Drug-Induced Immune-Mediated Thrombocytopenia From

Purpura to Thrombosis

In 1949, Ackroyd reported the abrupt onset of severe thrombocytopenia and purpura in patients receiving the
sedative allylisopropylacetylcarbamide (Sedormid).1 All the patients had taken Sedormid previously and had
become sensitized to it. Today, this classic picture of drug-induced, immune-mediated thrombocytopenia is
most often caused by quinine in outpatients and by vancomycin in hospitalized patients, as discussed by Von
Drygalski et al. in this issue of theJournal (pages 904910).
In 1973, Rhodes, Dixon, and Silver described thrombocytopenia and thrombosis occurring a week after the
initiation of heparin therapy and provided evidence of an immune pathogenesis for this complication of heparin
therapy.2 In clinical trials of glycoprotein IIb/IIIa antagonists (abciximab, eptifibatide, or tirofiban), the abrupt
onset of severe thrombocytopenia occurred in about 0.5 to 1% of patients who were receiving the agent for the
first time; this unusual pattern of drug-induced thrombocytopenia was also found to have an immune-mediated
pathogenesis.3 These three distinct drug-induced immune-mediated thrombocytopenic syndromes quinineinduced immune thrombocytopenia, heparin-induced thrombocytopenia and thrombosis, and thrombocytopenia
within hours after a first exposure to a glycoprotein IIb/IIIa antagonist differ from one another considerably
with respect to pathogenesis, severity of thrombocytopenia, clinical manifestations, diagnostic laboratory tests,
and treatment.
Classic drug-induced immune-mediated thrombocytopenia (the quinine type) is caused by unusual antibodies
that bind not to the drug alone but to complexes of drug (or drug metabolite) bound to platelet glycoproteins
typically, glycoprotein IIb/IIIa (fibrinogen receptor), glycoprotein Ib/IX (von Willebrand factor receptor), or both.
The antibody-coated platelets are cleared from the circulation by macrophages of the mononuclearphagocytic
system, which recognize the Fc tails of the drug-dependent antibodies. Platelets bear thousands of copies of
glycoproteins IIb/IIIa and Ib/IX, and consequently, the antibodies in these cases cause severe
thrombocytopenia; in about 85 to 90% of patients, the nadir platelet count is less than 20,000 per cubic
millimeter.
A useful clinical rule, in fact, is that immune-mediated thrombocytopenia is unlikely to be drug-induced unless it
is this severe. One exception is the immune thrombocytopenia caused by carbimazole: in that instance, the
moderate degree of thrombocytopenia (median platelet count at nadir, 60,000 per cubic millimeter) can be
explained by the fact that the drug forms a complex with a less abundant glycoprotein, plateletendothelial-cell
adhesion molecule 1. Another, and a major, exception to this clinical rule is heparin-induced thrombocytopenia

(see graph

Nadir Platelet Counts Shown on a Log10Scale.).

In classic drug-induced immune-mediated thrombocytopenia, isolated thrombocytopenia and purpura

(especially petechiae) are prominent. Especially with quinine, a minority of patients evince concomitant immune
neutropenia, disseminated intravascular coagulation, or the hemolyticuremic syndrome. Only about three
dozen drugs have been convincingly implicated as causes of immune-mediated thrombocytopenia.4,5 These
drug reactions are rare, occurring in only a few exposed patients among many thousands. When the implicated
drug (such as vancomycin) is given infrequently to a particular patient, onset of thrombocytopenia typically
occurs about a week after therapy begins. When a person is exposed to a drug intermittently (as with quinine
contained in tonic water or used to treat leg cramps), the onset is usually abrupt, reflecting re-exposure in a
sensitized patient. Along with the rapid drop in the platelet count, there may be an anaphylactoid reaction. This
type of rapidly developing thrombocytopenia can occur in a patient who had previously received the drug many
weeks or even years earlier. Treatment includes cessation of use of the drug and either simple support or
measures to increase the platelet count (e.g., intravenous immune globulin), depending on the severity of the
bleeding. Fatal hemorrhage, usually from intracranial bleeding, is rare.
Immune-mediated thrombocytopenia associated with glycoprotein IIb/IIIa antagonists resembles the classic
syndrome with respect to the severity of thrombocytopenia, the risk of bleeding, and occasional anaphylactoid
reactions. In these cases, however, the thrombocytopenia is usually evident within hours after drug
administration begins, even though most patients do not have a history of previous exposure to the
glycoprotein IIb/IIIa antagonist. In the cases of eptifibatide and tirofiban, an explanation of this paradox is that
naturally occurring antibodies against glycoprotein IIb/IIIa can bind to structures in the glycoprotein that are
revealed by drug-induced conformational changes (a neoepitope) in the glycoprotein complex (see diagram

Immune-Mediated Thrombocytopenia.). In the case of abciximab, which is a chimeric

(humanmouse) Fab fragment, naturally occurring antibodies against the mouse antiglycoprotein IIb/IIIa
domain could explain an abrupt onset of thrombocytopenia.
With all three glycoprotein IIb/IIIa antagonists, antibodies induced by the first administration can lead to rapidonset thrombocytopenia on re-exposure to the drug. With abciximab, which binds irreversibly to platelets,
thrombocytopenia can occur even a week after an initial brief exposure to the drug. Platelet transfusions can
raise the platelet count in cases of thrombocytopenia caused by abciximab but are usually less helpful with
thrombocytopenia caused by eptifibatide or tirofiban. In some patients who seem to have thrombocytopenia
after the administration of a glycoprotein IIb/IIIa antagonist, there is platelet clumping in vitro, caused by
naturally occurring EDTA-dependent antibodies; in such cases, no treatment is indicated, since the
thrombocytopenia is spurious.
Heparin-induced thrombocytopenia is a distinctive antibody-mediated syndrome. The degree of
thrombocytopenia is usually moderate (median platelet count at nadir, 60,000 per cubic millimeter); in 85 to
90% of patients, the platelet count is above 20,000 per cubic millimeter. The thrombocytopenia is caused by
heparin-dependent IgG antibodies that bind to multimolecular complexes consisting of platelet factor 4 (PF4)
bound to heparin. The antibodies activate platelets by means of their FcIIa receptors, releasing platelet-

derived procoagulant microparticles. These microparticles accelerate coagulation reactions and the generation
of thrombin. Venous thromboembolism (the most common complication), arterial thrombosis (especially
involving limb and cerebral arteries), adrenal hemorrhagic necrosis (due to adrenal-vein thrombosis),
necrotizing skin lesions at heparin-injection sites, anaphylactoid reactions after an intravenous bolus of heparin,
and overt disseminated intravascular coagulation can occur.
Stopping heparin therapy does not prevent further thrombosis, necessitating inhibition of thrombin or its
generation by rapidly acting non-heparin anticoagulants. Anticoagulation with coumarin (warfarin) substantially
increases the risk of microvascular thrombosis (causing venous limb gangrene and skin necrosis), and it is
therefore contraindicated during the acute thrombocytopenic phase.
The pathogenic antibodies appear in the blood only transiently, which means that a rapid onset of
thrombocytopenia on beginning heparin therapy occurs only in patients who have been exposed to heparin
within the previous several weeks. Indeed, deliberate brief re-exposure to heparin, such as for cardiac surgery,
is feasible after recovery from an episode of heparin-induced thrombocytopenia. Sometimes, thrombocytopenia
and thrombosis begin a week or two after all heparin therapy has been stopped (delayed-onset heparininduced thrombocytopenia). Unlike the purpura-inducing drug reactions discussed above, which only rarely
have long-term effects, heparin-induced thrombocytopenia is often associated with long-term sequelae from
thrombosis.
Laboratory detection of drug-dependent antibodies can be invaluable. For the classic syndrome, detection of
drug-dependent (or drug-metabolitedependent) binding of antibodies to platelet glycoproteins has high
specificity but only moderate sensitivity, perhaps because relevant drug metabolites may not be present within
the test system. In contrast, with thrombocytopenia associated with glycoprotein IIb/IIIa antagonists or heparin,
the challenge is to distinguish nonpathogenic from pathogenic antibodies. Thus, for heparin-induced
thrombocytopenia, test sensitivity is high, but specificity (especially with the use of enzyme immunoassays for
antibodies against the PF4heparin complexes) is only moderate. This is because heparin frequently induces
formation of heparin-dependent antibodies, but only some of these have the biologic properties needed to
activate platelets and thereby evince their pathogenic potential. Although commercial enzyme immunoassays
permit many hospitals to offer standardized testing for antibodies against the PF4heparin complexes, all the
other tests for drug-dependent antibodies require referral to a handful of specialized reference laboratories.
Dr. Warkentin reports receiving consulting or lecture fees from GlaxoSmithKline, Organon, GTI, the Medicines
Company, Oryx Pharmaceuticals, and Sanofi-Aventis, as well as grant support from Sanofi-Aventis, Organon,
and GlaxoSmithKline. No other potential conflict of interest relevant to this article was reported.

SOURCE INFORMATION

Dr. Warkentin is a professor of pathology and molecular medicine and medicine at the Faculty of Health
Sciences, McMaster University, Hamilton, ON, Canada.

Terjemahan

Pada tahun 1949, Ackroyd melaporkan timbulnya mendadak dan purpura

trombositopenia berat pada pasien yang menerima obat penenang
allylisopropylacetylcarbamide (Sedormid) .1 Semua pasien telah mengambil Sedormid
sebelumnya dan telah menjadi peka untuk itu. Hari ini, gambaran klasik dari obatinduced, kekebalan-dimediasi trombositopenia yang paling sering disebabkan oleh kina
pada pasien rawat jalan dan dengan vankomisin pada pasien rawat inap, seperti yang
dibahas oleh Von Drygalski dkk. dalam edisi ini theJournal (halaman 904-910).
Pada tahun 1973, Rhodes, Dixon, dan Silver dijelaskan trombositopenia dan
trombosisterjadi seminggu setelah mulai terapi heparin dan bukti yang
diberikan dari patogenesiskekebalan untuk komplikasi therapy.2 heparin Dalam uji klinis
dari glikoprotein IIb / IIIaantagonis (abciximab, eptifibatide , atau tirofiban),
onset mendadak trombositopenia berat terjadi di sekitar 0,5 sampai 1% dari pasien yang
menerima agen untuk pertama kalinya, ini pola yang tidak biasa obatinduced trombositopenia juga ditemukan memilikikekebalandimediasi pathogenesis.3 ketiga obat yang berbeda-dimediasi kekebalan
akibat sindrom thrombocytopenic - kina-induced trombositopenia imun, heparininducedtrombositopenia dan trombosis, dan trombositopenia dalam beberapa jam setelah
paparan pertama untuk antagonis IIb / IIIa glikoprotein - berbeda satu sama
lain jauhsehubungan dengan patogenesis , keparahan trombositopenia, manifestasi klinis, tes
laboratorium diagnostik, dan pengobatan.
Klasik obat-induced trombositopenia imun (jenis kina) disebabkan oleh antibodi yang tidak biasa
yang tidak mengikat obat saja tetapi untuk kompleks obat (atau obatmetabolit) terikat
pada platelet glikoprotein biasanya, glikoprotein IIb / IIIa (fibrinogenreseptor) , glikoprotein Ib / IX (von Willebrand reseptor
faktor), atau keduanya. Antiboditrombosit berlapis dibersihkan dari sirkulasi oleh
makrofag sistem fagosit mononuklear-,yang mengakui "ekor" Fc dari antibodi obatdependen. Trombosit menanggung ribuansalinan dari glikoprotein IIb / IIIa dan Ib / IX, dan
akibatnya, antibodi dalam kasus inimenyebabkan trombositopenia berat, dalam sekitar 85
sampai 90% dari pasien, jumlah platelet kurang dari titik nadir 20.000 per milimeter kubik.
Aturan klinis yang berguna, pada kenyataannya, adalah bahwa trombositopenia imuntidak
mungkin obat-diinduksi kecuali ini parah. Satu pengecualian adalah kekebalan yang disebabkan
oleh trombositopenia carbimazole: dalam contoh itu, tingkat moderattrombositopenia (jumlah
trombosit rata-rata pada titik nadir, 60.000 per milimeter kubik)dapat dijelaskan oleh
fakta bahwa obat bentuk-bentuk kompleks dengan glikoproteinkurang berlimpah, trombosit endotel-sel adhesi molekul 1. Lain, dan seorang mayor,pengecualian terhadap
aturan klinis heparin-induced trombositopenia

Dalam klasik obatinduced trombositopenia dimediasi kekebalan, purpuratrombositopenia terisolasi

dan (terutama petechiae) yang menonjol. Terutama dengankina, sebagian
kecil pasien memperlihatkan secara bersamaan neutropenia kekebalan
tubuh, koagulasi intravaskular diseminata, atau sindrom uremik hemolitik-. Hanya sekitar tiga
lusin obat telah meyakinkan terlibat sebagai penyebab kekebalan yang
dimediasi thrombocytopenia.4, 5 Reaksi-reaksi obat jarang terjadi, hanya sedikit di
antara pasien
yang terkena ribuan. Ketika obat terlibat (seperti vankomisin) jarangdiberikan kepada pasien
tertentu, timbulnya trombositopenia biasanya terjadi sekitar satu minggu setelah
terapi dimulai. Ketika seseorang terkena obat sebentar-sebentar(seperti kina yang
terkandung dalam air tonik atau digunakan untuk mengobati kram kaki), timbulnya gejala
biasanya tiba-tiba, mencerminkan pajanan ulang pada pasienpeka. Seiring dengan
penurunan cepat dalam jumlah trombosit, mungkin
ada reaksianafilaktoid. Jenis trombositopenia cepat berkembang dapat terjadi pada pasien yang
sebelumnya menerima obat beberapa minggu atau bahkan bertahuntahunsebelumnya. Pengobatan meliputi penghentian penggunaan obat dan
baik dukungansederhana atau langkah-langkah untuk meningkatkan
jumlah trombosit (misalnya,immune globulin intravenous), tergantung pada tingkat
keparahan perdarahan.Perdarahan fatal, biasanya dari perdarahan intrakranial, jarang.
Trombositopenia imun berhubungan dengan glikoprotein
IIb / IIIa antagonis menyerupaisindrom klasik sehubungan dengan keparahan trombositopenia,
risiko pendarahan, dananaphylactoid sesekali. Dalam kasus
ini, bagaimanapun, trombositopenia biasanyaterlihat beberapa jam setelah dimulai pemberian
obat, meskipun sebagian besar pasien tidak memiliki riwayat
pajanan sebelumnya antagonis IIb / IIIa glikoprotein. Dalam kasuseptifibatide dan tirofiban, penj
elasan tentang paradoks ini adalah bahwa antibodi alamiterhadap glikoprotein IIb / IIIa dapat
mengikat struktur dalam glikoprotein yangdiungkapkan oleh obat-induced
perubahan konformasi (neoepitope a) di kompleksglikoprotein
Immune-Mediated Trombositopenia.). Dalam kasus abciximab, yang
merupakanfragmen (manusia-tikus) Fab chimeric, antibodi alami terhadap domainantiglikoprotein tikus IIb / IIIa bisa menjelaskan onset mendadak trombositopenia.
Dengan semua tiga antagonis glikoprotein IIb / IIIa, antibodi yang diinduksi
olehadministrasi pertama dapat menyebabkan onset cepat trombositopenia pada repaparan terhadap obat tersebut. Dengan abciximab, yang
mengikat ireversibel untuktrombosit, trombositopenia dapat terjadi
bahkan seminggu setelah paparan singkatawal untuk obat. Transfusi trombosit dapat
meningkatkan jumlah platelet dalam kasustrombositopenia yang disebabkan
oleh abciximab tapi biasanya kurang membantudengan trombositopenia yang disebabkan
oleh eptifibatide atau tirofiban. Padabeberapa pasien yang tampaknya
memiliki trombositopenia setelah pemberianantagonis IIb / IIIa glikoprotein,
ada penggumpalan trombosit in vitro, yang disebabkan oleh EDTA alami yang

tergantung antibodi, dalam kasus tersebut, tidak ada perawatan yang diindikasikan,
karena trombositopenia adalah palsu.
Heparin-induced trombositopenia adalah sindrom antibodimediated khas. Tingkatbiasanya moderat trombositopenia (jumlah trombosit rata-rata pada titik
nadir, 60.000per milimeter kubik), dalam 85 sampai 90% dari pasien, jumlah trombosit di
atas 20.000per milimeter kubik. Trombositopenia disebabkan oleh heparin-tergantung antibodi
IgGyang mengikat kompleks multimolecular terdiri dari faktor trombosit 4 (PF4) terikatdengan
heparin. Antibodi mengaktifkan trombosit dengan cara reseptor
mereka FcIIa,melepaskan plateletderived mikropartikel prokoagulan. Mikropartikel ini mempercepat reaksi koagulasi dan
generasi trombin. Tromboemboli vena (komplikasi yang paling
umum), trombosis arteri (terutama melibatkan ekstremitas dan arteri serebral),
nekrosishemoragik adrenal (adrenal karena trombosis vena), nekrosis lesi kulit
di injeksiheparin-situs, anaphylactoid bolus intravena setelah heparin, dan koagulasi
intravaskulardiseminata terbuka dapat terjadi.
Menghentikan terapi heparin tidak mencegah trombosis lebih
lanjut, memerlukanpenghambatan trombin atau generasi dengan cepat bertindak nonheparin antikoagulan.Antikoagulan dengan kumarin (warfarin) secara substansial meningkatkan
risikotrombosis mikrovaskular (vena menyebabkan gangren tungkai dan nekrosis kulit), dan
karena itu kontraindikasi selama fase akut thrombocytopenic.
Antibodi patogen muncul dalam darah hanya transiently, yang berarti bahwa onset yang
cepat trombositopenia pada mulanya terapi heparin hanya terjadi pada pasien yang
telah terkena heparin dalam beberapa minggu sebelumnya. Memang, sengaja singkatpajanan
ulang dengan heparin, seperti untuk operasi jantung, adalah layak setelah sembuh
dari episode heparin-induced trombositopenia. Kadang-kadang,trombositopenia dan
trombosis memulai atau dua minggu setelah semua terapi heparintelah dihentikan ("tertundaonset" heparin-induced trombositopenia). Berbeda denganpurpura-merangsang reaksi
obat dibahas di atas, yang hanya jarang memiliki efek jangka panjang, heparininduced trombositopenia sering dikaitkan dengan gejala sisajangka panjang dari trombosis.
Laboratorium deteksi obat tergantung antibodi dapat tak ternilai. Untuk sindrom klasik,
deteksi obat-tergantung (atau obat-metabolit-bergantung) yang mengikat antibodi
terhadap glikoprotein trombosit memiliki spesifisitas tinggi tetapi
hanya sensitivitasmoderat, mungkin karena metabolit obat yang relevan tidak dapat hadir dalam
sistemuji. Sebaliknya, dengan trombositopenia terkait dengan glikoprotein
IIb / IIIa antagonisatau heparin, tantangannya adalah untuk
membedakan nonpathogenic dari antibodipatogen. Jadi, untuk heparininduced trombositopenia, uji sensitivitas tinggi, tetapispesifisitas (terutama dengan
penggunaan enzim immunoassay untuk antiboditerhadap PF4-heparin kompleks)
hanya moderat. Hal ini
karena heparin seringmenginduksi pembentukan antibodi bergantung heparin, tetapi
hanya beberapamemiliki sifat biologis yang dibutuhkan untuk mengaktifkan trombosit dan

dengandemikian memperlihatkan potensi patogenik mereka. Meskipun enzim immunoassayizin

komersial banyak rumah sakit untuk menawarkan pengujian standar untuk
antiboditerhadap PF4-heparin kompleks, semua tes lainnya untuk obatdependent antibodimemerlukan rujukan ke beberapa laboratorium rujukan khusus.
Dr Warkentin laporan menerima biaya konsultasi atau kuliah dari
GlaxoSmithKline,Organon, GTI, Perusahaan Obat, Farmasi Oryx, dan Sanofi-Aventis,
serta dukungan hibah dari Sanofi-Aventis, Organon, dan GlaxoSmithKline. Tidak ada potensi
konflikkepentingan lainnya yang relevan dengan artikel ini dilaporkan.