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Chapter 9
Disorders of platelet number and function
Donald M. Arnold and A. Koneti Rao
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CHAPTER
09
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Figure 9-1 Schematic representation of selected platelet responses to activation and inherited disorders of platelet function. AC adenylyl
cyclase; ADP adenosine diphosphate; BSS Bernard-Soulier syndrome; CO cyclooxygenase; DAG diacylglycerol; G guanosine
triphosphatebinding protein; IP3 inositol trisphosphate; MLC myosin light chain; MLCK myosin light chain kinase; PAF platelet
activating factor; PIP2 phosphatidylinositol bisphosphate; PKC protein kinase C; PLC phospholipase C; PLA2, phospholipase A2;
TK tyrosine kinase; TS thromboxane synthase; TxA2 thromboxane A2; vWF von Willebrand factor; vWD von Willebrand disease.
The Roman numerals in the circles represent coagulation factors. Modified with permission from Rao AK. Congenital disorders of platelet
function: disorders of signal transduction and secretion. Am J Med Sci. 1998;316:69-76.
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Drug-induced thrombocytopenia
Unexpected thrombocytopenia is often caused by drugs,
and drug-induced thrombocytopenia (DITP) should be
suspected in any patient who presents with acute thrombocytopenia. Many drugs have been reported to cause thrombocytopenia, the most common of which are quinine and
quinidine (present in tonic water, bitter melon, and certain
medications), nonsteroidal anti-inflammatory agents, sulfamethoxazole, vancomycin, anticonvulsants, sedatives, and
the platelet GPIIb-IIIa inhibitors tirofiban, eptifibatide,
and abciximab. A case-control study of drug use among
patients with acute reversible thrombocytopenia compared
with nonthrombocytopenic controls showed that trimethoprim/sulfamethoxazole was most frequently implicated,
followed by quinine/quinidine, dipyridamole, sulfonylureas,
and salicylates. A systematic review of individual patient
data also documented that the most commonly reported
drugs with a definite or probable causal relation to
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Table 9-2 Criteria for assessing reports of drug-induced thrombocytopenia and levels of evidence for a causal relationship between the drug
and thrombocytopenia.
Criterion
Description
3
4
Level of evidence
Definite
Probable
Possible
Unlikely
Adapted from George JN, Raskob GE, Shah SR, et al. Drug-induced thrombocytopenia: a systematic review of published case reports.
Ann Intern Med. 1998;129:886-890, with permission.
Mechanism of DITP
DITP should be suspected when thrombocytopenia occurs
approximately 7 days after drug exposure. Notable exceptions are the GPIIb-IIIa antagonists eptifibatide, tirofiban,
and abciximab, which may cause acute thrombocytopenia
within a few hours of the first exposure. Several mechanisms
of DITP have been proposed. Recent data suggest that quinine-type DITP is caused by naturally occurring autoantibodies that acquire strong binding affinity for platelet antigen
targets after they have been conformationally altered by the
drug. Tight antibody binding stimulates B cells to produce
excess antibodies within approximately 7 days. The epitope
targets of these antibodies usually reside on GPIIb-IIIa or
GPIb-IX. Other drugs such as gold, procainamide, sulfonamide antibiotics, and interferon alfa or beta (but not quinine) can induce platelet autoantibodies causing a syndrome
that resembles ITP.
Tirofiban and eptifibatide (fibans) are small synthetic
molecules that bind GPIIb-IIIa and inhibit platelet function. Thrombocytopenia may occur because of preexisting
antibodies that recognize structural changes (neoepitopes)
induced in GPIIb-IIIa when a fiban binds to it. Abciximab,
a chimeric (mousehuman) Fab fragment that is specific
for GPIIIa, causes acute profound thrombocytopenia in
0.5% to 1.0% of patients on their first exposure, presum-
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Diagnosis of DITP
Criteria for levels of evidence for DITP have been proposed
that may be helpful in the evaluation of patients in whom the
condition is suspected (Table 9-2). Clinical criteria used to
judge the likelihood of drug being implicated in DITP
are temporal association between drug exposure and
thrombocytopenia, the exclusion of other causes of thrombocytopenia, and recurrence upon drug rechallenge. The
detection of an antibody that binds tightly to normal platelets in the presence of the drug establishes the diagnosis in
many cases; however, such testing is not widely available.
Furthermore, drug-dependent platelet antibodies cannot be
detected when the antibodies recognize a metabolite of the
drug instead of the drug itself, such as with nonsteroidal
anti-inflammatory drugs and acetaminophen. Thus, DITP
remains a clinical diagnosis.
Patients with severe thrombocytopenia (platelets
10 109/L) are at risk of fatal bleeding. Other symptoms
might include faintness, chills, fever, nausea, and hypotension. Treatment is to stop the drug and administer platelet
transfusions for patients with severe thrombocytopenia.
Bleeding symptoms usually subside after 1 to 2 days, and the
platelet count usually returns to normal in 4 to 8 days. Rarely,
thrombocytopenia can persist for several weeks.
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Clinical features
Key points
A careful drug history must be taken in any patient presenting
with thrombocytopenia.
Quinine-induced thrombocytopenia presents after 5 to 7 days
and is associated with severe thrombocytopenia and bleeding.
Thrombocytopenia induced by quinine is caused by antibodies that bind to platelets only in the presence of the drug.
DITP caused by GPIIb-IIIa antagonists may develop within
hours of first exposure to the drug and is mediated by preexisting antibodies.
Heparin-induced thrombocytopenia
Heparin-induced thrombocytopenia (HIT) is a drug reaction caused by antibodies against complexes of PF4 and
heparin. Binding of HIT antibodies to platelet Fc receptors
activates platelets, endothelial cells, and macrophages,
resulting in the production of platelet microparticles and an
intensely prothrombotic state. HIT is characterized by
thrombocytopenia in a patient receiving unfractionated
heparin or (less frequently) low molecular weight heparin
(LMWH). Despite the occurrence of thrombocytopenia,
bleeding is rare, and the risk of thrombosis is high (50%).
HIT is a clinicopathologic syndrome, meaning that the
diagnosis relies on a compatible clinical history and supportive laboratory testing. Transient thrombocytopenia
following the administration of heparin (previously called
type I HIT, or nonimmune HIT) is an innocuous syndrome
caused by platelet agglutination because of heparins strong
negative charge. This section will focus on immunemediated HIT.
Table 9-3 A clinical scoring system (low, 03; intermediate, 45; high, 68) to determine the pretest probability of heparin-induced
thrombocytopenia.
4Ts
2 points
1 point
0 point
Thrombocytopenia
Thrombosis or other
sequelae
Possible
None
Definite
Adapted from Lo GK, Juhl D, Warkentin TE, et al. Evaluation of pretest clinical score (4 Ts) for the diagnosis of heparin-induced
thrombocytopenia in two clinical settings. J Thromb Haemost. 2006;4:759-765, with permission.
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HIT testing
There are 2 types of tests available for the detection of HIT
antibodies: quantitative PF4/heparin immunoassays (PF4/
heparin enzyme-linked immunosorbent assay [ELISA]) and
functional assays demonstrating the platelet-activating
potential of these antibodies, such as the serotonin release
assay, considered the gold standard for HIT diagnosis.
HIT is caused by anti-PF4/heparin immunoglobulin (Ig)
G antibodies that activate platelets; thus, although many
susceptible patients form IgG, IgM, and IgA antibodies to
PF4/heparin complexes after exposure to heparin, only a few
will have platelet-activating IgG antibodies that cause HIT
(Figure 9-2).
Treatment of HIT
According to the American College of Chest Physician guidelines, monitoring for HIT should be done with platelet count
measurements at least every second day from day 4 of heparin exposure until day 14 (or until heparin is discontinued)
Figure 9-2 Iceberg model of heparin-induced thrombocytopenia (HIT) testing: anti- platelet factor 4 (PF4) immunoglobulin (Ig) G antibodies
by enzyme immunoassay (EIA) along with a positive platelet activation assay occur in most HIT patients. Many patients without HIT will have a
positive EIA, especially for non-IgG subclasses. HIPA heparin-induced platelet aggregation; SRA serotonin release assay. Modified with
permission, from Warkentin TE. Heparin-induced thrombocytopenia: pathogenesis and management. Br J Hematol. 2003;121:535555.
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should be performed. Vitamin K antagonists (such as warfarin) should not be given to patients with HIT at least until
the platelet count has recovered (100150 109/L). Adequate anticoagulation with a nonheparin anticoagulant is
required before warfarin is initiated and should overlap with
warfarin to avoid the risk of thrombosis associated with initial reduction in protein C and S levels. Due to the substantial (50%) frequency of thrombosis, which may occur
weeks after thrombocytopenia has resolved, continued treatment with warfarin for 30 days following diagnosis of isolated HIT is advisable.
Key points
HIT is associated with a high risk of thrombosis.
HIT should be suspected in a patient with a 50% decrease in
platelet count 5 to 10 days after starting unfractionated heparin
or LMWH, or sooner in patients with recent heparin exposure.
HIT is caused by platelet-activating IgG antibodies directed
against PF4/heparin complexes.
Treatment of HIT is to stop heparin and start an alternate,
nonheparin anticoagulant in therapeutic doses.
Nonimmune causes of
thrombocytopenia
Thrombotic microangiopathies
Clinical case
A 31-year-old woman presents with a 5-day history of progressive headache, fever, and weakness. Laboratory examination reveals a platelet count of 23 109/L. Other laboratory
abnormalities include anemia with fragmented red blood cells
on the blood smear and increased serum creatinine, alanine
aminotransferase (ALT), aspartate aminotransferase (AST),
and lactate dehydrogenase (LDH). While in the emergency
department, she develops left hemiplegia and has a grand
mal seizure.
Clinical features
The thrombotic microangiopathies discussed here are
thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). Distinguishing between TTP
and HUS is sometimes difficult but may be important for
prognosis and therapy. For example, neurologic features
commonly occur with TTP, which must be treated with
plasma exchange, whereas acute renal failure is generally
associated with HUS for which plasma therapy may not be
required. In addition, contact tracing is important for
patients with diarrhea-associated HUS. TTP and HUS are
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Figure 9-3 A schematic representation of the mechanism of platelet thrombi in thrombotic thrombocytopenic purpura (TTP). ADAMTS13 a
disintegrin and metalloprotease with thrombospondin-1-like repeats; GPIb glycoprotein Ib; vWF von Willebrand factor. From Sadler JE.
Thrombotic thrombocytopenic purpura: a moving target. Hematology Am Soc Hematol Educ Program. 2006:415420.
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Management
The use of plasma exchange has dramatically changed acute
TTP from a disorder with approximately 85% mortality to
one with 85% survival. In a randomized trial of 103 adults
with TTP, plasma exchange was more effective than plasma
infusion. Fresh frozen plasma and cryosupernant plasma
(depleted of vWF) are the replacement fluids of choice. The
exchange of 1 to 1.5 plasma volumes is standard initial treatment; however, larger volume exchanges may have additional
benefit in patients with an inadequate response. Generally,
plasma exchange is continued daily until the platelet count
reaches normal levels (150 109/L), LDH is normal, and
symptoms have resolved. Once a response is achieved, plasma
exchange may be discontinued or tapered. The role of aspirin
and platelet-inhibiting drugs remains to be established. For
patients who do not respond to plasma exchange, adjunctive
therapies may be required including corticosteroids, immunosuppressive medications, or splenectomy. Promising
results of observational studies using rituximab for the treatment of relapsed or refractory TTP are beginning to emerge.
In addition to disease-related morbidities, the procedure
of plasma exchange itself is often associated with complications. In a large prospective registry of 249 patients followed
from 1996 to 2008, 83 major complications occurred among
64 patients (26%), including catheter-related infection or
thrombosis, pneumothorax, pulmonary hemorrhage, severe
hypotension, and anaphylaxis. Transfusion-related acute lung
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Splenic sequestration
Splenic enlargement, usually from advanced liver disease or
cirrhosis, results in pooling of platelets in the rich splenic vascular network and mild to moderate thrombocytopenia. Other
mechanisms of thrombocytopenia in patients with cirrhosis
include immune destruction by autoantibodies, the myelosuppressive action of viral agents such as hepatitis C virus, and
the toxic effects of excessive alcohol ingestion. Therapy of
chronic hepatitis with interferon may also induce thrombocytopenia. Recently, decreased TPO production in the cirrhotic
liver has been shown to be an important contributing factor.
Familial thrombocytopenia
Familial thrombocytopenic syndromes are uncommon,
and patients are often misdiagnosed as having ITP. Recognition of these disorders is important to avoid unnecessary
and potentially harmful treatments including splenectomy.
The diagnosis should be considered in any patient with
thrombocytopenia (or chronic ITP) and a family history
of thrombocytopenia or in the absence of a platelet count
increase after typical ITP treatments. The presence of anatomic defects, including absent radii (thrombocytopenia
with absent radii syndrome) or right heart defects (as seen
in DiGeorge syndrome), and laboratory features including
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Bernard-Soulier syndrome. The detection of clusters of myosin in granulocytes using an immunofluorescent antibody
against nonmuscle myosin heavy chain type IIa may aid in
the diagnosis of MYH9-related disorders.
Other thrombocytopenic disorders
Thrombocytopenia with infection
Mild and transient thrombocytopenia predictably occurs
with many systemic infections. Thrombocytopenia may be
caused by a combination of mechanisms, including decreased
production, increased destruction, and increased splenic
sequestration. In some infections, specific mechanisms may
predominate. In viral infections, platelet production may be
suppressed; in rickettsial infections, platelets may be consumed in vasculitic lesions; in bacteremia, platelets may be
consumed because of disseminated intravascular coagulation (DIC). Thrombocytopenia is commonly associated with
HIV infection. Platelet kinetic studies in patients with HIV
infection show that decreased platelet production occurs
despite the presence of adequate numbers of normalappearing marrow megakaryocytes. Thrombocytopenia will
often improve during treatment with highly active antiretroviral therapy.
Hemophagocytic syndrome
Epstein-Barr virusassociated hemophagocytic syndrome is a
rare but important cause of infection-related thrombocytopenia. The diagnosis is supported by hepatosplenomegaly, elevated ferritin, and triglycerides and confirmed by bone marrow
or tissue biopsy showing evidence of hemophagocytosis.
Thrombocytopenia in the critically ill
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Table 9-4 provides a classification of inherited disorders associated with impaired platelet function, based on the platelet
function or responses that are abnormal (Figure 9-1). Of
note, not all of them are due to a defect in the platelets per se.
Some, such as vWD and afibrinogenemia, result from deficiencies of plasma proteins essential for normal platelet function. Some of these disorders are distinctly rare, but they shed
enormous light on platelet physiology. Moreover, in many
patients with inherited abnormalities in platelet aggregation
responses, the underlying molecular mechanisms remain
unknown. In patients with defects in plateletvessel wall
interactions (adhesion disorders), adhesion of platelets to
subendothelium is abnormal. The 2 disorders in this group
are vWD, due to a deficiency or abnormality in plasma vWF,
and the Bernard-Soulier syndrome (BSS), in which platelets
are deficient in GPIb (and GPV and GPIX); in both disorders,
plateletvWF interaction is compromised. Binding of fibrinogen to the GPIIb-IIIa complex is a prerequisite for platelet
aggregation. Disorders characterized by abnormal platelet
platelet interactions (aggregation disorders) arise because of
a severe deficiency of plasma fibrinogen (congenital
afibrinogenemia) or because of a quantitative or qualitative
abnormality of the platelet membrane GPIIb-IIIa complex,
which binds fibrinogen (Glanzmann thrombasthenia).
Patients with defects in platelet secretion and signal transduction are a heterogeneous group lumped together for
convenience of classification rather than based on an understanding of the specific underlying abnormality. The major
common characteristics in these patients, as currently perceived, are abnormal aggregation responses and an inability
to release intracellular granule (dense) contents upon activation of platelet-rich plasma with agonists such as ADP, epinephrine, and collagen. In aggregation studies, the second
wave of aggregation is blunted or absent. The patient described
in the clinical case at the beginning of this section falls in this
large group; the platelet dysfunction may arise from a variety
of mechanisms. A small proportion of these patients have a
deficiency of dense granule stores (storage pool deficiency).
In other patients, the impaired secretion results from aberrations in the signal transduction events that govern end
responses such as secretion and aggregation. Another group
consists of patients who have an abnormality in interactions
of platelets with proteins of the coagulation system; the best
described is the Scott syndrome, which is characterized by
impaired transmembrane migration of procoagulant
phosphatidylserine. Defects related to platelet cytoskeleton or
structural proteins may also be associated with platelet
dysfunction. Recent studies document impaired platelet
function associated with mutations in transcription factors
(eg, RUNX1, GATA1, FLI-1) that regulate expression of
important platelet proteins. In addition to the above groups,
there are patients who have abnormal platelet function
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secretion. These hemostatic defects may be linked to the accumulation of dialyzable and nondialyzable molecules in the
plasma. One such compound, guanidinosuccinic acid, accumulates in plasma, inhibits platelets in vitro, and stimulates
generation of nitric oxide, which inhibits platelet responses by
increasing levels of cellular cyclic guanosine monophosphate.
Aggressive dialysis can ameliorate uremic bleeding diathesis in many patients. Hemodialysis and peritoneal dialysis
are equally effective. Platelet transfusions are indicated in the
management of acute major bleeds. Other treatments including DDAVP, cryoprecipitate, and conjugated estrogens have
also been shown to be beneficial. Elevation of the hematocrit
with packed red blood cells or recombinant erythropoietin
may shorten bleeding times, improve platelet adhesion, and
correct mild bleeding in uremic patients. The beneficial effect
of red blood cells has been attributed to rheologic factors
whereby the red blood cells exert an outward radial pressure
promoting plateletvessel interactions.
Other factors predisposing to bleeding in patients with
renal failure include concomitant administration of antiplatelet agents or anticoagulant medications.
Acquired SPD
Several patients have been reported in whom the dense granule SPD appears to be acquired. This defect probably reflects in
vivo release of dense granule contents due to platelet activation
or production of abnormal platelets. Acquired SPD has been
observed in patients with antiplatelet antibodies, systemic
lupus erythematosus, chronic ITP, DIC, HUS, renal transplantation rejection, multiple congenital cavernous hemangioma,
MPD, acute and chronic leukemias, and severe valvular disease, and in patients undergoing cardiopulmonary bypass.
Antiplatelet antibodies and platelet function
Binding of antibodies to platelets may produce several effects,
including accelerated destruction, platelet activation, cell
lysis, aggregation, secretion of granule contents, and outward
exposure of PS. Patients with ITP have decreased platelet
survival and may have impaired platelet function and prolonged bleeding times even at adequate counts. In many
patients, the antibodies are directed against specific platelet
surface membrane glycoproteins that play a major role in
normal platelet function, including GPIb, GPIIb-IIIa, GPIaIIa, and GPVI, and glycosphingolipids. These antibodies, in
effect, induce acquired forms of BSS and thrombasthenia.
Drugs that inhibit platelet function
Many drugs affect platelet function. For several, the effects on
platelets have been studied in vitro, and the relevance of such
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Moxalactam has been reported to induce platelet dysfunction associated with prolonged bleeding times and clinical
hemorrhage. Other third-generation cephalosporins appear
to show little effect on normal platelet function. The clinical
significance of the effect of antibiotics on platelet function
remains unclear. The general context in which the bleeding
events are encountered in patients on antibiotics prevents
identification of the precise role played by the antimicrobials
because of the presence of concomitant factors (eg, thrombocytopenia, DIC, infection, vitamin K deficiency). Discontinuation of a specifically indicated antibiotic is usually not
an option or necessary.
There is growing evidence that selective serotonin reuptake
inhibitors (SSRIs) inhibit platelet function, and this has clinical relevance. Serotonin in plasma is taken up by platelets,
incorporated into dense granules, and secreted on platelet
activation. The SSRIs inhibit the uptake of serotonin and
platelet aggregation and secretion responses to activation. In
epidemiologic studies, patients on SSRIs have had increased
gastrointestinal bleeding and increased bleeding with surgery. Lastly, given the increasing use of herbal medicines and
food supplements, their role and interaction with pharmaceutical drugs need to be considered in the evaluation of
patients with unexplained bleeding.
Key points
Alterations in platelet function are described in many disorders
of diverse etiologies; the clinical significance in terms of
relationship to bleeding manifestations remains unclear in many.
A careful drug history should be taken in any patient
suspected to have platelet dysfunction.
Aspirin nonsteroidal anti-inflammatory agents and other
medications are a major cause of acquired platelet dysfunction.
Patients with MPD may have altered platelet function that
contributes to the bleeding manifestations.
High platelet counts, as observed in MPD patients, may be
associated with a loss of high molecular weight multimers of
vWF in plasma.
Patients with renal failure may have impaired platelet function
related to accumulation of substances in plasma that increase
platelet cyclic guanosine monophosphate levels.
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