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The Art and Science of Infusion Nursing

Thrombocytopenia
A Destruction of Platelets
Edythe M. Greenberg, PhD, RN, FNP-BC

ABSTRACT
Platelets, or megakaryocytes, are irregular, disk-shaped cell fragments circulating in the blood. They are a primary compo-
nent in maintaining hemostasis. Low platelet counts, or thrombocytopenia, leave patients at an increased risk of hemor-
rhage. This article discusses various etiologies of disorders of low platelets and current therapies for management.
Key words: autoimmune thrombocytopenia, drug-induced thrombocytopenia, heparin-induced thrombocytopenia,
hypersplenism, thrombocytopenia

P
latelets are the first line of defense against bleed- Thrombopoietin, a hormone produced primarily in the
ing. They are part of the extrinsic clotting pathway. liver, is the most potent stimulator of thrombopoiesis.
When our platelet count is low, spontaneous bleeding Thrombopoietin production is increased with inflamma-
may occur in the mucosa, skin, lungs, gastrointesti- tion, specifically by interleukin 6. A reduction in the platelet
nal tract, central nervous system, and genitourinary tract.1 count will stimulate thrombopoietin production, which
Thrombocytopenia can occur as the result of decreased bone promotes both the proliferation of megakaryocyte (plate-
marrow production, increased destruction of platelets, and let) progenitors and the maturation of the megakaryocytes.
sequestration in the spleen.1,2 Although common causes On maturation, megakaryocytes generate and release new
of thrombocytopenia will be discussed in this article, the platelets (thrombocytes) into the circulation.2,5
primary focus will be on thrombocytopenia resulting from Approximately 30 000 platelets are created each day for
increased platelet destruction. each microliter of blood.4 About one-third of platelets are
stored in the spleen, but this number may vary according
to the spleen size.2 Platelets remain inactive in the blood-
PHYSIOLOGY OF PLATELETS stream until a blood vessel is injured.2,3
The normal life span for a platelet is 7 to 10 days, but its
Platelets are small anucleate discoid cell fragments that cir- life span may be shortened from increased platelet destruc-
culate in the bloodstream.3 Megakaryocytes are large cells tion. The number of circulating platelets is determined by
produced by hematopoietic cells in the bone marrow. They platelet production or number of platelets entering the
fragment either in the bone marrow or soon after entering circulation and platelet destruction under steady-state con-
the blood. A platelet (thrombocyte) is a fragment of the ditions.2 Old platelets are destroyed through phagocytosis
megakaryocyte.4 in the spleen and liver (Kupffer cells).3
Thrombopoiesis is the process of making new plate- Although most often associated with blood hemostasis,
lets and is regulated by cytokines and chemokines. platelets can also be an invaluable inflammatory marker
because of their sensitivity to different disease states.
Author Affiliation: Family Nurse Practitioner, Department of Platelet interaction is associated with cardiovascular dis-
Leukemia, University of Texas M.D. Anderson Cancer Center, ease progression. There is also hyperaggregation in diabetic
Houston, Texas.
patients with cardiovascular disease.3
Edythe M. Greenberg, PhD, RN, FNP-BC, is a family nurse
practitioner who has worked with the Department of Leukemia at
the University of Texas MD Anderson Cancer Center for 10 years.
Dr. Greenberg also has previous nursing experience in nursing HEMOSTASIS
education, emergency health, and family health.
The author has no conflicts or interest to disclose.
Corresponding Author: Edythe M. Greenberg, PhD, RN, FNP-BC, MD
Hemostasis, the prevention of blood loss, can occur when a
Anderson Cancer Center, Department of Leukemia, 1515 Holcombe blood vessel is severed or injured. Platelets are part of the
Blvd, Houston, TX 77030 (emgreenberg@mdanderson.edu). extrinsic clotting pathway. The normal vascular endothelium
DOI: 10.1097/NAN.0000000000000204 is smooth and has an antithrombotic surface that prevents

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platelets from adhering to it.2,5 When a blood vessel is HISTORY AND PHYSICAL EXAMINATION
injured, it becomes prothrombotic, leading to platelet acti-
vation and inhibition of fibrinolysis.2 History
When injured, the blood vessel constricts, followed by The history of present illness includes any circumstance
the formation of a platelet plug. Constriction of the smooth associated with thrombocytopenia, although it is often an
muscle in the blood vessel slows the blood flow to the rup- incidental finding. The past medical history should include
tured blood vessel. Normally a coat of glycoprotein on the any previous illnesses and recent infections; malignancies
platelet cell membrane prevents the platelet from adhering (myelodysplastic syndrome, leukemia, lymphoma, aplastic
to normal endothelial tissue. When endothelial tissue or anemia); recent travel (dengue fever, malaria, Rickettsial
collagen deep in the vessel wall is injured, the glycoproteins infections, possible tick bite); recent new medications;
cause the platelet to adhere to the injured area.4 The plate- organ transplant; transfusion history; alcohol or drug use;
let membrane contains phospholipids, which activate the recent hospitalizations; immunizations; high-risk behaviors;
blood clotting process.4 over-the-counter medications/herbs; autoimmune disor-
Upon adherence to the endothelial surface, pseudopods ders; and pregnancy. Review for the use of food and natural
protrude from the platelet surface, and the platelets swell products including walnuts, cows milk, cranberry juice,
into irregular shapes.4 Platelets also secrete adenosine dis- sesame seeds, African beans, and jui. Consider when the
phosphate (ADP) and enzymes that form thromboxane A2. thrombocytopenia occurred in relation to the ingestion of
Thromboxane A2 activates nearby platelets. The mobilized the medication, food, or beverage.7 Ask about any family
platelets stick to the original activated platelets to form a history of bleeding disorders. Questions should include any
platelet plug.4 The platelet plug remains loose, but is effec- bleeding episodes (ie, nosebleeds), easy bruising, melena,
tive in closing the injury. Platelet plugs prevent bleeding as fever, rashes, pain, headache, heavy menses in a woman
a result of daily minute injuries. of childbearing age, prolonged bleeding after procedures,
The platelet also contains contractile proteins, which bleeding gums, blood in sputum, blood in urine, and vision
contract forcefully and release granules containing nucleo- changes.1,8 If the individual has a central venous catheter,
tides, adhesive proteins, growth factors, and procoagulants ask if it is being flushed with normal saline or heparin.
into the bloodstream.2,4 These granules are involved in HELLP (hemolysis, elevated liver enzymes, and low plate-
blood clot formation, inflammation, atherosclerosis, anti- let count) syndrome should be discussed with pregnant
microbial host defense, angiogenesis, wound repair, and women exhibiting visual symptoms, headaches, abdominal
tumorigenesis.2,3 The platelets become sticky and adhere pain, or flu-like symptoms.1
to collagen and the von Willebrands factor, which is a pro-
tein released from injured tissue into the plasma. Finally, Physical Examination
fibrous tissue grows in the blood clot to permanently close The physical examination should make note of bleeding,
the injury to the blood vessel.4 unexplained bruising (petechiae, purpura, ecchymosis),
enlarged liver or spleen, and ischemic limb or skin necrosis
associated with heparin-induced thrombocytopenia.9 A
THROMBOCYTOPENIA stool for occult blood should be obtained to evaluate for
gastrointestinal and/or rectal bleeding. A fundoscopic exam
Thrombocytopenia can occur from bone marrow suppres- can provide evidence of central nervous system bleeding
sion, sequestration from an enlarged spleen, and increased if hemorrhages are present. Any areas of bruising should
platelet destruction.2 It is defined as a platelet count less than be marked in order to note the bleeding pattern. Evaluate
150000 mm3. Thrombocytopenia is considered to be mild for painful, swollen joints. Note any epistaxis, hematuria,
when the platelet count is between 70000 and 150000 mm3, bloody sputum, bleeding from the gums, menorrhagia,
and severe if less than 20000 mm3. Most individuals are heavy bleeding after procedures, heavy and prolonged
asymptomatic if the platelet count is 50000 mm3 or greater. bleeding after childbirth, and alterations in mental status.3
Surgical procedures may be performed when the platelet Note abdominal tenderness and distention. Soft tissue or
count is 50000 mm3 or greater. Patients rarely have purpura joint bleeding is not usually associated with thrombocyto-
with platelet counts between 30000 mm3 and 50000 mm3. penia. In these cases, look for other coagulation disorders.6
Bleeding from minimal trauma may occur with a platelet
count of 30000 mm3 or less, and spontaneous bleeding may Laboratory Data
occur when the platelet count is less than 10000 mm3.1 Initial laboratory evaluation includes a complete blood cell
For patients with cancer receiving treatment, the sever- count and differential, liver function tests (LDH, total and
ity of thrombocytopenia changes. Grade 1 thrombocytope- direct bilirubin, AST, ALT), and serum creatinine. If dissem-
nia is 75000 to 150000 mm3; Grade 2 thrombocytopenia inated intravascular coagulation (DIC) is suspected, then a
is 50000 to <75000 mm3; Grade 3 thrombocytopenia is d-dimer and coagulation studies are obtained in addition
25000 to <50000 mm3; and Grade 4 thrombocytopenia is to a platelet count. Performing a direct antiglobulin test
< 25000 mm3.6 (Coombs test), reticulocyte count, and haptoglobin when

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hemolysis is suspected may also be desired.6 Schistocytes disease, Feltys syndrome, myelofibrosis, and chronic lym-
(red blood cell fragments) seen on the peripheral smear phocytic leukemia (CLL).6,12
may indicate thrombotic thrombocytopenia purpura (TTP) With hypersplenism, platelets are shifted into the spleen.
or DIC. Human immunodeficiency virus (HIV) testing may Normally, monocytes from the bone marrow migrate to dif-
be warranted. Nutrition causes of thrombocytopenia can ferent parts of the body to help protect the organism. These
be ruled out with vitamin B12 and folate levels. Serology can monocytes become part of the reticuloendothelial system
help eliminate autoimmune causes of thrombocytopenia.6 and are called reticular cells. Splenic reticular cells primar-
When reviewing the complete blood cell count with ily function to remove the senescent cells from circulation
differential, all 3 cell lineages (white blood cells, red blood and to provide phagocytic cells for both inflammatory and
cells/hemoglobin, and platelets) are evaluated. Rapid eval- immune responses. In hypersplenism, the reticular cells
uation and treatment are indicated when peripheral blood may be triggered to sense normal platelets as abnormal or
blasts are seen as this indicates an acute leukemia. Red foreign and cull them from the circulation.13
blood cell fragmentation is associated with thrombotic The thrombocytopenia in hypersplenism is usually high-
microangiography9 and also requires an astute evaluation. er than 40000 mm3 and does not require treatment.
The hemoglobin and hematocrit may be normal unless Platelet transfusions are generally not helpful, because
there is also an autoimmune hemolytic anemia.1,2 the additional platelets are sequestered in the spleen.6
A bone marrow study may be ordered to evaluate Management includes treating the underlying disorder and,
the thrombocytopenia. It can help identify poor platelet if indicated, a splenectomy.6 Splenic artery embolization
production from excessive destruction or consumption may be an alternative in patients who do not medically
of platelets. It is most useful in identifying a platelet pro- qualify for a splenectomy.12
duction issue. It will not provide useful information if the
platelet problem occurs from immune thrombocytopenia,
DIC, or TTP. In patients with other myeloid cell abnormal- INCREASED DESTRUCTION OF
ities (red blood cells, white blood cells), it can diagnose PLATELETS
a primary bone marrow disorder such as myelodysplastic
syndrome, leukemia, or lymphoma.6 Autoimmune Syndromes
A pseudothrombocytopenia can occur with platelet Immune-mediated thrombocytopenia purpura (ITP), also
clumping, and has no clinical significance. It can be confirmed known as idiopathic thrombocytopenic purpura, is an auto-
by a peripheral blood smear.1 Pseudothrombocytopenia immune disorder resulting in a low platelet count from
accounts for approximately 15% to 30% of all isolated cases increased destruction of antibody-coated platelets by tissue
of thrombocytopenia.10 Normally, platelet count measure- macrophages, impaired thrombopoiesis by antiplatelet anti-
ments by electronic particle counters are more accurate bodies attacking megakaryocytes, and impaired release from
and less expensive than manual techniques. Unfortunately, the megakaryocyte.14 The International ITP Working Group
underestimation of platelets occurs by in vitro platelet recommends that the diagnosis of ITP be made on a platelet
clumping or platelet adherence to leukocytes. This is not count less than 100000 instead of 150000 mm3. It is divided
detected by the electronic particle counters, and the into 3 phases: (1) newly diagnosed ITP, (2) persistent ITP, and
reports produced are inaccurate. Pseudothrombocytopenia (3) chronic ITP. Newly diagnosed ITP is less than or equal to
has been reported with ethylene diamine tetra-acetic acid 3 months duration. Persistent ITP remains from 3 months to
as an anticoagulant, platelet cold agglutinins, and multiple 1 year. Chronic ITP continues for more than 1 year.14-16
myeloma.10 If pseudothrombocytopenia occurs, a micro- ITP occurs in 100 cases per 1 million persons annually,
scopic examination for platelet clumping and a repeat plate- of which approximately 50% of the cases are in children.1
let count should be repeated using a different anticoagulant Immune-mediated thrombocytopenia is usually chronic in
such as heparin or sodium citrate as the anticoagulant.11 adults and acute in children.17 Many children will have a
febrile illness (rubella, varicella, mumps, rubeola, Epstein-
Barr virus, the MMR vaccination) prior to developing
HYPERSPLENISM autoimmune thrombocytopenia, and it is usually self-limit-
ed.2,8,18 There is an increased incidence with advancing age,
Splenomegaly is defined as an enlarged spleen by either and a higher occurrence in women.2,15
physical examination or imaged studies (CT scan, ultra- ITP can occur in the absence of other medical conditions
sound). The primary features of hypersplenism include (1) or secondary to an underlying medical condition, such as
an enlarged spleen; (2) cytopenias, including thrombocyto- CLL, HIV, hepatitis, or systemic lupus erythematosus.1,2
penia; and (3) correction of cytopenias with a splenectomy. Lymphoproliferative disorders and myelodysplastic syn-
The splenomegaly is most often the result of disorders such drome should be a consideration in an isolated thrombo-
as cirrhosis, portal hypertension, chronic malaria, rheuma- cytopenia in an adult older than 60 years of age.1 ITP in
toid arthritis, tuberculosis, polycythemia vera, sarcoidosis, association with severe autoimmune hemolytic anemia is
lymphomas, hemolytic anemia, mononucleosis, Gauchers known as Evans syndrome.6

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Secondary immune thrombocytopenia is associated Asymptomatic individuals may be managed with obser-
with autoimmune disorders such as systemic lupus ery- vation and frequent monitoring. Treatment is usually not
thematosus, Graves disease, antiphospholipid syndrome, indicated if the platelet count is greater than 50000 mm3,
lymphoproliferative disorders, infections (HIV, Epstein-Barr unless active bleeding is present.1 Symptomatic ITP is
virus, cytomegalovirus, varicella-zoster virus, hepatitis C treated with oral steroids, intravenous immunoglobulin
virus, Helicobacter pylori), and sarcoidosis.1,19 Individuals G (IVIG), the monoclonal antibody rituximab (Rituxan),
with CLL may initially present with an autoimmune throm- thrombopoietin receptor agonist drugs (Promacta, Nplate),
bocytopenia. In individuals with a viral illness, it is suspect- or a splenectomy.1,2
ed that antibodies to viral and bacterial antigens cross-react The dosage for prednisone is 1 mg/kg/day for 1 to 2
with platelets. When the illness is eradicated, the ITP may weeks, then slowly tapered. Pulse doses of dexamethasone
resolve spontaneously.4 may also be effective. Dexamethasone 40 mg may be given
Autoimmune thrombocytopenia is a disease of exclu- for 4 consecutive days and repeated every 2 to 4 weeks.20
sion, and is diagnosed from the history, physical exam- The dosage for Rituxan, a CD20 monoclonal antibody, is 375
ination, complete blood cell count, and peripheral blood mg/m2 weekly for 4 weeks.20 The dosage for IVIG is 2 g/kg
smear. An isolated thrombocytopenia in an otherwise nor- in divided doses over 2 to 5 days.2
mal complete blood cell count with differential should alert Second-line treatment includes the use of thrombopoi-
the clinician to suspect autoimmune thrombocytopenia. etin mimetic medications such as eltrombopag (Promacta)
Laboratory testing is aimed at eliminating other causes of or romiplostim (Nplate).1,2 The thrombopoietin mimetic
the thrombocytopenia.17 The hemoglobin and white blood medications increase platelet production by improving
cell count is usually normal. Anemia may occur if there is proliferation and differentiation of platelet progenitors.
acute bleeding or an autoimmune hemolytic anemia. These medications require regular treatment and frequent
The peripheral blood smear can identify other causes monitoring as discontinuation may decrease the platelet
of thrombocytopenia, or a bone marrow disorder, should count.20 Alternative treatments for refractory autoimmune
the erythrocyte or leukocytes be abnormal. Congenital thrombocytopenia include Vinca alkaloids (vincristine, vin-
disorders are identified by large platelets, or an increased blastine), cyclophosphamide (Cytoxan), Azathioprine, and
mean platelet volume. Pseudothrombocytopenia is another Danazol.8
consideration.15 In this case, the circulating thrombopoietin A splenectomy is a second-line treatment in patients
level is usually normal.16 Iron deficiency may be present. with persistent thrombocytopenia. However, the risks from
Other laboratory studies should include serology for the splenectomy, including surgery, anesthesia, increased
systemic lupus erythematosus, a hepatitis panel, a test for risk of infection, and increased risk of vascular complica-
HIV, and immune globulins. A Coombs test helps rule out tions, must be weighed against the benefits of the sur-
autoimmune hemolytic anemia.2 A bone marrow study may gery.20 Splenectomy is usually reserved for individuals who
be ordered in patients refractory to conventional therapy; have autoimmune thrombocytopenia for at least a year;
in patients who relapse, exhibit systemic symptoms, or cannot maintain an adequate platelet count with medical
show atypical physical findings; or before a splenectomy.2,15 management; have adverse reactions to traditional thera-
The risk of bleeding is determined by the platelet count. py; or a physically active lifestyle.16
ITP is most often associated with mucocutaneous bleeding
(purpura, petechiae) in association with thrombocytopenia Drug-induced Thrombocytopenia
in an otherwise normal peripheral blood count and blood Drug-induced thrombocytopenia is a common cause of low
smear.2,15 Although rare, internal bleeding (ie, gastrointesti- platelets in patients in the outpatient setting. Annually, 10
nal bleeding and intracranial bleeding) can occur. It usually cases per 1 million individuals have been recorded in the
occurs in older adults with other comorbidities and with United States and Europe, but the incidence may be high-
platelet counts less than or equal to 30 000 mm3.15 The er in older adults and hospitalized patients.1 Medications
spleen is often normal in size unless associated with a viral should be reviewed in anyone with an acute drop in their
illness or autoimmune hemolytic anemia.17 platelet count. A medication history includes prescription
The goal of treatment is to improve the platelet count medications, over-the-counter medications, and herbal/
without need for continuation of treatment. Treatment is nutritional supplements.1 The goal of management is to
recommended for patients who are bleeding or are at risk remove the offending medication before any clinically
for bleeding. This may include older adults, patients at risk significant bleeding or, in the case of heparin, thrombosis.
for trauma, and those with previous history of bleeding or Individuals with drug-induced thrombocytopenia pres-
low platelet count.16 When planning treatment, consider- ent with moderate to severe thrombocytopenia and evi-
ation should be given to the patients age, comorbidities, dence of bleeding, which can range from bleeding into
and patients lifestyle. Treatment is aimed at raising the the skin or mucosa to life-threatening bleeding.21 The
platelet count to a safe level and preventing bleeding. history includes when the medication was started and the
Response to corticosteroids, intravenous immune globulin, onset of the thrombocytopenia. Drug-induced thrombocy-
and anti-RhD supports the diagnosis of ITP.16 topenia usually occurs within 5 to 10 days after starting a

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medication, and resolves within 7 to 14 days after stopping to CD20 on the platelets. With Rituxan, the thrombocyto-
the medication.1,7 It can occur from repetitive daily expo- penia is often preceded by infusion reactions or features of
sure to a medication or reexposure to a medication that is disseminated vascular coagulation.7
being taken for a period of time.7 Drug-induced thrombo- Chemotherapy and radiotherapy may be held if the
cytopenia can present like primary thrombocytopenia, so a platelet count is less than 100000 mm3. Supportive care
comprehensive history is important to avoid unnecessary may include platelet transfusions.23 Chemotherapy-induced
treatment and to prevent repeat exposures.7 Most instanc- thrombocytopenia is managed by eliminating the underly-
es of drug-induced thrombocytopenia occur in individuals ing cause (infection, antibiotics, coagulopathy); reducing
who are taking multiple agents to control other medical the dose of chemotherapy; platelet transfusion support;
conditions. It may be difficult to identify the causative and thrombopoietin receptor agonists (eltrombopag) if a
medication.22 patient cannot be supported with platelet transfusions.
Clinical criteria for drug-induced thrombocytopenia These agents are only used if the platelet count has
include whether (1) the thrombocytopenia began during not recovered to 100000 mm3 before the next cycle of
the administration of a medication; (2) other causes of chemotherapy.23
thrombocytopenia are eliminated; (3) readministration of Immune-mediated thrombocytopenia results from
the medication, food, or beverage results in a thrombocy- increased platelet destruction leading to accelerated plate-
topenia; and (4) an in vitro test for drug-dependent platelet let destruction from drug-related antibodies leading to
antibodies was present.7 The diagnosis is considered when increased platelet clearance (quinine, quinidine) or platelet
thrombocytopenia is associated with bleeding approxi- activation (heparin), or suppression of platelet production
mately 5 to 10 days after beginning the medication. A drug from antibodies affecting the megakaryocyte.7 Thiazide
rechallenge at a lower dose can confirm the diagnosis. If diuretics, ethanol, and tolbutamide can cause an iso-
the drug is rechallenged, it should be performed in a super- lated thrombocytopenia by suppressing megakaryocyte
vised setting because of the increased risk of bleeding.7 production.21 Many drugs are capable of causing immune-
The main mechanisms for drug-induced thrombocytope- mediated thrombocytopenia. Some drugs bind to platelet
nia are either immune-mediated or nonimmune-mediated. membrane glycoproteins, which stimulate production of
Nonimmune-mediated thrombocytopenia can be the antibodies that interact with antigens on the platelets,
result of a loss of megakaryocytes and an impairment resulting in a thrombocytopenia.2 Quinidine, quinine, and
in megakaryocyte proliferation and maturation.7 Non sulfonamides can produce a thrombocytopenia from this
immune-mediated reactions can affect the megakaryocytes type of antibody-antigen reaction. When the drug is discon-
causing suppression of the bone marrow resulting in low tinued, the platelet count recovers.2 Drug-dependent plate-
platelet production (chemotherapy), dose-dependent mye- let antibodies can continue to bind to the platelets even in
losuppression (Zyvox), and interference with megakaryo- the absence of the medication, and the thrombocytopenia
cyte function (bortezomib).7 Impaired platelet production can persist in the absence of the medication. Examples of
is most frequently caused by high-dose chemotherapeutic these medications include gold, L-dopa, procainamide, sul-
agents in a dose-dependent, inverse relationship. fonamides, and alemtuzumab.7
High-dose chemotherapy and radiotherapy lower the Other agents known to produce drug-induced throm-
platelet count because they suppress the bone marrow. bocytopenia include heparin, quinine, quinidine, rifamp-
Breast and lung cancers commonly metastasize to the bone. in, vancomycin, trimethoprim-sulfamethoxazole, chloram-
Primary blood cancers such as lymphoma and leukemia can phenicol, and phenylbutazone. Gold treatments can cause
present with a pancytopenia when more than 80% of the bone marrow suppression, but only in susceptible people.
bone marrow is affected.23 Myelodysplastic syndrome can Valproic acid has a dose-dependent pattern of thrombocy-
be a secondary result of previous radiotherapy and high- topenia. Ganciclovir is also directly myelosuppressive.22,24
dose chemotherapy. Bone marrow suppression may occur Linezolid can affect platelets over a prolonged period of
up to 5 years after treatment.10 After chemotherapy, the time in high serum concentrations. Thiazide diuretics and
lowest blood counts (nadir) usually occur within 7 to 10 days tolbutamide can also cause a transient thrombocytopenia.7
after the administration of the chemotherapy, and it may When evaluating drug-induced thrombocytopenia, one
take up to 2 to 3 weeks for the blood counts to recover.23 must consider how quickly the thrombocytopenia occurred.
The megakaryocyte and platelet pathways can be affect- A rapid onset of thrombocytopenia suggests an immune-
ed at different levels of platelet production. Busulfan mediated response, whereas a slow onset usually suggests
affects the pluripotent stem cells. Cyclophosphamide bone marrow suppression.22 A baseline platelet count is
affects later megakaryocyte progenitors.23 Etoposide can obtained and then trends are monitored. An individual may
lead to increased platelet destruction. Other chemothera- begin with a low platelet count, but have a significant drop
peutic agents, such as fludarabine, enhance platelet clear- from his or her baseline platelet count. A baseline platelet
ance by immune-mediated mechanisms.2 Rituximab may count can also help attribute the platelet changes to the
cause a formation of circulating immune complexes, which most appropriate agent.22 A platelet count should be repeat-
cause platelet lysis by complement activation or by binding ed a week after discontinuing the suspected medication.1

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Testing for drug-induced thrombocytopenia includes a include platelet transfusions, IVIG, and corticosteroids.
bone marrow aspiration and biopsy; radioimmunoassay Drug-dependent platelet antibodies can be present for
and immunofluorescence techniques identifying drug-spe- many years. Also, the individual should be counseled to
cific platelet antibodies; and the heparin/platelet factor 4 avoid the drug in the future.7
(PF4) enzyme-linked immunosorbent assay (ELISA).22 The A complete list of medications that induce thrombocyto-
megakaryocyte numbers will increase in the bone marrow penia can be found at www.ouhsc.edu/platelets.
with immune-mediated or platelet aggregation because
the platelet destruction is occurring in the periphery. With Heparin-induced Thrombocytopenia
peripheral destruction, the bone marrow tries to increase Heparin-induced thrombocytopenia can occur after expo-
the number of platelets. This can also occur with acute sure to low-molecular weight heparin, unfractionated
hemorrhage and hypersplenism. A decrease in megakaryo- heparin, and rarely, fondaparinux. This results in a hyperco-
cytes occurs with bone marrow suppression from marrow agulable state.25 It is different from other types of thrombo-
suppression agents or aplastic anemia.22 cytopenia because the platelet level rarely drops to lower
The MPV is the average volume of platelets in a blood than 20000/mm3; and it is not associated with bleeding,
sample. It can help differentiate thrombocytopenia from but thromous formation.2 Heparin-induced thrombocy-
hypersplenism (increased MPV) and bone marrow sup- topenia typically begins within 5 to 10 days after starting
pression (normal MPV). An increased MPV can result heparin and is caused by antibodies formed between hep-
from immune-mediated processes. In this case, the bone arin and PF4.25
marrow is releasing younger, larger platelets to keep up These antibody complexes most likely activate platelets
with the loss of platelets. The MPV may be falsely low or as well as endothelial cells, which leads to clot formation.
normal with increased peripheral losses because of a delay Other environmental factors, such as infection, produce
in new platelets being released from the bone marrow.22 similar antigens to that produced by the heparin/PF4 com-
Bone marrow suppression can be generalized or selective. plexes. PF4 binds to heparin on the surface of the platelet
Generalized myelosuppression occurs when the medication and is recognized by IgG antibodies.25 This evolves into
has a direct toxic effect on the hematopoietic stem cells. In an environment conducive to thrombosis formation, with
this case, all blood cell lines can be affected. Most often, deep vein thrombosis, pulmonary embolism, stroke, and
this is an effect of chemotherapeutic agents. A selective myocardial infarction being the most common complica-
bone marrow suppression involves only the megakaryo- tions.1,22,24,26
cytes. Thiazide diuretics, diethylstilbestrol, ethanol, and Heparin-induced thrombocytopenia commonly occurs
tolbutamide cause selective bone marrow suppression. in individuals after surgery (orthopedic, cardiovascular) or
Platelet counts may improve within 7 to 21 days following trauma rather than medical patients, and is uncommon in
abstinence from alcohol ingestion.22 patients receiving prophylactic doses of heparin. Other risk
Radioimmunoassay and immunofluorescence tech- factors include age, sex, and patient population. It is rare
niques most commonly identify elevated platelet-associated in individuals less than 40 years of age. Heparin-induced
immunoglobulin G (IgG). However, IgM increases with thrombocytopenia is rare in hemodialysis patients, critically
thrombocytopenia from hydrochlorothiazide, rifampin, and ill patients, and pregnant women. Also, there is a higher
valproic acid. IgA may increase with thrombocytopenia incidence in women.1,25,27
from acetaminophen.22 Serotonin release is used to iden- Heparin-induced thrombocytopenia may occur earlier
tify type II heparin-induced thrombocytopenia. The sero- in individuals with previous exposure to heparin or who
tonin release test is performed with 2 concentrations of have existing antiheparin/PF4 antibodies.2 It is an acute
heparin: a therapeutic dose (0.1-1.0 units/mL) and a higher self-limited illness, and usually platelets recover within a
concentration (100 units/mL). The test is positive if greater week of discontinuing the heparin. However, individuals can
than 20% of labeled serotonin is released at the therapeu- remain prone to thrombus formation for approximately 4 to
tic dose, but not at the higher heparin concentration. A 6 weeks after the diagnosis.28
negative test results if serotonin release does not occur at The best way to prevent heparin-induced thrombocyto-
either concentrations or it occurs at both concentrations.22 penia is to limit the use of heparin, and rely more heavily on
A heparin/PF4 ELISA diagnoses type II heparin-induced newer anticoagulants such as rivaroxaban, dabigatran, and
thrombocytopenia. The heparin reacts with PF4, which is apixaban.25 The probability of heparin-induced thrombocy-
located on endothelial cells and circulating platelets. A PF4/ topenia is increased when no other causes for the throm-
heparin complex forms and binds to heparin-specific IgG bocytopenia (eg, drug-induced or other medical conditions)
antibodies. The complex binds to platelets, which are then are identified as causes for the thrombocytopenia.25
activated to produce platelet aggregation.22 Also, drug- The 4T clinical scoring system has been developed to
specific platelet antibody testing can be performed.22 help identify heparin-induced thrombocytopenia. The 4Ts
The most important element of management is to include thrombocytopenia, timing of platelet count drop,
discontinue the medication or offending agent. Platelets thrombosis, and no other etiology for the thrombocyto-
should begin to recover in 1 to 2 days. Other options penia.2 Heparin-induced thrombocytopenia is seen more

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commonly in full anticoagulation treatment with a con- anticoagulant will be influenced by renal function, cardiac
tinuous heparin infusion, than with lower-dose treatment surgery, pregnancy, cost, availability, and ability to monitor
such as treatment for deep vein thrombosis, heparin the anticoagulant effect.25 Nonheparin anticoagulants such
flushes, intravenous infusion during dialysis, and hepa- as argatroban, lepirudin, and bivalirudin (direct thrombin
rin-impregnated catheters. However, it can occur at any inhibitors) are options. In renal insufficiency, argatroban is
dosage. Heparin-induced thrombocytopenia can occur the preferred anticoagulant.25,27
after the use of fondaparinux, but the incidence is rare. Argatroban is given as an intravenous infusion and
An individual is at greater risk for heparin-induced throm- monitored with the PTT. The dose is reduced in patients
bocytopenia when heparin has been administered for with liver dysfunction, heart failure, anasarca, and recent
longer than 6 days.22 When treating a patient for a pulmo- cardiac surgery.27 Lepirudin is also an intravenous infusion.
nary embolus or a venous thrombosis, it is better to start Dose reduction is recommended in patients with renal
warfarin and heparin on day 1. The warfarin should reach insufficiency, and anaphylaxis may occur with reexposure.27
therapeutic levels within 3 to 5 days, and the heparin can Bivalirudin has a short half-life, so it is easily titrated. This
be discontinued before day 6.22 makes it more attractive with percutaneous intravascular
Manifestations of heparin-induced thrombocytopenia procedures, cardiac surgery, and patients with multiorgan
include red or necrotizing skin reactions at the site of the failure.27
injection or thromboembolic phenomenon (deep vein In patients who have a normal platelet count, citrate
thrombosis, pulmonary emboli, stroke, acute myocardial anticoagulation can be used in hemodialysis. Normal saline
infarction).25 Symptoms may include shortness of breath, flushes are recommended in lieu of heparin flushes. The
chest pain, tachycardia, leg edema, leg tenderness or discol- nonheparin anticoagulants are not recommended during
oration, hypotension, and focal neurological deficits. Acute pregnancy.27 Low-molecular weight heparin is contrain-
systemic symptoms such as fever, chills, rapid heart rate, dicated in patients suspected or confirmed to have hepa-
shortness of breath, and cardiac arrest may occur within rin-induced thrombocytopenia. Any patient with a history
30 minutes of administration of heparin. Necrosis may be of heparin-induced thrombocytopenia should not receive
present at the site of the heparin injection. Patients with heparin at a later time. It is unclear if reexposure can
adrenal hemorrhagic necrosis may present with abdominal cause a recurrence of heparin-induced thrombocytopenia.
pain, hypotension, and Addisonian crisis. Central venous The exception is in the patient undergoing cardiac bypass
thrombosis presents with headache, nausea, vomiting, and surgery. If there is no evidence of PF4-heparin antibodies,
other focal neurological symptoms.25 then the patient can receive heparin during the proce-
A complete blood cell count with differential is ordered dure, but should receive a different anticoagulant pre- and
in anyone suspected of heparin-induced thrombocytopenia. post-surgery.28
The timing of the thrombocytopenia to the administration In patients with confirmed heparin-induced thrombo-
of heparin is important. Coagulation studies are ordered cytopenia and thrombosis, treatment with a nonheparin
to eliminate any other coagulopathy.25 The enzyme-linked anticoagulant is continued for 3 months. If no thrombosis
immunosorbent assay with the PF4/anion complex as the is present, then treatment may continue for only a month.
antigen is an available laboratory test used to diagnose Once the platelets have returned to normal, warfarin is an
heparin-induced thrombocytopenia.1 However, it has a high option for continuation of treatment for approximately 3
false-positive rate. These antigen assays detect all heparin to 6 months.27 Fondaparinux is another option. Warfarin
antibodies, whether or not they are activating the plate- is safe in breastfeeding mothers, and fondaparinux can
lets.1,25 Individuals who have undergone a cardiopulmonary be used in pregnancy. Complications of heparin lead to
bypass may develop these antibodies postoperatively.2 If thrombocytopenia, bleeding, limb amputation, and venous
a thrombosis is suspected, then the appropriate imaging gangrene. Patients should be advised to list heparin as a
should be ordered (ie, venous Doppler ultrasonography, medication allergy.27 Bilateral lower extremity compression
perfusion-ventilation scan, or pulmonary angiography). A ultrasonography may be ordered because of a higher inci-
CT scan or MRI of the brain is performed if cerebral venous dence of silent vein thrombosis.27
thrombosis is suspected.25
Treatment of heparin-induced thrombocytopenia is to
discontinue heparin immediately, including heparin flush DECREASED PLATELET PRODUCTION
for central catheters. A blood sample is sent to the lab-
oratory for a complete blood cell count and differential, Infections
coagulation studies, and possibly an enzyme-linked immu- Viral and bacterial infections are a common cause of
nosorbent assay. Warfarin should not be administered noniatrogenic causes of thrombocytopenia. Infections can
until the platelet count has recovered as it may lead to also be associated with DIC, especially in patients with a
microvascular thrombosis in patients with heparin-induced gram-negative infection. They are associated with platelet
thrombocytopenia. Vitamin K can be administered if war- production and survival. Infectious mononucleosis and HIV
farin was started as an anticoagulant.25,29 The choice of infections may cause an autoimmune thrombocytopenia.2

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Viral Infections LIVER DISEASE AND CHRONIC
Viral infections such as HIV, hepatitis B, hepatitis C, ALCOHOL ABUSES
Epstein-Barr, cytomegalovirus, parvovirus B19, varicel-
la-zoster, rubella, and mumps are associated with throm- Thrombocytopenia occurs in chronic liver disease such as
bocytopenia due to bone marrow suppression.1 HIV infec- drug-induced liver disease, infectious hepatitis, nonalcohol-
tions may initially present with a downward trend in the ic liver disease, and metabolic disorder.1 In patients with
platelet count, but this is more common in untreated chronic liver disease associated with portal hypertension
HIV infections. This trend is a result of a combination of and advanced fibrosis, 15% to 70% may experience throm-
shortened platelet life span, splenic sequestration, and bocytopenia.31 Thrombocytopenia in the presence of alcohol
HIV-infected megakaryocytes, decreasing the ability to abuse and advanced liver disease is related to cirrhosis of
produce platelets.10 the liver, decreased production of thrombopoietin, seques-
As hepatitis C advances, the thrombocytopenia can tration of platelets in the spleen, direct toxicity to mega-
become multifactorial because of decreased thrombopoi- karyocytes in the bone marrow, and folic acid deficiency.
etin production from the liver, bone marrow inhibition, Thrombocytopenia may also be higher in chronic alcoholism
immune dysfunction, hepatic fibrosis, and hypersplenism. associated with megaloblastic anemia from vitamin B12 and
Chronic hepatitis C produces autoantibodies that attach folic acid deficiency.1,2,31 However, alcohol-induced thrombo-
to platelet surfaces promoting platelet sequestration in cytopenia can occur in the absence of liver disease or nutri-
the liver and destruction by macrophages in the liver ent deficiency. When the alcohol consumption is stopped,
and spleen.30 Portal hypertension may also redistribute the platelet count gradually rises, and recovers normal
blood to the spleen, further increasing pooling of plate- counts in 7 to 10 days.33 Treatment includes discontinuing
lets and additional removal of platelets from the blood.31 alcohol ingestion and nutritional and vitamin replacement.1
Thrombopoietin in hepatitis C is a reflection of thrombopoi-
etin production and its degradation, platelet turnover, and
decreased platelets. The thrombopoietin levels may be low, RENAL DISORDERS
normal, or increased. Treatment with peginterferon may
also cause thrombocytopenia from bone marrow suppres-
Thrombotic Thrombocytopenia Purpura (TTP)
sion leading to decreased production of megakaryocytes.
and Hemolytic Uremic Syndrome (HUS)
And if the thrombocytopenia is present, it can influence
TTP and HUS are uncommon, life-threatening conditions. In
whether treatment with interferon can be initiated or if
patients with microangiopathy and thrombocytopenia, and
dose reductions are required.31 In a self-limited viral illness
acute renal failure, always consider TTP-HUS. The under-
such as H1N1, the platelet counts usually recover.1
lying pathology of TTP is suspected to be an inherited or
acquired deficiency of von Willebrands factor-cleaving prote-
Bacterial Infections ase that leads to an accumulation of von Willebrands factor,
Malaria and tuberculosis influence the platelet count resulting in spontaneous platelet aggregation and thrombi.6
through a combined effect of immune-mediated destruc- Microangiopathy results from strands of platelets and fibrin
tion, splenic sequestration, and shortened platelet surviv- being deposited in small vessels, resulting in passing platelets
al.32 Granulomatosis infiltration of the bone marrow can and red blood cells being damaged. Small thrombi utilize
occur with tuberculosis, resulting in thrombocytopenia, or the platelets. This results in anemia and thrombocytopenia.
in rare cases, ITP in addition to other cytopenias.13 A tran- Thrombi form in organs, especially in the brain, heart, and
sient thrombocytopenia can be seen with Rocky Mountain kidneys, leading to microangiopathy.17
spotted fever and Lyme disease.1 TTP and HUS differ only in the degree of renal failure.2,17
Other diseases that can cause TTP include Escherichia coli
Bone Marrow Suppression and Malignancies diarrhea, HIV infections, pregnancy, bone marrow trans-
Thrombocytopenia occurs with primary neoplastic dis- plant, metastatic carcinomas, and drugs including quinine,
orders of the bone marrow. These include the myeloid cyclosporine A, cisplatin, and clopidogrel.6
disorders such as acute myeloid leukemia, myelodysplastic Although not present in all patients, the diagnostic pen-
syndrome, myeloproliferative syndromes, and paroxys- tad criteria for TTP include (1) microangiopathic hemolytic
mal nocturnal hemoglobinuria. Lymphoid malignancies anemia, (2) thrombocytopenia, (3) renal insufficiency, (4)
such as acute lymphoid leukemia, hairy cell leukemia, fever, and (5) mental status changes.6 Mental status chang-
chronic lymphoid leukemias, non-Hodgkins lymphoma, es include confusion, headaches, fatigue, seizures, and
T-cell malignancies, multiple myeloma, and Waldenstroms stroke-like syndrome.6 Other symptoms include nausea,
macroglobulinemia also may present with a thrombocyto- vomiting, diarrhea, fever, and dysrhythmias. Fever associat-
penia. Fibrotic tissue, myelofibrosis, and nonhematologic ed with chills indicates sepsis. Cardiac dysrhythmias may be
malignancies such as prostate, ovarian, and breast cancer, associated with an acute myocardial infarction.17
can also infiltrate the bone marrow, resulting in a throm- Laboratory data include severe thrombocytopenia,
bocytopenia.1 schistocytes on the peripheral blood smear, an elevated

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LDH, and renal insufficiency. The coagulation studies will sulfate and delivering the fetus. In severe HELLP syndrome,
be normal, which differentiates TTP-HUS from DIC. The plasma exchange is the treatment for a pregnant woman
Coombs test is negative, which helps differentiate this with a fetus of less than 34 weeks gestation or no improve-
syndrome from Evans syndrome.6 Other laboratory find- ment in the first postpartum week.2 Complications of HELLP
ings are an increased LDH, increased indirect bilirubin, syndrome include placenta abruption, pulmonary edema,
decreased haptoglobin, increased reticulocyte count, and a DIC, adult respiratory distress syndrome, acute renal fail-
negative direct antiglobulin test.2 ure, ruptured liver hematoma, intrauterine growth restric-
The appearance of the diagnostic pentad criteria is a tion, infant respiratory distress, and complications of blood
late finding. The key to treatment is identifying the disorder and platelet transfusions.35
early.6 The primary treatment is emergent plasma exchange.
Fresh frozen plasma can be started if plasma exchange is not
immediately available. Platelet transfusions can worsen the CONCLUSION
condition and should not be used unless life-threatening
hemorrhage is present.6 Glucocorticosteroids may be used Thrombocytopenia can result from many causes. It can be
in conjunction with plasma exchange.2 the result of the destruction of platelets, myelosuppression,
or splenic sequestration. The clinician must take a complete
Uremia history, including medication history, and perform a compre-
Uremic patients, especially those undergoing dialysis, may hensive physical examination to determine the etiology of
develop thrombocytopenia. The kidneys also produce the thrombocytopenia. Laboratory studies will help eliminate
thrombopoietin, to a lesser degree than the liver. Decreased potential causes of the thrombocytopenia. Once the etiology
thrombopoietin production can lead to decreased plate- is determined, then a management plan can specifically be
let production.5 During hemodialysis, additional platelet developed for the patient. The nurses health information
destruction may occur because of platelet consumption in is important in the management of the patient with throm-
the dialyzer membrane.34 bocytopenia. Infusion therapy nurses see these patients
regularly and can make a significant difference in their lives.

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