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42 Part I: Clinical Evaluation of the Patient Chapter 4: Consultative Hematology 43

coagulation [DIC], hemolysis, elevated liver enzymes, low platelet PANCYTOPENIA
count [HELLP]) or autoimmune platelet removal (immune throm-
bocytopenia [ITP], drug-induced thrombocytopenia, heparin-in- The presentation of a patient with new-onset pancytopenia requires
duced thrombocytopenia [HIT]). immediate medical attention. In formulating an approach to a patient
• Platelets are being sequestered: Massive splenomegaly or hemangiomas. who presents with a combination of anemia, thrombocytopenia, and
leukopenia it is useful to think of the pathophysiology in mechanis-
If one encounters a new finding of severe thrombocytopenia, one
must immediately review the blood film for the presence of microangio- tic terms. It is also important in constructing a differential diagnosis
pathy. If present, concern is raised for TTP, and immediate intervention to determine whether the leukopenia is balanced, neutropenia, or
is required (Chap. 132). lymphopenia.
The history provides key information. Comorbid autoimmune The blood counts may be low because the normal hematopoietic
and lymphoproliferative diseases may be associated with ITP. Culprit marrow has been replaced (fibrosis, infiltrative malignancy), is absent
drugs, such as heparin or quinidine, must be explored. Hepatic disease (aplastic anemia), or is ineffective (MDS, vitamin B deficiency).
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is a common cause of thrombocytopenia and should be queried. The Hypersplenism can also result in the rapid removal of cells from the
EMR should be used to explore the temporal nature of the thrombocy- blood, for example in the context of a malignant lymphoma.
topenia and other associated CBC anomalies. The physical exam should The history provides several critical pieces of information: How
pay special attention to petechiae, oral blood blisters, ecchymoses, ade- severe is the pancytopenia? How long has it been present? Is it getting
nopathy, and organomegaly. In reviewing the blood film, one should better or worse? What was going on when it began? Was there an infec-
exclude spurious thrombocytopenia (Chap. 117) that may include eth- tion at onset, or has the patient had any new medications or occupational
ylenediaminetetraacetic acid (EDTA)-induced platelet clumping (pseu- exposures? Symptoms of anemia (fatigue, shortness of breath), throm-
dothrombocytopenia), presence of megathrombocytes that are too large bocytopenia (mucosal bleeding, bruising), and leukopenia (recurrent
to be recognized as such by automatic cell counters, or adherence of infections, stomatitis) are important to determine, as are risk factors for
platelets to neutrophils (platelet satellitism) which can be ameliorated hepatic disease (as cirrhosis commonly results in pancytopenia).
by using sodium citrate as an anticoagulant. Next, one should check The physical exam should be comprehensive with a particular
for the presence of microangiopathy which, if present, would lead to focus on organomegaly and adenopathy.
consideration for TTP, HUS, or DIC. Spherocytes and polychromasia If the MCV is greater than 100 fL, consider MDS. Chemistry pan-
would raise the possibility of combined ITP and autoimmune hemo- els are obtained to evaluate for evidence of renal or hepatic dysfunc-
lytic anemia, otherwise known as Evans syndrome. Giant hypogran- tion. An increase in MCV of greater than 115 fL is more common in
ulated platelets raise consideration of MDS, and more than six lobed megaloblastic anemia than in MDS. Folate deficiency may be seen in
polymorphonuclear neutrophils (PMNs) associated with an MCV >115 settings of alcohol abuse or celiac sprue. Pernicious anemia is an impor-
suggest vitamin B or folate deficiency (Chap. 41). In a patient with tant consideration for vitamin B deficiency because it is treatable with
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newly developed isolated thrombocytopenia, megathrombocytes, plate- cobalamin and, if unrecognized, may proceed to severe neurologic
lets greater in diameter than one-third of a red cell diameter (>2.5 μM), impairment. Uncommonly, the latter may be the presenting feature (in
are the parallel of the reticulocyte count. More than 10 percent such addition to the cognitive abnormalities known as megaloblastic mad-
platelets are suggestive of immune platelet destruction with a compen- ness; Chap. 41).
satory increase in thrombopoiesis. As always, a critical review of the blood film may suggest the diag-
In the case of isolated thrombocytopenia, the most common cause nosis, including the presence of dysplasia (MDS), hypersegmented neu-
is autoimmune thrombocytopenia. ITP may also be drug-induced. An trophils (vitamin B and folate deficiency), and myelophthisic features
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important feature of autoimmune thrombocytopenia is the absence of (leukoerythroblastic findings such as nucleated RBCs and teardrops)
splenomegaly, thus an enlarged spleen points to other diagnoses such as that might suggest primary myelofibrosis (Chap. 86) or a marrow-
lymphoproliferative disease, hypersplenism, or lupus. Approximately 25 replacing process (Chap. 45). The presence of abnormal or neoplastic
percent of patients with the antiphospholipid antibody syndrome have cells in the blood may be diagnostic, such as leukemic blasts, hairy cells,
mild thrombocytopenia (50 to 130 × 10 /L). Bleeding is not a feature of or circulating lymphoma cells.
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this phenomenon and it may be confused with autoimmune thrombo- With this information one can decide on a further diagnostic strat-
cytopenia. HIT is an event seen in hospitalized patients or those receiv- egy. Occasionally one sees patients where the pancytopenia is mild and
ing heparin through home care (Chap. 118). The thrombocytopenia resolves spontaneously within 1 month, which may represent a viral
can be mild (e.g., 20 to 100 × 10 /L) and bleeding is unusual. It usually infection with transient suppression of hematopoiesis.
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occurs 5 to 10 days after exposure to heparin and is associated with If, in a patient with pancytopenia, the reticulocyte count is very
both venous and arterial thrombosis. Often, the patient may be quite low, aplastic anemia becomes a primary consideration. Other malig-
ill, postoperative, and have other plausible explanations for thrombosis, nant causes of severe cytopenias, such as acute leukemia or MDS, are
thus requiring a high index of suspicion. It is less frequent with low- uncommonly associated with reticulocyte counts less than 0.4 percent.
molecular-weight heparin (LMWH) preparations, but still can occur in An enlarged spleen is not a feature of aplastic anemia, and its presence
that setting. The specifics of diagnostic tests and management are dis- would argue against the diagnosis.
cussed in Chap. 118. Nearly all patients with unexplained severe and persistent pancy-
With baseline data from history, exam, and routine labs, a prelimi- topenia will require a diagnostic marrow aspirate and biopsy.
nary analysis should be performed to focus subsequent specialized test-
ing. For example, in a patient with CNS symptoms, microangiopathic LEUKOCYTOSIS
hemolysis, and an elevated serum creatinine, a disintegrin and metallo-
protease with a thrombospondin type 1 motif member 13 (ADAMTS13) An elevated leukocyte count often raises concern for marrow pathology,
activity level should be ordered in addition to instituting prompt plas- but may be seen in nearly any systemic disorder. There is no numeric
mapheresis for the tentative diagnosis of TTP. In a patient who received cutoff that reliably distinguishes between primary hematolymphoid and
heparin 5 days prior during cardiac surgery, HIT is considered and an secondary causes of leukocytosis. Rather, a thorough history, physical,
immunoassay for antiplatelet factor 4 obtained. and focused laboratory evaluation is required.

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