Chapter 144. Hematologic Diseases

Hematology includes the study of blood and blood-forming tissues. Given the number and variety of hematologic disorders, it is not surprising that mucocutaneous manifestations of hematologic disorders are common. Many hematologic malignancies and pseudomalignancies can involve the skin through atypical cell infiltration (specific lesions), and some of these may present preferentially in the skin. These conditions, such as leukemias and lymphomas, plasma cell dyscrasias including myeloma, and Langerhans and non-Langerhans histiocytoses, are discussed in other chapters. Likewise, complications of chemotherapy, radiotherapy, cytokine use, or marrow transplantation are discussed elsewhere.

The first section of this chapter is directed toward the differential diagnosis of purpura with an emphasis on those subsets of purpura with important underlying hematologic abnormalities. The second major section of this chapter is directed toward nonspecific (nontumor-containing) findings that may be associated with hematologic disorders. Although the ready availability of laboratory testing has made early recognition of such conditions as anemia and polycythemia much less dependent on physical findings, cutaneous associations still may aid in the diagnosis of a hematologic condition or complicate its management. A comprehensive listing of these associations is presented in Table 144-1.

Selected associations are covered in more detail in the text.

Hemostasis

Hemostasis can be defined as the arrest of bleeding, and has two phases, primary and secondary, though research findings are blurring the compartmentalization of this process.65 Primary hemostasis depends both on the vasoconstriction of the injured vessel and on formation of a platelet plug at the injury site. It is usually sufficient for focal microcirculatory injury repair. Larger defects or injury in larger cutaneous vessels require secondary hemostasis to reinforce the platelet plug.

Primary hemostasis is characterized by vascular contraction, platelet adhesion and activation, and subsequent development of a plug at the site of vessel injury. Vascular contraction leads to slowing of the blood flow, so the platelets can adhere to the injured site and diminish blood loss.66 Secondary hemostasis promotes vascular integrity when primary hemostasis is insufficient and when larger vessels are involved. This phase maintains vasoconstriction through the secretion of prostaglandins, thromboxane, and serotonin. It also solidifies the platelet plug formed during primary hemostasis, through a series of clotting cascade pathways.

Because of the rich and highly visible nature of the skin microcirculation, and because of the very dynamic alterations of cutaneous blood flow (e.g., increasing to promote heat exchange, decreasing dramatically in shock states) as well as hydrostatic pressure variations by anatomic site and body position, the skin can be a very early and sensitive locale for signs of hemostatic alterations and coagulopathy. In nondisease states, the blood participates in an ongoing homeostatic balance between site-specific hemostasis or clot formation, clot extension inhibition, and clot lysis at the appropriate stage of injury repair. The platelet and coagulation cascade participate in clot formation, the antithrombin III and thrombomodulin/protein C/protein S systems in clot inhibition, and the plasminogen/plasmin system in clot lysis.

Differential Diagnosis of Purpura

The bedside dissection of the likely differential diagnosis of purpura can be summarized by five Ps: are lesions purpuric, primary, palpable, and what is their pattern and placement? For a lesion to qualify as purpuric, it must have a color that is compatible with hemorrhage—usually some shade of red, blue, or purple, but sometimes yellow–brown, green, or black—and at least some of this color must persist on compression of the skin. If the vessels are compressible, and if the color is due to mobile red cells within the vessels, then the skin color should completely blanch on compression, and no hemorrhage is clinically evident. False-positive results occur if the lesions contain tortuous vessels that kink on compression, or if compression is incomplete. Extravasated cells are not free to move, and therefore color persists on compression. It is important not only to determine the persistence of some color on compression, but also to assess in early lesions the proportion of erythema to hemorrhage. Complete blanching is a nonpurpuric lesion, but may be the physical presentation of mild urticarial vasculitis with clinically nonevident hemorrhage. Significant partial blanching of early lesions suggests an inflammatory etiology of the purpuric process. No detectable color change suggests no inflammatory component, and is characteristic of simple hemorrhage and most microvascular occlusive lesions.

Purpura may be primary or secondary in etiology. Hemorrhage may occur in inflammatory syndromes such as cellulitis, psoriasis, stasis dermatitis, or eczema, and these should be considered secondary purpura syndromes. In these and similar settings, the hemorrhage is generally secondary to nonvessel-directed inflammation increasing vascular permeability, and usually hydrostatic pressure increasing the likelihood of incidental red cell extravasation in areas of dependency.

Palpability rarely reflects the amount of cutaneous hemorrhage except for very large and deep focal cutaneous hemorrhage, resulting in a hematoma typically localizing in or below the fat layer of skin. Upward movement of the hemorrhage may occasionally result in an overlying ecchymosis. Most simple hemorrhage in the skin is nonpalpable. Instead, palpability typically results from protein-rich edema secondary to inflammation or microvascular ischemia with vascular and tissue injury. While the presence of palpability should exclude simple hemorrhage as a pathogenesis, the absence of palpability does not exclude inflammatory or occlusive hemorrhagic etiologies.

Many approaches to the differential diagnosis of purpura begin with pathophysiologic mechanisms. However, pathophysiology is usually what the physician is attempting to ascertain, and the diagnostic process begins with clinical clues. Some of the most important clinical information available from the bedside examination is lesional number, distribution, and morphology. Exploration of the differential diagnosis can begin with helpful patterns of lesional number and distribution are listed in Table 144-2.

The initial diagnostic considerations based on these patterns should then be combined with information gleaned from the lesional morphologic differential diagnosis (Tables 144-3, 144-4, and 144-5; Fig. 144-1).

The goal of the history and examination is to develop a narrow differential diagnosis or testable clinical hypothesis as to the etiology of purpura in a particular patient, and to order or review the appropriate laboratory studies that may prove or disprove suspected pathophysiologies. While the differential diagnosis of purpura could easily include hundreds of possible etiologies, the diagnostic process can be powerfully refined if one is able to determine clinically whether the early primary purpuric lesions is likely due to simple hemorrhage, inflammatory hemorrhage, or ischemia/occlusion.67,68,73 In concert with the number and distribution, lesional morphology is critical in facilitating this determination. Simple hemorrhage not severe enough to produce hematoma presents as nonpalpable (macular), nonblanchable purpura, and usually is either primarily petechial or ecchymotic, each pattern having its own differential composition (Tables 144-3, Figs. 144-2 and 144-3). Partially blanchable purpura, often palpable, is the expected clinical manifestation of inflammatory hemorrhage, including but not limited to necrotizing vasculitis (Table 143-4). If early lesions are both partially blanchable and retiform, the differential diagnosis is further narrowed (Fig. 144-4). Finally, if early lesions are retiform with minimal to no blanchable component, microvascular occlusion becomes the likely differential category, always with the caveat that some occlusive syndromes may be accompanied by inflammation when lesions are large and deep, and two vasculitides in particular [granulomatosis with polyangiitis (Wegener's) and microscopic polyangiitis] may present with purpura lesions which show no clinical evidence of inflammation. The differential diagnosis of minimal inflammatory retiform purpura, with these caveats, is listed in Table 143-5.

Nonpalpable, Nonblanchable Petechiae (<4 mm)

Palpable or partially blanching petechiae do not fit in this category; such lesions should instead prompt consideration of the differential diagnosis of classical palpable purpura. Nonpalpable petechial hemorrhage is typically the dominant type of hemorrhage resulting from problems in platelet number, always below 50,000/mm, and almost always below 10,000/mm (Table 144-3). In patients with immune thrombocytopenia, either idiopathic or alloimmune, the marrow is healthy, and platelet production is increased, leading to larger and more effective platelets. In such instances, spontaneous formation of petechiae is often minimal, even when platelet numbers are below 5,000. However, when thrombocytopenia is due to marrow failure (medications, especially chemotherapy, radiation exposure, marrow infiltration from leukemia, lymphoma, or other neoplasms), the platelets in circulation are often small, old, and poorly functional, and hemorrhage may occur despite platelet counts many thousands higher than in the immune thrombocytopenias. Drug-related thrombocytopenia can be due to several different mechanisms, including immune, destructive, and cytotoxic.69

Immune Thrombocytopenias

Idiopathic thrombocytopenic purpura (ITP) is a common bleeding disorder in children caused by autoantibodies against platelet surface antigens, especially glycoproteins IIb/IIIa and Ib. It presents with increased immunoglobulin (Ig) M, IgG, and IgA autoantibodies with decreased platelet surface antigens (CD41, CD61, and CD42b).74,75 Patients are usually asymptomatic with mostly petechiae and a few ecchymoses found on their physical examination. Oral blood blisters with gastrointestinal or mucocutaneous bleeding can also occur and are referred to as wet purpura. As in ITP, immunothrombocytopenic purpura can be associated with recent viral illness and vaccination.76 Alloimmune thrombocytopenic purpura occurs when alloantibodies against human platelets form during blood or platelet transfusion, or maternal–fetal blood exchange, leading to posttransfusion purpura and fetal and neonatal alloimmune thrombocytopenia, respectively.46 CD109 is a protein expressed on platelets, T lymphocytes, and endothelial cells. Antibodies against HPA-1, HPA-5, and HPA-15 on CD109+ cells should be sought.

Unique localization of petechial hemorrhage may result from intravascular pressure spikes. For example, vigorous Valsalva maneuver-like actions from crying in children, vigorous retching, or bearing down during childbirth may result in petechial hemorrhage above the clavicles. A ligature, blood pressure cuff, or attempted strangulation may result in hemorrhage in the affected venous drainage area.

Chronic pigmented purpuras, especially Schamberg type, may mimic simple petechial hemorrhage in the legs, despite histologic evidence of mild nonvasculitic hemorrhage such lesions. Clinically, the inflammation may not be evident, but clues to this diagnosis consist of a tendency of pigmented purpura and petechiae to cluster, leaving an orange–brown pigmentation in affected areas. The pigmented purpuric dermatoses are discussed in detail in Chapter 168.

Thrombotic Thrombocytopenic Purpura/Thrombotic Microangiopathies

Thrombotic thrombocytopenic purpura (TTP) is most commonly seen in adults, whereas hemolytic-uremic syndrome (HUS) is more frequent in children.77 TTP can result from pregnancy, cancer, drugs (chemotherapeutic-bevacizumab, and immunosuppressives—cyclosporine/tacrolimus, oral contraceptives, ticlopidine, and quinine), bone marrow transplantation, and autoimmune diseases. The most common pathogenesis is from antibodies, which interfere with the function of ADAMTS13. The result is improper cleavage of von Willebrand factor (VWF) and platelet-fibrin thrombotic microangiopathy.78,79 Patients have increased levels of LDH with associated schistocytes, helmet cells, and megakaryocytes; clinical signs include fever, renal (especially in HUS), and central nervous system (headache, seizures, hemiparesis, disorientation) abnormalities. Despite clear evidence of visceral vessel occlusion from platelet plugging, the mechanism of petechial hemorrhage in TTP is far from clear. Occlusive disease was reported in a small series of mucous membrane lesions, but biopsies of cutaneous lesions are not reported, and the morphology of these lesions is more in keeping with simple hemorrhage. Deficiency of ADAMTS13 has been shown in familial TTP (congenital TTP, Upshaw–Schulman syndrome). The treatment of choice is fresh frozen plasma/plasmapheresis. Acquired functional deficiency of ADAMTS13 is known to occur in several other settings, most commonly with lupus and other autoimmune diseases.80 HUS is commonly caused by Shiga toxin, producing Gram-negative bacilli, especially Escherichia coli O157:H7 infection. It presents with bloody diarrhea and hemorrhagic colitis, and usually causes oliguric or anuric renal failure. Cutaneous lesions are not seen. Diarrhea-negative or atypical HUS is not associated with Shiga toxin-producing organisms, and occurs without an obvious predisposing condition. Preeclampsia-HELLP (hemolysis, elevated liver enzymes, low platelets) is another thrombotic microangiopathy that can mimic TTP/HUS syndromes.

TTP typically presents as round nonpalpable petechial hemorrhage, in contrast to the typical cutaneous presentation of heparin-induced thrombocytopenia (HIT), in which the retiform morphology of purpura is consistent with platelet-related occlusion of the cutaneous microvasculature. The platelet aggregation is triggered by an antibody, which recognizes antigenic sites on both heparin and platelet factor 4 on the platelet surface. Treatment of heparin necrosis typically involved anticoagulation with coumarin, but this treatment may worsen the vascular occlusion, leading to limb necrosis.81 Worldwide, three accepted drugs are used in the treatment of patients with HIT: (1) danaparoid (not available in the United States), (2) recombinant hirudin (lepirudin), and (3) argatroban.79

Nonpalpable, Nonblanchable Ecchymoses (>1 cm)

The cutaneous lesions associated with scurvy are characterized by purpura that surrounds corkscrew hairs on the lower extremities (see Chapter 130), but nonspecific hemorrhage is more typical. True senile purpura is uncommon, and is usually the misdiagnosis for solar damage in poorly pigmented, often elderly individuals. Solar purpura usually occurs on the extensor surfaces of the forearms and results from the photo-induced loss of cutaneous elasticity and weakened dermal capillary support. Erythrocyte (RBC) extravasation occurs with minor trauma to the hands and other sites (see Chapter 109). Ecchymotic hemorrhage after minor trauma generally results from procoagulant defects, poor dermal vessel support, or Waldenstrom hypergammaglobulinemic purpura (on the legs) (Table 144-3, Fig. 144-2).

Partially Blanching Round Purpura (Classical Palpable Purpura) and Partially Blanching Retiform Purpura

Lesions of inflammatory hemorrhage are round, partially blanching, and palpable, and most commonly represent leukocytoclastic or necrotizing vasculitis. The differential diagnosis of this morphologic presentation is listed in Table 144-4 (Fig. 144-3).

When purpura is retiform in configuration, but also associated with prominent early partial blanching, the potential causes of the inflammatory hemorrhage are more limited (Table 144-4, Figs. 144-4 and 144-5, inflammatory retiform purpura). Given the lesional number and distribution, a highly probable clinical hypothesis can be formulated. However, four occlusive syndromes may occasionally present with a few, large, indurated plaques of early inflammation of the dermis and subcutaneous tissue surrounding retiform purpura or eschar. These include: (1) antiphospholipid antibody syndrome; (2) warfarin necrosis; (3) heparin necrosis; and (4) cutaneous calciphylaxis. Among inflammatory causes of hemorrhage/vasculitis, only benign cutaneous polyarteritis nodosa is likely to cause such large necrotic thick plaques with early inflammation.

Nonblanching Retiform Purpura

The differential diagnosis of cutaneous microvascular occlusion is extensive, and differs considerably from the usual list of causes of venous thrombosis and pulmonary emboli. Underlying causes can be organized by pathophysiology into eight categories, as shown in Table 144-5 (Figs. 144-6, 144-7, and 144-8, nonblanching retiform purpura). Of note, although early lesions of cutaneous vasculitis typically blanch partially, occasionally patients with granulomatosis with polyangiitis (Wegener's) and microscopic polyangiitis may present with necrotic or retiform lesions without discernible erythema. Discussion of all occlusive syndromes is beyond the space limitations of this chapter, but two syndromes merit discussion because of frequent confusion in their use and definition: (1) disseminated intravascular coagulation (DIC) and (2) purpura fulminans. A newly recognized vasculopathy thought secondary to levamisole used to cut illicit cocaine typically presents with nonblanching retiform purpura and necrosis, typically involving ears and trunk or extremities (Fig. 144-8).82,83 Though associated with both antineutrophil cytoplasmic antibodies and antiphospholipid antibodies, and both vasculitic and thrombotic histologic findings are reported, early lesional findings seem most consistent with thrombotic vasculopathy, with secondary vasculitic changes (personal observation, author).

Disseminated Intravascular Coagulation

DIC is not a disease, but rather always secondary to an underlying disorder. The disorders most commonly associated with DIC are listed in Table 144-6.

DIC is characterized by systemic activation of coagulation, insufficiently controlled by natural anticoagulant mechanisms, in concert with clot lysis, leading to the intravascular deposition of fibrin in the (micro) vasculature and the simultaneous consumption of coagulation factors and platelets.84 In addition to evidence of clot formation, DIC is also defined by prolonged prothrombin and partial thromboplastin times (PT and PTT) as well as depleted fibrinogen. Elevated fibrin degradation products or d-dimers typically provide evidence of active clot lysis, although increased plasma soluble fibrin may be more specific. This combination can result in three clinical scenarios: (1) no clinical evidence of thrombosis or hemorrhage; (2) clinically evident thrombosis; or (3) simple bleeding into skin or tissues, including at from puncture sites. The pathogenetic pathways that play a role in the development of thrombosis include tissue factor-dependent activation of coagulation, defective physiologic anticoagulant pathways (such as the antithrombin system and the protein C system), and impaired fibrinolysis, caused by elevated levels of plasminogen activator inhibitor type 1.85 Therapeutic strategies are based on the pathogenesis of DIC (trauma, burns, postsurgical, sepsis). These include administration of anticoagulants and strategies to restore physiologic anticoagulant pathways (such as activated protein C concentrate or antithrombin III.84)

Purpura Fulminans

Purpura fulminans is a severe skin disorder typically associated with DIC that was first reported in children and infants.86 This term has been used by some to describe widespread cutaneous hemorrhage of any type in seriously ill patients. However, use of the term is best limited to neonatal, sepsis-related, and postinfectious syndromes associated with histologic evidence of small vessel thrombi, typically with clinical lesions of nonblanching retiform purpura or eschar.68,73

Purpura fulminans occurs in three clinical settings: (1) in relation to acute sepsis, (2) after infection, and (3) in neonates. Catastrophic antiphospholipid antibody syndrome is a mimic. In acute sepsis-associated or secondary purpura fulminans, the related overwhelming infection is most commonly meningococcal (see Chapter 181), but may be caused by many other Gram-positive and Gram-negative organisms. Patients are hypotensive with reduced peripheral perfusion, contributing to the skin necrosis on distal extremities and elsewhere (Fig. 144-6). Sometimes, skin necrosis occurs in a patchy distribution. Postinfectious purpura fulminans can manifest within 10 days of an antecedent illness, most commonly following streptococcal and/or varicella infections in children. Neonatal purpura fulminans is most often seen in association with homozygous protein C deficiency, in which massive intravascular thrombosis and abdominal wall gangrene can also develop.87

Pallor

Pallor of the mucocutaneous tissue is observed most readily in the palms, nail beds, face, and conjunctivae. In these areas, the microvascular bed is visible through the skin. Pallor is the result of lowered hemoglobin content. Among the multiple causes for pallor are acute and chronic hemorrhage, emotion, drugs (i.e., vasopressors), cold, shock, and pathophysiologic adjustments that lead to anemia. Cutaneous edema can also produce pallor. Successful treatment of the underlying etiology corrects the pallor as well.

Anemia

The definition of anemia depends on the patient's age and sex. The palmar creases are a good indicator of the severity of anemia. Unless the hemoglobin level drops below 7 g/dL, palmar creases appear pink.88 Constitutional signs and symptoms of anemia include malaise, fatigue, dizziness, postural hypotension, dyspnea on exertion, and tachycardia.

Anemias may be classified based on RBC volume as microcytic, normocytic, and macrocytic.89 Review of the blood smear may also reveal distinctive morphologic red cell changes, such as targeting, spherocytosis, red cell fragmentation, or poikilocytosis, which narrow the diagnostic possibilities. Laboratory evaluation should be based on the suspicion of the underlying cause of anemia. In addition to complete blood count with white blood cell differential and red cell morphology, iron studies (iron, total iron blood count, percent saturation of iron), ferritin, B12, lactate dehydrogenase (LDH), haptoglobin, folate levels, platelet and reticulocyte counts may be warranted based on initial laboratory evaluation.

Microcytic Anemias

Microcytic anemias are most often due to (1) iron deficiency, (2) anemia of chronic disease, (3) autoimmune hemolytic anemias, or (4) thalassemias. Of these, the first two are by far the most common.

Iron Deficiency

Sixty percent to 70% of the body stores of iron are in the RBCs in the form of hemoglobin.90 Heme-containing proteins are essential for metabolic processes in virtually all cells.91 Hemoglobin, myoglobin, and the cytochromes are heme-containing proteins and enzymes. The average life of an erythrocyte is 120 days, after which it is phagocytized by macrophages of the liver, spleen, and bone marrow. The iron is then stored in the form of ferritin to be recycled.

Iron deficiency anemia can result from increased iron demand in the setting of inadequate iron stores. This is most commonly seen during pregnancy, because increased blood volume is necessary for fetal growth and development.

Symptoms of iron deficiency include fatigue, headache, tinnitus, irritability, paresthesias, burning sensations of the tongue, akathisia (restless leg syndrome), and pica (the craving to eat substances such as dirt, clay, ice, laundry starch, salt, or cardboard).90 The physical findings of anemia in their approximate order of frequency include: pallor, glossitis (smooth red tongue), stomatitis, and angular cheilitis.68 Skin dryness and coarsening, brittle nails, and fine, dry hair may also occur. Blue sclerae and koilonychias (spooning of nails) are rare. Retinal hemorrhages or exudates may develop with severe anemia (hemoglobin <5 g/dL), and iron deficiency may accelerate proliferative retinopathy in diabetics. Generalized fatigue often disrupts the patient's ability to focus on daily activities at work, home, and school, resulting in poor performance.92

Anemia of chronic disease is a common finding in chronically ill patients. Associated laboratory features somewhat mimic those of iron deficiency anemia with mild microcytosis and low serum iron, but with normal (i.e., not elevated) serum iron-binding capacity and transferrin. In some cases, bone marrow biopsy to stain for iron stores may be required to assess iron status.91 This form of anemia appears to result from altered recycling of iron in chronic diseases states, and is not repaired by iron replacement. Appropriate diagnosis is important before beginning iron supplementation for microcytic anemia, since iron supplementation may worsen iron storage overload in patients with thalassemia.

Treatment of iron deficiency anemia requires replacing lost iron and maintaining the daily iron dietary requirement. The recommended daily dose for treatment of iron deficiency is between 150 to 200 mg/day of elemental iron (325 mg ferrous sulfate = 65 mg of elemental iron), usually continued until the hemoglobin reaches a normal value.52

Macrocytic Anemia

Megaloblastic anemia is classified as a macrocytic anemia characterized by enlarged erythroid precursor cells. There are numerous etiologies for macrocytic anemia; folate and cobalamin (vitamin B12) deficiency are the most common. Folate and vitamin B12 deficiencies are distinguishable by their noncutaneous clinical presentations (see below), but not by hematologic findings. Their deficiency leads to impaired purine and pyrimidine synthesis, preventing normal DNA replication. The macrocytic cells are a result of nuclear-cytoplasmic asynchronization.

Vitamin B12 is found only in meat and dairy products, making vegetarians prone to deficiency.93 In nonvegetarian populations (especially of Scandinavia, Turkey, and Israel), vitamin B12 deficiency is caused by a rare genetic disorder of malabsorption, the Imerslund–Grasbeck syndrome. Pernicious anemia (PA) is the most common cause of vitamin B12 deficiency. It is an autoimmune disorder that attacks intrinsic factor in the ileum, which is essential to absorb vitamin B12. The second cause of PA, chronic atrophic gastritis, results in autoantibodies against gastric parietal cells, which produce intrinsic factor.

Folate is found in animal products and in green leafy vegetables. Its deficiency is usually attributed to dietary inadequacy, alcohol abuse, malabsorption, and drugs that interfere with folate metabolism, i.e., methotrexate, phenytoin, trimethoprim. The demand for folate by the placenta and fetus usually doubles. Therefore, it is now standard care to give prophylactic folic acid supplements to all pregnant women to reduce the risk of neural tube defects in newborns.94 Exfoliative skin disease and hemolysis can also lead to folate deficiency due to increased demand. Hereditary folate malabsorption results in impaired folate transport in the gastrointestinal tract and the blood–brain barrier.

Clinical findings of megaloblastic anemia develop slowly and vary, depending on the level of hemoglobin concentration and the etiology. The commonly shared signs and symptoms are malaise, fatigue, palpitation, glossitis, shortness of breath, and light-headedness. Mild jaundice can also be seen when ineffective erythropoiesis leads to hyperbilirubinemia and this, combined with anemic pallor, may lead to a characteristic lemon-yellow skin color. Hyperpigmentation is common in vitamin B12- and folate-deficient patients, especially skin types III–VI. Patients with PA may also develop vitiligo or Hashimoto thyroiditis.95 Hyperpigmentation is a common cutaneous manifestation of vitamin B12 deficiency.96 The hyperpigmentation is usually prominent on the knuckles of the hands and feet, especially in darkly pigmented individuals.97

Neurologic findings in vitamin B12 deficiency, but not folate deficiency, help to clinically distinguish between the two causes of megaloblastic anemia.93,94 Memory loss, dementia, tremor, Lhermitte's sign, irritability, atrophic glossitis, and neuropathy may occur. Specifically, patients with vitamin B12 deficiency develop subacute combined degeneration of the dorsal and lateral spinal columns—paresthesia (initial presentation), loss of vibration and position sense, shuffling gait, ataxia, spasticity, and paraplegia. The signs are symmetric in presentation and affect the lower extremities more than the upper extremities.

Typically, patients with folate deficiency are malnourished and often have diarrhea. Patients with alcoholism are prone to folate deficiency. Another distinguishing marker is that vitamin B12 deficiency takes many years to occur, given the large liver stores. Folate deficiency, on the other hand, can occur in a few months.

Correcting the underlying etiology usually resolves the anemia and reverses the signs and symptoms. Vitamin B12 is best administered parenterally. Prophylactic folic acid supplementation of 400 μg/day is recommended for all women of childbearing age. In folate-deficient patients, 1–5 mg/day of oral folic acid is recommended with subsequent maintenance therapy.

Anemia of Endocrine Disorders

Panhypopituitarism, hypothyroidism, and Addison disease are the most common endocrine disorders in association with anemia, although anemia may occur in hyperthyroidism and gonadal disease as well (see Chapter 151).

Flushing

Differential Diagnosis

Flushing occurs as a result of cutaneous vasodilation, and when associated with sweating is mediated through the sympathetic cholinergic fibers (Box 144-1; see Chapter 151).

Polycythemia Vera

The hallmark cutaneous finding of polycythemia vera (PV) is ruddy cyanosis and plethora. Other skin findings are aquagenic pruritus, neutrophilic dermatosis, pyoderma gangrenosum, and purpura. Acrocyanosis is seen in conditions with elevated hemoglobin levels, but deoxygenated blood through the dilated vessels in the skin. Increased red cell mass is either a direct result of compensation for hypoxia or from primary disorders such as PV. These changes lead to an increase in blood viscosity and vascular volume, resulting in a hypercoagulable state, especially when associated with thrombocytosis, and occasionally paradoxical hemorrhage from platelet dysfunction.98

Other symptoms are headache, paresthesia, and erythromelalgia. Erythromelalgia is a syndrome of altered acral responses, resulting in erythema and burning pain, especially when triggered by touching a warm object.99 In myeloproliferative diseases, this syndrome is most probably secondary to platelet abnormalities, and may result in microvascular occlusion and necrotic lesions in affected areas. The catastrophic symptoms include large vessel arterial cerebrovascular (stroke) or cardiovascular (myocardial infarction) events, and peripheral arterial occlusion. PV has an unusually high incidence of portal and hepatic vein thrombosis (Budd–Chiari syndrome), lower extremity deep venous thrombosis, leg ulcers, Raynaud phenomenon, and pulmonary emboli. Bleeding manifestation is assumed to be a direct cause of dysfunctional platelets or von Willebrand disease. Defective primary hemostasis manifests with ecchymosis, menorrhagia, epistaxis, gingival hemorrhage, and, less frequently, gastrointestinal hemorrhage. Risk factors for PV are age (more than 60 years of age), history of thrombosis, cardiovascular risk factors (hypertension, smoking, hypercholesterolemia, diabetes), hereditary and acquired thrombophilic states (congenital deficiency of anticoagulants: antithrombin III, protein C and S; genetic mutation in factor V Leiden, prothrombin G20210A, or methylenetetrahydrofolate reductase), and acquired conditions (anticardiolipin antibodies and/or lupus anticoagulants).98

Diagnosis of PV has been greatly simplified in most cases by the ability to test for the JAK2617F mutation present in 95% of all patients.100

There is no specific therapy for PV. Treatment is directed toward preventing thrombohemorrhagic episodes and progression to myelofibrosis or leukemia. Aspirin may be of minor help in preventing thrombosis. Those not benefiting symptomatically from aspirin usually require platelet cytoreduction, (hydroxyurea, busulfan, radioactive phosphorus, chlorambucil, interferon) or anagrelide to inhibit platelet function. Phlebotomy is useful in controlling red cell mass, but may exacerbate thrombocytosis or leukocytosis.100

Cyanosis

Cyanosis refers to discoloration of the mucocutaneous tissue that results in a blue or purple tinge, particularly in the peripheral tissues such as lips, ears, and nail beds. Central cyanosis refers specifically to the lingual and sublingual regions, and is more reflective of reduced hemoglobin in the blood; in peripheral cyanosis (skin, hands, feet, earlobes, etc.), the cause is often vasoconstriction. Cyanosis may be difficult to detect and is often missed on physical examination. Many factors, including natural skin pigment, thickness of the skin, and blood flowing through the cutaneous capillaries, determine the degree of cyanosis.

Cyanosis is detectable when at least 5 g of deoxygenated hemoglobin are circulating in the capillary blood, which correlates with an arterial concentration of deoxygenated hemoglobin of 3.4 g/dL. A patient with severe anemia of less than 7 g/dL Hg may never manifest cyanosis because they may become fatally hypoxic long before they reach 5 g/dL of desaturated hemoglobin, whereas a patient with PV frequently manifests ruddy cyanosis because the total increased hemoglobin content of their blood allows adequate oxygenation of tissue despite reaching the 5g/dL level at which the cyanosis becomes clinically evident (Box 144-2). Fluorescent light is best for detecting cyanosis. The diagnostic workup for a complete assessment of cyanosis includes complete blood cell count, arterial blood gas, pulse oximetry, partial arterial pressure of oxygen (PaO2) level, and arterial oxygen saturation. If cyanosis is positional, an intracardiac mass must be considered.24

The causes of cyanosis are broad, but best if characterized into two groups: (1) disorders involving deoxygenated hemoglobin and (2) disorders of abnormal hemoglobin.101,102 The latter includes acquired and inherited methemoglobinemia, sulfhemoglobinemia, and low oxygen-affinity hemoglobin. Methemoglobinemia causes clinically discernible cyanosis when the absolute level of methemoglobin exceeds 1.5 g/dL; this correlates with approximately 10%–15% methemoglobin. Offending agents are nitrates (found in drinking water, drugs, and food), topical anesthetic agents (lidocaine, benzocaine, and prilocaine), drugs (i.e., dapsone, phenazopyridine, sulfamethoxazole), and aniline dyes. Congenital methemoglobinemia is caused by deficiency in nicotinamide adenine dinucleotide (reduced form)–cytochrome b5 reductase.103 Treatment of choice for methemoglobinemia is intravenous methylene blue. Methylene blue should not be administered to patients with glucose-6-phosphate dehydrogenase deficiency. 104 If methylene blue is contraindicated, ascorbic acid can be given. RBC exchange transfusion has also been reported to be an effective treatment in symptomatic methemoglobinemic patients with coexistent glucose-6-phosphate dehydrogenase deficiency (see Chapter 225).

Sulfhemoglobin in concentrations greater than 0.5 g/dL in capillary blood also causes cyanosis, and cannot be reversed. Medications (especially sulfonamides, phenacetin, acetanilide, and phenazopyridine are the usual causes, but this condition has occurred independent of drug use in association with chronic constipation and purging. Offending agents in cases of acquired methemoglobinemia should be discontinued. No other therapy may be required. But if the patient is symptomatic, methylene blue, 1–2 mg/kg over 5 minutes, provides an artificial electron acceptor for the reduction of methemoglobin via the NADPH-dependent pathway. Response is usually rapid; the dose can be repeated in 1 hour, but frequently this is unnecessary. Caution should be exercised to avoid an overdose because large (more than 7 mg/kg) cumulative doses have been reported to cause dyspnea, chest pain, and hemolysis. Because co-oximetry detects methylene blue as methemoglobin, it cannot be used to monitor methemoglobin levels after treatment with methylene blue; however, the specific Evelyn-Malloy method allows for the discrimination of methemoglobin from methylene blue. Sulfhemoglobinemia occurs as sulfur binds to hemoglobin, resulting in irreversible deoxyhemogobinemia. It produces cyanosis at levels of only 0.5-g/dL capillary blood. Etiologies are drugs (sulfonamides, phenacetin, acetanilide, and phenazopyridine), constipation, and purging.

Low oxygen hemoglobin affinity occurs at altitude of 5,000 m (16,000 ft) or higher and can cause hypoxemia severe enough to result in cyanosis. Emotion, cold exposure, Raynaud phenomenon, and cryoglobulins (cold agglutinins) are some nonhematologic causes of peripheral cyanosis.

Disorders involving deoxygenated hemoglobin include congenital heart defects in the newborn (i.e., transposition of the great vessels, tetralogy of Fallot, and Ebstein's anomaly). X-linked dyskeratosis congenita presents with abnormal pigmentation, telangiectasias, nail dystrophy, leukoplakia; rarely, arteriovenous fistulas with central cyanosis occur. Arteriovenous fistulas are a feature of Osler–Weber–Rendu syndrome as well. Other disorders of the central nervous system, respiratory tract, and musculoskeletal and circulatory systems can also disrupt the oxygen supply to the tissues.

Jaundice

Jaundice (icterus) refers to the yellowish discoloration of the skin, caused by elevated bilirubin levels. The discoloration is a direct result of the bile pigment that stains the skin, suggesting an abnormality in bilirubin clearance or increased production due to hepatobiliary disease (see Chapter 150) or a hemolytic disorder. Kernicterus or permanent damage to the neonatal brain associated with hyperbilirubinemia is a serious risk.

Infiltrative Lesions

Extramedullary Hematopoiesis

Synthesis of blood elements outside the bone marrow usually takes place in the spleen and liver but can also affect the skin. The dermis is a normal site of hematopoiesis during early fetal development. Cutaneous lesions of extramedullary hematopoiesis include nodules (can be sclerosing), ulcers, erythematous papules, violaceous plaques, and diffusely erythematous induration. Neonates with dermal hematopoiesis present as blueberry muffin babies with dark blue-colored to violaceous nodules. In neonates, the causes are erythroblastosis fetalis, chromosomal abnormalities, infections, congenital hemolytic anemia, thalassemia, and twin-to-twin transfusion.105 Older individuals may show dermal hematopoiesis from hemolytic anemias, myeloproliferative syndromes such as chronic idiopathic myelofibrosis and PV, thalassemia, and osteoporosis. The histologic findings are intradermal proliferation of immature granulocytes, megakaryocytes, and erythroid and myeloid precursor cells.

Leukemia Cutis

Leukemia cutis (LC) is a localized or disseminated skin infiltration by leukemic cells. It is usually a sign of dissemination of systemic disease or relapse of existing leukemia. Reported incidence varies from less than 5%–40%, depending on the type of leukemia, both acute and chronic, including the leukemic phase of non-Hodgkin lymphoma and hairy cell leukemias. It most commonly occurs with acute monocytic leukemia (AML-M5) and acute myelomonocytic leukemia (AML-M4).

Pattern of presentation of skin lesions in LC is variable and may have features that overlap with other (inflammatory) eruptions. Most common lesions are small (2–5 mm) papules (Figs. 144-9 and 144-10), nodules (Fig. 144-11), or plaques. LC lesions are usually somewhat more pink, violaceous, or darker than normal skin, always palpable, indurated, firm, or guttate psoriasiform or lymphomatoid papulosis-like lesions, but usually not tender. They are localized or disseminated; usually on trunk (Fig. 144-9), extremities, and face (Fig. 144-10), but may occur at any site. They may be hemorrhagic when associated with thrombocytopenia or may ulcerate. Erythroderma may (rarely) occur. Leukemic gingival infiltration (hypertrophy) occurs with acute monocytic leukemia. Similar lesion morphologies occur with different types of leukemia or specific types of leukemia may present with a variety of morphologies.

Inflammatory disorders occurring in patients with leukemia are modified by the participation of leukemic cells in the infiltrate, resulting in unusual presentations of such disorders (e.g., psoriasis with hemorrhage or erosions/ulcerations). Also, there are a number of cutaneous inflammatory diseases that may be associated with leukemia: Sweet syndrome (see Chapter 32), bullous pyoderma gangrenosum (see Chapter 33), urticaria (see Chapter 38), and necrotizing vasculitis (see Chapter 163).

Systemic symptoms are those associated with hematologic malignancy. Not infrequently, cutaneous manifestation may be the initial presenting symptom and may contribute importantly to the diagnosis.

The diagnosis is made by suspicion and verified by skin biopsy, immunophenotyping, and B- or T-cell receptor rearrangement studies. Hematologic studies with complete analysis of bone marrow aspirate and peripheral blood smear are then needed to make the diagnosis. If cutaneous findings precede any systemic disease, careful assessment of peripheral blood smears and bone marrow biopsies must be made.

The prognosis of LC is directly related to the prognosis for systemic disease. Therapy is usually directed at the leukemia itself.