Download Thrombocytopenia: How Best to Determine the Cause

Thrombocytopenia: How Best to Determine the Cause
Published on Diagnostic Imaging (http://www.diagnosticimaging.com)
Thrombocytopenia: How Best to Determine the Cause
January 01, 2006
By Melanie R. Drake, MD [1] and Gregory W. Rutecki, MD [2]
ABSTRACT: A scheme-based approach, supported by a simple mnemonic, can narrow the broad
differential diagnosis of thrombocytopenia. This approach uses findings from the complete blood cell
count and the peripheral smear to organize the possible causes of thrombocytopenia into those that
affect only platelet count, those that produce both a low platelet count and hemolytic anemia, and
those that produce disturbances in all 3 blood cell lines. Causes of isolated thrombocytopenia include
viral infections, immune-mediated platelet destruction, congenital diseases, gestational
thrombocytopenia, conditions in which splenomegaly is a prominent feature, antiphospholipid
antibody syndrome, infectious diseases of bacterial origin, and drugs. Causes of thrombocytopenia in
conjunction with hemolytic anemia include hemolytic uremic syndrome, thrombotic
thrombocytopenia purpura, and disseminated intravascular coagulation. Disorders that produce
disturbances in all 3 blood cell lines include aplastic anemia, myeloproliferative syndromes,
myelodysplasia (both primary and secondary), myelofibrosis, myelophthisis, and several other
diseases in which splenomegaly is prominent.
Identifying the cause of thrombocytopenia is crucial because the patient's life may depend on
prompt treatment. For example, thrombocytopenia that results from a reaction to quinine requires
discontinuation of the drug and symptomatic treatment of bleeding.1 A decreased platelet count can
also be a secondary manifestation of serious disease, such as disseminated intravascular
coagulation (DIC), hemolytic uremic syndrome (HUS), or leukemia.
The differential diagnosis of thrombocytopenia is extensive and often daunting. As an alternative to
sifting through a long list of potential causes, we present here a simplified approach that aorganizes
diagnoses into categories and thus narrows the differential. Accompanying cases (see page 114 of
this issue) illustrate how this approach can be applied in various clinical settings.THREE
CATEGORIES OF THROMBOCYTOPENIA
Scheme-based problem solving organizes possible diagnoses into categories based on relevant
associated data. For example, a scheme-based approach is sometimes used in the differential
diagnosis of hypokalemia, which, like thrombocytopenia, has many possible causes.2 The causes of
low potassium levels can be grouped by the associated acid-base status. Thus, if potassium
depletion is accompanied by normal- anion gap acidemia, the possible causes are limited to renal or
gut- related (diarrheal) potassium and bicarbonate wasting.
The differential diagnosis of thrombocytopenia can be condensed into 3 shorter lists based on the
status of the other blood cell lines (red and white cells). A low platelet count can be part of any of 3
possible scenarios:
The decreased number of platelets is an isolated phenomenon.
Thrombocytopenia is part of a pathologic process that also causes hemolytic destruction
(mechanical or immune) of red cells; white cells are unaffected.
Thrombocytopenia is a manifestation of a single disease process that affects all 3 blood cell
lines in some way.
The possibilities included in these 3 categories can be summarized by the mnemonic "VIC G. SAID to
TED and SAMMM" (Table). "VIC G. SAID" represents the possible causes of thrombocytopenia as an
isolated phenomenon or accompanied by a disease-specific leukocytosis or lymphocytosis (such as
that associated with a viral or bacterial infection) but without any changes in the red cell line. "TED"
represents the causes of thrombocytopenia associated with hemolytic anemia, and "SAMMM"
represents the disease processes that affect all 3 blood cell lines—red and white cells as well as
platelets.
A caveat: when using this mnemonic, you need to determine whether disturbances in the red or
white blood cell lines that accompany thrombocytopenia are manifestations of the same primary
process that caused the decrease in platelet count. For help in discerning whether a disturbance in
Page 1 of 4
Thrombocytopenia: How Best to Determine the Cause
Published on Diagnostic Imaging (http://www.diagnosticimaging.com)
the red or white blood cell line is related to a patient's thrombocytopenia, see the Box.
The severity of the decrease in platelet number—mild (100,000 to 150,000/µL), moderate (50,000 to
100,000/µL), or severe (less than 50,000/µL)—and the morphologic appearance of red and white
cells can help narrow the differential still further. In fact, all data necessary to arrive at a diagnosis
are available from the history, physical examination, complete blood cell (CBC) count, and peripheral
smear.THROMBOCYTOPENIA AS AN ISOLATED ABNORMALITY
The differential diagnosis of thrombocytopenia as an isolated abnormality (that is, unaccompanied
by hemolytic anemia or bone marrow pathology affecting all 3 cell lines) includes:
Viral infections.
Immune-mediated platelet destruction.
Congenital diseases.
Gestational thrombocytopenia.
Splenomegaly.
Antiphospholipid antibody syndrome.
Infectious diseases of bacterial origin.
Drugs.
Any one of a spectrum of viral infections—including rubella, influenza, and infectious
mononucleosis—can cause a drop in platelet count. The decrease usually results from an immune
mechanism brought on by the infection.
However, platelet destruction that is immune-mediated also occurs independently of infection.
Immune-mediated thrombocytopenia is common. One of the most frequently seen types is idiopathic
thrombocytopenic purpura (ITP) (see Case 1 on page 114). In addition, antibodies to platelet surface
antigens triggered by a blood transfusion can develop—primarily in multiparous women; this
phenomenon is known as post-transfusion purpura. Vasculitis can also produce a decrease in platelet
count via an autoimmune mechanism. HIV-induced thrombocytopenia results from an autoimmune
mechanism; it can be classed with either immune-mediated causes or viral causes of platelet
destruction. Immune-mediated thrombocytopenias can cause severe reductions in platelet count.
Rare congenital diseases, such as thrombocytopenia with absent radii (TWAR) and the May-Hegglin
anomaly, are associated with lowered platelet counts.
Gestational thrombocytopenia is one of a number of conditions seen in pregnancy that are
characterized by lowered platelet counts. Others include ITP, the HELLP (Hemolysis, Elevated Liver
enzyme levels and Low Platelet count) syndrome, and preeclampsia/eclampsia. Of these, only ITP
and gestational thrombocytopenia are not associated with changes in the other blood cell lines. The
two can be difficult to distinguish; however, the reductions in platelet count seen in gestational
thrombocytopenia are typically mild, whereas those seen in ITP that develops during pregnancy tend
to be more severe. For a more detailed discussion of the differences between gestational
thrombocytopenia and ITP that develops during pregnancy, see Case 1 (page 114).
Splenomegaly can cause a decrease in platelet count, either with or without decreases in the other
parameters of the CBC. (Splenomegaly that produces changes in the other blood cell lines along with
thrombocytopenia is discussed below.) Splenomegaly causes mild or moderate reductions in platelet
count rather than severe thrombocytopenia.
The cause of splenomegaly must be determined. It may be associated with a viral infection, such as
infectious mononucleosis, or it may be a clue to other conditions, such as cirrhosis or portal
hypertension.
Antiphospholipid antibody syndromes can produce thrombophilia, prolonged partial thromboplastin
time (PTT), and thrombocytopenia in some patients.
Infectious diseases that are associated with a reduction in platelet count range from rickettsial
infections to more common bacterial illnesses, such as Gram-negative bacteremia. Infection can
cause mild as well as moderate to severe thrombocytopenia.
Finally, thrombocytopenia is a prominent potential adverse effect of a number of drugs and
medications. In fact, so many drugs are associated with thrombocytopenia that it is prudent to do a
quick computer search whenever a patient presents with a lowered platelet count to determine
whether any medication he or she is taking should be stopped. In drug-related thrombocytopenia,
there is significant variation in both the mechanism of platelet destruction and the resultant degree
of reduction in platelet count. For example, in susceptible persons, quinine can cause severe,
life-threatening thrombocytopenia, whereas a heparin-induced low platelet count seldom falls below
50,000/µL(see Case 2, page 115). (Because heparin-induced thrombocytopenia lowers the platelet
Page 2 of 4
Thrombocytopenia: How Best to Determine the Cause
Published on Diagnostic Imaging (http://www.diagnosticimaging.com)
count through an immune mechanism, it can be grouped with immune-mediated causes as well as
with drug-related causes.) THROMBOCYTOPENIA ASSOCIATED WITH HEMOLYTIC ANEMIA
If thrombocytopenia is accompanied by hemolytic anemia, the underlying cause is one of the
following:
Thrombotic microangiopathy (hemolytic uremic syndrome [HUS] or thrombotic
thrombocytopenic purpura [TTP]).
Evans syndrome.
DIC.
Because thrombotic microangiopathies and DIC have similar presentations, we will discuss these
together and then return to Evans syndrome. Patients with DIC or a thrombotic microangiopathy
typically have severe thrombocytopenia, anemia of varying severity that results from mechanical
hemolysis (as demonstrated by the presence of schistocytes on the peripheral smear), and renal
insufficiency; patients with DIC and those with TTP usually have fever as well.
DIC, unlike TTP and HUS, is a consumptive coagulopathy. However, a battery of tests may be
required to establish consumption, since neither the international normalized ratio nor the PTT is
particularly sensitive in this regard (see Case 3, page 119).
DIC, like splenomegaly, always results from another significant pathology. Hence, whenever DIC is
diagnosed as the cause of thrombocytopenia, it is imperative to search for the primary cause. This
might be a bacterial infection with sepsis, cancer, or another serious illness.
Two other thrombocytopenic-hemolytic syndromes that are similar in many ways to TTP, HUS, and
DIC are seen only in pregnant women. These are the thrombocytopenia of severe
preeclampsia/eclampsia and that of the HELLP syndrome. Both syndromes occur primarily in the
third trimester.
Evans syndrome is an autoimmune-mediated decrease in the number of both platelets and red blood
cells (a Coombs-positive, warm antibody hemolytic anemia with thrombocytopenia). It usually is the
result of systemic lupus erythematosus (SLE) or another stimulus to the production of warm
antibodies directed at red cells, such as chronic lymphocytic leukemia or lymphoma.
Occasionally, patients who have SLE make antibodies that target white blood cells in addition to
platelets and red blood cells. These patients present with pancytopenia. In such cases, the diagnosis
can be made based on clinical and laboratory signs of SLE, Coombs positivity, leukopenia,
thrombocytopenia, and the presence of spherocytes on the peripheral smear.
The peripheral smear is often helpful in the identification of Evans syndrome. Red blood cells that
are partially destroyed as a result of warm reacting antibodies become spherocytes, not
schistocytes. The partial phagocytosis of portions of the antibody-covered red cell membrane
decreases the surface area of these cells. Consequently, they morph from their typical dumbbell
shape into that of a sphere. Thus, evidence of spherocytes on the peripheral smear is a clue to this
diagnosis.
The mean cell hemoglobin concentration (MCHC) can be another clue. Because spherocytes contain
the same amount of hemoglobin as normal red cells but have less surface area, the MCHC is often
elevated in patients with Evans syndrome.THROMBOCYTOPENIA ASSOCIATED WITH
DISTURBANCES OF BOTH RED AND WHITE BLOOD CELL LINES
A number of conditions can produce thrombocytopenia along with disturbances in both red and
white blood cell lines (either pancytopenia or thrombocytopenia with anemia and leukocytosis [the
latter often accompanied by abnormal white blood cells]). These include:
Splenomegaly.
Aplastic anemia.
Myelodysplasia (both primary and secondary).
Myeloproliferative syndromes.
Myelofibrosis and myelophthisis.
In the majority of instances in which splenomegaly accompanies a 3-cell line disturbance, 1 of the
last 3 entities in this part of the mnemonic (myelodysplasia, myeloproliferative syndromes,
myelofibrosis, or myelophthisis) is the underlying cause. However, there are a few diseases not
otherwise covered by the mnemonic in which splenomegaly accompanies disturbances in all 3 blood
cell lines. One of these is leishmaniasis; massive splenomegaly and pancytopenia are typical
findings.
Page 3 of 4
Thrombocytopenia: How Best to Determine the Cause
Published on Diagnostic Imaging (http://www.diagnosticimaging.com)
Aplastic anemia is characterized by pancytopenia. The size of the spleen in affected patients is
usually normal.
Myelodysplasia can cause pancytopenia or thrombocytopenia with anemia and leukocytosis3; the
condition may be secondary or primary. Secondary myelodysplasia can result from any process or
deficiency that interferes with cellular maturation in the marrow (eg, vitamin B12 deficiency).
Distinctive features of the CBC count and peripheral smear assist with the diagnosis. In secondary
myelodysplasia, the red blood cells are macrocytic (mean corpuscular volume is increased).
If thrombocytopenia is associated with anemia and leukocytosis, the appearance of the white blood
cells is key to identification of the specific underlying disease process (see Case 4, page 120). For
example, hypersegmented neutrophils are typical of vitamin B12 deficiency, while the presence of
blast cells signals leukemia. Interpretation of the peripheral smear can be supplemented by the use
of specialized stains and "cluster differentiation" analysis, which can identify the exact source of the
abnormal myeloproliferation.
Red blood cell morphology is similar in both myelofibrosis and myelophthisis. Peripheral smears in
these 2 diseases show nucleated and "teardrop" red cells because both fibrosis and infiltration of the
bone marrow (by either tumor or infection) push red cell precursors into the circulation prematurely
and in so doing "pinch" the shape of the cells. Because splenomegaly, disturbances in all 3 blood cell
lines, and similar peripheral smear abnormalities are seen in both myelofibrosis and myelophthisis, a
bone marrow examination may be necessary to distinguish between the 2 entities. This can establish
definitively whether the marrow involvement is primary (myelofibrosis) or secondary to cancer or
infection (myelophthisis).
References: REFERENCES:
1. Stasi R, Provan D. Management of immune thrombocytopenic purpura in adults. Mayo Clin Proc.
2004;79:504-522.
2. Bartholow C, Whittier FC, Rutecki GW. Hypokalemia and metabolic alkalosis: algorithms for
combined clinical problem solving. Compr Ther. 2000;26: 114-120.
3. Bick RL. Disseminated intravascular coagulation: current concepts of etiology, pathophysiology,
diagnosis, and treatment. Hematol Oncol Clin North Am. 2003;17:149-176.
4. Bergin J. Anemia: a strategy for the workup. Consultant. 2002;42:869-882.
Source URL:
http://www.diagnosticimaging.com/articles/thrombocytopenia-how-best-determine-cause
Links:
[1] http://www.diagnosticimaging.com/taxonomy/term/36951
[2] http://www.diagnosticimaging.com/authors/gregory-w-rutecki-md
Page 4 of 4