Medical hematologic disorder exam

Folic acid deficiency (another cause of megaloblastic anemia) • Myelodysplastic syndrome (another cause of macrocytic anemia with abnormal morphology) • Other causes of peripheral neuropathy, ataxia, or dementia

Muscular strain • Baker cyst • Achilles tendon rupture • Cellulitis • Superficial thrombophlebitis • Lymphatic obstruction (eg, from pelvic tumor) • Reflex sympathetic dystrophy • Tumor or fibrosis obstructing venous flow • May-Thurner syndrome (left iliac vein compressed by the right common iliac artery)

Complete blood count, including platelet count, PT/INR, and aPTT. • Assays and polymerase chain reaction to measure activated protein C resistance and AT, protein C, and protein S levels. • Lupus anticoagulant: prolonged aPTT that does not correct completely on mixing study (mixing with normal plasma containing clotting factors) indicates the presence of an anticoagulant and not a factor deficiency. • Specialized testing for lupus anticoagulant confirmation: hexagonal phase phospholipid neutralization assay, dilute Russell viper venom time, platelet neutralization assays.

Patients with symptoms or signs of DVT or PE should receive ultrasonography with Doppler of lower extremity venous system or helical chest CT scanning, respectively.

Serum ferritin <12 or <30 μg/L if also anemic; and response to iron therapy • Caused by bleeding in adults unless proved otherwise

Ferrous sulfate, 325 mg orally three times daily, is the treatment of choice; it may cause nausea and constipation; introducing the medicine slowly in gradually escalating doses may increase its tolerability, as may taking it with food (reduces side effects but also its absorption) • Extended-release ferrous sulfate with mucoprotease is the best tolerated oral preparation. • Continue iron therapy for 3 to 6 months after restoration of normal CBC to replenish bone marrow iron stores. • Failure of response to iron therapy is usually caused by medication nonadherence but may be caused by ongoing blood loss, poor absorption, or incorrect diagnosis (eg, anemia of chronic disease, thalassemia, celiac disease). • Refractory response is defined as a hemoglobin increment of <1 g/dL (10 g/L) after 4 to 6 weeks of 100 mg/d of elemental oral iron. • Causes of malabsorption include malabsorption from autoimmune gastritis, Helicobacter pylori gastric infection, celiac disease, and hereditary iron-refractory iron deficiency. • Indications for parenteral iron are intolerance or refractoriness to oral iron or continued blood loss that cannot be corrected. • Parenteral iron preparations include iron dextran or polyglucose sorbitol carboxymethyl ether coated magnetite (ferumoxytol). • For patients with end-stage chronic kidney disease, ferric pyrophosphate citrate (Triferic) can be added to the dialysate to replace the 5 to 7 mg of iron lost at each hemodialysis.

Anticoagulation with heparin and then warfarin for most patients with thrombosis. • Target–specific oral anticoagulants have a predictable dose effect, few drug–drug interactions, rapid onset and freedom from laboratory monitoring. Dabigatran, rivaroxaban, and apixaban are approved, and are noninferior to heparin and warfarin, for treatment of acute DVT and PE. Rivaroxaban and apixaban entail a lower bleeding risk. • If thrombosis is recurrent, lifelong anticoagulation is usually recommended. • Unfractionated heparin therapy is difficult to monitor in lupus anticoagulant because of the in vitro prolongation of the aPTT in that condition; therefore, low-molecular-weight heparin (LMWH) is preferred. • During pregnancy, prophylaxis with LMWH should be provided for lupus anticoagulant.

Microcytic anemia resulting from other causes Thalassemia Anemia of chronic disease Sideroblastic anemia Lead poisoning

Diagnosis can be made by Laboratory confirmation of an iron-deficient state Evaluation of response to a therapeutic trial of iron replacement • Reticulocyte count is low or inappropriately normal. • A ferritin value <12 μg/L is a highly reliable indicator of depletion of iron stores. • A ferritin level of <30 μg/L almost always indicates iron deficiency in anyone who is anemic. • As iron deficiency progresses, serum iron values decline to <30 μg/dL and transferrin levels rise to compensate, leading to transferrin saturations of <15%. • As deficiency progresses, anisocytosis (variation in red blood cell [RBC] size) and poikilocytosis (variation in RBC shape) develop. • An abnormal peripheral blood smear shows markedly hypochromic cells, target cells, hypochromic pencil-shaped or cigar-shaped cells, and occasionally small numbers of nucleated RBCs in severe iron deficiency; platelet count is commonly increased, but it usually remains <800,000/μL. • Bone marrow biopsy for evaluation of iron stores Rarely performed If done, shows the absence of iron in erythroid progenitor cells by Prussian blue staining • As the MCV falls (ie, microcytosis), the blood smear shows hypochromic microcytic cells.

Bone marrow morphology shows marked erythroid hyperplasia, megaloblastic changes in erythroid series, and giant bands and metamyelocytes in myeloid series.

Anticoagulant therapy is the cornerstone of medical therapy. • LMWHs are more effective than unfractionated heparin in the immediate treatment of DVT and PE and are preferred because of predictable pharmacokinetics. • Fondaparinux (a factor Xa inhibitor) may be used for immediate treatment and shows no increase in bleeding risk. Its lack of reversibility, long half-life, and primarily kidney clearance are limitations to its use. • After initial therapy with either LMWH or fondaparinux, dose-adjusted vitamin K antagonist (eg, warfarin) is started. • The target-specific oral anticoagulants rivaroxaban and apixaban are approved as monotherapy immediately following diagnosis and eliminate the need for parenteral therapy. Dabigatran requires 5 to 10 days of parenteral anticoagulation followed by transition to this oral agent. All three are approved and noninferior to LMWH and warfarin with respect to prevention of recurrent VTE; both rivaroxaban and apixaban entail a lower bleeding risk. These agents have a predictable dose effect, few drug–drug interactions, and freedom from laboratory monitoring. • LMWH is still the preferred agent for treatment of cancer-related VTE. • Duration of treatment is for a minimum of 3 months for provoked DVT; lifelong treatment should be considered in patients with unprovoked DVT.

Surgical thrombectomy or directed thrombolysis, especially in large iliofemoral thromboses.

Predisposition to venous thrombosis • Pain, swelling, and redness below the level of the thrombus • Presence of thromboembolic disease such as PE

Ferrous sulfate, 325 mg orally three times daily, is the treatment of choice; it may cause nausea and constipation; introducing the medicine slowly in gradually escalating doses may increase its tolerability, as may taking it with food (reduces side effects but also its absorption) • Extended-release ferrous sulfate with mucoprotease is the best tolerated oral preparation. • Continue iron therapy for 3 to 6 months after restoration of normal CBC to replenish bone marrow iron stores. • Failure of response to iron therapy is usually caused by medication nonadherence but may be caused by ongoing blood loss, poor absorption, or incorrect diagnosis (eg, anemia of chronic disease, thalassemia, celiac disease). • Refractory response is defined as a hemoglobin increment of <1 g/dL (10 g/L) after 4 to 6 weeks of 100 mg/d of elemental oral iron. • Causes of malabsorption include malabsorption from autoimmune gastritis, Helicobacter pylori gastric infection, celiac disease, and hereditary iron-refractory iron deficiency. • Indications for parenteral iron are intolerance or refractoriness to oral iron or continued blood loss that cannot be corrected. • Parenteral iron preparations include iron dextran or polyglucose sorbitol carboxymethyl ether coated magnetite (ferumoxytol). • For patients with end-stage chronic kidney disease, ferric pyrophosphate citrate (Triferic) can be added to the dialysate to replace the 5 to 7 mg of iron lost at each hemodialysis.

Temporary inferior vena cava filters may be placed in selected clinical situations.

DVT and PE are two manifestations of the same disease. • DVT may be in the upper or lower extremity, although it most commonly occurs in the legs. • DVTs proximal to the knee (popliteal and iliofemoral) embolize more often than distal thrombi. • Risk factors include venous stasis (eg, immobility, hyperviscosity, low cardiac output), injury to the vessel wall, and hypercoagulability (eg, oral contraceptives, inherited hypercoagulable states, malignancy).

Normal vitamin B12 level is >210 pg/mL. • Serum vitamin B12 levels in overt deficiency: 1000 nmol/L) or serum homocysteine (>16.2 mmol/L). • The anemia of vitamin B12 deficiency is typically moderate to severe with the MCV quite elevated (110–140 fL); however, MCV may be normal. • Peripheral blood smear is megaloblastic, defined as red blood cells that appear as macro-ovalocytes, (although other shape changes are usually present) and neutrophils that are hypersegmented (six [or greater]-lobed neutrophils). • Reticulocyte count is reduced. • In severe cases, white blood cell count and platelet count are reduced. • Serum lactate dehydrogenase (LDH) is elevated, and indirect bilirubin is modestly increased.

Symptoms of anemia (eg, easy fatigability, dyspnea, tachycardia, palpitations and tachypnea on exertion). • Skin and mucosal changes (eg, smooth tongue, brittle nails, spooning of nails [koilonychia], and cheilosis) in severe iron deficiency. • Dysphagia resulting from esophageal webs (Plummer-Vinson syndrome) in severe iron deficiency. • Pica (ie, craving for specific foods [eg, ice chips, lettuce] often not rich in iron) is frequent.

Pain, swelling, and redness below the level of the thrombus; usually unilateral. • Normal arterial pressures and perfusion in the distal extremity. • Homan sign: pain in the calf with dorsiflexion of the ankle (limited sensitivity). • DVT may be detectable as a palpable cord in the calf. • DVT may be associated with symptoms and signs of PE (eg, dyspnea, chest pain, tachycardia, and tachypnea).

Hypercoagulable states may be inherited or acquired. • Inherited causes: activated protein C resistance or factor V Leiden (most common); protein C, protein S, or AT deficiency; hyperprothrombinemia (prothrombin 20212AG mutation); hyperhomocysteinemia; dysfibrinogenemia; abnormal plasminogen. • Acquired causes: immobility—bedrest (especially postoperative), stroke, obesity; cancer; inflammatory disorders, eg, ulcerative colitis; myeloproliferative disorder, eg, polycythemia vera causing hyperviscosity or essential thrombocytosis; estrogens; pregnancy; heparin-induced thrombocytopenia; lupus anticoagulant; nephrotic syndrome; paroxysmal nocturnal hemoglobinuria; disseminated intravascular coagulation; heart failure. • Lupus anticoagulants may occur in patients with or without systemic lupus erythematosus or other underlying diseases. • Patients with recurrent or serious thrombosis, a family history of thrombosis, spontaneous abortions, and systemic lupus erythematosus as well as patients without DVT or PE risk factors should be evaluated for hypercoagulable states.

Thrombosis, often in the deep veins of the legs • Clues to a hypercoagulable state are personal or family history of clotting, presence of systemic disease, and no provoking factor associated with thrombosis • Prolonged clotting times in some diseases

Macrocytic anemia • Megaloblastic peripheral blood smear (macro-ovalocytes and hypersegmented neutrophils on peripheral blood smear) • Low serum vitamin B12 level

A negative D-dimer result can rule out DVT in patients with low pretest probability. • Patients may need further laboratory tests for inherited hypercoagulable disorders. The evaluation should be delayed for 3 months because factors such as proteins C and S are consumed during the acute PE.

Causes a moderate-to-severe anemia of slow onset such that patients may have few symptoms relative to their degree of anemia • Pallor and mild icterus or sallow complexion • Glossitis and vague gastrointestinal disturbances (eg, anorexia, diarrhea) • Neurologic manifestations Peripheral neuropathy usually occurs first. Then, subacute combined degeneration of the spinal cord affecting posterior columns may develop, causing difficulty with position and vibration sensation and balance. In advanced cases, dementia and other neuropsychiatric changes may occur. Neurologic manifestations occasionally precede hematologic changes; patients with suspicious neurologic symptoms and signs should be evaluated for vitamin B12 deficiency despite normal mean cell volume (MCV) and absence of anemia.

Inherited causes of hypercoagulable states: activated protein C resistance or factor V Leiden (most common); protein C, protein S, or AT deficiency; hyperprothrombinemia (prothrombin 20212AG mutation); hyperhomocysteinemia; dysfibrinogenemia; abnormal plasminogen. • Acquired causes of hypercoagulable states: immobility—bedrest (especially postoperative), stroke, obesity; cancer; inflammatory disorders, eg, ulcerative colitis; myeloproliferative disorder, eg, polycythemia vera causing hyperviscosity or essential thrombocytosis; estrogens; pregnancy; heparin-induced thrombocytopenia; lupus anticoagulant; nephrotic syndrome; paroxysmal nocturnal hemoglobinuria; disseminated intravascular coagulation; heart failure • DVT: cellulitis, trauma, superficial thrombophlebitis, venous insufficiency • PE: MI, pneumothorax, thoracic aneurysmal rupture, pneumonia, pleuritic infection or inflammation, chest wall trauma, asthma or COPD exacerbation

Vitamin B12 is absorbed from the diet (foods of animal origin) in the terminal ileum after binding to intrinsic factor, a protein secreted by gastric parietal cells, and stored in the liver. • Stores take at least 3 years to deplete after vitamin B12 absorption ceases. • Causes of vitamin B12 deficiency Decreased intrinsic factor production: pernicious anemia (most common cause), gastrectomy Dietary deficiency (rare but seen in vegans) Competition for vitamin B12 in the gut: blind loop syndrome, fish tapeworm (rare) Decreased ileal vitamin B12 absorption: surgical resection, Crohn disease Pancreatic insufficiency Helicobacter pylori infection Transcobalamin II deficiency (rare) • Pernicious anemia is associated with atrophic gastritis and other autoimmune diseases (eg, immunoglobulin A [IgA] deficiency, polyglandular endocrine failure syndromes).

Increased risk of thrombosis and recurrent spontaneous abortions with lupus anticoagulants. • May present with DVT, including pain, swelling, and redness of the limb with normal pulses and extremity perfusion. • May present with pulmonary emboli with or without obvious DVT, including an acute onset of shortness of breath, hypoxemia, tachycardia, and chest pain. • Hypercoagulable states may present with thrombosis at unusual sites (eg, the central nervous system sagittal sinus, the abdominal mesenteric veins).

Directed thrombolytic therapies may be used for large thromboses with high-risk, massive PE (hemodynamic instability). • Inferior vena caval (IVC) filters are used in patients with absolute contraindication for anticoagulation.

Treat the underlying cause of the iron deficiency such as the source of GI bleeding.

Intramuscular or subcutaneous injections of 100 μg of vitamin B12 are adequate for each dose. • Replacement is usually given daily for the first week, weekly for the first month, and then monthly for life. • Oral or sublingual methylcobalamin (1 mg/d) may be used instead of parenteral therapy once initial correction of the deficiency has occurred. • Oral or sublingual replacement is effective, even in pernicious anemia, since approximately 1% of the dose is absorbed in the intestine via passive diffusion in the absence of active transport. • Vitamin B12 replacement must be continued indefinitely and serum vitamin B12 levels must be monitored to ensure adequate replacement. • Simultaneous folic acid replacement (1 mg daily) is recommended for the first several months of vitamin B12 replacement. • Red blood cell transfusions are rarely needed despite the severity of anemia, but when given, diuretics are also recommended to avoid heart failure. • Hypokalemia may complicate the first several days of parenteral vitamin B12 therapy in pernicious anemia, particularly if anemia is severe.