Page 881 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPter 62 Immunohematological Disorders 853

(MHC). Eight percent of transfused patients mount detectable antibodies following infections. Human immunodeficiency virus
antibodies to HPA antigens and 45% to HLA antigens. Platelet (HIV), hepatitis C virus (HCV), and Helicobacter pylori infections
antibodies cause rapid clearance of transfused platelets and lead have been associated with ITP. H. pylori CagA antigen appears
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patients to become refractory to platelet transfusions. Post- to cross-react with platelet antigens, which may explain the
transfusion purpura (PTP) can follow transfusion with platelets association with ITP and H. pylori infection. Interestingly, empiric
or RBCs (in which platelets are found in numbers sufficient to treatment of Helicobacter infection with amoxicillin, clarithro-
sensitize the recipient). mycin, and proton pump inhibitors in patients suspected of
infection leads to 53% remission of ITP whether or not Helico-
Drug-Induced Thrombocytopenia bacter is eradicated, suggesting immunomodulatory effects of
Drug-induced thrombocytopenia (DITP) is an idiosyncratic treatment that do not involve elimination of the bacterial antigen
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immune-mediated reaction. The drug-dependent antibodies bind with cross-reactivity to platelet antigens. Patients who are not
to specific epitopes on platelet surface glycoproteins only in the infected with H. pylori but are treated empirically with antibiotics
presence of the sensitizing drug. The drugs bind noncovalently and do not have a significant platelet response rate (6.5%), which
reversibly to platelets, commonly to GPIIb-IIIa and GPIb-V-IX, suggests that empiric therapy is not useful in the absence of a
and also to the antibody. The Fab domains of the antibodies documented infection. 41
bind to the drug-platelet epitope. Drug-dependent antibodies NAT is caused by maternal antibodies against the HPAs that
inducing thrombocytopenia typically develop 1–2 weeks after the fetus carries but which the mother lacks (most commonly
exposure to a drug; exceptions to this rule include eptifibatide, HPA-1a). It is more likely to cause intracerebral hemorrhage
tirofiban, and abciximab, as naturally occurring antibodies to (10–20% of cases) than is maternal ITP, and it is very likely to
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these drugs can cause thrombocytopenia within a few hours of the recur if it has occurred in a previous pregnancy. IVIG and
first exposure. Thrombocytopenia with platelet counts frequently platelet transfusions using maternal platelets (to ensure that the
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below 20 × 10 /L develops acutely, recovery occurs 1–2 days offending antigen is not present in the transfused product) are
after discontinuation of the drug and is usually complete after often necessary.
1 week, but rarely thrombocytopenia persists for several weeks. Antibodies against human platelet antigens are also responsible
Quinidine, quinine, rifampin, tegretol, TMP-SMX, vancomycin, for PTP, in which the recipient has an acquired antibody directed
danazol, acetaminophen, abciximab, eptifibatide, tirofiban, and against a platelet antigen on the donor platelets. It is not under-
gold salts are the most common culprits. Treatment consists stood why the antibodies also destroy the patient’s own “antigen-
of discontinuing the offending drug; platelet transfusions are negative” platelets. Treatment consists of IVIG and corticosteroids,
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sometimes necessary. 37,38 and sometimes plasma exchange. Transplantation-mediated
Heparin-induced thrombocytopenia (HIT) is a special case alloimmune thrombocytopenia (TMAT) may occur as the result
that is caused by antibodies to platelet factor 4 (PF4)–heparin of donor-origin antibodies produced by passenger B cells directed
complexes. It can be associated with life-threatening thrombosis. against the recipient platelet alloantigen (HPA-1a). 43
The antibody–PF4–heparin complex activates platelets, resulting The most common epitopes for platelet antibodies in ITP
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in a high risk of both arterial and venous thrombotic events. are the platelet GPIIb/IIa and GPIb-IX receptors. The autoan-
Thrombocytopenia occurs as a result of clearance of platelet tibodies serve as opsonins resulting in the clearance of platelets
aggregates induced by the antibody and usually appears 5–7 by FcγR-bearing cells in the reticuloendothelial system (see Fig.
days after treatment with heparin (or low-molecular-weight 62.3). There is upregulation of genes involved in cell-mediated
+
+
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heparin) unless a patient has been previously exposed to heparin. cytotoxicity via CD3 CD8 T lymphocytes, with T-helper 1
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In the event of prior exposure, especially within the last 100 (Th1)–associated cytokines predominating. Regulatory T cells
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days, thrombocytopenia can occur within 1 day of heparin (Tregs) are decreased, and B-cell activation is increased. There
administration. Even small doses of heparin given as “flushes” is evidence of suppression of megakaryopoiesis by both T
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to maintain intravenous catheter patency can be sufficient to cause lymphocytes and ITP plasma/IgG. In addition, megakaryocyte
HIT with thrombosis. In cases of suspected HIT, all heparins and platelet production are dependent on thrombopoietin signal-
should be stopped, and an alternative anticoagulant agent, such as ing through binding to the Mpl receptor, and patients with ITP
the direct thrombin inhibitors argatroban and lepirudin, should have reduced thrombopoietin levels despite the presence of low
be used. Fondaparinux is an anticoagulant synthesized from the platelet counts. 51
pentasaccharide core of the heparin molecule and may be another 52
option for the treatment of HIT, since it binds to HIT antibodies Laboratory Diagnosis
but does not activate platelets and cause thrombosis. In cases of Peripheral blood smear examination is important to evaluate
confirmed or strongly suspected HIT, anticoagulation should be for the presence of schistocytes, leukocyte adhesion bodies in
continued for 3 months because the risk of thrombosis persists in MYH-9-related disease, and giant or large platelets in inherited
this group of patients. Coumadin is generally used for long-term thrombocytopenias and to exclude ethylenediaminetetraacetic
anticoagulation; it should be started concomitant with a heparin acid (EDTA)–dependent platelet agglutination.
alternative because of the increased risk of thrombosis during Bone marrow aspirate, biopsy, flow cytometry, and cytogenetics
the initial depletion of anticoagulant factors (proteins C and S) should be considered in patients older than 60 years of age and
by warfarin (Coumadin). The role of direct oral anticoagulants in patients with systemic symptoms. The detection of H. pylori
that target thrombin or activated factor X remains to be defined. with the urea breath test is recommended in adults, and testing
in children is recommended in high prevalence areas. Routine
Pathogenesis serological evaluation for HIV and HCV is recommended in
In the majority of patients the underlying defects leading to adults. Baseline Igs (IgG, IgA, IgM) should be measured in both
autoantibody production remain unclear. In some patients, ITP adults and children to diagnose such conditions as common
follows exposure to viral or bacterial antigens. Molecular mimicry variable immunodeficiency and selective IgA deficiency (Chapter
appears to play a role in the development of self-reactive platelet 34), in which ITP is a common complication.