLE is not organ spe-
platelet destruction, immune platelet destruction by antibodies against cific; it may affect any tissue in the body. The diagnostic criteria for
platelet GPs, complement-mediated platelet destruction, and platelet SLE are based on a classification system proposed by the American
aggregation and consumption. Evidence indicates APLAs bind platelet College of Rheumatology. 277,278 The presence of hematologic findings
membranes and cause platelet destruction, but the link is not definitive. (leukopenia, thrombocytopenia, or hemolytic anemia) is one of the
Some investigators suggest that antibodies against platelet GPs, rather criteria in the diagnosis and classification of SLE. Thrombocytopenia
than APLAs, are responsible for thrombocytopenia in patients with is common in patients with SLE, occurring in 20 to 40 percent of
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APS. Antibodies against the integrin α β or GPIb–IX–V complexes are patients, and may be a presenting symptom. Immunologic destruc-
IIβ 3
found in approximately 40 percent of thrombocytopenic patients with tion of platelets is also seen in several other autoimmune conditions,
APS. Such antibodies do not cross-react with antibodies against phos- including polyarteritis nodosa, rheumatoid arthritis, mixed connec-
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pholipids or β -GPI. Immunosuppressive treatment in these patients tive tissue disease, and Sjögren syndrome, albeit at much lower rates
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increases the platelet count and reduces the titers of anti-GP antibodies than in SLE.
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but not the titers of APLAs. These data suggest that thrombocytopenia The causes of thrombocytopenia in SLE are many and include
is a secondary immune phenomenon that develops concomitantly with platelet destruction (ITP, DIC, thrombotic thrombocytopenic purpura
APS. Against this conclusion, platelet antigens in thrombocytopenic [TTP] or hemolytic uremic syndrome [HUS], sepsis, drugs), ineffec-
patients with APS were found to be different from those in ITP and tive hematopoiesis (megaloblastic anemia), abnormal platelet pooling
the antibodies to display virtually no reactivity with membrane GPs. (hypersplenism), marrow hypoplasia (from drugs and infections), and
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CD40 ligand on platelets is another possible antibody target. Anti-CD40 dilutional thrombocytopenia related to therapy. Severe thrombocy-
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ligand antibodies have been found in patients with APS (13 percent) topenia is relatively rare, occurring in 5 percent of patients. Although
and ITP (12 percent), but not in healthy controls; and it was suggested clinically significant bleeding is uncommon even in patients with severe

Kaushansky_chapter 117_p1993-2024.indd 2008 9/21/15 2:32 PM