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Chapter 132 Thrombocytopenia Caused by Platelet Destruction, Hypersplenism, or Hemodilution 1969

gangrene, livedo reticularis), or acute multiorgan failure associated and multiple myeloma. Sometimes the thrombocytopenia responds
with DIC or widespread thrombosis of the microvasculature (cata- to treatment of the neoplasm, although in some patients (par-
strophic APS). ticularly those with Hodgkin disease), the thrombocytopenia is
The mechanism of the prothrombotic tendency in patients with indistinguishable from ITP and is not related to the activity of the
APS remains elusive, but interference with endothelial cell function, lymphoma.
impaired fibrinolysis, antibody-mediated platelet activation, forma- DIC occurs with certain malignancies, particularly adenocarci-
tion of endothelial microparticles, interference with thrombin and noma of the pancreas, stomach, lung, colon, breast, and prostate.
factor Xa degradation by antithrombin, disturbance in the protein C Some patients present with venous or, less commonly, arterial throm-
anticoagulant pathway or anticoagulant activity of β 2 GPI have all bosis as the first clinical manifestation of their malignancy. In these
been described. Disruption of the antithrombotic annexin V anti- patients, the presence of thrombocytopenia is an important clue that
thrombotic “shield” by aPL antibodies has been proposed to explain should prompt investigations for DIC, such as measurement of
pregnancy losses through placental vascular thrombosis. Evidence fibrinogen or D-dimer levels. In the author’s experience, the platelet
indicates that thrombocytopenia in patients with APS is associated count typically rises to normal or even elevated levels with heparin
with platelet GP-reactive autoantibodies. therapy because heparin ameliorates the DIC process; however, recur-
aPL antibodies are detected by either of two methods: (1) solid- rent thrombocytopenia and thrombosis can occur within hours of
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phase ELISA with purified phospholipids (usually cardiolipin) as discontinuing the heparin therapy. Cancer patients with DIC and
target antigens or (2) a “functional” assay for so-called lupus antico- venous thrombosis are also at increased risk for warfarin-associated
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agulant (LA) activity, shown by demonstrating inhibition of certain venous limb gangrene. The role of various tumor-associated proco-
phospholipid-dependent coagulation assays, such as the activated agulant substances—such as “cancer procoagulant” (a 68-kDa cysteine
partial thromboplastin time or the Russell viper venom time. proteinase that activates factor X independently of tissue factor/factor
Although aPL antibodies are frequently detected in patients with VIIa) and cancer-associated tissue factor (which is expressed on tumor
SLE, they can also be found in patients with other autoimmune cells, as well as circulating microparticles)—suggest pathophysiologic
disorders, malignancy, or infections or as a complication of certain parallels with microthrombosis in HIT because both cancer-associated
drugs (e.g., procainamide). Often no associated condition is identi- DIC and acute HIT are risk factors for phlegmasia cerulean dolens
fied (“primary” APS). aPL antibodies of low titer are sometimes found and venous limb gangrene during anticoagulation with warfarin.
in normal persons, particularly elderly individuals, or during normal Thus cancer patients with DIC should receive heparin (especially
pregnancy. Autoantibody “cluster” studies show that anticardiolipin, LMWH) rather than warfarin anticoagulation (see box on Diagnostic
LA, and anti–double-stranded DNA antibodies occur together more Considerations in the Patient With Limb Ischemia and Thrombocy-
often than with other SLE-associated autoantibodies (e.g., anti-Sm, topenia in Chapter 133). DIC with hemorrhagic manifestations is
anti-Ro, anti-RNP). characteristically seen in some patients with prostate cancer and in
There are intriguing parallels between the APS and HIT: in both many patients with acute promyelocytic leukemia. It is crucial to
disorders, the antibodies are directed at a protein target (β 2 GPI and recognize promyelocytic leukemia because treatment with all-trans-
PF4, respectively) bound to a negatively charged species (anionic retinoic acid produces differentiation of the malignant cells, thereby
phospholipid and heparin, respectively). For both, high-titer IgG rapidly reducing the life-threatening bleeding risks attributable to
antibodies that result in a positive “functional” test result (LA activity hyperfibrinolysis.
and HIT-IgG–induced platelet activation, respectively) are most A destructive thrombocytopenic disorder that resembles HUS or
likely to be associated with clinical disease. Both disorders are char- TTP has been described in patients with advanced cancer. In some
acterized by the paradox of thrombocytopenia associated with patients, mitomycin, gemcitabine, or other drugs may have contrib-
increased risk for venous and arterial thrombosis. uted to the microangiopathy. DIC is not usually present. Some
To help physicians diagnose the APS, clinical and laboratory cri- patients respond transiently to plasmapheresis, but for many, response
teria have been developed. The laboratory criteria include the pres- to any therapy is poor.
ence of anticardiolipin, anti-β 2 GPI, or LA antibodies (moderate- to
high-titer IgG or IgM) on two or more occasions at least 12 weeks
apart. The major clinical criteria are thrombosis and complications Macrophage Activation (Hemophagocytic) Syndrome
of pregnancy. Thrombosis can involve large arteries or veins or small
vessels within any organ. The complications of pregnancy include one The macrophage activation (or hemophagocytic) syndrome comprises
or more unexplained deaths of normal fetus(es) after week 10 of a heterogeneous group of disorders characterized by variable cytope-
gestation or premature births (before 34 weeks) or more than three nias and morphologic evidence of macrophage phagocytosis of RBCs,
spontaneous abortions before week 10 of gestation. Some experts granulocytes, and platelets; hyperferritinemia, hypercytokinemia, and
advocate for thrombocytopenia to be included within the criteria for sepsis-like features are characteristic, with potential for evolution to
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APS. 25 fatal multiple organ failure. Some adult patients have an aggressive
Specific treatment for the thrombocytopenia is not usually disease characterized by high fever, weight loss, prominent hepato-
required. For many patients, long-term anticoagulant or antiplatelet splenomegaly, severe pancytopenia, elevated liver enzymes, and often
therapy, or both, are needed to prevent recurrent thrombosis. For a terminal infection. Both T- and B-cell lymphomas can explain such
patients with recurring pregnancy losses and aPL antibodies, random- a dramatic syndrome. However, similar patients with fulminant
ized trials have documented the benefit of low-dose aspirin com- illness have been described after otherwise unremarkable bacterial or
bined with either low-dose UFH or low-molecular-weight heparin viral infections (particularly those caused by Epstein-Barr virus). In
(LMWH). children, the high mortality rate associated with hemophagocytic
lymphohistiocytosis warrants aggressive treatment, including anti-
neoplastic chemotherapy and BM transplantation. Nonneoplastic
Malignancy but nonetheless severe hemophagocytosis can be seen in patients with
certain infections (e.g., babesiosis, ehrlichiosis, HIV infection), as
Thrombocytopenia complicating malignant disorders most frequently well as in patients with rheumatologic disorders (SLE, Still disease,
results from antineoplastic treatment or BM replacement by tumor. ankylosing spondylitis). Laboratory indicators of macrophage activa-
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However, certain thrombocytopenic syndromes have been associated tion syndrome include markedly elevated ferritin, high levels of
with malignancy, including autoimmune thrombocytopenia, DIC, soluble CD163 and CD25, and morphologic evidence of hemo-
and thrombotic microangiopathy. phagocytosis. Treatment should be directed at the underlying illness.
ITP attributable to platelet GP-reactive autoantibodies can Early administration of corticosteroids and high-dose IVIg appears
complicate neoplastic lymphoproliferative diseases such as Hodgkin to benefit some patients with nonneoplastic macrophage activation
disease, non-Hodgkin lymphoma, chronic lymphocytic leukemia, syndrome.