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2014 Part XII: Hemostasis and Thrombosis Chapter 117: Thrombocytopenia 2015

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high-dose glucocorticoids, IFN-α, 412,413 vincristine, cyclophos- disorder caused by antibodies that recognize a neoepitope in platelet
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phamide, combination chemotherapy, and radiation. 417–419 For factor 4 that is exposed when platelet factor 4 binds heparin. The result
severe cases, interventions such as arterial embolization, 420,421 surgical is activation of platelets and the coagulation cascade and, ultimately,
resection, 422,423 and pneumatic compression can be attempted. venous and arterial thrombosis. HIT affects up to 5 percent of patients
The mortality rate for advanced Kasabach-Merritt syndrome is exposed to therapeutic doses of unfractionated heparin (Chap. 133).
approximately 12 percent; the rate is higher when associated with retro- This section discusses drugs, other than heparins, that cause isolated
peritoneal or intraabdominal tumors. Patients die of complications thrombocytopenia by immune platelet destruction; Chap. 34 discusses
resulting from DIC, low platelet count, and infections secondary to drug-induced aplastic anemia with thrombocytopenia.
immunosuppression.
ETIOLOGY
CYCLIC THROMBOCYTOPENIA Reviews of drug-induced thrombocytopenia often contain such exten-
sive lists of implicated drugs, many of which are commonly used, that
Cyclic thrombocytopenia (CTP) is a very rare acquired disorder charac- they are not helpful for decisions regarding which therapy to interrupt
terized by a periodic decrease in the platelet count, sometimes followed first. To address the issue of which drugs most likely cause thrombocy-
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by rebound thrombocytosis without therapy (>500 × 10 /L). Fluctuat- topenia, a systematic review of all published case reports defined lev-
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ing levels of endogenous TPO, inversely related to the platelet count, was els of evidence to document the causal relation between the drug and
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reported in one case. Each thrombocytopenic cycle typically spans a thrombocytopenia. This review distinguished drugs with definite or
430
period of 3 to 6 weeks, and women are more often affected than men. probable causal relationships from those for which the evidence was
The platelet counts may fluctuate across a wide range. In reported cases, weaker. Table 117–7 lists the drugs for which there is definite evidence
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the median nadir and peak platelet counts were 10 × 10 /L (range: 1 to of a causal role in producing thrombocytopenia (which includes recur-
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90 × 10 /L) and 330 × 10 /L (range: 72 to 2300 × 10 /L), respectively. rent thrombocytopenia with rechallenge in the same patient) and drugs
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Rebound thrombocytosis is an important and distinctive feature of for which the causal relation to thrombocytopenia has been validated by
CTP. Although some cases are reported as associated with myelopro- at least two reports with probable evidence (thus meeting all of the crite-
liferative neoplasms, most CTP cases are idiopathic. 427,428 The patho- ria for definite evidence except for the lack of rechallenge). Quinidine is
physiology is unclear and a number of potential mechanisms have been by far the most commonly cited drug. Other commonly cited drugs are
proposed, including autoimmune platelet destruction, megakaryocytic similar to drugs documented in a case-control study. A remarkable
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hypoplasia/aplasia, infections, and hormonal disturbances. Although observation from the systematic review was how many case reports did
most premenopausal female CTP patients studied have had low plate- not provide sufficient clinical information to allow a determination of
let counts during their menstrual periods, hysterectomy with bilateral even a probable causal relation. 319
salpingo-oophorectomy has not been shown to affect the course of the
platelet fluctuations. 426
The clinical presentation of CTP is similar to that of ITP. The bleed- PATHOGENESIS
ing tendency ranges from asymptomatic, to easy bruising, gingival Thrombocytopenia is usually assumed to result from immune platelet
bleeding, recurrent epistaxis, menorrhagia, and hematuria, to more destruction by drug-dependent antibodies. Most of these antibodies
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serious bleeding, including gastrointestinal or central nervous system bind the platelets only in the presence of the offending drugs. Drugs
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hemorrhage. CTP is rarely considered in the differential diagnosis may trigger different immune mechanisms, as depicted in Table 117–8.
of thrombocytopenia, so patients are usually diagnosed and treated as Drugs may bind covalently to membrane proteins, and may induce
having ITP. CTP is a rare disorder, but the diagnosis should be con- hapten-dependent antibodies in patients receiving penicillin and
sidered in patients with “ITP” who have not responded to therapies cephalosporin. In quinine-induced thrombocytopenia, antibodies bind
such as glucocorticoids, splenectomy, and IVIG, and who have rebound to membrane proteins only in the presence of soluble drug. In patients
thrombocytosis. Responses have been reported to respond to hormone receiving tirofiban or eptifibatide, the drug binds to integrin α β , cre-
IIb 3
therapy and cyclosporine. In female patients, oral contraceptives may ating a conformation-dependent neoepitope and inducing antibody
be useful to prolong the menstrual cycle and cover low-platelet-count production. Gold salts and procainamide, however, may induce true
days. Antifibrinolytic drugs such as aminocaproic acid or tranexamic autoantibodies, with those induced by gold being unique in targeting
acid may also be useful to decrease bleeding symptoms. platelet GPV. These antibodies can bind and destroy platelets in the
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absence of the drug. In HIT, heparin–platelet factor 4 complexes induce
DRUG-INDUCED THROMBOCYTOPENIA autoantibodies.
Initial experimental observations suggested that drug–antibody
Development of thrombocytopenia after quinine was first described by complexes bind to platelets via the platelet Fcγ receptor. This mech-
Vipan in 1865, and since then a large number of drugs have been found anism is confirmed for HIT (see below in this section), but for other
to cause thrombocytopenia. Drugs should be considered as poten- drugs, the drug-dependent antibodies appear to bind to platelets via
tially causative in any thrombocytopenic patient on medication, taking their Fab regions. 433
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herbal remedies, or using iodinated radiocontrast solutions. Drug-in- The target antigens are the major platelet surface GPs (GPIb-IX-V
duced thrombocytopenia generally affects only a small percentage of and integrin α β ). Different drugs may provoke drug-dependent anti-
IIb 3
patients taking a particular drug, and is usually not severe, although it bodies that preferentially react with one of these GPs, or drug-depen-
can be fatal. Genetic and environmental factors both influence suscep- dent antibodies from a single patient may react with multiple epitopes
tibility to drugs. Discontinuation of the causative drug(s) is the main on both GPs. For example, a study of sera from 15 patients with qui-
treatment strategy; glucocorticoids may help in some patients. Drugs nine-induced thrombocytopenia demonstrated that, in the presence of
may cause thrombocytopenia by different mechanisms. Dose-depen- quinine, the antibodies bound to two distinct domains on GPIb-IX, one
dent myelosuppression and immune destruction of the platelets are on GPIbα, and one on GPIX. Some patients had only one of the anti-
two well-known causes. One of the most severe and life-threatening bodies; some had both. The same domains on GPIb-IX also appear
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forms of drug-induced thrombocytopenia is HIT, an immune-mediated to be the antigenic targets for quinidine- and ranitidine-dependent

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