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clinical manifestations are mild; often limited to easy bruis- tients with TTP can present with mental status changes. The
ing. Below 10,000/L, the risk of spontaneous mucocutane- presence of lymphadenopathy and splenomegaly can also pro-
ous bleeding (gingival bleed, epistaxis, menorrhagia, pete- vide clues to the diagnosis.
chiae and ecchymoses) and life threatening, spontaneous Initial laboratory evaluation should include a peripheral
intracranial hemorrhage or gastrointestinal bleeding increases blood smear, serum creatinine, DIC panel, LDH, total and
rapidly. It is important to remember that the platelet count is direct bilirubin, AST and ALT. This allows an initial deter-
an imprecise predictor of risk, and several factors such as mination of whether thrombocytopenia is an isolated abnor-
functional defects modify the bleeding risk. mality or part of a constellation of abnormalities that may
suggest a specific diagnosis. If hemolysis is suspected then a
direct antiglobulin test (Coombs test), reticulocyte count and
haptoglobin should be checked. The presence of schistocytes
Diagnostic Approach on the smear is suggestive of TTP or DIC. Differentiation is
When faced with an asymptomatic patient with a low
usually made by the presence of normal coagulation param-
platelet count, the clinician should initially seek to exclude
eters in TTP and elevated PT, PTT, fibrin split products, and
artifactual or pseudothrombocytopenia as the etiology. This low fibrinogen in DIC. An HIV test is indicated in patients
is caused by in vitro clumping of platelets when ethylenedia- with any risk factors. Vitamin B12 and folate levels can help
minetetraacetic acid (EDTA) is used as an anticoagulant (see diagnose nutritional causes of thrombocytopenia. Suspicion
below). The presence of platelet clumps on examination of of connective tissue disorders should lead to appropriate se-
the peripheral blood smear and normal repeat platelet count rologic testing. In considering potential causes of thrombo-
using citrated blood confirms pseudothrombocytopenia as the cytopenia, it may be helpful to take a pathophysiology-based
cause. approach as suggested in Table 1, keeping in mind that dis-
If thrombocytopenia is confirmed, a stepwise evaluation tinct pathogenetic mechanisms are not mutually exclusive. A
should be undertaken to assess the causes and the urgency of clinical approach based on common diagnostic considerations
treatment. If diagnoses such as thrombotic thrombocytopenic under different clinical scenarios is outlined in Table 2.
purpura (TTP) or heparin-induced thrombocytopenia (HIT)
are suspected, immediate intervention is required. In addition, Role of Bone Marrow Exam
any patient with severe thrombocytopenia or evidence of hem- A bone marrow biopsy may help differentiate inadequate
orrhage should receive immediate attention and possible plate- production versus excessive destruction/consumption as the
let transfusion. predominant cause of thrombocytopenia. In general, a bone
A detailed comprehensive history can provide valuable
diagnostic information. The history should focus on identi-
fying the presence of bleeding with particular attention to Table 1. Pathophysiologic classification of
critical sites including the head and gastrointestinal tract, as thrombocytopenia
patients with TTP can present with intermittent confusion. A
Decreased Production Increased Destruction
recent viral respiratory illness can sometimes be associated
with transient thrombocytopenia. A complete medication his- Hematologic malignancies Immune
tory including use of over-the-counter (OTC) products should Aplastic anemia ITP
be elicited. A history of prior low platelet counts or bleeding Myelodysplasia HIT
tendency should be sought and previous blood counts re- Drugs: chemotherapy, alcohol Drug-induced antibodies
viewed. Family history of platelet disorders should be elic- Radiation HIV
ited. Occasionally, congenital thrombocytopenia will be first HIV Post transfusion purpura
diagnosed in an adult. History pertaining to alcohol consump- Vitamin D deficiencies Connective tissue diseases
tion and HIV risk factors should be obtained. Hereditary thrombocytopenias Nonimmune
Physical examination should focus on finding the pres- Metastatic cancer to bone marrow DIC
ence of bleeding in the skin, mucous membranes, gastroin- Sepsis
testinal tract, brain, urinary tract, and retroperitoneum. The Cardiac valves
presence of retinal hemorrhage on ocular fundus examination TTP-HUS
is a predictor of CNS hemorrhage. Typically, patients with Kasabach Merrit syndrome
thrombocytopenia do not have soft tissue or joint bleeding. Splenic Sequestration
Their presence should raise suspicion of additional coagula- Hypersplenism
tion problems. Presence of vascular thrombi raises the pos-
sibility of HIT or disseminated intravascular coagulation HIV, human immunodeficiency virus; ITP, idiopathic thrombocytopenic pur-
pura; HIT, heparin-induced thrombocytopenia; DIC, disseminated intravas-
(DIC). A diligent neurologic examination should indicate the cular coagulation; TTP-HUS, thrombotic thrombocytopenic purpura-hemo-
need for imaging in patients with a suspected IC bleed. Pa- lytic uremic syndrome.
HIV, human immunodeficiency virus; ITP, idiopathic thrombocytopenic purpura; HIT, heparin-induced thrombocytopenia; DIC, disseminated intravascular
coagulation; TTP-HUS, thrombotic thrombocytopenic purpura-hemolytic uremic syndrome; EBV, Epstein-Barr virus; SLE, systemic lupus erythematosus;
HELLP, hemolysis, elevated liver function, and low platelets.
marrow biopsy is indicated when a platelet production prob- any patient with thrombocytopenia. In one study, 15.3% of
lem is suspected to help delineate the cause of underproduc- ambulatory patients with isolated thrombocytopenia had
tion. If peripheral destruction/sequestration is suspected, such pseudothrombocytopenia.4
as in immune thrombocytopenic purpura (ITP), DIC, or TTP,
a bone marrow biopsy is unlikely to provide useful additional Immune Thrombocytopenic Purpura (ITP)
information. However, in elderly patients, patients with si- Immune thrombocytopenia is a relatively common dis-
multaneous abnormalities in red and/or white cells, and in ease in adults. A Danish study noted an incidence rate of 2.68
patients without a definitive cause after initial workup, a bone per 100,000.5 ITP is an autoimmune condition caused by
marrow examination can elucidate the presence of a primary antiplatelet antibodies, which result in decreased platelet sur-
marrow disorder, such as myelodysplasia, leukemia or lym- vival. These antibodies are frequently IgG in nature and di-
phoma. The incidence of these conditions generally rises with rected against platelet antigens GP IIb/IIIa and GP Ib/IX com-
age. plexes. The spleen is the major site of platelet destruction.
A suggested algorithm for evaluation of thrombocytope- While all ages may be affected, frequently patients are young
nia is presented in the Figure. adult females. Severe thrombocytopenia typically presents
without anemia or leukopenia. Autoimmune hemolytic ane-
Common Etiologies mia is sometimes seen in association with ITP and this is
referred to as Evans syndrome. Usually a bone marrow ex-
Pseudothrombocytopenia amination is not necessary unless atypical features are present
This is a laboratory artifact caused by platelet clumping and an alternative diagnosis is suspected. The antiplatelet
due to naturally occurring antibodies directed against nor- antibody test lacks sensitivity and specificity and is generally
mally hidden epitopes of platelet surface antigens. EDTA, the not helpful clinically.
anticoagulant in purple top Vacutainer tubes, causes cal- In adults, ITP is typically a chronic disease which can
cium chelation and induces conformational change exposing remit and relapse over time. Many patients do not require
the target epitopes of platelet antigens.3 Pseudothrombocyto- treatment and the decision to initiate treatment is individual-
penia is seen in approximately 1 in 1,000 individuals and has ized, depending on platelet counts, the presence of hemor-
no clinical significance. It is evident on a peripheral smear by rhage, and the lifestyle-related bleeding risk of the patient.6
the presence of platelet clumps. If pseudothrombocytopenia Initial management is undertaken with corticosteroids. A com-
is suspected, repeat testing using citrated blood (blue top monly used regimen utilizes prednisone 1 mg/kg/d for 1 to 2
tube) will yield the true platelet count. It is essential to rule weeks, followed by a gradual taper. Recently, short pulses
out this condition before embarking on further evaluation of of dexamethasone have been found to be very effective.7 IV
immunoglobulin (IVIG) infusion (1gm/kg/d for 2 d) or anti- mon differential diagnosis. Coombs test is negative and helps
RhD antibodies (WinRho) can be used when rapid platelet differentiate this condition from Evans syndrome. However,
increment is desirable.8,9 Anti-RhD antibodies are effective the appearance of the entire pentad is a late finding and is
only in patients who are RhD-positive and have an intact associated with very poor outcome. Early diagnosis is of
spleen. Persistent or recurrent severe thrombocytopenia of 4 paramount importance for optimal outcome. A diagnosis of
to 6 weeks duration is usually considered an indication for TTP-HUS should be considered in any patient with throm-
splenectomy. Other treatment options include danazol, cyclo- bocytopenia and evidence of microangiopathy.13,14 TTP can
phosphamide, azathioprine, rituximab or autologous trans- be idiopathic or secondary, associated with Escherichia coli
plantation.6,10 O157:H7 diarrhea, HIV infection, certain drugs (ticlopidine,
clopidogrel, quinine, cyclosporine A, mitomycin A, cisplatin,
Thrombotic Thrombocytopenic Purpura etc), pregnancy, bone marrow transplant and metastatic car-
Hemolytic Uremic Syndrome (TTP-HUS) cinomas.15
TTP-HUS is a relatively uncommon, life-threatening The pathogenesis of idiopathic TTP has been elucidated
cause of thrombocytopenia. The classic diagnostic pentad of over the last few years. An inherited or acquired deficiency
TTP includes 1) microangiopathic hemolytic anemia, 2) (due to autoantibodies) of von Willebrand factor-cleaving
thrombocytopenia, 3) renal insufficiency, 4) fever, and 5) protease known as ADAMTS13 leads to accumulation of
mental status changes.11 However, the pentad is seen in less large multimers of von Willebrand factor which cause spon-
than 40% of cases.12 Neurologic symptoms can range from taneous platelet aggregation and thrombi.16 A clinical assay
confusion, headaches and fatigue to seizures and stroke-like for ADAMTS13 has been introduced into clinical practice but
syndrome. These can wax and wane over time. The presence because the results are usually not immediately available, the
of thrombocytopenia and schistocytes (red cell fragments) at diagnosis of TTP and the decision to initiate treatment re-
1 per high power field on smear is commonly seen. Throm- mains clinical.
bocytopenia can be severe with median platelet counts of Emergent plasma exchange is the cornerstone of TTP
20,000/L. The LDH can be elevated and renal insufficiency treatment.13,17 If this is not immediately available, infusion of
is common. Coagulation parameters are usually normal and fresh frozen plasma can be initiated before plasma exchange.
help differentiate this condition from DIC, which is a com- Corticosteroids, dipyridamole, and aspirin have been used but
are of uncertain value.17 Platelet transfusions can theoreti- Table 3. Drugs commonly associated with
cally worsen the clinical situation and should be avoided
thrombocytopenia
unless life-threatening hemorrhage occurs.
Abciximab
Amiodarone
Drug-induced Thrombocytopenia Amphotericin B
Drugs are a common cause of thrombocytopenia.18 Drugs Carbamazepine
commonly associated with thrombocytopenia are listed in Cimetidine
Table 3. However, this list is not comprehensive and practi- Digoxin
Eptifibatide
cally any drug can cause thrombocytopenia. When evaluating
Fluconazole
a patient with thrombocytopenia, a medication history (in- Furosemide
cluding over-the-counter medications) should be carefully Heparin
elicited and any recently initiated drug should be suspected. Interferon Alpha
Cytotoxic chemotherapy and ethanol cause thrombocytopenia Phenytoin
by directly inhibiting megakaryocytes. Most other drugs cause Piperacillin
Quinidine
thrombocytopenia by immune mechanisms. Quinine
Heparin is the most common cause of drug-induced Ranitidine
thrombocytopenia and is discussed in further detail below. Trimethoprim/Sulfamethoxazole
GPIIb/IIIa inhibitors are associated with severe thrombocy- Valproic Acid
topenia in approximately 0.5 to 2% of cases.19 Unlike other Vancomycin
Acetaminophen
drug-induced thrombocytopenias, GPIIb/IIIa inhibitor-in-
Aminoglutethimide
duced thrombocytopenia develops within 24 hours of expo- Aminosalicylic Acid
sure. This may be related to the presence of preformed nat- Ampicillin
urally occurring antibodies against neoepitopes exposed by Amrinone
alteration of the GPIIb/IIIa molecule.20 Treatment of drug- Captopril
Chlorothiazide
induced thrombocytopenia is discontinuation of the offending
Chlorpromazine
drug and supportive care. Recovery of platelet counts can be Chlorpropamide
expected in 5 to 7 days. Platelet transfusions may be needed Danazol
in severely thrombocytopenic and/or bleeding patients. Deferoxamine
Diatrizoate Meglumine
Diazepam
Chemotherapy-induced Diazoxide
Thrombocytopenia Diclofenac
With the increasing prevalence of cancer, chemotherapy Diethylstilbestrol
Gold
has become a common cause of thrombocytopenia. The his-
Haloperidol
tory is usually readily available and patients often have cy- Hydrochlorothiazide
topenia in other cell lines also. With most chemotherapy Ibuprofen
agents, nadir blood count occurs 7 to 10 days after chemo- Isoniazid
therapy and recovery over 2 to 3 weeks. Some agents like Levamisole
Lithium
nitrosoureas and mitomycin can cause more prolonged my-
Meclofenamate
elosuppression. Platelet transfusions are occasionally needed Methicillin
and dose adjustment of future chemotherapy doses may be Methyldopa
necessary. It is important to recognize that certain agents like Minoxidil
mitomycin can also cause TTP. Nalidixic Acid
Naphazoline
Oxyphenbutazone
Heparin-induced Thrombocytopenia (HIT) Oxytetracycline
HIT is a common cause of drug-induced thrombocyto- Procainamide
penia in hospitalized patients. Two types of HIT have been Rifampin
Sulfasalazine
described. Type 1 HIT is a modest transient decrease in plate-
Sulfisoxazole
let counts that occurs within the first 2 to 3 days after heparin Sulindac
initiation and returns to normal spontaneously, even with con- Tamoxifen
tinuation of heparin. It is generally of no clinical significance. Thiothixene
Type 2 HIT (also called heparin-induced thrombocytopenia Tirofiban
and thrombosis [HITT], and white clot syndrome) is less
More common associations are in bold print.
common, seen in about 0.3 to 5% of patients treated with
unfractionated heparin. It is caused by antibodies against bolism, abruptio placentae, trauma, snakebite, acute leuke-
platelet factor 4-heparin complex.21 It usually occurs 4 to 14 mias, and other malignancies, particularly adenocarcino-
days after heparin initiation, but may occur earlier in patients mas.27 Thrombocytopenia is almost universal in patients with
with prior exposure to heparin. It should be suspected in any DIC due to activation of the clotting mechanism. The diag-
patient with falling platelet counts below the normal range, or nosis is usually easily made in sick hospitalized patients with
a greater than 50% drop in the platelet count within the nor- oozing venipuncture sites, ecchymosis, falling platelet counts,
mal range. An ELISA assay for antiplatelet factor 4-heparin poor platelet survival after platelet transfusion and elevated
IgG antibody is available and has a sensitivity of 90%, but PT, aPTT, fibrin split products and low fibrinogen levels. It
specificity ranges from 50 to 93%. Severe thrombocytopenia may be less obvious in an ambulatory patient with chronic
with platelet counts below 10,000/L can occur, but patients compensated DIC, such as a patient with metastatic prostate
are paradoxically hypercoagulable due to platelet activation. or GI malignancy in whom a slower rate of consumption of
In fact, abnormal thrombosis, sometimes catastrophic, is the coagulation factors may be balanced by enhanced synthesis.
predominant manifestation of HIT and bleeding is uncom- Thus, patients may have only a modest thrombocytopenia and
mon. Treatment consists of stopping heparin and using alter- normal PT and aPTT. The diagnosis is based on the presence
nate anticoagulants like argatroban, lepirudin, or bivalirudin. of microangiopathy on peripheral blood smear and elevated
Fondaparinux is a heparin pentasaccharide analogue that does fibrin degradation products (FDP) and D-dimer levels. It is
not bind to platelet-factor 4 and thus should not cause HIT.22 important to consider TTP-HUS as a differential. Treatment
Low molecular weight heparin is not an appropriate antico- is supportive and consists of treating the underlying cause and
agulant in the setting of HIT because of cross reactivity of the providing supportive blood product transfusionsplatelets,
antibody.23 As in TTP, platelet transfusions are relatively cryoprecipitate, and/or fresh frozen plasma as needed are used
contraindicated in the absence of severe thrombocytopenia to replace consumed coagulation factors. If thrombosis is the
with life-threatening hemorrhage. Evidence-based guidelines predominant manifestation of DIC, heparin may be consid-
for managing HIT have recently been published.24,25 ered for treatment.
Sepsis/Infection Hypersplenism
Patients with sepsis often have varying degrees of throm- Splenomegaly from any cause can result in sequestration
bocytopenia. This is usually multifactorial in etiology; related of blood elements leading to cytopenia. The cardinal features
to associated DIC, nonspecific immune destruction of plate- of hypersplenism are (a) splenomegaly; (b) reduced levels of
lets, excessive consumption, marrow suppression, and med- one or more blood elements in circulation associated with
ications. Therapy consists of correction of the underlying increased precursors; and (c) correction of cytopenia after
cause of sepsis, identification of offending medications, and splenectomy. Splenomegaly is almost always secondary to
supportive care. Thrombocytopenia may also be seen in a other disorders, most commonly cirrhosis with portal hyper-
variety of infections without sepsis syndrome. tension. Thrombocytopenia is usually of moderate severity
Certain specific infections can be associated with throm- and is rarely seen below 40,000/L. In most cases, specific
bocytopenia. Cytomegalovirus and Epstein-Barr viral infec- treatment of thrombocytopenia is not necessary. Platelet trans-
tions can cause transient thrombocytopenia. HIV infection is fusions are not effective as transfused platelets are also se-
perhaps the most important infectious cause in North Amer- questered in the spleen. Treatment is directed against the
ica.26 Thrombocytopenia is thought to be related to direct underlying cause of splenomegaly. Although splenectomy can
marrow toxicity of the virus as well as immune-mediated correct thrombocytopenia, the benefit of that should be care-
mechanisms. Worldwide, malaria is a common cause. Ehrli- fully weighed against the potential risks of splenectomy, in-
chiosis, a tick bite-transmitted infection, is seen in the US, cluding long-term infection risk.
predominantly in southeastern and south central regions. In
appropriate geographic locations, dengue, Hantavirus and
other viral hemorrhagic fevers should be considered in the Post Transfusion Purpura (PTP)
differential diagnosis. Some of these viruses are also potential Post transfusion purpura is a rare complication of blood
bioterrorism agents. transfusion. Seen mostly in women, it presents as severe
thrombocytopenia 5 to 10 days after red cells or platelet trans-
fusion. This is an alloimmune complication that occurs in
Disseminated Intravascular Coagulation patients who have developed antiplatelet antibodies (most
(DIC) commonly against PlA1 antigen) from prior transfusion or
DIC is a systemic process caused by pathologic thrombin pregnancy.28 Re-exposure to PlA1 antigen later triggers im-
generation. Clinically, it is characterized by both thrombosis mune-mediated destruction of platelets, including the patients
and bleeding. DIC is a complication of an underlying illness. own (PlA1 negative) platelets, resulting in profound throm-
Common etiologies include sepsis, burns, amniotic fluid em- bocytopenia. Platelet counts spontaneously recover in about 2
18. George JN, Raskob GE, Shah SR, et al. Drug-induced thrombocytope- 26. Scaradavou A. HIV-related thrombocytopenia. Blood Rev 2002;16:
nia: a systematic review of published case reports. Ann Intern Med 7376.
1998;129:886890.
27. Levi M, Ten Cate H. Disseminated intravascular coagulation. N Engl J
19. Abrams CS, Cines DB. Thrombocytopenia after treatment with platelet Med 1999;341:586592.
glycoprotein IIb/IIIa inhibitors. Curr Hematol Rep 2004;3:143147.
28. Gonzalez CE, Pengetze YM. Post-transfusion purpura. Curr Hematol
20. Bougie DW, Wilker PR, Wuitschick ED, et al. Acute thrombocytopenia
Rep 2005;4:154159.
after treatment with tirofiban or eptifibatide is associated with antibodies
specific for ligand-occupied GPIIb/IIIa. Blood 2002;100:20712076. 29. British Committee for Standards in Haematology, Blood Transfusion
21. Visentin GP, Ford SE, Scott JP, et al. Antibodies from patients with Task Force: guidelines for the use of platelet transfusions. Br J Haematol
heparin-induced thrombocytopenia/thrombosis are specific for platelet 2003;122:1023.
factor 4 complexed with heparin or bound to endothelial cells. J Clin 30. Rebulla P, Finazzi G, Marangoni F, et al. The threshold for prophylactic
Invest 1994;93:8188.
platelet transfusions in adults with acute myeloid leukemia: Gruppo
22. Hirsh J, ODonnell M, Weitz JI. New anticoagulants. Blood 2005;105: Italiano Malattie Ematologiche Maligne dellAdulto. N Engl J Med 1997;
453463. 337:18701875.
23. Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocy-
topenia in patients treated with low-molecular-weight heparin or unfrac- 31. Schiffer CA, Anderson KC, Bennett CL, et al. Platelet transfusion for
tionated heparin. N Engl J Med 1995;332:13301335. patients with cancer: clinical practice guidelines of the American Society
of Clinical Oncology. J Clin Oncol 2001;19:15191538.
24. Alving BM. How I treat heparin-induced thrombocytopenia and throm-
bosis. Blood 2003;101:3137.
25. Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia: rec- Please see Ashok K. Malanis editorial on page
ognition, treatment, and prevention: the Seventh ACCP Conference on 451 of this issue.
Antithrombotic and Thrombolytic Therapy. Chest 2004;126:311S337S.