✅ Ddx: Anemias, Transfusion reaction, Leukemia Flashcards

Question

Sickle cell Disease

Answer 1

**Hx:** Seen in persons of African, Middle Eastern, Mediterranean, or Indian ancestry; vasoocclusive crisis (acidosis, hypoxemia, dehydration, acute chest syndrome, acure brain, priapism) **Dx:** Serum ferritin and transferrin saturation are usually **normal**. Hgb electrophoresis shows predominantly **Hgb S** but also variable amounts of **Hgb A (5%-30%),** an increased percentage of **Hgb A2 (\>3.5%)**, and a normal to variably increased percentage of **Hgb F (2%-10%).** Smear shows sickled cells **Tx:** **Hydroxyurea**, a chemotherapy agent used in SCD to decrease the frequency of vaso-occlusive pain crises. Hydroxyurea works by further increasing the amount of HbF in circulation, which dilutes the number of sickled cells in circulation and reduces vaso-occlusive episodes, the need for transfusions, and episodes of acute chest syndrome. Although patients with SCD typically have **HbF concentration 5%-15%,** those with SCD on hydroxyurea will often have **HbF \>15%**. This elevation in HbF also explains the slightly lower HbS concentration seen in this patient (compared to a patient with SCD not on hydroxyurea). **Cx:** the major adverse effect of hydroxyurea is **myelosuppression**. Any myelosuppression is generally reversible with discontinuation of the medication but may predispose the patient to infection. **IVF, O2 and pain control** in crises; exchange transfusion; deferoxamine in cases of iron overload). **Cx:** **Acute chest syndrome** is established by identifying an infiltrate on chest radiographs that involves at least one lung segment and that is not thought to be due to atelectasis; associated findings include one or more of the following: **chest pain; temperature less than 38.3°C (100.9°F); tachypnea, wheezing, cough, or the development of increased work of breathing** (such as retractions); and **hypoxemia** relative to baseline oxygen saturation values. **Aplastic crisis** can occur when patients with chronic hemolytic anemia and shortened erythrocyte survival are infected with parvovirus B19, which leads to suppression of erythrocyte production (red blood cell aplasia) and the inability to maintain erythrocyte production needed to replace the hemolyzed cells, as reflected in her very low reticulocyte count. **Dx**: Confirmation may be obtained by demonstrating IgM antibodies against parvovirus B19 or polymerase chain reaction studies detecting parvovirus B19 DNA. **Splenic autoinfarction** Thus, more susceptible than other patients to infection with encapsulated organisms, such as Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis. 💉 Vaccination with the conjugated **S pneumoniae** vaccine decreases the incidence of invasive infections caused by this organism. Twice daily administration of prophylactic ✏ **penicillin** should also be given to **👶🏽**children with sickle cell disease **until they reach five years of age.** **AVN**: Repeated vaso-occlusive crises lead to infarcts and degeneration in marrow-containing bone. AVN has a high likelihood of progressing to femoral head collapse, necessitating surgical intervention with decompression or possibly joint replacement.

Answer 2

**Hx:** Common forms of G6PD deficiency usually cause only episodic moderate hemolysis, precipitated by oxidant drugs or infection. ❗ Avoid * Diaminodiphenyl sulfone (**dapsone**) * Isobutyl nitrite * **Nitrofurantoin** * Primaquine * Rasburicase Use with caution * Acetaminophen * Acetylsalicylic acid (aspirin) * Chloramphenicol * Chloroquine * Colchicine * Diphenhydramine (Benadryl) * Glyburide * Isoniazid * L-dopa * Quinine * Sulfamethoxazole * Trimethoprim * Vitamin K **Dx:** G6PD level (best)[6-8wk post attack]; Blood smear: findings include bite cells, spherocytes, heinz bodies, and minimal abnormalities of erythrocytes other than polychromasia (from reticulocytosis). **Hyperbilirubinemia** - heme is catabolized to bilirubin, which causes scleral icterus and jaundice **Hemoglobinuria** – heme is excreted in the kidneys, which causes dark-colored urine and a false-positive urine dipstick for blood (the heme in hemoglobin causes a positive urine dipstick test, but no erythrocytes are seen on urine microscopy) **Tx:** supportive Pyruvate kinase deficiency is rare and causes moderately severe anemia; blood smear shows acanthocytes

Answer 3

Chronic or episodic hemolysis. Hgb A2 level is increased with β-thalassemia; Hgb F also may be increased. No structural Hgb abnormality is detectable with α-thalassemia; diagnosis is based on hematocrit, MCV, blood smear, and family study. Abnormal Hgbs (eg, E and D) are uncommon in the United States. Blood smear changes suggest certain hemoglobinopathies; Hgb electrophoresis reveals the abnormal Hgb

Answer 4

TTP usually presents as neurologic symptoms and severe fragmentation anemia and thrombocytopenia. With HUS (children), kidney abnormalities predominate, and anemia and thrombocytopenia are milder. In other causes of microangiopathic anemia (DIC, malignant hypertension, scleroderma renal crisis), the anemia and thrombocytopenia are usually mild to moderate; these disorders are diagnosed by peripheral blood smear in the proper clinical context

Answer 5

Symptoms of infection, particularly fever, usually dominate. Splenomegaly is the rule with malaria; babesiosis usually produces a milder malaria-like illness, unless patients are asplenic. Finding intraerythrocytic parasites on blood smear is diagnostic

Answer 6

Splenomegaly (any cause) can cause hemolysis; hypersplenism may also decrease the number of leukocytes, platelets, or any combination of cell lines. Hypersplenism produces no erythrocyte morphologic changes in erythrocytes, but the blood smear may show changes related to the underlying cause (eg, target cells with liver disease)

Answer 7

Seen in various disorders associated with ineffective erythropoiesis, including thalassemia.

Answer 8

PNH is an autoimmune **hemolytic** disorder characterized by intravascular and extravascular hemolysis and hemoglobinuria. The disease is due to an acquired genetic defect that results in lack of the glycosylphosphatidylinositol anchor, which connects proteins, including **CD55** and **CD59**, to the cell surface. These proteins normally inhibit the activation of complement on red blood cells, but their absence allows the **complement membrane attack complex to form** and results in hemolysis. On average, patients have manifestations in the fourth decade of life resulting from one of the following: * **Hemolysis** leading to **hemoglobinuria (dark urine; fatigue)** * **Cytopenias** - fatigue and dyspnea from anemia * **Hypercoagulable state** (eg, portal vein thrombosis) - acute abdominal pain that may be due to severe hemolysis or portal vein thrombosis **Dx:** Anemia and **low haptoglobin** accompanied by **elevated 🔰 bilirubin** and **LDH** are all consistent with intravascular Nocturnal (hypoxemia and acidosis) **Flow cytometry** tests are used to confirm the diagnosis by assessing for the absence of the CD55 and CD59 proteins on the surface of the red blood cells. **Tx:** Supportive; Eculizumab **Cx:** Patients with autoimmune hemolytic anemia have a tendency for **venous thromboembolism**, but those with PNH are at particular risk, especially within intraabdominal or cerebral veins.

Answer 9

Iron overload should be considered among patients who present with any one or a combination of the following: hepatomegaly, weakness, hyperpigmentation, atypical arthritis, diabetes, impotence, unexplained chronic abdominal pain, or cardiomyopathy. Diagnostic suspicion should be particularly high when the family history is positive for similar clinical findings. The most frequent cause of iron overload is the common genetic disorder, idiopathic hemochromatosis. Secondary iron storage problems can occur after multiple transfusions in a variety of anemias. The most practical screening test is the determination of serum iron, transferrin saturation, and ferritin. T ransferrin saturation greater than 50% in males or 45% in females suggests increased iron stores. Substantially elevated serum ferritin levels confirm total body iron overload. Genetic screening is now used to assess which patients are at risk for severe fibrosis of the liver. Definitive diagnosis can be established by liver biopsy. Determination of serum copper is needed when Wilson disease is the probable cause of hepatic abnormalities. Wilson disease does not cause hypogonadism, heart failure, diabetes, or arthropathy. Chronic liver disease caused by hepatitis B would not account for the heart failure, hyperpigmentation, or diabetes. Nocturnal penile tumescence and echocardiogram can confirm clinical findings but will not establish the underlying diagnosis.

Answer 10

Von Willebrand factor plays a critical role in platelet adhesion to injured vessels. It also functions as a carrier for factor VIII. Disorders of secondary hemostasis can occur due to low factor VIII levels in vWD **Hx:** Patients have mild to moderate bleeding evidenced by nosebleeds, heavy menstrual flow, gingival bleeding, easy bruising, and bleeding associated with surgery or trauma. **Dx:** The aPTT is dependent on factor VIII activity. Platelet aggregation does not detect abnormal adhesion; vWF level and ristocetin cofactor are abnormal. Ristocetin cofactor is a platelet aggregation study measuring the function of vWF. The structure of vWF can be determined by a vWF multimer assay Diagnostic testing includes a PFA (although this may be normal in mild cases), vWF antigen level, vWF activity assay, factor VIII level (which may also be normal in mild cases), and a multimer study used to diagnose subtypes of vWD **Tx:** Desmopressin releases stored vWF and factor VIII from endothelial cells and is used as first-line therapy for most subtypes of vWD. Intermediate-purity factor VIII concentrates, which contain vWF, can also be given. Cryoprecipitate is rich in vWF but carries the risk of transfusion-transmitted infection.

Answer 11

**Disorders of primary hemostasis,** such as platelet-related bleeding, tend to occur immediately after injury and often affect the mucous membranes or the skin in the form of petechiae. **Disorders of secondary hemostasis**, such as coagulation-related bleeding, may be delayed in onset and manifested more by deep tissue bruises (ecchymoses) and may produce hemarthroses in patients with congenital factor deficiencies.

Answer 12

Inheritance * X-linked recessive Clinical features * Delayed/prolonged bleeding after mild trauma * Hemarthrosis, intramuscular hematomas * Gastrointestinal or genitourinary tract bleeding * Intracranial hemorrhage * Complications: hemophilic arthropathy Laboratory findings * ↑ Activated PTT * Normal platelet count & PT * Absent or ↓ factor VIII (hemophilia A) or factor IX (hemophilia B) activity Treatment * Factor replacement * Desmopressin for mild hemophilia A Disorder of secondary hemostasis X-linked recessive bleeding disorder caused by deficiency of **Factor VIII (hemophilia A)** or **Factor IX (hemophilia B)**. Disease severity varies based on degree of factor activity. Often, patients present with joint pain and swelling following little or no trauma due to spontaneous bleeding into a joint (hemarthrosis). Recurrent hemarthroses can result in long-term complications such as hemophilic arthropathy. **Hx: Hemarthrosis** presents with joint pain and swelling after minimal or no trauma, and episodes typically begin during toddlerhood when the child is ambulatory. Hemorrhage into the skeletal muscle (ie, **hematoma**) after minor trauma is also common. Hemophilic arthropathy refers to joint damage caused by intra-articular bleeding. **Hemosiderin deposition** within the joint triggers synovial inflammation, which leads to fibrosis and destruction of cartilage and bone. Chronic, worsening joint pain and swelling are accompanied by limited mobility on examination. Although severe hemophilic arthropathy may be visible on x-ray, MRI allows for earlier detection and characterization of the degree of joint damage. Early prophylaxis with factor concentrates can significantly reduce the risk of developing arthropathy. **Dx:** Normal prothrombin time (PT) and prolonged activated partial thromboplastin time (aPTT) that fully **corrects** on mixing with a 1:1 ratio of normal plasma (as opposed to the presence of an **inhibitor, such as to factor VIII, which does not correct on a mixing study).** Laboratory findings in hemophilia A and B are indistinguishable. **Tx:** Replacement of the deficient factor is the treatment of choice. Desmopressin for Hemophilia A.

Answer 13

Pseudothrombocytopenia is a laboratory error caused by platelet aggregation *in vitro*. Most cases are due to incompletely mixed blood samples or the presence of serum antibodies to ethylenediaminetetraacetic acid (EDTA), an anticoagulant used in hematologic testing. The error is generally identified when a patient with mild thrombocytopenia has peripheral blood smearevidence of large **clumps of platelets**. **Dx:** Drawing blood samples in **tubes with a non-EDTA anticoagulant (eg, heparin, sodium citrate) normalizes the automated platelet count and confirms the diagnosis.** Because patients with pseudothrombocytopenia do not have true thrombocytopenia, they do not require intervention or monitoring.

Answer 14

**Type 1 HIT** is marked by **nonimmune-mediated platelet aggregation**. It results in mild thrombocytopenia (platelets rarely \<100,000/mm3), usually within 2 days of heparin initiation. Type 1 HIT does not require intervention and does not cause ill effects; the thrombocytopenia resolves without cessation of heparin. Heparin induces a conformational change to a platelet surface protein (platelet factor 4 [PF4]), which exposes a neoantigen. In patients with **type 2 HIT**, the ✨**immune system** responds by forming an IgG autoantibody (HIT antibody) that then coats the surface of platelets and forms complexes (heparin-PF4-HIT antibody), resulting in: **Thrombocytopenia** - the reticuloendothelial system (largely the spleen) removes antibody-coated platelets, causing a mild to moderate thrombocytopenia (rarely \<20,000/mm3). **🔴Arterial AND 🔵_venous_ thrombus** - HIT antibodies activate platelets, resulting in platelet aggregation and the release of procoagulant factors. The risk of thrombus is as high as 50% in untreated HIT. In patients receiving **subcutaneous** **heparin** (eg, enoxaparin), a classic thrombotic complication of HIT is **skin necrosis** at the abdominal injection site. Typically, type 2 HIT manifests with a \>50% drop in platelets **5-10 days after the initiation of heparin**, but it may occur earlier (sometimes \<1 day) in patients previously exposed. **Hx:** HIT occurs in approximately **5% of patients treated with☝ unfractionated heparin** for 5 or more days but develops in only about 1% of patients treated with 👇 **low-molecular-weight heparin.** **Dx:** The criteria for diagnosing HIT include: (1) thrombocytopenia (defined as a platelet count **\<150,000/µL** OR a **50% decrease in the platelet count from baseline)** in the presence of current heparin administration or its use **over the past 3 months**; (2) exclusion of other causes of thrombocytopenia; (3) reversal of thrombocytopenia on cessation of heparin. HIT is diagnosed by **immunoassay** (only if high titer) or **functional assay** (eg, serotonin release assay [gold standard]). 4T's for the diagnosis of HIT: **T**iming Thrombosis - **5-10 days (+2)**, \>10 days (+1), \<5 days (0) **T**hrombosis - **New**, progressive or recurrent, None **T**hrombocytopenia - **\>50%**, 30-50%, \<30% al**T**ernative, **None**, acceptable, Clear **Tx:** Lepirudin; Once HIT is detected or even suspected, heparin must be stopped immediately and an alternative rapidly acting anticoagulant begun with a nonheparin medication (eg, 🐊**argatroban**, fondaparinux). Warfarin is used for anticoagulation maintenance in patients with HIT but only after the patient has received another anticoagulant and the platelet count is \>150,000/mm3. **All heparin products**, including low molecular weight heparin, **should be avoided** in patients with HIT. **Cx:** The most serious complication of HIT is a **_thrombotic event_**, triggered by a number of mechanisms including **release of procoagulant agents from platelets and endothelial activation. _Venous thromboses_** are most common (about two thirds of events), but arterial thromboses also occur and can be life-threatening.

Answer 15

Epidemiology * Commonly **acquired** form of thrombocytopenia * **Autoantibody** formation * Often recent viral infection or comorbidity (eg, HIV, HCV, CLL) Manifestations * Frequently asymptomatic * **Mucocutaneous bleeding** (eg, menorrhagia, epistaxis) * Ecchymoses, petechiae, purpura * Severe hemorrhage is rare Laboratory findings * **Isolated thrombocytopenia** \<100,000/mm3 * Few platelets (size normal to **large**) on peripheral smear Treatment * Children * Observe if cutaneous symptoms only * Glucocorticoids, IVIG, or anti-D if bleeding * Adults * **Observation** if cutaneous symptoms **AND platelets ≥30,000/mm³** * Glucocorticoids, IVIG, or anti-D if **bleeding OR platelets \<30,000/mm3** Immune thrombocytopenia (ITP) is an autoimmune disorder in which IgG antibodies form against platelet membrane proteins, resulting in isolated thrombocytopenia. **Hx:** Clinical findings may include signs or symptoms of mild to severe **bleeding**. Isolated (extreme) thrombocytopenia in the absence of systemic disease, or a causative drug defines the idiopathic form of ITP. Variants of ITP may be drug induced or part of a broader illness of abnormal immune regulation, such as systemic lupus erythematosus, HIV infection, or lymphoproliferative malignancies. **Dx: 🔴Platelets may be large** because they typically have recently been released from the bone marrow. Increased megakaryocytes on bone marrow evaluation (marrow evaluation is usually not required for diagnosis in the absence of other features listed for bone marrow disorders). Diagnosis of exclusion. **Tx:** **Observation alone** if asymptomatic Most cases of ITP **self-resolve** within 3 months; however, some patients continue to have platelets **\<100,000/mm³** for \>1 year, which is known as **chronic ITP.** Therapy may be required for **those with platelet counts lower than 30,000 to 40,000/µL** or if **bleeding** is present. Combination of glucocorticoids, anti-D immune globulin (if Rh-positive and Coombs-negative), and/or intravenous immunoglobulin for bleeding episodes. 🌑 **Glucocorticoid/Corticosteroids**, IVIG, rhogam, splenectomy, rituximab. **Anti-D immune globulin** is a potential first-line therapy for ITP in patients with the ➕ **Rh antigen**. Anti-D binding to Rh(D)-positive erythrocytes is thought to saturate Fc receptors on macrophages within the reticuloendothelial system (RES), thereby limiting the ability of the RES to clear platelets. **Chronic ITP** Patients with beeding and thrombocytopenia requiring repeated pharmacologic interventions and should be considered for s**econd-line therapies (eg, rituximab, thrombopoietin receptor agonists) or 🔪splenectomy**. Although not without risk (eg, sepsis, thrombosis), splenectomy removes the source of platelet destruction and is often curative in patients with ITP. **❗Platelet transfusions** are reserved for **life-threatening hemorrhage** in patients with ITP because antibody production destroys the transfused platelets. In contrast, this patient's bleeding is limited to mucocutaneous.

Answer 16

**Idiopathic thrombocytopenia purpura (ITP)** is usually diagnosed after excluding other possible causes of thrombocytopenia based on history, physical examination, complete blood count, and peripheral blood smear. Thrombocytopenia can be due to increased platelet destruction, decreased platelet production, dilutional, or splenic sequestration. Thrombocytopenia may be the presenting finding in up to 5%-10% of patients with **chronic HIV infection**. Therefore, all patients with presumed ITP should be tested for **HIV** and **hepatitis C** virus as platelet counts can be affected by treating the underlying disease. Bone marrow biopsy may be required in patients with negative tests and unexplained thrombocytopenia.

Answer 17

A life-threatening disorder of the microvasculature characterized by the formation of small vessel **thrombi** that consume platelets, shear red blood cells, and often cause end organ damage (primarily renal and central nervous system). A pathologic process characterized by abnormal activation of platelets and endothelial cells, deposition of **fibrin in the microvasculature**, and peripheral **destruction of erythrocytes and platelets**. **Hx:** TTP is typically a disease of young adults (unlike hemolytic uremic syndrome, which primarily affects children) and is often idiopathic but may be triggered by infections (eg, **HIV, HEP C**), malignancy, or medications. TTP should be suspected in patients who have: Increased levels of indirect **bilirubin, aspartate aminotransferase [AST], alanine aminotransferase [ALT], and lactate dehydrogenase,** with a reticulocyte count \>2.5% should always raise suspicion for TTP. ***Hyaline*** clots Pentad * **F**ever * **Anemia** (Microangiopathic hemolytic anemia)**[MAHA]** * **T**hrombocytopenia (nonimmune) * **R**enal Failure * **N**eurologic symptoms (headache, confusion, sleepiness, coma, seizures, and stroke) Not all patients have the full pentad; the essential features are the **red blood cell fragmentation** (❗**schistocytes** and **helmet cells**) and the **thrombocytopenia**. TTP is usually due to an acquired autoantibody to ADAMTS13, a plasma protease that cleaves von Willebrand factor (vWF) off the endothelial surface. As **ADAMTS13** levels fall (due to the antibody), vWF multimers accumulate on the endothelial wall, trapping platelets at areas of high shearing force (eg, small arterioles, capillaries) and leading to the formation of thrombi. **Dx:** A **peripheral blood smear** is essential to determine whether the anemia is caused by a microangiopathic hemolytic process, as indicated by the presence of **schistocytes** on blood smear. Also see **elevated serum LDH 🥛 (60-100) [\>100]** level and **decreased haptoglobin (50-150) [\<50]** concentration. **Tx:** ❗**Plasma exchange** (with the infusion of fresh frozen plasma to provide the missing ADAMT S 13 protein) should be instituted **emergently** at diagnosis because 10% of patients die of this disease despite therapy. **Cx:** **🦍 Hemolytic uremic syndrome (HUS)** often associated with Shigatoxin-producing strains of E coli O157:H7), is similar but is usually **NOT** accompanied by 🧠 CNS changes. Shiga-like toxin is destructive against small blood vessels such as those found in the digestive tract and the kidneys; one specific target for the toxin is the vascular endothelium of the glomerulus, causing cell death, breakdown of the endothelium, hemorrhage, and activation of platelets and inflammatory pathways resulting in intravascular thrombosis and hemolysis. **HUS** is characterized by ❗ **more severe renal involvement (hematuria, elevated serum creatinine levels, and proteinuria)**; primarily a disease of children.

Answer 18

Late pregnancy complication of thrombocytopenia associated with microangiopathic hemolytic anemia, and elevated liver enzymes, and hypertension. **(H**emolysis, **E**levated **L**iver enzymes, **L**ow **P**latelets**)**

Answer 19

Major causes * Sepsis * Severe **traumatic injury** ****Traumatic injury increases the risk of DIC due to endothelial (exposes tissue factor) and tissue damage (releases procoagulant proteins and phospholipids); other common causes of DIC include sepsis, malignancy, and obstetrical complications. * Malignancy * Obstetric complications Pathophysiology * Procoagulant excessively triggers coagulation cascade → * Formation of fibrin-/platelet-rich thrombi & fibrinolysis → * Bleeding & organ damage (eg, kidneys, lungs) Laboratory findings * Thrombocytopenia * Prolonged PT & PTT * ↓ Fibrinogen * ↑ D-dimer * Microangiopathic hemolytic anemia (schistocytes) DIC is marked by: * Overactivation of the coagulation cascade, leading to the formation of fibrin- and platelet-rich thrombiand the consumption of coagulation factors (prolonged PT/PTT), platelets (thrombocytopenia), and fibrinogen. * Subsequent fibrinolysis (to break up the clots), which increases fibrin degradation products (eg, D-dimer). Anticoagulation proteins (eg, protein C/S) are also consumed. Patients with acute DIC usually develop **bleeding from venipuncture/surgical sites,** ecchymosis, and petechiae. Organ damage (eg, renal insufficiency [reduced urine output in the setting of intravascular fluids]) is also commonly seen. **Hx:** Coagulopathy typically occurs in the setting of sepsis, metastatic cancer, or obstetric catastrophe; patients with infections (with gram-negative organisms being the most common), cancer, and obstetrical complications. **Dx:** Prolonged coagulation times: **Prothrombin time (PT)[_11-13s_] and activated partial thromboplastin time (PTT)[_25-35s_]**, an elevated D-dimer titer, a **decreased serum fibrinogen** level and **platelet count,** and the presence of microangiopathic hemolytic anemia. Erythrocyte consumption causes a microangiopathic hemolytic anemia with characteristic fragmented erythrocytes seen on a peripheral blood smear. (schistocytes). **Tx:** Underlying disease, Plt, Cryo, FFP, pRBC

Answer 20

IgA-mediated leukocytoclastic vasculitis Clinical manifestations * **Palpable purpura** * Arthritis/arthralgia * Abdominal pain, intussusception * Renal disease similar to IgA nephropathy Laboratory findings * **Normal platelet count** **& coagulation studies** * Normal to ↑ creatinine * **Hematuria** ± RBC casts ± proteinuria Treatment * **Supportive** (hydration & NSAIDs) for most patients * Hospitalization & systemic glucocorticoids in patients with severe symptoms HSP is IgA mediated and is the most common systemic vasculitis of childhood. The classic tetrad of clinical findings includes: * Lower extremity palpable purpura * Lower extremity arthralgia/arthritis * Abdominal pain/intussusception * Renal disease Renal manifestations are present in over one third of children with HSP and can develop at symptom onset or months after the initial presentation. **Hematuria** is the most common finding, followed by mild (non–nephrotic-range) proteinuria. Nephrotic syndrome, hypertension, and elevated creatinine are less common and typically occur more frequently in adults with HSP. In addition, children usually make a full recovery with rare cases of end-stage renal failure. **Cx: Intussusception** is the most common GI complication, as intestinal edema and bleeding associated with HSP act as a lead point for the intestines to telescope into the adjacent bowel. In contrast to most idiopathic intussusception in children, which is typically **ileocolic**, intussusception in HSP is usually confined to the small bowel (**ileoileal**). Presentation typically involves severe, episodic abdominal pain and **"currant jelly"** or bloody stools; the presence of a **"target" sign** on ultrasound is diagnostic. Although ileocolic intussusceptions are treated with air or contrast enema, ileoileal intussusceptions that do not reduce spontaneously often require **surgical management.**

Answer 21

Inherited: Resistance to activated protein C most commonly due to factor V Leiden Prothrombin gene mutation 20210A Antithrombin deficiency Protein C deficiency Protein S deficiency Hyperhomocysteinemia Elevated factor VIII Acquired: Surgery – most commonly orthopedic (hip and knee replacement), cancer surgery Malignancies – most commonly pancreas, GI, lung, ovaries, acute promyelocytic leukemia Myeloproliferative disorders – most commonly polycythemia vera and essential thrombocythemia Paroxysmal nocturnal hemoglobinuria Trauma Prolonged immobilization – (eg, air travel \>6 hours, bed rest for ≥3 days) Pregnancy/postpartum Nephrotic syndrome Medication related – including oral contraceptives, hormone replacement therapy, tamoxifen/raloxifene, chemotherapy, thalidomide, heparin-induced thrombocytopenia, warfarin-induced necrosis Presence of a central venous catheter or PICC line Antiphospholipid syndrome Acquired states of hyperhomocysteinemia, activated protein C resistance, and antithrombin deficiency

Answer 22

The **most commonly found disorder** is factor V Leiden (FVL), especially in **Caucasian** patients (4%-5% prevalence). Most patients with FVL have an autosomal dominant point mutation in the gene for factor V that makes it unable to respond to activated protein C, an innate anticoagulant. This mutation leads to slowed degradation of procoagulant active factor V, leading to **continued thrombin formation and to slowed degradation of active factor VIII.** Prothrombin time and activated partial thromboplastin time can be **normal** as the major procoagulant effects are due to continued thrombin formation Heterozygosity of this gene increases the lifetime risk of thrombosis 7 fold, whereas homozygosity increases the risk 20 to 80 fold. This mutation is found in approximately 20% of individuals presenting with a VTE. **Dx:** This mutation can be detected by gene analysis or by a coagulation assay (the activated protein C resistance assay)[(sensitivity = 98%, specificity = 99%)].

Answer 23

Antiphospholipid syndrome (APS) is the most common form of acquired thrombophilia resulting from the development of antibodies directed toward plasma proteins that are bound to phospholipids. APS is characterized by: * Venous thromboembolism or recurrent early miscarriages * Presence of an antiphospholipid antibody such as the **lupus anticoagulant (LA), anticardiolipin antibody, or beta 2 glycoprotein 1 antibody** **Dx:** The LA occurs in 10%-30% of patients with SLE. The exact mechanism by which LA promotes coagulation in vivo is unclear. In vitro, it **prolongs the partial thromboplastin time (PTT)** as it binds the phospholipids used in most assays. This is a laboratory **artifact** and does not correlate with bleeding in vivo. The prothrombin time may also be prolonged. The PTT will not correct if mixed in a 1:1 dilution with normal plasma. Prolonged PTT is an indirect indicator for the presence of LA and highly suggestive in the correct clinical setting. Specific tests include the diluted Russell viper venom test and the kaolin clotting time. **Anticardiolipin antibodies** are antiphospholipid antibodies that react with proteins associated with cardiolipin (phospholipid), and these antibodies are also responsible for false-positive tests for syphilis (such as the rapid plasma reagin test) that use cardiolipin in their assay. **Dx:** ELISA testing for anticardiolipin and anti-β2-glycoprotein-I (IgG and/or IgM) antibodies **Lupus anticoagulants** are antiphospholipid antibodies that, when bound to their target proteins, prolong clotting times (such as the prothrombin time and activated partial thromboplastin time); despite this clotting time prolongation, patients with lupus anticoagulants are actually thrombophilic. Because lupus anticoagulants act as inhibitors, these measures do not correct when a mixing study is performed in which the patient's plasma is combined with plasma that contains all of the normal clotting factors. **Dx:** Requires a 3-step procedure including screening tests (eg, diluted Russell viper venom and sensitive aPTT); mixing studies; and confirmatory phospholipid tests **Antiphospholipid autoantibodies** APS is an acquired autoimmune disorder associated with venous or arterial thromboembolism, pregnancy loss, thrombocytopenia, kidney impairment, vasculitis, and cardiac valvular abnormalities; Antibodies are directed against the phospholipid β2-microglobulin, which is an inhibitor of coagulation and platelet aggregation. **Dx:** Can be detected with enzyme immunoassays or phospholipid-dependent coagulation tests such as the (prolonged) activated partial thromboplastin time (aPTT) and the dilute Russell viper venom time. **Tx:** A systematic review reported that the absolute risk of new venous thromboembolic (VTE) disease in patients with antiphospholipid antibodies is low (less than 1% per year). However, this risk may be increased to up to 10% per year in women with antiphospholipid antibodies or APS and recurrent fetal loss and more than 10% per year in patients with antiphospholipid antibodies and previous VTE who have discontinued anticoagulants within 6 months. Current recommendations are to treat these latter high-risk patients with **anticoagulants** indefinitely.

Answer 24

**⛑ Warfarin** inhibits production of vitamin K–dependent clotting factors II, VII, IX, and X. It also inhibits production of the natural anticoagulants proteins C and S. This **decreases protein C anticoagulant activity to 50% within the first day** while levels of procoagulant factors (II, IX, and X) decline more slowly, leading to a transient hypercoagulable state. This increases the risk for venous thromboembolism and skin necrosis, especially in patients with underlying hereditary protein C deficiency. **Hx:** Skin lesions typically occur on the extremities, breast, trunk, and penis and marginate over a period of hours. If left untreated, affected areas become edematous, purpuric, and ultimately necrotic. **Tx:** Treatment involves immediate cessation of warfarin and administration of **protein C concentrate.**

Answer 25

Inherited as an autosomal dominant trait; it is a **cofactor of protein C**, so decreased levels of this protein also lead to less protein C activity, resulting in **increased fibrin formation**. Protein S deficiency is very **rare**. **Dx:** Consider both functional level and antigenic assays

Answer 26

A mutation in the prothrombin gene at position G20210A causes increased levels of prothrombin that leads to **excess thrombin** formation. This condition occurs in approximately 3**% of Caucasians** in the United States and confers a 3- to 4-fold risk for VTE. **Dx:** Direct PCR gene test (sensitivity = 100%, specificity = 100%)

Answer 27

Antithrombin deficiency is an autosomal dominant genetic mutation associated with thrombophilia. It should be suspected in a patient whose clot does not respond to heparin therapy, since **heparin requires the presence of antithrombin** that is deficient in this condition. **Dx:** Consider both functional level and antigenic assays

Answer 28

Homocysteine is a highly reactive amino acid. Increased levels predispose to venous thrombosis as well as atherosclerosis, presumably due to a combination of direct vascular damage, activation of clotting mechanisms, and inhibition of antithrombotic pathways. Hyperhomocysteinemia can rarely be inherited through mutations of the **MTHFR gene.** Levels of homocysteine increase, leading to increased clot formation. Elevated plasma factor VIII coagulant activity (VIII:C) also increases thrombotic risk independently **Dx:** Fasting plasma homocysteine level (risk increases when levels \>1.35 mg/L (10 μmol/L) Homocysteine can be metabolized to cysteine or methylated to form methionine. If either of these pathways is disrupted by an enzyme or cofactor deficiency, elevated homocysteine levels result. The homocysteine to cysteine pathway is catalyzed by cystathionine β-synthase (CBS) using the cofactor pyridoxine (B6). The homocysteine to methionine pathway is catalyzed by methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MS), with folate and cobalamin (B12) as essential cofactors. **Tx:** Independent of the underlying cause, homocysteine levels can usually be normalized by administration of **pyridoxine (B6)** and **folate.** Vitamin B12 should be added if a B12 deficiency is documented. Although this treatment does correct homocysteine levels, it is still unclear whether it reverses hypercoagulability.

Answer 29

Acquired hyperhomocysteinemia has been associated with both arterial and venous thrombosis. The increased homocysteine can stem from vitamin B6, vitamin B12, and folate deficiencies. The thrombotic risk is most closely associated with the increased fasting plasma homocysteine level, regardless of etiology, and roughly doubles the risk of venous thrombosis.

Answer 30

Cancer increases the risk of VTE by 4- to 20-fold. Cancers express tissue factor on their surface and induce tissue factor expression by endothelial cells and monocytes, contributing to a prothrombotic state. Thrombotic risk varies by cancer type and stage; risk is highest with pancreatic and brain tumors, intermediate with lung cancer and lymphoma, and lower with breast and prostate cancer. Metastatic disease increases thrombotic risk twofold.

Answer 31

Pathophysiology * Plasma cell neoplasm produces **monoclonal paraprotein** (immunoglobulin) Manifestations * **Bone pain,** fractures * Constitutional symptoms (weight loss, fatigue) * **Recurrent infections** Laboratory * Normocytic anemia * Renal insufficiency * **Hypercalcemia** (constipation, muscle weakness) * Monoclonal paraproteinemia **(M-spike)** Radiology * **🦴Osteolytic lesions/osteopenia** (osteoclast activation) Plasma cell neoplasm that often presents with **constitutional symptoms** (weight loss, fatigue) or **bone pain**. **Dx:** MM should be suspected in elderly patients with laboratory findings of **hypercalcemia, normocytic anemia,** renal insufficiency, and a **_protein gap_ (difference between total protein and albumin \>4 g/dL)**. Multiple myeloma is a malignancy of **plasma cells**. **Hx:** Bone pain, pancytopenia, kidney disease, and hypercalcemia. Patients with MM are prone to 🦠**infection**. Neoplastic infiltration of the bone marrow alters and impairs the normal lymphocyte population, resulting in **ineffective antibody production and _hypogammaglobulinemia_**. Respiratory (eg, streptococcal pneumonia) and urinary tract infections are the most common infections seen in MM. **Dx:** Monoclonal **IgG, IgA, or light chains.** **CBC, Blood smear** * **🛢Rouleaux formation**, leukopenia and thrombocytopenia. * May cause **acute kidney injury (AKI)**, anemia, **hypercalcemia**, and a **decreased anion gap**. * The anion gap, normally approximately 12 plus or minus 2 mEq/L (12 ± 2 mmol/L), may be decreased in patients with multiple myeloma because of the presence of an unmeasured cationic light chain that causes an increase in negative ions to maintain electroneutrality, thereby decreasing the calculated gap between measured positive and negative serum ions. **Serum/Urine Protein electrophoresis (SPEP)** Most myelomas produce a monoclonal (M) protein consisting of an intact immunoglobulin composed of a heavy chain (IgG, IgA, or IgD) and a κ or λ light chain, but they may secrete free light chains alone (16% of cases), or, rarely, no immunoglobulin. **🚽 Urine Immunofixation:** Immunofixation confirms the presence of an M protein and determines its type. The **absence of an M protein in the serum** and the finding of hypogammaglobulinemia suggest that the M protein is a light chain, which is filtered by the glomerulus and is readily found by urine immunofixation but not found in the serum **(Bence Jones protein).** **Serum Immunofixation:** **🍖 Bone marrow Biopsy:** **Asymptomatic (smoldering) multiple myeloma** is characterized by a serum **M protein level of 3 g/dL** or more, regardless of isotype, or 10% or more of clonal plasma cells on bone marrow examination and the **absence of myeloma-related end-organ damage**. The risk of asymptomatic multiple myeloma progressing to symptomatic multiple myeloma or AL amyloidosis is 73% at 15 years, with a median time to progression of 4.8 years. **Symptomatic myeloma** is diagnosed by the presence of **10% or more** clonal plasma cells on **bone marrow biopsy**, the presence of an M protein, and evidence of myeloma-related end-organ damage. Definitive diagnosis of multiple myeloma is made by demonstrating greater than **30% plasma cells** in the bone marrow.

Answer 32

MGUS is defined as the presence of a serum monoclonal **(M) protein level of less than 3 g/dL**, **bone marrow plasma cells \<10%; asymptomatic**, normal hemoglobin, serum calcium, serum creatinine, and bone survey (no evidence of anemia, kidney failure, bone disease, or other myeloma-related end-organ damage). **Dx:** The initial evaluation of most patients with an established M protein abnormality includes a complete blood count; serum calcium, albumin, and creatinine measurement; urinalysis; serum protein and urine electrophoresis and immunofixation; quantitative immunoglobulin measurement (IgG, IgM, IgA); serum free light-chain testing; and a skeletal survey. **Tx:** May evolve to MM, but no therapy reduces the likelihood of malignant transformation

Answer 33

A nonclonal increase in serum immunoglobulins. No increased risk of evolving into MM. Associated with liver disease, connective tissue disease, chronic infections (eg, HIV), lymphoproliferative disorders, and nonhematologic malignancies

Answer 34

Circulating plasma cells seen on peripheral blood smear. Worse prognosis than typical MM

Answer 35

Rare variant of MM consisting of Peripheral neuropathy, Organomegaly, Endocrinopathy, Monoclonal plasma cell proliferative disorder, Skin changes, sclerotic bone lesions, papilledema, fingernail clubbing, edema, effusions, and, possibly, Castleman disease. Not all features required for diagnosis; minimum of peripheral neuropathy, plasma cell dyscrasia, and either sclerotic bone lesion or Castleman disease. Better overall prognosis than MM

Answer 36

A clonal **plasma cell** proliferative disorder in which fibrils of **monoclonal light chains are deposited in the kidney and other tissues** (liver, heart, peripheral nervous system), **Hx: Nephrotic syndrome**, **cardiomyopathy**, orthostatic hypotension, cholestatic liver disease, symmetric distal sensorimotor neuropathy, macroglossia, and carpal tunnel syndrome. **Px:** Periorbital purpura and macroglossia are characteristic of AL amyloidosis. **Dx:** Most patients have small serum M proteins and approximately 5% bone marrow plasma cells; 6% to 15% of patients with AL amyloidosis have coexisting MM Characteristic findings on **tissue biopsy**, the presence of a monoclonal plasma cell disorder, and evidence that the amyloid deposits are composed of clonal light chains. An abdominal **fat pad aspirate** revealing amorphous eosinophilic material that demonstrates **apple-green birefringence** when stained with **Congo red** and viewed under polarized light

Answer 37

WM is a B-cell malignancy characterized by the excessive production of monoclonal IgM antibody. IgM is a large immunoglobulin, and high levels can **clog the microvasculature,** resulting in **hyperviscosity syndrome**. **Hx:** Symptoms typically include **vision changes, headaches, vertigo, dizziness, and/or ataxia**; rarely, stroke or coma may occur. Other IgM-mediated conditions commonly seen in patients with WM include **peripheral neuropathy, cryoglobulinemia, and renal insufficiency**. **Px:** Physical examination typically shows **sausage-link" (dilated, segmented, tortuous) retinal veins**, and laboratory studies usually reveal anemia, a **gamma gap** (difference between total protein and albumin), and elevated erythrocyte sedimentation rate (ESR). **Dx:** Peripheral blood smear may show **rouleaux formation** (or **erythrocyte agglutination**) due to elevated serum protein. **_Serum protein electrophoresis (SPEP)_** is an important screening study; patients with WM have a **_monoclonal spike (M-spike) of IgM_**. Diagnosis is then confirmed by bone marrow biopsy showing \>10% clonal B cells with specific cytogenetic features. **Tx:** More responsive to **purine nucleoside analogues** and **anti-CD20 immunotherapy**

Answer 38

A localized collection of plasmacytes that may occur as a single lytic lesion in bone or extramedullary (upper respiratory tract, especially sinuses, nasopharynx, or larynx) sites. Patients may or may not have M protein in the serum or urine. No increase in bone marrow plasma cells, anemia, hypercalcemia, or renal insufficiency. Treated with local therapy (excision, radiation). Patients have increased risk for developing MM

Answer 39

Acute Hemolytic Transfusion Reaction Delayed Hemolytic Transfusion Reaction Transfusion-Associated Circulatory Overload Transfusion-Related Acute Lung Injury Febrile Nonhemolytic Transfusion Reaction Allergic Reactions and Anaphylaxis Transfusion Graft-Versus-Host Disease Infectious Complications

Answer 40

Anaphylaxistypically occurs **seconds to minutes** after transfusion. Mild allergic reactions consisting of urticaria commonly occur, especially in multiply transfused patients. Most reactions are caused by donor plasma proteins reacting with preexisting IgE antibodies in the recipient and may not recur with subsequent transfusions. After stopping the transfusion, if the urticaria resolves without signs of anaphylaxis, the transfusion can resume. Rarely is urticaria the first sign of a more serious reaction. Pretreatment with antihistamines or washing of cellular blood products to remove plasma proteins is often effective in preventing recurrence. **Severe anaphylactic** reactions are rare and typically occur in patients who are **IgA deficient** and have anti-IgA antibodies. These antibodies react to IgA contained in the transfused blood. **Hx:** Patients present with rapid onset of **hypotension, gastrointestinal symptoms, angioedema, stridor, and respiratory distress.** **Tx:** When transfusing IgA-deficient patients, plasma products must be obtained from IgA-deficient donors and all subsequent cellular products should be **washed** thoroughly to remove plasma proteins. **Tx:** Requires prompt and rapid cessation of the transfusion, epinephrine, airway maintenance, and fluid resuscitation.

Answer 41

The acute hemolytic transfusion reaction (AHTR) is a rapid intravascular hemolysis that is the most feared complication of transfusion. It is almost always caused by **ABO incompatibility** between donor and recipient and, in most cases, results from a clerical or procedural error such as the mislabeling of a pretransfusion specimen. **Hx:** Patients often present with **fever, chills, flank pain, and hemoglobinuria** **within an _hour_** of transfusion. This can progress to renal failure and disseminated intravascular coagulation (DIC). **Tx:** When AHTR is suspected, the transfusion must be stopped immediately and a specimen sent to the blood bank to evaluate for incompatibility. Treatment is supportive.

Answer 42

A delayed hemolytic transfusion reaction (DHTR) occurs **3 to 10 days** after erythrocyte transfusion. In contrast to AHTR, the DHTR is a gradual extravascular hemolysis caused by an amnestic minor, non-ABO erythrocyte antibody. Following a transfusion, there is a 1.0% to 1.6% chance of developing these minor non-ABO **alloantibodies**, and DHTR occurs when the patient is re-exposed to the same antigen with a subsequent transfusion. **Hx:** Clinical symptoms include an unexpected drop in hemoglobin, jaundice, and fever, although many patients will be asymptomatic. Life-threatening complications are rare, but patients with sickle cell disease may present with a worsening pain crisis. **Tx:** Treatment is supportive. **Dx:** A repeat type and screen will identify the presence of a new alloantibody, and subsequent transfusions should be minimized, but not withheld, when indicated. All subsequent transfusions should be tested to ensure they do not have the identified antigen.

Answer 43

Transfusion-associated circulatory overload (TACO) is a frequent and serious transfusion complication, which most commonly affects those with limited cardiopulmonary reserve, including the very young and the elderly. **Hx:** Presenting symptoms occur during or **within 1 to 2 hours** of a transfusion and include **dyspnea, cough, tachycardia, cyanosis, edema, and chest tightness**. **Px:** Physical examination will typically reveal signs of **fluid overload**, and unlike TRALI, there will be an elevated **N-terminal pro-B-type natriuretic peptide.** **Tx:** Treatment consists of supplemental oxygenation and intravenous diuretics. The risk of TACO can be reduced by avoiding overly rapid transfusion rates.

Answer 44

Transfusion-related acute lung injury (TRALI) occurs in 1 of 5000 transfusions and is the most common cause of transfusion-related death, with a mortality rate of 5%. Transfusions containing higher concentrations of plasma, such as platelets and whole blood, pose the greatest risk. The pathogenesis of TRALI is not completely understood, but is thought to be due to the “priming” of neutrophils in the lung vasculature (by insults such as surgery, infection, or trauma) that make them vulnerable to activation, which occurs with exposure to an antineutrophil or HLA antibody contained in the transfusion. Upon activation, leukocyte sequestration occurs in the lung, and capillary leak ensues. **Dx:** The diagnostic criteria for TRALI includes the acute onset of **dyspnea, hypoxia, and bilateral infiltrates on chest radiograph** occurring **within 6 hours** of transfusion with no other cause for acute lung injury. The clinical and radiographic differential diagnosis includes TACO, acute respiratory distress syndrome, and heart failure. **Tx:** Unlike patients with acute respiratory distress syndrome, patients with TRALI typically improve within days. As such, treatment of TRALI is primarily **supportive** and prevention entails exclusion of the implicated donor from future transfusions.

Answer 45

The febrile nonhemolytic transfusion reaction (FNHTR) is the most common transfusion reaction and is benign. It presents with fever and chills 1 to 6 hours after erythrocyte or platelet transfusion. However, it cannot be clinically differentiated from the more severe and life-threatening AHTR. Recipient-derived leukoreactive antibodies and donor-derived cytokines are thought to represent the most common causes. When fever develops, the transfusion should be stopped immediately until AHTR can be excluded and causes of fever unrelated to the transfusion considered. After AHTR has been excluded, the transfusion can continue with close monitoring. Pretransfusion antipyretics such as acetaminophen, or leukoreduction of cellular blood products, may prevent recurrence.

Answer 46

Transfusion-associated GVHD (T-GVHD) is a rare, but often fatal, transfusion complication. It usually occurs in **immunocompromised** patients who receive a **transfusion** product that is **contaminated with lymphocytes**. Immunocompetent patients are not usually affected because their immune system destroys the lymphocytes in the donor transfusion. Patients at risk for T-GVHD include hematopoietic stem cell or solid organ transplant recipients, recipients of transfusions from first-degree relatives, and patients with immunosuppression associated with **hematologic malignancies** such as Hodgkin lymphoma. An immune-mediated, multisystem inflammatory condition that occurs in 35%-50% of patients who undergo allogeneic hematopoietic stem cell transplantation (HSCT). Acute GVHD arises when **donor T cells** (particularly **cytotoxic T cells**) identify antigens on host epithelial cells as foreign and subsequently generate a strong proinflammatory response. The target organs for GVHD are the **skin** (maculopapular rash involving palms, soles, and face that may generalize is typical), **intestine** (blood-positive diarrhea), and **liver** (abnormal liver function tests and jaundice). Patients with acute GVHD generally develop symptoms within 100 days of transplantation, including the following: * **Maculopapular rash 🤡** that is often painful and can become confluent (resembling Stevens-Johnson syndrome) * **Profuse, watery diarrhea 💩** that has a secretory pattern (eg, persistent, unrelated to eating, occurs at night) and is often associated with crampy abdominal pain, nausea, and vomiting * **Liver inflammation** with damage to the biliary tract epithelium, leading to elevated bilirubin, alkaline phosphatase, and transaminases No treatment has proved effective; therefore, prevention is key. Gamma irradiation of cellular products virtually eliminates the risk for T-GVHD and should be performed before transfusion for all at-risk patients.

Answer 47

Given improved donor screening and pretransfusion testing, blood is currently safer than ever before. For example, the risk of HIV is less than 1 in 1,900,000 units; hepatitis C is less than 1 in 1,000,000 units; and hepatitis B is less than 1 in 205,000 units. However, infectious risk, including the transmission of West Nile virus, dengue virus, prions causing Creutzfeldt-Jakob disease, Chagas disease, and babesiosis, still remain, and new bloodborne pathogens will continue to emerge. The risk for bacterial infection is higher than viral infection and can come from donor blood, donor skin, phlebotomists' skin, and environmental contamination. Because platelets are stored at room temperature, bacterial contamination occurs more commonly with platelet transfusions, with an estimated frequency of 1 in 3000 platelet units. There are other bacteria such as Yersinia enterocolitica that may survive refrigeration of erythrocyte units and can lead to fatal sepsis.

Answer 48

Can develop in patients with aggressive hematologic malignancies who begin cytotoxic chemotherapy. Large-scale cell death increases vascular concentrations of intracellular products, resulting in potentially life-threatening electrolyte and metabolic abnormalities. The following are often observed: **Hyperuricemia** – Nucleic acids are released and metabolized into uric acid. **Hyperkalemia** and hyperphosphatemia – Intracellular ions are liberated. **Hypocalcemia** – Phosphate binds and precipitates calcium, reducing intravascular levels. Symptoms of TLS are primarily due to electrolyte abnormalities and include nausea, vomiting, diarrhea, muscle cramps, seizures, and tetany. Cardiac arrhythmias (hyperkalemia, hypocalcemia) and acute kidney injury (renal tubule deposition of uric acid and/or calcium phosphate) are common complications. Tx: The use of **intravenous fluids** to flush the kidneys and **uric acid metabolism inhibitors (allopurinol, rasburicase 🍉)** helps moderate the risk of uric acid-mediated renal damage; however, calcium phosphate-induced renal injury may still occur.

Answer 49

**C**ancer **H**ypersensitivity **I**nfection **C**onnective tissue disease **A**typical lymphoproliferative disorder **G**ranulomatous disease **O**ther unusual cause

Answer 50

Chronic myeloid leukemia (CML) Acute myeloid leukemia (AML) Myelodysplastic Syndrome (MDS) Leukemoid Reaction Aplastic Anemia Chronic lymphocytic leukemia (CLL) Acute lymphoblastic leukemia (ALL) Chronic lymphocytic leukemia (CLL) Hodgkin lymphoma (HL) B-cell NHL: Follicular lymphoma Marginal zone lymphoma Small lymphocytic lymphoma Mantle cell lymphoma Diffuse large B-cell lymphoma Burkitt lymphoma Infectious Mononucleosis

Answer 51

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm caused by the **BCR-ABL** fusion gene. It is marked by a dramatic leukocytosis (often but not always \>100,000/mm3), absolute basophilia, and a preponderance of early immature neutrophil precursors (promyelocytes, myelocytes). **Dx:** The **leukocyte alkaline phosphatase (LAP) score** 💯 can help differentiate CML from leukemoid reaction. In CML the neutrophils are cytochemically and functionally abnormal, so the LAP score is usually low. **Dx:** In chronic-phase CML, the leukocyte count is high, the hemoglobin level is low or normal, and the platelet count is normal or high. The peripheral blood smear shows neutrophilia and left-shifted granulopoiesis. **Basophilia** is common. [Leukocytosis with circulating myeloid precursors in all stages of development.] CML is often found on routine blood work in asymptomatic patients but may present with fatigue, weight loss, night sweats, or abdominal fullness (from splenomegaly). Thrombocytosis and anemia are common. **Hx:** Fatigue, night sweats, weight loss, abdominal discomfort, early satiety (splenomegaly), and bleeding. Peripheral blood smear in CML reveals dramatic leukocytosis (often \>100,000/mm3) with absolute basophilia and a shift toward very early neutrophil precursors (promyelocytes, myelocytes). Detection of the **(9;22) translocation** by routine cytogenetic studies or fluorescence in situ hybridization assay or of the **BCR-ABL** fusion transcript by reverse transcriptase-polymerase chain reaction is diagnostic of CML **Px:** Splenomegaly **Tx:** First-line treatment for most CML patients involves **tyrosine kinase inhibitors** such as **imatinib**. Although these drugs are not curative, they often can induce long-term remission.

Answer 52

**Severe infections** can cause LR due to the mobilization of mature and immature leukocytes from the bone marrow. **Dx:** Usually defined as a non-leukemic leukocytosis exceeding 50,000/µL (50 × 109/L) and is characterized by an increase in early neutrophil precursors in the peripheral blood. Leukocyte count is dramatically elevated, with a predominance of **late neutrophil precursors (metamyelocytes, bands)** rather than early precursors (promyelocytes, myelocytes). This, combined with a high leukocyte alkaline phosphatase (LAP) score, suggests leukemoid reaction (LR). LR must be differentiated from chronic myelogenous leukemia (CML), a myeloproliferative disorder that also presents with neutrophilia and dramatic leukocytosis. Unlike LR, CML is characterized by a low LAP score (due to cytochemically abnormal neutrophils) and a peripheral smear that features absolute basophilia and early neutrophil precursor cells. Given the severity of the infection, it may take \>24 hours for clinical improvement with antibiotics.

Answer 53

Background * **Most common** adult acute leukemia * Median age 65 Manifestations * Fatigue is common (other B symptoms unusual) * Often presents with symptoms from cytopenias: * Fatigue, weakness (anemia) * Bleeding, bruising (thrombocytopenia) * Infection (granulocytopenia) * Hepatosplenomegaly/lymphadenopathy rare * **Disseminated intravascular coagulation (if APML)** Laboratory * Cytopenias (leukocytes may be ↑, normal or ↓) * Elevated **lactate dehydrogenase** * Peripheral smear - myeloblasts with Auer rods Diagnosis * Bone marrow biopsy - usually hypercellular with myeloid blasts Malignancy of myeloid progenitor cells characterized by a median age at diagnosis of 67 years. AML is a clonal myeloproliferative disorder characterized by the accumulation of blastic or immature myeloid cells in the bone marrow and peripheral blood. Patients often develop fatigue and symptoms related to \>1 cytopenias, including fatigue/weakness (anemia), bleeding/bruising (thrombocytopenia), and/or infection (granulocytopenia). Examination may show pallor and ecchymosis, but lymphadenopathy and hepatosplenomegaly are rare. Leukocyte count may be elevated (sometimes \>100,000/mm3), normal, or low. **Cx: APML** is characterized by life-threatening coagulopathy due to **disseminated intravascular coagulation** (prolonged PT/active PTT, hypofibrinogenemia). In APML, bone marrow biopsy would reveal atypical promyelocytes. **Hx:** While AML most commonly occurs in patients with no antecedent risk factors, its incidence is increased in patients who are Exposed to radiation or benzene or following therapy with chemotherapy, especially alkylating agents. Clinical manifestations of marrow failure develop over days to months and include fatigue, dyspnea, and easy bleeding. Fever is commonly caused by infection. **Dx:** The **bone marrow biopsy** in patients with AML would show an abundance of **myeloid blasts.** **_Auer rods_**, which are clumps of azurophilic granular material that form elongated needles seen in the cytoplasm of leukemic blasts are sometimes seen on the peripheral smear. **Tx:** Given the risk for central nervous system involvement in ALL, **intrathecal chemoprophylaxis** is routinely administered with or without cranial irradiation. **Acute promyelocytic leukemia (APL)** is a subtype of AML that occurs in 10% of patients with AML. **Dx:** Patients with APL may have circulating blasts, but the predominant cell is a large immature granulocyte with multiple granules overlying the cytoplasm and nucleus. **Tx:** The disorder is exquisitely sensitive to anthracycline cytotoxic therapy. The addition of **all-trans-retinoic acid** and arsenic trioxide to the therapy has resulted in high cure and salvage rates in patients with APL.

Answer 54

Clonal hematopoietic progenitor cell disorders characterized by ineffective hematopoiesis and a variable rate of transformation to acute myeloid leukemia. The myelodysplastic syndromes are progenitor cell clonal disorders characterized by ineffective hematopoiesis and various peripheral cytopenias. The incidence of MDS increases with age. **Hx:** Fatigue and easy bleeding. Patients have signs and symptoms referable to a specific cytopenia (most often, megaloblastic anemia) and bone marrow findings showing a hypercellular marrow with dyserythropoiesis. Many chromosomal abnormalities are associated with myelodysplastic syndromes, including abnormal numbers of chromosomes, translocations, and structural abnormalities. **Dx:** Normocytic or macrocytic anemia. Dysplastic changes on the peripheral blood smear may include nucleated erythrocytes and hypolobated, hypogranular neutrophils. Bone marrow findings showing a hypercellular marrow with dyserythropoiesis. **Tx:** Patients with myelodysplastic syndrome treated with **azacitidine** have significantly delayed transformation to leukemia and improved quality of life.

Answer 55

Pathogenesis * Bone marrow failure due to hematopoietic stem cell deficiency (CD34+) Causes * Autoimmune * **Infections** (eg, parvovirus B19, Epstein-Barr virus) * Drugs (eg, carbamazepine, chloramphenicol, sulfonamides) * Exposure to radiation or toxins (eg, benzene, solvents) Clinical & laboratory findings * Laboratory studies: **Pancytopenia** * **Anemia** (fatigue, weakness, pallor) * **Thrombocytopenia** (mucosal bleeding, easy bruising, petechiae) * **Leukopenia** (recurrent infections) * Biopsy: Hypocellular bone marrow with fat and stromal cells Aplastic anemia is an acquired deficiency or **absence of pluripotent stem cells**. It is associated with **exposures** (eg, drugs, toxins, radiation), **viral infections** (eg, parvovirus B19, HIV, Epstein-Barr virus), and **autoimmune conditions** (eg, lupus, eosinophilic fasciitis). Direct damage to and autoimmune targeting of stem cells are 2 potential mechanisms that result in aplasia. Bone marrow fails to produce blood cells, resulting in a hypocellular bone marrow and pancytopenia. Epstein-Barr virus and cytomegalovirus infection, can cause aplastic anemia. **Dx:** The complete blood count and peripheral smear are notable for pancytopenia and inadequate erythropoiesis demonstrated by a low reticulocyte count; however, the cells are all morphologically normal and the anemia is usually normocytic. A definitive diagnosis is made by bone marrow biopsy demonstrating hypocellular marrow with a few normal hematopoietic cells, no myeloid infiltration or fibrosis, and predominantly stroma and adipocytes.

Answer 56

ALL is the most common childhood cancer, with peak incidence in boys age 2-5. Epidemiology * Most common childhood cancer * Peak age: 2-5 years * Male \> female Clinical features * Nonspecific systemic symptoms * Bone pain * Lymphadenopathy * Hepatosplenomegaly * Pallor (from anemia) * Petechiae (from thrombocytopenia) Diagnosis * Bone marrow biopsy with \>25% lymphoblasts Treatment * Multidrug chemotherapy About half of patients with ALL have bruising, petechiae, and mucosal bleeding (eg, oozing from the gums) as a result of cancer cells infiltrating the bone marrow and impairing platelet production. Bone marrow failure leads to pallor and fatigue (from anemia) and recurrent infections (from neutropenia). In addition, the spread of leukemic cells out of the bone marrow can cause the liver, spleen, and lymph nodes to enlarge. Bone marrow biopsy is diagnostic. A disorder of committed progenitor cells characterized by a proliferation of immature lymphoblasts. ALL constitutes less than 20% of acute leukemias in adult patients, with the highest incidence occurring in the seventh decade of life. **Hx:** Patients present with lymphocytosis, neutropenia, anemia, and thrombocytopenia, as well as lymphadenopathy and hepatosplenomegaly. Rapidly increasing blast cells in the blood and bone marrow, bulky lymphadenopathy (especially in the mediastinum), and cytopenia secondary to bone marrow involvement are the usual presenting clinical features.

Answer 57

Pathophysiology * Inherited **DNA repair defect** * **Bone marrow failure** Clinical findings * Short stature * Hypo-/hyperpigmented macules * Abnormal thumbs * Genitourinary malformations Laboratory findings * Pancytopenia * Positive chromosomal breakage testing Treatment * Hematopoietic stem cell transplant Fanconi anemia (FA) is the **most common congenital cause of** 🦴 **aplastic anemia** (ie, bone marrow failure, pancytopenia). FA is typically an autosomal recessive disorder caused by a **DNA repair defect**. Damaged, unstable DNA impairs normal hematopoietic stem cell production and can also lead to increased susceptibility to malignancy (eg, leukemia). Patients usually present in childhood with signs of **thrombocytopenia** (eg, bleeding, bruising), with progression to leukopenia (eg, infections) and anemia (eg, fatigue) over time. Anemia is usually **macrocytic** due to fetal erythropoiesis that occurs during periods of chronic hematopoietic stress. Additional characteristic features of FA include short stature, hyper- or hypopigmentation, and absent or **hypoplastic thumbs**. Additional abnormalities of the hand may include polydactyly or a **flat thenar eminence 👍🏽**. Diagnosis of FA is made by demonstrating chromosomal breakage following DNA exposure to interstrand crosslinking agents. Definitive treatment is **hematopoietic stem cell transplantation.**

Answer 58

**Dx:** Indolent. Second most common type of NHL. Average age at diagnosis is 60, and 80% have advanced disease at presentation. **Tx:** **Observation** in asymptomatic patients. When symptoms occur, options include chemotherapy, immunotherapy, or chemoimmunotherapy. Some patients may receive radiation therapy. Incurable. Average survival may exceed 8 to 10 years.

Answer 59

**Dx:** Indolent. Derives from the marginal zone of lymph nodes or spleen. Average age is 60. Includes splenic marginal zone lymphoma, mucosa-associated lymphoid tissue (MALT) lymphoma, and nodal marginal zone lymphoma. **Tx:** Same as for follicular lymphoma.

Answer 60

**Dx:** Indolent. Characterized by an excess of small, mature-appearing lymphocytes in the blood, bone marrow, or lymph nodes. When a peripheral blood lymphocytosis is seen, it is also called chronic lymphocytic leukemia (CLL). **Tx:** Same as for follicular lymphoma.

Answer 61

**Dx:** May be indolent or aggressive. Associated with the cyclin D1 protein overexpression. Most patients have widely advanced disease at presentation. **Tx:** Chemoimmunotherapy. Incurable. Average survival is 3 to 5 years.

Answer 62

**Dx:** Aggressive. **Most common type of NHL.** May occur outside the lymph nodes in up to 40% of patients, including within the CNS, the gastrointestinal tract, genitourinary tract, or bones. 5-year overall survival rate ranges from 30% to 50% for all stages. Early-stage, low-risk patients may have overall survival rates up to 90%. **Tx:** Treatment for all patients with large B-cell NHL includes **chemotherapy** (usually cyclophosphamide, doxorubicin, vincristine, and prednisone with rituximab [R-CHOP]) and **immunotherapy** with **rituximab**. **Radiation** therapy is used after chemoimmunotherapy for patients with localized or bulky disease. Curable.

Answer 63

**Dx:** On histology, the “starry sky” pattern is classic and all cases have a translocation of the c-myc oncogene. Often associated with tumor lysis at the time of, or even before, treatment. **Tx:** Chemoimmunotherapy. Prophylactic intrathecal chemotherapy is given to reduce the likelihood of relapse within the CNS. Curable. 5-year overall survival rate in adults is 50% to 70%.

Answer 64

Chronic lymphocytic leukemia (CLL) (sometimes referred to as small lymphocytic lymphoma) is the most common type of leukemia in the United States. It is almost always seen in the elderly (median age at diagnosis is 70). **Hx:** Patients are often asymptomatic but can present with extreme fatigue, B symptoms (eg, night sweats, fevers), infection, or weight loss. **Px:** Painless lymphadenopathy (cervical, supraclavicular, axillary), hepatosplenomegaly, and anemia or thrombocytopenia. **Dx:** **Dramatic lymphocytosis (\>5000/µL)[50,000?]** is the classic hallmark of CLL.Immunophenotyping **(flow cytometry)** demonstrates clonality of the circulating B-lymphocytes. Immunophenotyping will show a monoclonal proliferation of mature B lymphocytes expressing CD19, CD20, and CD5. Peripheral smear reveals mature lymphocytes with the presence of smudge cells (a pathognomonic characteristic of CLL).

Answer 65

Epidemiology * Bimodal peak incidence: age 15-35 & \>60 * Association with **EBV** in the immunosuppressed Manifestations * Painless lymphadenopathy * **Mediastinal mass** * B symptoms (ie, fever, sweats, weight loss) * Pruritus Diagnosis * Lymph node biopsy * Reed-Sternberg cells on histology HL usually arises in a single lymph node and disseminates to contiguous nodes via the lymphatic and thoracic ducts. Patients generally present with painless peripheral LAD, particularly in the cervical and supraclavicular chains. The most common cancer that occurs during **late adolescence (age 15-19)** **Hx:** Weight loss, fever, and night sweats are often referred to as “B” symptoms based on the Ann Arbor classification system for lymphomas that adds the suffix B to a stage if systemic symptoms are present. B symptoms are frequently seen in patients with HL. Cough and dyspnea on exertion are generally caused by an anterior mediastinal mass, a common finding in classical HL. **Cx:** The most common secondary solid tumor malignancies are lung (especially in smokers), breast, thyroid, bone, and gastrointestinal (eg, colorectal, esophageal, gastric tumors).

Answer 66

Castleman disease (giant lymph node hyperplasia)

Answer 67

Kikuchi disease (histiocytic necrotizing lymphadenitis)

Answer 68

**Primary** (↓ EPO) * **Polycythemia vera** (JAK2 mutation) * EPO receptor mutations Primary polycythemia is largely caused by malignant transformation of erythrocyte progenitor cells, which results in unregulated erythrocyte production (eg, polycythemia vera). Erythropoietin (EPO), the hormone that stimulates red blood cell production, will be low or absent because elevated red blood cell mass exerts a negative feedback effect on EPO-producing cells in the renal cortex. **Secondary** (normal/↑ EPO) * Hypoxemia * Cardiopulmonary disease * Obstructive sleep apnea * High altitude * EPO-producing tumors (renal, hepatic) * Congenital (high-affinity hemoglobin) * Following renal transplantation * Androgen supplementation Secondary polycythemia is typically due to elevated circulating EPO levels. Most cases are caused by conditions associated with chronic hypoxia (eg, cardiopulmonary disease, obstructive sleep apnea), which stimulates EPO secretion, or by EPO-producing tumors (eg, renal cell carcinoma).

Answer 69

Manifestations * ↑ Blood viscosity * Hypertension * Erythromelalgia (burning cyanosis in hands/feet) * Transient visual disturbances * ↑ RBC turnover (gouty arthritis) * Aquagenic pruritus * Bleeding Examination * Facial plethora (ruddy cyanosis) * Splenomegaly Laboratory findings * Elevated hemoglobin * Leukocytosis & thrombocytosis * **Low erythropoietin level** * JAK2 mutation positive Complications * Thrombosis * Myelofibrosis & acute leukemia Treatment * Phlebotomy * Hydroxyurea (if ↑ risk of thrombus) PV is a clonal **myeloproliferative** disorder characterized by erythrocytosis (increase in red blood cell mass). It is a primary form of polycythemia, almost always caused by a JAK2 mutation. Normally, red blood cell production is dependent on erythropoietin (EPO), a cytokine released by the kidneys (and liver) in response to **tissue hypoxia**; EPO activates the JAK2 tyrosine kinase, which differentiates late myeloid cells into erythrocytes. In PV, red blood cell production is driven by a constitutively active JAK2 gene rather than by tissue hypoxia; therefore, **EPO levels tend to be low.** **Px: Aquagenic pruritus** (itching after bathing), **facial plethora** (ruddy cyanosis), **splenomegaly**, and elevations in all 3 cell lines on complete blood count. Findings of a hemoglobin level greater than 18.5 g/dL in men or greater than 16.5 g/dL in women invariably indicate an elevated red blood cell mass. Concomitant leukocytosis (often with basophilia) and thrombocytosis (suggesting trilineage myeloproliferation) as well as hepatosplenomegaly further support the diagnosis. In addition, more than 97% of patients with PV have an activating mutation in the signaling protein **JAK2 (JAK2 V617F mutation)**. Serum erythropoietin levels are usually suppressed; measurement of the red blood cell mass, previously a diagnostic study for PV, is no longer done. Tx: 🧯**Low-dose aspirin** has been shown to decrease the risk of thrombosis and should be given to all patients in the absence of contraindications. **Phlebotomy** results in the highest overall survival rates and should be performed **once or twice weekly** until a target hematocrit value of less than 45% is achieved, followed by intermittent phlebotomy to maintain the hematocrit value between 40% and 45%.

Answer 70

Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome), an autosomal dominant disorder characterized by diffuse telangiectasias (eg, ruby-colored papules that blanch with pressure), recurrent epistaxis, and widespread arteriovenous malformations (AVMs). In hereditary hemorrhagic telangiectasia, AVMs tend to occur in the mucous membranes, skin, and gastrointestinal tract, but may also be present in the liver, brain, and lung. AVMs in the lungs can shunt blood from the right to the left side of the heart, causing chronic hypoxemia, digital clubbing, and a **reactive polycythemia**. Pulmonary AVMs can also present as massive, sometimes fatal, hemoptysis.

Answer 71

Patients with complement deficiencies are at increased risk for **disseminated bacterial infections,** particularly with 🔮 **encapsulated bacteria (eg, Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis)**.

Answer 72

Clinical features * Majority of cases X-linked recessive * Recurrent pulmonary & cutaneous infections * **🐱 Catalase-positive pathogens** (eg, Staphylococcus aureus, Serratia, Burkholderia, Aspergillus) Diagnosis * Neutrophil function testing * Dihydrorhodamine 123 test * Nitroblue tetrazolium test Chronic granulomatous disease involves abnormalities of the enzyme **NADPH oxidase**, which is responsible for the **"respiratory burst"** (formation of **superoxide radicals**). Patients have decreased production of superoxide anions, so phagocytes migrate to and surround infection sites but are unable to neutralize invading organisms, resulting in characteristic **granuloma formation** and susceptibility to infections with **fungal organisms** and **catalase-positive bacteria** (eg, S aureus, Serratia). Diagnosis is made by the **dihydrorhodamine 123 test or the nitroblue tetrazolium test.** There is no specific treatment for chronic granulomatous disease. Management is focused on infection prevention (prophylaxis against bacterial and fungal pathogens) and appropriate detection and treatment of infections that do arise.

Answer 73

LAD is caused by defective integrins on the leukocyte surface, which normally allow neutrophils to adhere to vascular endothelium, exit the vasculature, and migrate to areas of infection or inflammation. Patients have decreased production of superoxide anions, so phagocytes migrate to and surround infection sites but are unable to neutralize invading organisms, resulting in characteristic **granuloma formation (pus?)** and susceptibility to infections with fungal organisms and catalase-positive bacteria (eg, S aureus, Serratia). Lack of neutrophil migration in LAD results in recurrent **skin 🤡 (eg, cellulitis, abscess, omphalitis) and mucosal (eg, periodontal) infections** as well as **poor wound healing.** Examination shows inflammation with a notable lack of purulence. Biopsy of infected tissue is devoid of neutrophils and culture often grows **Staphylococcus aureus or Gram-negative bacilli.** Peripheral serum studies show marked leukocytosis and **neutrophilia**, particularly during episodes of infection. Classically, the first presenting sign of LAD is ⌚**delayed umbilical cord separation** (age \>3 weeks).

Answer 74

Etiology * X-linked recessive defect in WAS protein gene * Impaired cytoskeleton changes in leukocytes, platelets Clinical features * Eczema * Microthrombocytopenia (small platelets, low platelet count) * Recurrent infections Treatment * Stem cell transplant WAS is caused by an X-linked recessive defect in the WAS gene. This gene is primarily expressed in hematopoietic cells and regulates cytoskeleton remodeling in response to cell signaling. In WAS, the actin **cytoskeleton** in white blood cells is abnormal, resulting in immune dysfunction due to impaired cellular migration and immune synapse formation. Patients are at increased risk for recurrent **bacterial, viral, and fungal infections.** Similarly, the cytoskeleton of platelets is also dysfunctional. Virtually all patients have significantly **decreased platelet counts** and size at the time of diagnosis. The resulting clinical findings can range from petechiae or purpura to severe bleeding such as intracranial hemorrhage, hematemesis, or hematochezia. In addition, autoimmune disorders (eg, eczema) occur in most patients with WAS. The treatment of WAS is hematopoietic stem cell transplantation.

Answer 75

Severe and recurrent **sinopulmonary infections** (including intubation, tympanostomy tubes, and poor growth) that are concerning for humoral immunodeficiency. Complete blood count with differential, lymphocyte T and B cell subsets, and serum IgG, IgA, and IgM are important screening tests. HIV infection should also be excluded.

Answer 76

One of the most common immunodeficiency syndromes. Most patients are **asymptomatic**, but some have **recurrent respiratory, gastrointestinal, and/or urogenital infections.** Serum IgA is low, whereas **IgM is normal**

Answer 77

Due to an X-linked genetic defect in the **CD40** ligand. The CD40 ligand is present on **T cells** and binds to CD40 expressed on B cells, which induces a change in B cell production of IgM to other immunoglobulins (class switching). The absence of the CD40 ligand **prevents class switching**, leading to: **"Elevated IgM levels AND a deficiency of ALL other immunoglobulin types**." CD40 ligand deficiency also inhibits plasma cell formation, which contributes to poor response to infection and immunization. Patients with hyper-IgM syndrome have **recurrent sinopulmonary infections (eg, acute otitis media, pneumonia, sinusitis)** with **encapsulated bacteria.** They also tend to have more frequent **viral** infections and increased risk of **opportunistic infections**, such as **Pneumocystis jirovecii** **pneumonia**. **Growth impairment** can result from high energy expenditure and poor intake during illness. **Tx:** Treatment includes antibiotic prophylaxis and interval administration of **intravenous immunoglobulin.**

Answer 78

Manifestations * **Recurrent respiratory** (eg, pneumonia, sinusitis, otitis) & GI (eg, Salmonella, Campylobacter) infections * **Autoimmune disease** (eg, RA, thyroid disease) * **Chronic lung disease** (eg, bronchiectasis) * **GI disorders** (eg, chronic diarrhea, IBD-like conditions) Diagnosis * **↓↓ IgG, ↓ IgA/IgM** * No response to vaccination * N**ormal B lymphocyte count** * Immunoglobulin replacement therapy Abnormal B-cell differentiation results in deficiency of multiple immunoglobulin classes (IgG and **either IgA, IgM, or both**). CVID is one of the most common primary immunodeficiencies in adults and is characterized mainly by increased susceptibility to bacterial infection. **Recurrent respiratory infections (eg, pneumonia, sinusitis, otitis)** and **gastrointestinal infections (eg, Salmonella, Campylobacter)** are common, and the latter may lead to episodes of 💩**bloody diarrhea**. Chronic giardiasis may occur, but opportunistic infections (eg, Candida, Pneumocystis jirovecii) are rare. Other characteristics of CVID include **concomitant autoimmune disease (eg, hemolytic anemia, rheumatoid arthritis, pernicious anemia),** inflammatory bowel-like disease, granuloma development, and increased risk for non-Hodgkin lymphoma. Enteropathy (eg, sprue-like illness) is common, and affected patients may present with malabsorption and weight loss. The majority of patients are diagnosed in adulthood **(age 20-45)** due to a combination of variable presentation and diagnostic delay. Diagnosis is made by quantitative measurement of immunoglobulin levels (significantly reduced serum IgG with low levels of IgA and/or IgM) as well as by markedly reduced or absent immune response to vaccination. Management of CVID is focused on avoiding infection, so the mainstay of treatment is **intravenous immunoglobulin infusion**. Early initiation of therapy may prevent some complications of chronic infection. Patients with CVID have increased risk of autoimmune disease and certain malignancies regardless of treatment.

Answer 79

**Defective 🅱 lymphocyte maturation** occurs in X-linked agammaglobulinemia (Bruton). Recurrent **sinopulmonary and gastrointestinal infections with low B cell and immunoglobulin concentrations** are typical. Characterized by **low IgG, IgM, and IgA** as well as **low or absent B lymphocytes**

Answer 80

SCID is a severe primary immunodeficiency caused by one of several gene defects leading to failure of **T cell** development. Without cellular immunity, patients with SCID are at high risk for infections with **viruses, fungi (eg, Candida [thrush]), and opportunistic pathogens (eg, Pneumocystis jirovecii)**. The loss of **helper T cell** function also **causes B cell dysfunction** (ie, impaired humoral immunity) and recurrent **sinopulmonary bacterial infections (eg, pneumonia, otitis media)**. In addition to infection, **failure to thrive** and **chronic diarrhea** in infancy are typical. A variety of gene defects can cause SCID and all prevent interleukin-7-driven maturation of T cells in the thymus. **Tx: Stem cell transplantation** is the only definitive therapy and should be performed as early as possible. Replacement of defective immature T cells with normal hematopoietic cells allows the development of a functional immune system. SCID is usually fatal in early childhood unless transplantation is performed.

Answer 81

**Adenosine deaminase deficiency** is an autosomal recessive form of severe combined immunodeficiency, which is characterized by deficient formation of mature B and T lymphocytes. Severe combined immunodeficiency presents with severe infections and failure to thrive. Laboratory studies show marked lymphopenia.

Answer 82

Type I * Lymphoproliferative or hematologic (eg, multiple myeloma) * Asymptomatic * Hyperviscosity (eg, blurry vision), thrombosis (eg, Raynaud phenomenon) * Skin: Livedo reticularis, purpura * Complement levels: **Normal** Mixed (types II & III) * Chronic HCV, HIV * Systemic lupus erythematosus * **Systemic: Fatigue, arthralgias** * Renal: **Glomerulonephritis**, HTN * Pulmonary: Dyspnea, pleurisy * Skin: **Palpable purpura**, LCV * **Low C4** **Mixed cryoglobulinemia syndrome (MCS)** is caused by immune complex deposition in small- to medium-size blood vessels, leading to endothelial injury and end-organ damage. It commonly presents with fatigue; nonblanching, palpable purpura; arthralgias; renal disease (eg, hematuria, proteinuria, glomerulonephritis); and peripheral neuropathies. Renal involvement is variable, but the most common manifestation is **hypertension**. Liver involvement (eg, e**levated transaminases**) is common. Patients rarely may have central nervous system or pulmonary involvement. MCS is most commonly associated with chronic inflammatory conditions such as hepatitis C virus (HCV) infection and systemic lupus erythematosus. Consequently, every patient suspected of having MCS should be tested for HCV, hepatitis B virus, and HIV. HCV-associated MCS immune complexes are formed from HCV, anti-HCV IgG, IgM anti-IgG antibodies (rheumatoid factor), and complement. Diagnosis of MCS can be confirmed serologically (**serum cryoglobulins, low complement levels**) or with a **skin/renal biopsy**. Treatment involves addressing the underlying disease and can also include **plasmapheresis** and **immunosuppression** (eg, glucocorticoids, rituximab) for patients with rapidly progressive or life-threatening courses.

Answer 83

**Galactosemia** is characterized by defective metabolism of galactose, a breakdown product of lactose that is then normally metabolized to glucose. First, lactose is broken down to galactose and glucose. Galactose is then phosphorylated to galactose-1-phosphate by the enzyme galactokinase (GALK). **GALK deficiency** causes galactose buildup and this excess is converted to galactitol, an osmotic agent that causes **cataracts**. Excess galactose also spills into the urine and causes it to test positive for a reducing substances (sugars). Serious systemic manifestations are not seen in GALK deficiency, and **cataracts** may be the only manifestation. **Galactose-1-phosphate uridyl transferase (GALT) deficiency** causes the most severe and **most common (classic)** form of galactosemia. This is related to the accumulation of galactose-1-phosphate, a toxic metabolite that causes hepatic and renal dysfunction. Consequently, patients with GALT deficiency present early, in the neonatal period, with **vomiting, jaundice, hepatomegaly, lethargy, and failure to thrive** during the first few days of life due to inability to digest breast milk or formula. Both direct and indirect bilirubin levels may be elevated. Excess galactose is converted to galactitol by aldose reductase, resulting in **cataracts** from excess galactitol deposition in the lens.

Answer 84

Single, round, blue inclusions within red blood cells (RBCs) on peripheral smear, consistent with **Howell-Jolly bodies**. These bodies are retained RBC nuclear remnants that are typically removed by the spleen. The presence of Howell-Jolly bodies usually indicates either physical absence of the spleen (ie, **asplenia**) due to congenital absence or surgical removal or functional hyposplenism due to splenic **autoinfarction** (eg, **sickle cell disease**), infiltrative disorders of the spleen (eg, **sarcoidosis**), or **splenic congestion** (eg, **thrombosis**). Both asplenia and functional hyposplenism increase the risk of **sepsis** because **the spleen is normally responsible for clearing bacteria,** particularly encapsulated organisms. However, splenectomy may be indicated in cases of chronic hemolysis.

Answer 85

Glucocorticoid use causes a leukocytosis due to the following: Mobilization of marginated neutrophils into the bloodstream (predominant mechanism): Marginated neutrophils are attached to the endothelium of blood vessels; glucocorticoid-induced mobilization of these neutrophils leads to a higher number of circulating neutrophils Stimulation of release of immature neutrophils from the bone marrow (as evidenced by the 3% band forms in this patient) Inhibition of neutrophil apoptosis In contrast, glucocorticoids decrease the number of circulating lymphocytes and eosinophils through a combination of increased apoptosis, increased emigration into the tissues, and decreased production.

Answer 86

ACE inhibitors are the most common cause of acquired angioedema. Patients present with edema in the face, mouth, lips, tongue, glottis and larynx. Laryngeal edema can cause airway obstruction and be life threatening. Angioedema occurs due to the pro-inflammatory action of bradykinin, which promotes edema, inflammation and the sensation of pain. Angiotensin converting enzyme (ACE) is also known as kininase; it functions to degrade bradykinin. When ACE is inhibited, levels of bradykinin increase, thereby leading to angioedema. ACE inhibitors are usually started on the first post-infarction day in non-hypotensive patients, and patients typically present with angioedema within days to weeks after starting therapy (as in this patient). However, it is important to note that angioedema from ACE inhibitors can occur at ANYTIME, not just within weeks of starting the medication. The first step in management of angioedema is to check for airway compromise and vasomotor instability, which require subcutaneous epinephrine administration if present. If airway obstruction fails to respond to epinephrine, an emergency tracheostomy is done. The ACE-inhibitor should be stopped immediately.

Answer 87

**Basophilic stippling** represents ribosomal precipitates that appear as blue granules of various sizes dispersed throughout the cytoplasm of red blood cells. It is seen with **thalassemias** as well as lead or **heavy metal poisoning.** **Burr cells** (also known as echinocytes) are spiculated appearing red blood cells (RBCs) with serrated edges that can be seen in liver disease and end-stage renal disease (ESRD). **Heinz bodies**, which appear as small inclusions within an erythrocyte, are aggregates of denatured hemoglobin and are commonly seen in patients with hemolysis due to **glucose-6-phosphate dehydrogenase deficiency** and thalassemia. When phagocytes extract this rigid precipitate, they form characteristic **bite cells**. **Helmet cells**, or schistocytes, are fragmented red blood cells. Their presence suggests traumatic microangiopathic **hemolytic conditions such as disseminated intravascular coagulation, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura.** **Howell-Jolly (HJ) bodies** are basophilic remnants of the nucleus that appear as small, black pellets in RBCs. They are seen in patients with a history of **splenectomy** or functional asplenia. HJ bodies are not seen in healthy individuals as a normal spleen efficiently removes them. **Spur cells (acanthocytes)** are RBCs with irregularly sized and spaced projections that are most commonly seen in **liver disease.** **Target cells** are red blood cells with a central density surrounded by pallor (bull's eye appearance). They are usually seen in patients with **hemoglobinopathies** (eg, thalassemia) or chronic liver disease (especially obstructive liver disease).

Answer 88

Encapsulated organisms such as **S pneumoniae, Haemophilus influenzae, and Neisseria meningitidis** have a polysaccharide exterior that conceals antigenic epitopes and resists innate phagocytosis. Therefore, these pathogens are largely eliminated via the humoral immune response with **antibody-mediated phagocytosis (opsonization) and antibody-mediated complement activation.** Much of this is dependent on splenic macrophages and the generation of splenic opsonizing antibodies. As such, patients with asplenia are at high risk for fulminant infection with encapsulated organisms. 💉These patients should be immunized with pneumococcal, **meningococcal**, and H influenzae type B vaccines and take oral antibiotics early in the course of any febrile illness.

Answer 89

History * Exposure to oxidizing substances (eg, dapsone, nitrites, * local/topical anesthetic) Clinical examination * Cyanosis * **Pulse oximetry saturation ~85%** * Dark chocolate-colored blood Laboratory findings * Saturation gap (\>5% difference between oxygen saturation on pulse oximetry & ABG) * **Normal PaO2** Methemoglobinemia is an uncommon complication that can occur after excessive exposure to an oxidizing agent (eg, dapsone, nitrites, local/topical anesthetics) and results in cyanosis. Additional clinical features may include lethargy, respiratory depression, seizures, and death. In normal hemoglobin, iron is in the ferrous (Fe2+) state. When exposed to an oxidizing agent, at least one of the four iron molecules is oxidized to the ferric (Fe3+) state, resulting in acute methemoglobinemia. Ferric iron is unable to bind oxygen; in addition, the ferric state changes the hemoglobin structure and causes ferrous sites to have an increased affinity for oxygen (ie, "left shift" on oxygen-dissociation curve). The increased oxygen affinity prevents oxygen release in peripheral tissues (ie, decreased oxygen delivery). Because methemoglobin absorbs light at a different wavelength than hemoglobin, patients have pulse **oximetry readings of ~85% regardless of the true oxygen saturation level**. Supplemental oxygen has no effect on the altered methemoglobin structure; therefore, it does not improve cyanosis, blood color, or pulse oximetry readings. In contrast, **arterial blood gas testing analyzes only unbound arterial oxygen (as opposed to hemoglobin-bound oxygen) and displays a falsely elevated oxygen saturation level, shown as normal PaO2.** **Tx:** The antidote for acquired symptomatic methemoglobinemia or high levels of methemoglobin (as measured by co-oximetry) is methylene blue. Methylene blue acts as an electron acceptor for NADPH and is reduced to leucomethylene blue, which in turn reduces methemoglobin to hemoglobin. High-dose ascorbic acid (vitamin C) acts as a reducing agent and can be used when methylene blue is unavailable or contraindicated (eg, glucose-6-phosphate deficiency).

Answer 90

Neutropenia is defined as an absolute neutrophil count (ANC) \<1500/µL (severe neutropenia is ANC \<500/µL). Patients with ANC \<1000/µL are at higher risk for overwhelming bacterial infection due to an absent or blunted neutrophil-mediated inflammatory response. Chemotherapy may also lead to disruption of the skin and mucosal barrier of the mouth and gastrointestinal tract, resulting in mucositis and subsequent translocation of the bacteria into the bloodstream. Gram-negative organisms, particularly Pseudomonas aeruginosa, are most frequently identified. Gram-positive infections are also common and increasing in frequency. Febrile neutropenia is a medical emergency, and starting early empiric antibiotic therapy can avoid progression of infection to severe sepsis and life-threatening complications. Initial evaluation includes blood and urine cultures, followed by immediate intravenous broad-spectrum antibiotics. Monotherapy with an anti-pseudomonal beta-lactam agent (eg, cefepime, meropenem, piperacillin-tazobactam) provides both gram-negative and gram-positive coverage and is recommended initially.

Answer 91

The location of the lymphadenopathy can be a helpful predictor of the likelihood of a pathologic versus benign cause. Specifically, whereas mediastinal, supraclavicular, and abdominal lymphadenopathy have a greater likelihood of a pathologic cause, cervical, axillary, and inguinal lymphadenopathy have a greater likelihood of a benign cause. Size can be a helpful predictor of whether lymphadenopathy is benign or pathological, lymph nodes \<2 cm frequently are from benign causes, and those ≥2 cm are more likely to be associated with a pathological cause. Most infectious and immunologic causes of lymphadenopathy resolve within 2 weeks, and persistence for less than 2 weeks is reassuring for a benign cause of lymphadenopathy. If a benign cause of lymphadenopathy is suspected, an observation period of at least 4 weeks is considered appropriate before pursuing additional diagnostic studies.

Answer 92

Squamous cell carcinoma in a **cervical lymph node**, especially in a smoker, likely has a mucosal **head and neck primary site** and requires examination of the laryngopharyngeal mucosa. Abdominal malignancies (eg, stomach, pancreas, colon, ovaries) can spread via the thoracic duct to the left **supraclavicular lymph nodes (Virchow node)**—an ominous sign. Most of these abdominal malignancies are **adenocarcinomas.** **Breast cancer** commonly affects the **axillary** and **internal mammary lymph nodes.** **HCC** typically metastasizes to the **lungs**, portal vein, and portal lymph nodes. **Thyroid cancer** metastasizes to cervical nodes. Cancers are **papillary**, **Gastrointestinal malignancies**, such as colorectal or pancreatic cancer, are the most frequent source of **liver** metastases as their venous drainage is through the portal system directly to the liver. Lung, breast, and skin cancers (melanoma) often also spread to the liver. The liver is a common site of metastatic disease due to its dual blood supply (systemic and portal) and hepatic sinusoidal fenestrations allowing for easier metastatic deposition. Multiple hepatic nodules are typically seen in metastatic disease; however, solitary lesions are not uncommon.

Answer 93

**Calcineurin inhibitors** (eg, **tacrolimus**, **cyclosporine**) inhibit the transcription of IL-2 to reduce T-lymphocyte activity and are an important component of chronic immunosuppression following solid-organ transplantation. Although these drugs are generally well tolerated, they have numerous adverse effects that must be monitored. These include: * **Nephrotoxicity**: Calcineurin inhibitors have **vasoconstrictive properties** that can lead to reversible acute kidney injury (usually in the setting of elevated blood levels of the drug) or slowly progressive, chronic kidney injury that is typically irreversible. Associated electrolyte abnormalities are also common and include hyperkalemia and hyperuricemia with increased rates of gout. * **Hypertension**: The **vasoconstrictive properties** can also cause hypertension, both by triggering increased sodium retention by the kidneys and through increased arteriolar peripheral resistance. * **Neurotoxicity**: These effects may be due to low levels of **vasoconstrictive** cerebellar or cerebral ischemia. **Tremor** is a common manifestation; it can be either resting or with intention and often improves over time. Other less common and more serious effects include visual disturbance and seizures. * **Glucose intolerance** (eg, increased insulin requirements): Calcineurin inhibitors impair the secretion of insulin from pancreatic islet cells, contributing to hyperglycemia. Tacrolimus appears to have a stronger hyperglycemic effect than cyclosporine. * **Cosmetic effects:** **Gingival hypertrophy** (mostly with cyclosporine), hirsutism, and alopecia can occur. * **Gastrointestinal disturbance:** These effects are usually mild and can include anorexia, nausea, vomiting, and diarrhea. As with most immunosuppression drugs, calcineurin inhibitors also **increase the risk of infection and malignancy** (eg, squamous cell skin cancer, lymphoma). **Cyclophosphamide** An alkylating agent frequently used as an immunosuppressant in systemic lupus erythematosus, vasculitis and certain cancers. Regarding SLE, cyclophosphamide is reserved for patients with significant renal or central nervous system problems. Unfortunately, cyclophosphamide has many side effects. Serious side effects include acute h**emorrhagic cystitis, bladder carcinoma, sterility, and myelosuppression**. Hemorrhagic cystitis and bladder cancer are caused by acrolein, a bladder-toxic metabolite of cyclophosphamide. Drinking plenty of fluids, voiding frequently, and taking **MESNA** are all helpful in preventing these complications. **Azathioprine** inhibits purine synthesis to impair the replication of lymphocytes and is sometimes used for chronic transplant immunosuppression. Common adverse effects include **bone marrow suppression** and **hepatotoxicity**. **Low-dose prednisone** is commonly used for chronic transplant immunosuppression. Adverse effects are many and include **glucose intolerance and hypertension**.

Answer 94

Methotrexate * Folate antimetabolite * **Hepatotoxicity** * Stomatitis * **Cytopenias** Leflunomide * Pyrimidine synthesis inhibitor * **Hepatotoxicity** * **Cytopenias** Hydroxychloroquine * TNF & IL-1 suppressor * **Retinopathy (after 5-7 years)** * **Renal toxixity (rare)** Sulfasalazine * TNF & IL-1 suppressor * Hepatotoxicity * Stomatitis * Hemolytic anemia TNF inhibitors (eg, adalimumab, certolizumab, **etanercept**, golimumab, infliximab) * Infection * Demyelination * **Congestive heart failure** * Malignancy

Answer 95

Bilateral edema: CHF (dyspnea, rales, or JVD) would necessitate a chest x-ray to rule in the diagnosis, followed by an echocardiogram. Liver Failure: Ascities; Dx: Liver function studies are needed. If these are absent, the clinician should check an urinalysis. If the sediment is abnormal, nephritic syndrome or acute tubular necrosis (ATN) is the likely diagnosis. Medications: Antihypertensives (ACE), such as calcium channel blockers are well known to cause this, but direct vasodilators, β-blockers, centrally acting agents, and antisympathetics also can cause edema. Of the diabetic medications, insulin sensitizers, such as rosiglitazone often cause edema. Hormones, corticosteroids, and NSAIDs also cause problems. Unilateral Edema: Angioedema Hereditary: Dx: C4 level and C1 esterase Drug-induced: Urticaria Chronic spontaneous Hx: