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Chapter 132 Thrombocytopenia Caused by Platelet Destruction, Hypersplenism, or Hemodilution 1961

Ultrasonography, computed tomography, and radionuclide imaging exemplified by quinine- and quinidine-induced thrombocytopenia.
are of comparable sensitivity for documenting splenomegaly, and an A complicating issue (discussed later in this chapter) is that quinine
imaging study should be performed if splenomegaly is not evident can also rarely cause thrombocytopenia with a clinical picture of
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on physical examination. The mean platelet volume is often slightly microangiopathic hemolysis and/or DIC.
decreased in hypersplenism, but this finding is not sufficiently specific Sometimes the Fab terminus binds to a neoepitope on platelet
to be diagnostically useful. An 111 In-labeled platelet survival study GPIIb/IIIa induced by the drug, and the drug itself is not part of the
can be diagnostic of hypersplenism, demonstrating reduced platelet neoepitope. This mechanism is exemplified by the GPIIb/IIIa recep-
recovery and a normal platelet life span. Determining the cause of tor antagonists, eptifibatide and tirofiban, which bind to the Arg-Gly-
the splenomegaly is usually the most important issue. Asp recognition site on GPIIb/IIIa, forming a neoepitope to which
the “fiban-dependent” antibodies bind.
Another distinct form of drug-induced thrombocytopenia is
Therapy exemplified by HIT (see Chapter 133). In this disorder, the Fab
portion of the pathogenic IgG binds to platelet factor 4 (PF4), an
Several maneuvers can improve or correct the cytopenias attributable α-granule protein that is immunogenic when complexed to heparin
to hypersplenism, including total or partial splenectomy; partial or certain other polyanions. The Fc portions of the IgG molecules
splenic embolization; and in patients with congestive splenomegaly, bind to platelet FcγIIa receptors, initiating intense platelet activation
surgical or transjugular intrahepatic portosystemic shunting. However, (see Fig. 132.4). Perhaps because HIT is a platelet activation syn-
cytopenias secondary to hypersplenism and thrombocytopenia in drome or because of the relatively low number of HIT antibodies
particular, are almost never of sufficient severity to justify such treat- that bind to platelet surfaces, the thrombocytopenia is typically mild
ment. Consequently the decision to perform one of these interven- to moderate rather than severe (see Fig. 133.3 in Chapter 133).
tions usually depends on other considerations. For example,
splenectomy should be considered for relief of pain or early satiety
associated with massive splenomegaly (e.g., in myelo- or lymphopro- DRUG-INDUCED IMMUNE THROMBOCYTOPENIA
liferative disorders) or for splenomegaly of unknown origin (for
investigation of possible splenic lymphoma). A large number of drugs can cause a syndrome that mimics acute
Short-term complications from splenectomy include infections, ITP (D-ITP); however, there are relatively few drugs for which causa-
bleeding, and thromboembolism. The major long-term risk associ- tion is well established on both clinical and serologic grounds (Table
ated with splenectomy is overwhelming septicemia; this risk can be 132.5). 10,12–14 Typically, severe thrombocytopenia (platelet count
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reduced by vaccination. All patients should be vaccinated against usually <20 × 10 /L), together with petechiae and purpura, develop
pneumococci, meningococci, and Haemophilus species at least 2 within approximately 1 week (although occasionally much longer)
weeks before elective splenectomy. Moreover, “booster” doses of after initiation of therapy with the responsible drug. D-ITP is much
pneumococcus and meningococcus vaccines are recommended after less common than HIT. For example, a relatively “common” cause of
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5 years. Splenectomy for congestive hypersplenism in the setting of this syndrome is TMP-SMX (co-trimoxazole), even though it occurs
portal hypertension is associated with high morbidity and mortality in only approximately one in 25,000 patients who receive this drug
rates. Splenectomy is also associated with high morbidity (50%) and combination.
mortality (10%–15%) rates in myeloid metaplasia and does not alter Important exceptions to these generalizations occur with D-ITP
the natural history of this disorder. Thus splenectomy is usually that results from GPIIb/IIIa receptor antagonists; these reactions are
performed for palliation of intractable symptoms. relatively common (affecting about 0.5%–1% of patients) and usually
Splenectomy in Gaucher disease usually corrects the cytopenias, occur within hours of first use as a result of preexisting, naturally
relieves abdominal discomfort, and improves growth in children. occurring antibodies. Another exception is carbimazole-induced
Partial, rather than total, splenectomy has been used in an attempt thrombocytopenia, in which mild thrombocytopenia is explained by
to avoid shifting the deposition of glucocerebroside from the spleen the presence of relatively small quantities of the platelet GP target
to the bones. Often, however, splenomegaly and hypersplenism recur (platelet endothelial cell adhesion molecule-1 [PECAM-1]) on the
after partial splenectomy. Enzyme replacement therapy can reduce platelet surface. Besides the atypical immune-mediated syndromes of
the morbidity from hypersplenism (see Chapter 53). HIT and GPIIb/IIIa antagonist thrombocytopenia, the most common
drugs (in absolute terms) implicated in the causation of classic D-ITP
syndrome are quinine (outpatients) and vancomycin (inpatients). 15
DRUG-INDUCED THROMBOCYTOPENIC SYNDROMES

Many drugs can cause thrombocytopenia. Some drugs (e.g., antican- Pathogenesis
cer chemotherapeutic agents, valproic acid) cause dose-dependent
thrombocytopenia, generally through myelosuppressive mechanisms. Drug-dependent binding of the Fab component of IgG to platelet
An important disorder encountered by hematologists is unexpected GP leads to platelet destruction. This occurs because the IgG-
thrombocytopenia caused by immunologic (idiosyncratic) sensitized platelets are recognized by Fc receptors of phagocytic cells.
mechanisms. 8–10 The frequency of these reactions varies considerably For quinine- and quinidine-induced ITP, both the GPIIb/IIIa and
among drugs and ranges from very rare (<1 : 10,000) for commonly GPIb/IX/V complexes have been implicated as targets for the drug-
used drugs such as acetaminophen, indomethacin, naproxen, quinine dependent IgG (see Fig. 132.4). By contrast, for sulfa antibiotic- and
or quinidine, and trimethoprim-sulfamethoxazole (TMP-SMX) to naproxen-induced ITP, the GPIIb/IIIa complex is predominantly
common (1%–5%) for other drugs such as gold and unfractionated involved. Sometimes, drug metabolites form the antigen rather than
heparin (UFH). the parent drug. A trimolecular complex is formed among IgG Fab,
Immunologic drug-induced thrombocytopenia can occur through the drug (or metabolite), and the platelet GP. In contrast to HIT,
different mechanisms (Fig. 132.4). For example, thrombocytopenia platelet Fc receptors are not involved in D-ITP pathogenesis. Drug-
can occur when the Fab terminus of the pathogenic IgG binds to a dependent IgG binding is remarkably heterogeneous with respect to
complex composed of drug (or drug metabolite) and a platelet binding affinity, number of binding sites per platelet, and the range
membrane component (typically, platelet GPIIb/IIIa or GPIb/IX/V). of drug concentrations required. A study of quinine-induced ITP
The Fc portions of the pathogenic IgG molecules do not bind to identified two different types of antibodies: quinine-dependent
platelets but interact with Fc receptors on phagocytic cells of the antibodies that bound to platelets in the presence of drug and
reticuloendothelial system, which ingest the platelets, leading to quinine-specific antibodies that reacted with quinine-conjugated
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accelerated platelet clearance. Severe thrombocytopenia (platelet albumin. The pathophysiologic implications of this latter group of
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counts <20 × 10 /L) is typically observed. This mechanism is antibodies remain unclear.