Chapter 4: Consultative Hematology

Detection of a low white blood cell (WBC) count is a common reason for hematologic consultation. Clinicians and patients are attentive to early signs of marrow pathology, such as myelodysplastic syndrome (MDS), although such diseases are found only in a minority of referrals. Nevertheless, the severity of potential pathology mandates leukopenia be taken seriously and approached thoughtfully.

One begins by determining if the predominant finding is neutropenia, lymphopenia, monocytopenia, or all of the above.

NEUTROPENIA

The potential causes of neutropenia are diverse and include congenital disorders, autoimmune disorders, infections, nutritional deficiencies, medications, and, of course, hematolymphoid neoplasias. These are discussed in detail in Chap. 65.

Degrees of neutropenia may be broadly classified as mild (absolute neutrophil count [ANC] 1000–1500 cells/μL), moderate (ANC 500–1000 cells/μL), or severe (ANC <500 cells/μL).

The three most important historical details are the degree of neutropenia, acuity of onset, and presence or absence of associated symptoms. Each is considered individually and within the context of other findings.

The degree of neutropenia is informative. There is no specific ANC threshold that mandates evaluation. In general, mild neutropenia with preservation of other lineages in the asymptomatic patient may be observed, whereas moderate or severe neutropenia increases the risk of infection and probability of underlying pathology. The degree of neutropenia is not a priori a measure of its potential consequences. For example, patients with chronic idiopathic neutropenia may have blood neutrophil counts approaching zero with no symptoms or increased risk of infection.

The acuity of neutropenia is quite helpful, and the advent of the electronic medical record (EMR) allows for the rapid evaluation of such trends. In acute onset neutropenia, it is useful to inquire about recent infections and new medications. The latter is often an important clue. The number of medications that might cause neutropenia is vast, and some representative agents are shown in Chap. 65, Table 65–1. The temporal association of new medications with cytopenias is often the strongest evidence of causality. If there is suspicion for drug-induced neutropenia, the offending medication should be discontinued. If this is not possible, switching to a congener with a different chemical structure should be strongly considered.

In cases of chronic neutropenia, one should explore possibilities such as congenital neutropenia, chronic idiopathic neutropenia, infection particularly hepatitis and HIV, and autoimmune disorders. With respect to the latter, systemic lupus erythematosus is important to be cognizant of, as nearly half of such patients will be leukopenic. Thus symptoms of photosensitivity, arthralgia, and recurrent pregnancy morbidity should trigger rheumatologic consultation.

Hematolymphoid neoplasias may present with either acute or chronic cytopenias. When considering the presence of malignancy, one should attempt to identify other concerning findings, such as other cytopenias, adenopathy, fever, organomegaly, or unintentional weight loss, in addition to isolated neutropenia.

LYMPHOPENIA

Lymphopenia, defined as an absolute lymphocyte count (ALC) less than 1500 cells/μL, may be seen in a variety of settings. One should begin by assessing the chronicity and severity of lymphopenia, along with a thorough physical examination. The latter should focus on any evidence of splenomegaly, adenopathy, or evidence of fungal infection, such as oral candidiasis. The numerous inherited and acquired causes of lymphopenia are noted in Chap. 79.

Notably HIV infection should be excluded in the lymphopenic patient. Similarly, a concomitant infection with a number of viral or bacterial pathogens may result in lymphopenia. One of the most common iatrogenic causes of lymphopenia is the use of glucocorticoids. Alcoholism may also result in lymphopenia.

MONOCYTOPENIA

Although monocytopenia is described in a number of settings (Chap. 70), the most notable entity to exclude is hairy cell leukemia. Although rare, this B-cell lymphoproliferative disorder presents with constitutional symptoms, splenomegaly, and the majority of patients are monocytopenic as well as neutropenic (Chap. 93). Thus, in a patient with compatible symptoms and monocytopenia, even without classic hairy cells on the blood film, it is worthwhile performing flow cytometry with attention to hairy cell markers, including clonal designator (CD) 11c and CD103.

Severe monocytopenia may rarely be seen in the MonoMAC (monocytopenia and mycobacterial infection) syndrome. Described in 2010, it is associated with extreme monocytopenia or amonocytosis, may be associated with mycobacterial and viral infections and results from a mutation in the GATA-2 gene. It has a high risk of progressing to MDS or acute myelogenous leukemia (Chap. 70).

The underlying pathophysiology of the anemia must be identified. We use three interacting analytic tools:

1. Standard hematologic indices, particularly mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH).

2. Kinetic analysis (Chaps. 32 and 33) seeking to determine if the underlying cause is a defect in red blood cell (RBC) production, an increase in RBC destruction (hemolysis), or blood loss. Humans replace 1 percent of their RBCs per day (Chap. 32). Any decrease in hemoglobin greater than 1 percent/day implies the patient is bleeding, hemolyzing, or both.

3. An awareness of patient demographics. For example, a pediatric practice may place hemoglobinopathies high on the differential, whereas a geriatric internal medicine practice will commonly encounter anemia of chronic disease and iron deficiency.

The history and medical records are important tools in identifying the severity and duration of anemia. The timeline of development is crucial: if it has been lifelong, congenital causes are likely. If not, then the events surrounding the development of anemia may also provide clues, as well as indicate if additional abnormalities in the other cell lines are present.

The physical should be a comprehensive exam with particular attention to lymphadenopathy, liver/spleen size, and assessment of cardiovascular status. Laboratory analysis requires a current complete blood count (CBC) and a blood film. Critically, one cannot rely on an isolated hemoglobin value without the remainder of the CBC. An absolute reticulocyte count, corrected for the degree of anemia, is also required. A comprehensive metabolic panel as well, including renal and liver function tests, is useful in narrowing the differential.

If the anemia is of recent origin with a normal MCV and a low corrected absolute reticulocyte count (meaning there is a production defect), then anemia of chronic disease (ACD) (Chap. 37) is likely. Additional labs evaluating inflammatory activity, such as ferritin, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP), may be helpful. If there is a RBC production defect, but no evidence of inflammatory disease, it is important to exclude renal dysfunction. In this setting, we evaluate serum creatinine and erythropoietin levels.

One must maintain a high suspicion for iron deficiency, even in the setting of a normal MCV and blood film (Chap. 43). Useful items include a ferritin, transferrin saturation, and clinical evaluation for blood loss. Conversely, consider a patient in which the hemoglobin is 10.5 g/dL, MCV 64 fL, MCH 19 pg, and absolute reticulocyte count is elevated to 180,000. The blood film shows microcytic, hypochromic RBCs with occasional target cells. Although iron levels should be determined, thalassemia will be much more likely (Chap. 48).

If the MCV is greater than 100 fL and the reticulocyte count suggests a production defect, examine both the WBC and platelet number and morphology. If either is abnormal, then primary marrow disorders such as MDS become more likely than nutritional deficiencies such as vitamin B₁₂ or folate. A marrow biopsy should be performed in this setting.

If the rate of hemoglobin fall is greater than 1 percent/day, and the corrected reticulocyte count is elevated, bleeding or hemolysis is occurring. One should search for specific RBC morphologic anomalies on the blood film. If spherocytes, fragmented cells, or Heinz bodies (Chaps. 2 and 31) are present, then hemolysis is likely. We obtain a haptoglobin, indirect bilirubin, lactate dehydrogenase (LDH), and a direct Coombs study. The history is informative. If the hemolysis is lifelong, then RBC intracorpuscular defects (either of hemoglobin, membrane, or enzymes [Chaps. 46, 47, and 49]) are likely. If the hemolysis is recent, then acquired extracorpuscular causes, such as autoimmune hemolysis, parasitic disease, renal/hepatic disease, or hypersplenism, are likely (Chaps. 51 to 54 and 56).

If the anemia is persistent, symptomatic, and the aforementioned workup has not provided a diagnosis, then marrow biopsy and aspiration are indicated.

Whereas the consultative approach to thrombocytosis is relatively straightforward, the opposite is true for thrombocytopenia. The clinical situation may be urgent and the differential diagnosis, upon which management is based, is huge (Chap. 117). It is helpful to think of the underlying cause(s) mechanistically:

• Platelet production is low: The marrow is replaced (leukemia, lymphoma), empty (aplastic anemia), or ineffective (MDS, vitamin B₁₂ deficiency).

• Platelets are being rapidly removed from circulation: Thrombotic microangiopathy (thrombotic thrombocytopenic purpura [TTP], hemolytic uremic syndrome [HUS], disseminated intravascular coagulation [DIC], hemolysis, elevated liver enzymes, low platelet count [HELLP]) or autoimmune platelet removal (immune thrombocytopenia [ITP], drug-induced thrombocytopenia, heparin-induced thrombocytopenia [HIT]).

• Platelets are being sequestered: Massive splenomegaly or hemangiomas.

If one encounters a new finding of severe thrombocytopenia, one must immediately review the blood film for the presence of microangiopathy. If present, concern is raised for TTP, and immediate intervention is required (Chap. 132).

The history provides key information. Comorbid autoimmune and lymphoproliferative diseases may be associated with ITP. Culprit drugs, such as heparin or quinidine, must be explored. Hepatic disease is a common cause of thrombocytopenia and should be queried. The EMR should be used to explore the temporal nature of the thrombocytopenia and other associated CBC anomalies. The physical exam should pay special attention to petechiae, oral blood blisters, ecchymoses, adenopathy, and organomegaly. In reviewing the blood film, one should exclude spurious thrombocytopenia (Chap. 117) that may include ethylenediaminetetraacetic acid (EDTA)-induced platelet clumping (pseudothrombocytopenia), presence of megathrombocytes that are too large to be recognized as such by automatic cell counters, or adherence of platelets to neutrophils (platelet satellitism) which can be ameliorated by using sodium citrate as an anticoagulant. Next, one should check for the presence of microangiopathy which, if present, would lead to consideration for TTP, HUS, or DIC. Spherocytes and polychromasia would raise the possibility of combined ITP and autoimmune hemolytic anemia, otherwise known as Evans syndrome. Giant hypogranulated platelets raise consideration of MDS, and more than six lobed polymorphonuclear neutrophils (PMNs) associated with an MCV >115 suggest vitamin B₁₂ or folate deficiency (Chap. 41). In a patient with newly developed isolated thrombocytopenia, megathrombocytes, platelets greater in diameter than one-third of a red cell diameter (>2.5 μM), are the parallel of the reticulocyte count. More than 10 percent such platelets are suggestive of immune platelet destruction with a compensatory increase in thrombopoiesis.

In the case of isolated thrombocytopenia, the most common cause is autoimmune thrombocytopenia. ITP may also be drug-induced. An important feature of autoimmune thrombocytopenia is the absence of splenomegaly, thus an enlarged spleen points to other diagnoses such as lymphoproliferative disease, hypersplenism, or lupus. Approximately 25 percent of patients with the antiphospholipid antibody syndrome have mild thrombocytopenia (50 to 130 × 10⁹/L). Bleeding is not a feature of this phenomenon and it may be confused with autoimmune thrombocytopenia. HIT is an event seen in hospitalized patients or those receiving heparin through home care (Chap. 118). The thrombocytopenia can be mild (e.g., 20 to 100 × 10⁹/L) and bleeding is unusual. It usually occurs 5 to 10 days after exposure to heparin and is associated with both venous and arterial thrombosis. Often, the patient may be quite ill, postoperative, and have other plausible explanations for thrombosis, thus requiring a high index of suspicion. It is less frequent with low-molecular-weight heparin (LMWH) preparations, but still can occur in that setting. The specifics of diagnostic tests and management are discussed in Chap. 118.

With baseline data from history, exam, and routine labs, a preliminary analysis should be performed to focus subsequent specialized testing. For example, in a patient with CNS symptoms, microangiopathic hemolysis, and an elevated serum creatinine, a disintegrin and metalloprotease with a thrombospondin type 1 motif member 13 (ADAMTS13) activity level should be ordered in addition to instituting prompt plasmapheresis for the tentative diagnosis of TTP. In a patient who received heparin 5 days prior during cardiac surgery, HIT is considered and an immunoassay for antiplatelet factor 4 obtained.

The presentation of a patient with new-onset pancytopenia requires immediate medical attention. In formulating an approach to a patient who presents with a combination of anemia, thrombocytopenia, and leukopenia it is useful to think of the pathophysiology in mechanistic terms. It is also important in constructing a differential diagnosis to determine whether the leukopenia is balanced, neutropenia, or lymphopenia.

The blood counts may be low because the normal hematopoietic marrow has been replaced (fibrosis, infiltrative malignancy), is absent (aplastic anemia), or is ineffective (MDS, vitamin B₁₂ deficiency). Hypersplenism can also result in the rapid removal of cells from the blood, for example in the context of a malignant lymphoma.

The history provides several critical pieces of information: How severe is the pancytopenia? How long has it been present? Is it getting better or worse? What was going on when it began? Was there an infection at onset, or has the patient had any new medications or occupational exposures? Symptoms of anemia (fatigue, shortness of breath), thrombocytopenia (mucosal bleeding, bruising), and leukopenia (recurrent infections, stomatitis) are important to determine, as are risk factors for hepatic disease (as cirrhosis commonly results in pancytopenia).

The physical exam should be comprehensive with a particular focus on organomegaly and adenopathy.

If the MCV is greater than 100 fL, consider MDS. Chemistry panels are obtained to evaluate for evidence of renal or hepatic dysfunction. An increase in MCV of greater than 115 fL is more common in megaloblastic anemia than in MDS. Folate deficiency may be seen in settings of alcohol abuse or celiac sprue. Pernicious anemia is an important consideration for vitamin B₁₂ deficiency because it is treatable with cobalamin and, if unrecognized, may proceed to severe neurologic impairment. Uncommonly, the latter may be the presenting feature (in addition to the cognitive abnormalities known as megaloblastic madness; Chap. 41).

As always, a critical review of the blood film may suggest the diagnosis, including the presence of dysplasia (MDS), hypersegmented neutrophils (vitamin B₁₂ and folate deficiency), and myelophthisic features (leukoerythroblastic findings such as nucleated RBCs and teardrops) that might suggest primary myelofibrosis (Chap. 86) or a marrow-replacing process (Chap. 45). The presence of abnormal or neoplastic cells in the blood may be diagnostic, such as leukemic blasts, hairy cells, or circulating lymphoma cells.

With this information one can decide on a further diagnostic strategy. Occasionally one sees patients where the pancytopenia is mild and resolves spontaneously within 1 month, which may represent a viral infection with transient suppression of hematopoiesis.

If, in a patient with pancytopenia, the reticulocyte count is very low, aplastic anemia becomes a primary consideration. Other malignant causes of severe cytopenias, such as acute leukemia or MDS, are uncommonly associated with reticulocyte counts less than 0.4 percent. An enlarged spleen is not a feature of aplastic anemia, and its presence would argue against the diagnosis.

Nearly all patients with unexplained severe and persistent pancytopenia will require a diagnostic marrow aspirate and biopsy.

An elevated leukocyte count often raises concern for marrow pathology, but may be seen in nearly any systemic disorder. There is no numeric cutoff that reliably distinguishes between primary hematolymphoid and secondary causes of leukocytosis. Rather, a thorough history, physical, and focused laboratory evaluation is required.

Leukocytosis refers to an elevated total leukocyte count. When combined with an elevated ANC, the term neutrophilic leukocytosis is used. If an elevated ANC is present without leukocytosis, the term neutrophilia is applied. The same terminology holds for elevations of the lymphocyte, monocyte, eosinophil, and basophil compartments. In practice, however, these distinctions are rarely made, nor do they have a major impact on diagnostic evaluations, and thus we use them interchangeably.

NEUTROPHILIA

Neutrophilia may be seen in a variety of settings as outlined in Chap. 65. Primary marrow disorders include chronic myelogenous leukemia (CML), other myeloproliferative neoplasms, neutrophilic leukemia, and sickle cell disease. Secondary disorders include infection, inflammation, smoking, stress (both physical and emotional), asplenia, and medications. With respect to the latter, common offenders include corticosteroids, lithium, and exogenous growth factors such as granulocyte colony-stimulating factor. Rare cases of dramatic neutrophilia (usually accompanied by mild anemia) can be associated with granulocyte colony-stimulating factor–secreting tumors (e.g., bronchogenic carcinoma). In a patient with persistent neutrophilia of unclear etiology, it is generally advisable to exclude CML with a qualitative breakpoint cluster region-Abelson (BCR-Abl) polymerase chain reaction (PCR) analysis. The other classic myeloproliferative neoplasms (MPNs), such as polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis, will typically have other manifestations suggesting the diagnosis, such as erythrocytosis, thrombocytosis, organomegaly, and/or a leukoerythroblastic blood film. Chronic neutrophilic leukemia (CNL), though often considered by clinicians, is a rare disorder. The WBC should be greater than 25,000/μL of which greater than 80 percent are neutrophils to consider this entity.

Smokers commonly demonstrate a mild neutrophilia, and if this has been longstanding in an otherwise asymptomatic patient, further measures other than smoking cessation are typically unnecessary. Similarly, mild neutrophilic leukocytosis may be seen in obese patients, perhaps reflective of an underlying inflammatory state. It is rarely useful to perform a marrow examination for neutrophilia during times of systemic infection or critical illness in the intensive care unit, except for the rare instance in which neutrophilia is felt to be the proximate illness, as in CNL.

LYMPHOCYTOSIS

The diverse causes of lymphocytosis are listed in Chap. 79. Primary marrow disorders include chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), and hairy cell leukemia. Reactive lymphocytosis may be seen in viral infection (classically infectious mononucleosis), HIV, bacterial infection, smokers, and autoimmune disorders (such as rheumatoid arthritis).

Lymphocyte morphology is generally more informative than is the case in neutrophilia. If the lymphocytes display coarse, clumped chromatin, suspicion is raised for CLL. Readily identifiable lymphoblasts suggest ALL. An excess of large granular lymphocytes, particularly in a patient with autoimmune disease such as rheumatoid arthritis, suggest large granular lymphocytic (LGL) leukemia. The presence of lymphocytes with villous projections might suggest splenic marginal zone lymphoma or hairy cell leukemia. Larger lymphocytes with cleaved nuclei may be seen in follicular lymphoma, and cells with cerebriform nuclei might represent the malignant T cells of Sézary syndrome. Hence, examination of the blood film is a critical component of the lymphocytosis evaluation. The laboratory evaluation might also include flow cytometric analysis, as the immunophenotype of atypical lymphocytes often leads to significant narrowing of the differential diagnosis.

EOSINOPHILIA

Eosinophilia has a daunting differential, as discussed in Chap. 62. On initial screen, we seek to identify patients with moderate (>1500 cells/μL) or greater eosinophilia, or those with evidence of end organ damage, as these groups are more likely to have serious pathology. The history should include assessment of B symptoms, rash, diarrhea, allergic symptoms, travel history, and food intake. Ingestion of raw or undercooked meat, especially pork, increases the chance of parasitic infection with Trichinella spiralis, which may be accompanied by significant eosinophilia, periorbital edema, myositis, and fever. This infestation usually occurs at festivities where a pig is roasted and served. Pork from abattoirs involves mixing of meat from a large number of pigs, diluting the Trichinella organisms that might have infected a rare animal. The geographic location and lifestyle of the patient determines if consideration of another parasitic infestation is a high probability. In underdeveloped countries, helminthic infections are the most common cause of eosinophilia (see Chap. 62, Table 62–5 for causes of helminthic-induced eosinophilia). Signs of adrenal insufficiency (fatigue, hypotension, hyperpigmentation) a rare cause of eosinophilia, may be subtle. Rhinosinusitis, asthma, and eosinophilia should trigger screening for eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). Mast cell disorders are also associated with eosinophilia, and should be kept in mind in patients with a rash suggestive of urticaria pigmentosa or symptoms of mediator release with identified triggers. Patients with extreme eosinophilia are often critically ill and nearly always require hospitalization because of the high probability of malignancy or infection, in addition to risks for life-threatening damage to the cardiac, respiratory, nervous, and gastrointestinal systems.

BASOPHILIA AND MONOCYTOSIS

Disorders associated with basophilia and monocytosis are more limited, and are listed in Chaps. 63 and 70, respectively. In the absence of an obvious infectious/inflammatory insult, basophilia should always trigger evaluation for CML and PV. Unexplained monocytosis, particularly in elderly patients with other cytopenias, should reflex concern for myeloid malignancies such as MDS and chronic myelomonocytic leukemia (CMML) and generally warrants examination of the marrow.

As opposed to hematologic consultation for the cytopenias, evaluation for polycythemia generally has a more limited differential diagnosis (Chaps. 57 and 84). Technically, “polycythemia” refers to increases in RBC, WBC, and platelets, while “erythrocytosis” more specifically refers to increases in RBCs alone. We are aware, however, that in common hematologic parlance the term polycythemia is frequently used to indicate erythrocytosis and here we use them interchangeably. The disorders that may cause polycythemia are diverse and have widely varying treatments. Attention to detail is critical.

First, the distinction between absolute and relative polycythemia should be made. The former refers to a true elevation of the red cell mass, whereas the latter refers to an apparent increase in hemoglobin caused by a contracted plasma volume. Reduced plasma volumes might be seen in patients who are dehydrated and are also reported in chronic smokers. However, smokers are more often polycythemic by virtue of their cardiopulmonary disease, so this distinction is difficult to make.

When evaluating a referral for elevated RBC, hemoglobin, or hematocrit, one begins by determining which measure is elevated. Although definitions vary, one may assume polycythemia is present if the hemoglobin is greater than 18.5 g/dL in men or greater than 16.5 g/dL in women.

If a referral is received for an elevated RBC count in the absence of true erythrocytosis, a major consideration is thalassemic trait. Additional clues for this would include a normal or low hemoglobin in addition to severe microcytosis, and a blood film showing targets, as well as hypochromia and microcytosis.

The history is critical in evaluation of erythrocytosis (Chap. 57). Key items after determining if the abnormality is acquired or congenital include:

• History of pulmonary disease or chronic hypoxia

• Risk factors for renal, hepatic, or CNS tumors

• History of obstructive sleep apnea

• Family history of polycythemia

• Use of androgens or anabolic steroids

• Surreptitious erythropoietin (EPO) injection (particularly in competitive athletes)

• Presence of symptoms related to polycythemia

Primary polycythemia refers to autonomous marrow production of erythrocytes, as in PV, whereas secondary polycythemia refers to increased erythrocyte production from stimulation by EPO (Chap. 57). Elevated EPO levels may be a compensatory response to hypoxia or produced in excess by malignancy. Secondary causes of polycythemia are discussed at length in Chap. 57.

Historical symptoms related to polycythemia should also be elicited, including headache, fatigue, visual changes, and shortness of breath. Symptoms of pruritus, erythromelalgia, or intolerance of hot water might be more suggestive of PV.

Clues during the physical exam include:

1. Digital clubbing, which might suggest pulmonary disease

2. Splenomegaly, which might suggest PV

3. Hepatomegaly, which might suggest PV or a hepatic tumor

4. Facial plethora, which is often seen in PV, although can be seen in erythrocytosis of any cause

The laboratory evaluation should include a CBC, EPO level, and venous blood gas measurement. The latter is useful in that it allows indirect calculation of the partial pressure required to achieve 50 percent saturation (p50) (reduced in high-affinity hemoglobinopathies, which should be considered in cases of familial polycythemia) and also provides information regarding carboxyhemoglobin (elevated in smokers or in carbon monoxide poisoning) and methemoglobin levels.

The combination of polycythemia and a low EPO level is highly suggestive of PV. This should trigger reflex mutational testing for JAK2^V617F (exon 14), and, if negative, Janus kinase 2 (JAK2) exon 12 mutation. These two mutations capture nearly all cases of PV, and if negative, should trigger the diagnosis to be reconsidered and/or tertiary referral.

More commonly, the EPO level is found to be normal or elevated. This makes PV less likely, although certainly not exclusionary. If the patient has symptoms suggestive of PV or otherwise unexplained polycythemia, JAK2 mutational testing should still be obtained.

If the EPO level is high normal/elevated and there are no PV-related symptoms, a thorough evaluation for secondary polycythemia should be performed. In the absence of cardiopulmonary disease or obvious offending medications, polycythemia with a significantly elevated EPO level should trigger evaluation for malignancy.

Although rare, familial polycythemia should always be in the differential, particularly if the family history is suggestive. The various mutations in regulators of erythropoiesis and hypoxia-sensing, and are discussed in detail in Chap. 57.

A diagnostic algorithm for erythrocytosis is shown in Chap. 57, Fig. 57–6.

When evaluating thrombocytosis, one must generally determine whether it is reactive or the manifestation of a MPN (Chaps. 84 to 86).

Historical details should include: When were the platelets first elevated? Is the elevation intermittent or constant? Have the platelets ever exceeded 1,000,000/μL? Has there been any thrombosis? Has there been paradoxical bleeding suggestive of acquired von Willebrand disease (VWD)? Causes of reactive thrombocytosis (Chap. 119), such as inflammatory disease, infection, recent splenectomy, iron deficiency, and malignancy, should be explored.

The physical exam should include evaluation for organomegaly, given this may be seen in a variety of MPNs.

In reviewing the CBC, a concomitant elevation of the hemoglobin and platelets might suggest PV. Neutrophilia, myeloid immaturity, or basophilia might suggest CML or myelofibrosis.

If there is significant suspicion for a MPN, such as organomegaly, persistent thrombocytosis, polycythemia, or neutrophilia, additional evaluation might include molecular testing for BCR-Abl, JAK2, and/or calreticulin mutations (Chaps. 84–86).

Hematologic issues arising during pregnancy are a common cause for consultation. In contrast to the nonpregnant patient, the consultant must consider both the patient and the fetus (Chaps. 7 and 8). In this section we will not consider hematologic disorders of the fetus such as hemolytic disease of the newborn and neonatal alloimmune thrombocytopenia (Chaps. 8 and 55).

During the transition from the second to third trimester, the plasma volume increases by approximately 1.0 L while the RBC mass increases by approximately 0.25 L. This partial hemodilution can cause a drop in hemoglobin values below the normal 12 g/dL for women. There are further complicating issues. The growing fetus requires approximately 500 mg of iron from the mother, and if the mother is already iron deficient and/or not taking adequate iron supplements, iron-deficiency anemia will develop. In mothers with thalassemia intermedia, the marrow is already stressed and providing close to maximum compensatory erythropoiesis at baseline. The marrow cannot provide the additional 0.25 L of RBC mass during pregnancy, causing hemoglobin levels to fall where both the patient and fetus may be stressed. Supportive transfusions are often necessary in this case.

One is often asked to consult because of a neutrophilic leukocytosis occurring during the second and third trimesters. This is typically physiologic and the film may show myeloid immaturity with bands, metamyelocytes, and even myelocytes. Observation is recommended.

Other than the variations noted above, the approach to anemia and WBC abnormalities is essentially identical to the nonpregnant patient.

Thrombocytopenia as low as 50,000 to 70,000/μL may be seen as a normal consequence of pregnancy and is termed gestational thrombocytopenia. It requires no specific management. Nongestational thrombocytopenia, however, requires particular care because the differential is broader in pregnancy and because of the risk of both maternal and fetal hemorrhage. For example, when treating patients with ITP, there is concern that the causative antiplatelet antibody will cross the placenta and cause fetal thrombocytopenia. The distortion of the fetus, particularly of the cranium during delivery, raises concern about intracranial hemorrhage if the neonate is thrombocytopenic. Newborns of mothers with ITP should generally have serial platelet counts over the first week of life as thrombocytopenia may be delayed as splenic function develops.

The appearance of low platelets along with hypertension in the third trimester raises concern for preeclampsia. Perhaps a more-severe variant of preeclampsia is the HELLP syndrome (Chaps. 8 and 51), an emergency where low platelets are accompanied by microangiopathic hemolysis and hepatic dysfunction. The blood film and liver function tests are essential in making this diagnosis.

Disorders of hemostasis/coagulation include placental abruption and retained products of conception. These two conditions are unique to pregnancy and release large amounts of necrotic tissue into the circulation, leading to DIC (Chap. 129). The consultant is often called because of severe bleeding from many sites, including the vagina, vascular access sites, and surgical incisions. Laboratory findings often demonstrate profound anemia and thrombocytopenia, and the blood film shows microangiopathy. The coagulation panel demonstrates a prolonged prothrombin time (PT) and partial thromboplastin time (PTT), low fibrinogen, and significantly elevated D-dimer. If assayed, virtually all coagulation factors will be low. The key to management is prompt recognition, establishment of adequate IV access, and massive replacement of RBCs, platelets, and coagulation factors, along with removal of the uterine contents.

Two disorders have a specific predilection for the immediate postpartum period: appearance of a factor VIII inhibitor and postpartum TTP. Patients with a factor VIII inhibitor will show a long PTT and mixing studies will identify and quantify the inhibitor. Patients with postpartum TTP will have a clinical presentation like other TTP patients: microangiopathic hemolysis, thrombocytopenia, and potentially CNS and renal involvement.

Clinical bleeding is a common request for hematologic consultation. The setting and context provide important clues about the diagnosis. Requests arising from the ICU or emergency room (ER) usually relate to a specific event like trauma or surgery. These requests may involve hemodynamic compromise and often mandate a rapid response. Conversely, complaints about “easy bruising” can be equally ominous, but often don’t rise to the same level of acuity.

The conventional wisdom is that mucosal and skin bleeding is likely to be caused by platelet abnormalities (qualitative or quantitative), vascular disorders, or VWD, whereas deep tissue or joint bleeding is caused by coagulation factor deficiencies. This is generally accurate, although there is substantial overlap caused by factors like age and comorbid medications (including aspirin, nonsteroidal antiinflammatory drugs [NSAIDs], and anticoagulants).

As expected, the history is critical. One must inquire about bleeding length, duration, and context. A long duration and early onset suggest a hereditary disorder. Bleedings that occurs after dental extractions or surgery are clues for mild hemophilia or VWD. If the bleeding always occurs at one site, there may well be a local issue, whereas bleeding at multiple sites points to a systemic disorder. Drug history is critical, not only for anticoagulant drugs, but also for the many agents that cause drug-induced platelet functional abnormalities (Chap. 121). A history of alcohol abuse, hepatic disease, or renal disease is relevant.

The exam should be used to identify petechiae, oral blood blisters, ecchymoses, hematomas, giant hemangiomas, hemarthroses, and liver/spleen size.

Laboratory analysis should include a blood film, CBC, and chemistry panel. A basic coagulation panel containing a PT, PTT, fibrinogen, D-dimer, thrombin time (TT), and reptilase time (RT) is also important (Chaps. 114 and 116). The PT and PTT screen both the intrinsic and extrinsic pathways. The fibrinogen and D-dimer provide useful information about DIC and fibrinolysis, while a discrepancy between the RT and TT can determine whether there is in vivo presence of heparin.

Before deciding that a prolonged PT or PTT is because of a factor deficiency, consider the possibility of an inhibitor by ordering a mixing study. If an inhibitor is ruled out, then one can determine whether specific factor assays are warranted. A prolonged PTT might also be the result of a lupus anticoagulant, which generally poses a risk for thrombosis rather than hemorrhage.

If there is recurrent mucosal bleeding and a family history of bleeding, we generally obtain screening for VWD. A platelet function analysis (PFA) is a highly sensitive test for VWD. Additional tests, such as a von Willebrand antigen, ristocetin cofactor activity, and factor VIII levels can be used to confirm the diagnosis. More expensive studies, such as multimer analysis and ristocetin-induced platelet aggregation (RIPA) are generally not needed if screening studies are negative. A variety of disorders are associated with acquired VWD, including cardiac valvular disorders, extreme thrombocytosis, paraproteinemias, and autoimmune disorders (Chap. 126).

Mucosal or posttraumatic bleeding might also suggest a platelet functional defect. Screening with a PFA is often useful before launching into more detailed studies, such as formal platelet aggregometry.

A low fibrinogen and markedly elevated D-dimer points to DIC, which can be seen in a variety of systemic illnesses and is associated with both bleeding and thrombosis.

Of course, not all bleeding is related to disorders of coagulation factors and platelets. One should not forget vasculitis or other vascular defects, such as hereditary hemorrhagic telangiectasia (HHT), when evaluating a patient with recurrent mucosal bleeding and epistaxis. Vitamin C deficiency (scurvy) can rarely be encountered in alcoholics or severely malnourished individuals and results in bruising and gingival bleeding because of defective collagen synthesis.

Pathologic fibrinolysis may also result in bleeding and is not easily assessed by standard coagulation panels (Chap. 135).

We have used thromboelastography to evaluate global hemostasis on an individualized basis, although this study lacks broad clinical utility.

Finally, preoperative consultations for bleeding can be frustrating because there are no generally accepted guidelines. The most important tool is the history including family and personal history of bleeding. The type, site, and timing of prior episodes of bleeding, whether postoperative, traumatic, or spontaneous, provide the requisite information upon which to base further testing as discussed above.

VENOUS THROMBOSIS

Consultations regarding deep venous thrombosis (DVT) may be daunting. The decision to commit a young patient to indefinite anticoagulation (AC), or to cease AC in an older patient at increased risk for recurrence often gives the physician pause.

Here we discuss some of the highlights of our approach to venous thromboembolism. The individual components are discussed at length in other chapters, including principles of AC (Chap. 25), DVT (Chap. 133), hereditary thrombophilia (Chap. 130), and the antiphospholipid antibody syndrome (APS; Chap. 131).

Patients often have significant anxiety after a thrombotic event. Although considerable progress has been made in the safety and convenience of AC, the process still poses serious risk and may impair the patient’s quality of life. It is important to communicate that AC management is inherently complex, therapeutic approaches must be individualized, and, ultimately, no approach is without risk, including life-threatening bleeding and/or thrombosis.

One should begin the evaluation of a new DVT by defining the context of the event. Critical questions include:

1. Were there any risk factors, such as surgery, immobility, trauma, indwelling catheters, cirrhosis, nephrotic syndrome, inflammatory disorders, or systemic estrogen therapy (Chap. 133)?

2. If present, are those risk factors modifiable and might they have reasonably provoked the event?

3. If dealing with a reoccurrence while on AC, had the patient been compliant with therapy?

4. Are there historical or physical clues that might suggest malignancy, APS, or a hereditary thrombophilia?

When probing hard enough, one is often able to identify a “risk factor” for thrombosis. This alone is insufficient to label an event “provoked”; rather, that risk factor must be thought to have reasonably caused the event. Attribution of causality is arduous and ultimately subjective.

When dealing with recurrent events in patients on AC, compliance must be probed at length. Labeling a patient as having “failed” therapy has significant consequences. First, this might suggest an underlying thrombophilia, such as malignancy or APS. Second, the lack of clear superiority data of one agent over another makes management decisions murky.

The physical exam must of necessity focus on the affected extremity. However, a comprehensive exam may provide valuable clues. Adenopathy or temporal wasting might suggest malignancy. Arthritis and malar rash might suggest an autoimmune diathesis such as lupus. Organomegaly and erythromelalgia should trigger concern for an MPN such as PV or ET. Spontaneous upper-extremity events might suggest thoracic outlet syndrome whereas unprovoked left iliofemoral DVT, particularly in young women, may represent May-Thurner syndrome.

Screening for underlying hereditary thrombophilias is often pursued although the general utility of this approach is not clear. This is discussed at length in Chap. 130. In general, such screening rarely changes management and has the potential for error if performed at the incorrect time. For example, levels of antithrombin III, protein C, and protein S may be falsely low in the acute setting. Functional protein S levels might be reduced when the factor V Leiden mutation is present, leading to erroneous diagnosis. Anticardiolipin antibodies require sustained elevation over 12 weeks to satisfy criteria for APS. Pregnancy and hepatic disease can also affect the serum levels of various pro- and anticoagulants and confound diagnosis.

The decision regarding the duration of therapy is complex (Chap. 133). These decisions must incorporate the risk of recurrence, risk of bleeding, and patient preferences. Generally, patients with either a provoked or distal DVT may be treated for a finite course, generally three months. Patients with unprovoked DVT/pulmonary embolism (PE), APS, recurrent thromboses, or active malignancy are often considered for indefinite therapy should the bleeding risk be acceptable.

In patients with unprovoked events who discontinue AC after a finite course, efforts aimed at risk stratification via D-dimer assays appear to be useful. Thromboprophylaxis with aspirin, has shown promise. However these approaches are not standardized. The American College of Chest Physicians publishes evidence-based antithrombotic guidelines that provide specific recommendations for a variety of scenarios and are a useful resource.

The availability of new, oral anticoagulants has dramatically changed AC management from both the patient and physician perspectives. Dabigatran, a direct thrombin inhibitor, and rivaroxaban, a factor Xa inhibitor, are FDA approved for the treatment of venous thromboembolism, with the former requiring an initial 5 to 10 days of parenteral AC. Both agents are oral, require adequate renal function, and produce a reliable anticoagulant effect that need not be monitored or titrated. They lack reliable antidotes in the event of bleeding, although such products are in development. It should be noted that patients with poor warfarin compliance are equally poor candidates for these agents. Because of their short half-life, skipped doses will result in a prompt loss of AC and increased risk of recurrent thrombosis.

In general, there is insufficient information regarding the superiority of one anticoagulant over another. There is abundant experience with warfarin (Coumadin) and LMWH. The latter is often preferred in patients with malignancy, although high-quality evidence in its support is lacking. Dabigatran and rivaroxaban lack specific data in hereditary thrombophilias, malignancy, and APS, and therefore caution should be exercised in these settings. Dabigatran showed an excess risk of bleeding and thrombosis when compared to Coumadin in patients with mechanical heart valves, exemplifying the potential peril in assuming anticoagulants are of equal efficacy in different settings.

Decisions regarding AC touch upon every aspect of a patient’s life and are not taken lightly. They are not as black and white as standardized chemotherapy regimens and require an understanding of the patient’s lifestyle, values, and risk of recurrence. Such assessment is difficult in the modern time-constrained environment. Furthermore, such decisions should not be made in a single-instance and then followed indefinitely. Rather, the decision to continue (or withdraw) AC is dynamic and should be revisited serially depending on the tolerance of therapy and other medical comorbidities.

ARTERIAL THROMBOSIS

Consultation is often requested in patients with arterial thrombosis, such as myocardial infarction, cerebrovascular accident, or acute limb ischemia. In the vast majority of cases, however, this is related to underlying atherosclerosis with local inflammation rather than a primary hypercoagulable state. Risk factors, mechanisms, and treatment of atherothrombosis are discussed in Chap. 134.

In rare cases where underlying risk factors for atherothrombosis are absent or there is a strong family history of thrombosis, particularly at young ages, we perform a limited hypercoagulable evaluation, including studies for the APS. Paroxysmal nocturnal hemoglobinuria (PNH) and MPNs may rarely result in arterial thromboses. We rarely find it helpful to obtain studies for protein C, protein S, or antithrombin III deficiency, and do not obtain studies for factor V Leiden or prothrombin 20210A mutations as these do not have a meaningful effect on management. Furthermore, routine screening for the thermolabile variant of the methylenetetrahydrofolate reductase (MTHFR) should be discouraged as there is no evidence of benefit in reducing plasma homocysteine levels.

Hence, broad hypercoagulable evaluations are not useful in isolated arterial thrombosis, as most findings are likely incidental rather than causal, and do not have a direct impact on patient management.

Consultations may arise from the discovery of incidental abnormalities on the blood film. Nucleated RBCs (nRBCs) and immature myeloid cells are relatively common.

NUCLEATED RED BLOOD CELLS

The clinical lab may report the finding of nRBCs, which is often reported in the differential as #nRBC/100 WBC.

Although there are several causes for the appearance of nRBCs, two predominate: stress erythropoiesis and extramedullary hematopoiesis.

Stress erythropoiesis occurs as a response to severe anemia. The marrow attempts to compensate by increasing erythropoiesis (Chaps. 32 and 33) and discharges reticulocytes of increasingly younger age to the blood. If the anemic stress is not ameliorated or deepens further, nRBCs, usually late normoblasts, leave the marrow. The blood film often shows abundant polychromasia, skip macrocytes, and late normoblasts.

Extramedullary hematopoiesis can occur if the normal marrow is replaced by fibrosis or cancer or if somatic mutation such as seen in primary myelofibrosis decreases stem cell adherence (Chap. 86). The hematopoietic stem cells travel through the blood to find suitable alternative sites for growth, often settling in the spleen. However, the sinusoidal structure there is not identical to that of the marrow. Hence, blood cells, particularly nRBCs, are released in an uncoordinated manner.

A leukoerythroblastic smear (nRBCs, teardrop RBCs, myeloid immaturity, giant platelets) is a significant clue. If clinically indicated, biopsy of the marrow will usually confirm the diagnosis.

IMMATURE MYELOID CELLS

The clinical lab may report the presence of metamyelocytes, myelocytes, promyelocytes, or blasts on the blood film. The differential is enormous, ranging from normal pregnancy to myeloid malignancies (Chaps. 61–63). One begins with a thorough history, CBC, and blood film. We inquire about recent stressors and the use of glucocorticoids. In patients with normal blood counts and rare metamyelocytes, observation is generally appropriate. The presence of peripheral blasts, particularly in association with cytopenias, is never normal and mandates examination of the marrow. A full spectrum of myeloid maturity, particularly in association with basophilia, should raise concern for CML.

On occasion, consultation is requested for lymphadenopathy without a tissue diagnosis. The differential diagnosis is vast, including benign adenopathy, viral infections, autoimmune disorders, and malignant lymphomas. A thorough history is critical (Chap. 1). Laboratory studies should include a CBC and blood film.

Generally with this information, the diagnostic studies can be focused and lymph node biopsy is not always required. For example, in adolescents with fever, pharyngitis, and cervical adenopathy, tests for infectious mononucleosis are pursued. If there is an accompanying lymphocytosis, the diagnosis might be established via flow cytometry of the blood, as in CLL. If the patient is well appearing, asymptomatic, and the nodes are minimally enlarged, a short period of observation is often prudent.

In patients with cytopenias, B symptoms, and organomegaly without obvious infections, lymph node biopsy is nearly always indicated. Fine-needle aspirates, although often more convenient, are discouraged because the lack of lymph node architecture impairs pathologic analysis. If a diagnosis of malignant lymphoma is suspected, treatment with glucocorticoids prior to tissue diagnosis is also discouraged as it may impair diagnostic sensitivity.

Referrals for splenomegaly open up an immense differential, including hemoglobinopathies, infection, liver disease, heart failure, autoimmune disorders, and malignant leukemia or lymphoma (Chap. 56).

Critical diagnostic elements include personal history, family history, CBC, and the blood film. Has the diagnosis been made on physical exam or was it detected incidentally on an imaging procedure? If prior studies are available for comparison, one may be able to use the EMR to determine how long the spleen has been enlarged. On exam, is the spleen tip barely palpable or does it extend into the pelvis and cross the midline as might be the case with primary myelofibrosis (Chap. 86)?

Evidence of cirrhosis or heart failure might suggest congestive splenomegaly. Erythrocytosis and pruritus would raise concern for PV.

A blood film showing basophilia and myeloid immaturity might indicate CML. If risk factors are present, HIV testing is appropriate. Thalassemia can readily be identified via the blood film. Because the diagnostic possibilities are innumerable, it is critical to avoid a shotgun approach, identify the likely diagnostic possibilities, and focus the workup accordingly. It is almost never necessary to do a diagnostic splenectomy.

Monoclonal gammopathies are increasingly detected given the wide availability of comprehensive metabolic panels and the subsequent use of serum protein electrophoresis (SPEP) as a screening tool. Referring physicians often have already requested a SPEP in cases of suspected myeloma, anemia, unexplained renal failure, or neuropathy. The finding of elevated serum protein or globulin fractions, or the report of extensive rouleaux formation on blood film may also trigger a request for SPEP. The SPEP can demonstrate the presence of a monoclonal protein whereas immunofixation defines the heavy-chain isotype and light-chain restriction.

Rouleaux formation reported on a CBC is not synonymous with a monoclonal protein. Rouleaux simply describes visible stacked red cells, either as a result of poor smear preparation, inappropriate viewing in the “thick” area of the slide, or as a consequence of increased plasma proteins, such as immunoglobulins and fibrinogen. Although rouleaux may result from a monoclonal gammopathy, it may also be seen in chronic infections, autoimmune disorders, and liver disease.

When seeing referrals for monoclonal gammopathies, one should obtain a CBC, renal and liver function studies, blood film, immunoglobulin panel, free light-chain ratio, urine protein electrophoresis (UPEP) with immunofixation, and skeletal survey. This analysis seeks to identify any evidence of end organ damage attributable to the monoclonal population, such as hypercalcemia, anemia, renal dysfunction, or lytic bone disease. The physical exam focuses on the presence of adenopathy or organomegaly that might suggest a lymphoproliferative disorder.

If there is no clear evidence of end organ damage, the term monoclonal gammopathy of undetermined significance (MGUS) is often applied, and observation is pursued. The natural history, risk stratification, and prognosis of such patients in discussed in Chaps. 106 and 107. Monoclonal proteins may also be seen in association with several disorders, including plasma cell dyscrasias, lymphoproliferative disorders, infections, and various autoimmune diseases. Notably, it is important to identify patients with signs concerning for immunoglobulin light-chain amyloidosis (nephrotic range proteinuria, macroglossia, neuropathy). In cases of immunoglobulin (Ig) M paraproteins, look for evidence of Waldenström macroglobulinemia (adenopathy, constitutional symptoms, organomegaly, bleeding). Although rare, in patients with anemia and IgM κ paraproteins, one should inquire about cold sensitivity and seek to exclude cold agglutinin hemolysis.

One is often faced with an elderly patient with multiple comorbidities, such as chronic renal dysfunction, peripheral neuropathy, diabetes mellitus, and osteoporosis in conjunction with a systemic paraprotein. In most cases, if these findings have been chronic and longstanding, they are thought to be unrelated to the paraprotein, and ongoing observation is appropriate rather than cytotoxic chemotherapy. In some cases, particularly those in which historical labs are unavailable, this distinction is more difficult to make, and marrow exam may be useful to assess the degree of marrow effacement. In younger patients with monoclonal proteins greater than 1.5 g/dL, non-IgG isotypes, or abnormal free light-chain ratios, we often obtain marrow biopsies given the higher likelihood of progression and potential intervention for patients with high-risk smoldering myeloma.

A good relationship and open line of communication between hematologists and referring physicians are imperative. A few points to keep in mind:

• The clinical history is invaluable. If there is lack of clarity, we recommend a quick phone call to the referring physician focusing on the salient features of the patient’s medical history and the reason for consultation. Much like pathologists, this information helps us place the labs and blood film in appropriate context and aids the diagnostic evaluation, particularly in cases with broad differentials such as anemia or leukopenia. The importance of the history and physical exam also reinforces the need for the attending hematologist to personally review the blood film, rather than relying solely on hematopathologists or laboratory technicians.

• Avoid the laboratory “shotgun” approach. For example, exhaustive hypercoagulable studies in patients with provoked thromboses are not particularly useful and can create patient anxiety. Patients have concerns about their “genetic disease,” and hematologists have a hard time explaining the implications of tests they would not typically order. The consulting hematologist should direct the laboratory evaluation to avoid unnecessary, duplicate, and/or costly tests.

• The increasing variety of molecular and genetic diagnostics, in addition to the evolving complexity of hematopathology, mandates one be aware of the resources of their local hematologist. For example, rare disorders such as systemic mastocytosis, CNL, severe eosinophilia, and atypical CML are often best evaluated in a tertiary center. Once the diagnosis is made and a treatment plan established, care should then be transitioned to local physicians, with intermittent input from an academic center if required. Value should always be placed on avoiding repeat marrow examinations.

• With rare exception, diagnoses should not be made off scant marrow specimens. Terms such as “aspiculate aspirate” and “subcortical biopsy” should trigger concern for an inadequate specimen. In such cases, a repeat biopsy should be obtained by an experienced provider rather than making diagnostic assumptions from a poor specimen.

• A referral to a hematologist, “cancer center,” or hematologist/oncologist often generates considerable patient anxiety, even if not verbalized. The waiting period of several days to weeks to see such a provider can cause significant distress. Unless the diagnosis is clear, it is useful to counsel patients that such a referral does not imply the presence of “cancer” or “leukemia” but rather a request for more information.