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44 Part I: Clinical Evaluation of the Patient Chapter 4: Consultative Hematology 45

If a referral is received for an elevated RBC count in the absence THROMBOCYTOSIS
of true erythrocytosis, a major consideration is thalassemic trait. Addi-
tional clues for this would include a normal or low hemoglobin in addi- When evaluating thrombocytosis, one must generally determine
tion to severe microcytosis, and a blood film showing targets, as well as whether it is reactive or the manifestation of a MPN (Chaps. 84 to 86).
hypochromia and microcytosis. Historical details should include: When were the platelets first
The history is critical in evaluation of erythrocytosis (Chap. 57). elevated? Is the elevation intermittent or constant? Have the platelets
Key items after determining if the abnormality is acquired or congenital ever exceeded 1,000,000/μL? Has there been any thrombosis? Has there
include: been paradoxical bleeding suggestive of acquired von Willebrand dis-
ease (VWD)? Causes of reactive thrombocytosis (Chap. 119), such as
• History of pulmonary disease or chronic hypoxia
• Risk factors for renal, hepatic, or CNS tumors inflammatory disease, infection, recent splenectomy, iron deficiency,
• History of obstructive sleep apnea and malignancy, should be explored.
• Family history of polycythemia The physical exam should include evaluation for organomegaly,
• Use of androgens or anabolic steroids given this may be seen in a variety of MPNs.
• Surreptitious erythropoietin (EPO) injection (particularly in com- In reviewing the CBC, a concomitant elevation of the hemoglobin
petitive athletes) and platelets might suggest PV. Neutrophilia, myeloid immaturity, or
• Presence of symptoms related to polycythemia basophilia might suggest CML or myelofibrosis.
If there is significant suspicion for a MPN, such as organomegaly,
Primary polycythemia refers to autonomous marrow production persistent thrombocytosis, polycythemia, or neutrophilia, additional
of erythrocytes, as in PV, whereas secondary polycythemia refers to evaluation might include molecular testing for BCR-Abl, JAK2, and/or
increased erythrocyte production from stimulation by EPO (Chap. 57). calreticulin mutations (Chaps. 84–86).
Elevated EPO levels may be a compensatory response to hypoxia or pro-
duced in excess by malignancy. Secondary causes of polycythemia are
discussed at length in Chap. 57. PREGNANCY
Historical symptoms related to polycythemia should also be Hematologic issues arising during pregnancy are a common cause for
elicited, including headache, fatigue, visual changes, and shortness of consultation. In contrast to the nonpregnant patient, the consultant
breath. Symptoms of pruritus, erythromelalgia, or intolerance of hot must consider both the patient and the fetus (Chaps. 7 and 8). In this
water might be more suggestive of PV. section we will not consider hematologic disorders of the fetus such as
Clues during the physical exam include: hemolytic disease of the newborn and neonatal alloimmune thrombo-
1. Digital clubbing, which might suggest pulmonary disease cytopenia (Chaps. 8 and 55).
2. Splenomegaly, which might suggest PV During the transition from the second to third trimester, the
3. Hepatomegaly, which might suggest PV or a hepatic tumor plasma volume increases by approximately 1.0 L while the RBC mass
4. Facial plethora, which is often seen in PV, although can be seen in increases by approximately 0.25 L. This partial hemodilution can cause a
erythrocytosis of any cause drop in hemoglobin values below the normal 12 g/dL for women. There
are further complicating issues. The growing fetus requires approxi-
The laboratory evaluation should include a CBC, EPO level, and mately 500 mg of iron from the mother, and if the mother is already iron
venous blood gas measurement. The latter is useful in that it allows deficient and/or not taking adequate iron supplements, iron-deficiency
indirect calculation of the partial pressure required to achieve 50 per- anemia will develop. In mothers with thalassemia intermedia, the mar-
cent saturation (p50) (reduced in high-affinity hemoglobinopathies, row is already stressed and providing close to maximum compensatory
which should be considered in cases of familial polycythemia) and erythropoiesis at baseline. The marrow cannot provide the additional
also provides information regarding carboxyhemoglobin (elevated 0.25 L of RBC mass during pregnancy, causing hemoglobin levels to fall
in smokers or in carbon monoxide poisoning) and methemoglobin where both the patient and fetus may be stressed. Supportive transfu-
levels. sions are often necessary in this case.
The combination of polycythemia and a low EPO level is highly sug- One is often asked to consult because of a neutrophilic leukocyto-
gestive of PV. This should trigger reflex mutational testing for JAK2 V617F sis occurring during the second and third trimesters. This is typically
(exon 14), and, if negative, Janus kinase 2 (JAK2) exon 12 mutation. physiologic and the film may show myeloid immaturity with bands,
These two mutations capture nearly all cases of PV, and if negative, metamyelocytes, and even myelocytes. Observation is recommended.
should trigger the diagnosis to be reconsidered and/or tertiary referral. Other than the variations noted above, the approach to anemia and
More commonly, the EPO level is found to be normal or elevated. WBC abnormalities is essentially identical to the nonpregnant patient.
This makes PV less likely, although certainly not exclusionary. If the Thrombocytopenia as low as 50,000 to 70,000/μL may be seen as a
patient has symptoms suggestive of PV or otherwise unexplained poly- normal consequence of pregnancy and is termed gestational thrombocy-
cythemia, JAK2 mutational testing should still be obtained. topenia. It requires no specific management. Nongestational thrombo-
If the EPO level is high normal/elevated and there are no PV- cytopenia, however, requires particular care because the differential is
related symptoms, a thorough evaluation for secondary polycythemia broader in pregnancy and because of the risk of both maternal and fetal
should be performed. In the absence of cardiopulmonary disease or hemorrhage. For example, when treating patients with ITP, there is con-
obvious offending medications, polycythemia with a significantly ele- cern that the causative antiplatelet antibody will cross the placenta and
vated EPO level should trigger evaluation for malignancy. cause fetal thrombocytopenia. The distortion of the fetus, particularly
Although rare, familial polycythemia should always be in the dif- of the cranium during delivery, raises concern about intracranial hem-
ferential, particularly if the family history is suggestive. The various orrhage if the neonate is thrombocytopenic. Newborns of mothers with
mutations in regulators of erythropoiesis and hypoxia-sensing, and are ITP should generally have serial platelet counts over the first week of
discussed in detail in Chap. 57. life as thrombocytopenia may be delayed as splenic function develops.
A diagnostic algorithm for erythrocytosis is shown in Chap. 57, The appearance of low platelets along with hypertension in the
Fig. 57–6. third trimester raises concern for preeclampsia. Perhaps a more-severe

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