✅ Ddx: Anemias, Transfusion reaction, Leukemia Flashcards
MICROCYTIC
Iron deficiency anemia
Hx: Fatigue, malaise, irritability, decreased exercise tolerance, and headaches. Usually due to menstrual (menometrorhagia) or GI blood loss (colon cancer, gastric ulcer)[nonsteroidal anti-inflammatory drug (NSAID) 🧯 and aspirin use]; less commonly due to celiac disease or chronic intravascular hemolysis. Search for a source of chronic (slow) blood loss. Poor nutrition and/or inadequate absorption are less common causes.
Dx: Hypochromia, microcytosis, and increased RDW.
Distinguishing laboratory findings of IDA include decreased erythrocyte count (inadequate synthesis) and elevated red cell distribution width (RDW) due to variable iron levels available throughout the day. Mentzer index >13 (due to a decline in RBC count). In addition, IDA may be associated with reactive thrombocytosis (platelets >400,000/mm3) in response to low red blood cell count. This change is due to megakaryocytes and erythrocytes sharing a common progenitor cell.
Low Iron (60 - 160 μg/dL is normal)
Low Ferritin (12-200 ng/mL is normal)
Increased TIBC (250 - 460 μg/dL is normal)
Increased RDW
Elderly patients with IDA should be evaluated with colonoscopy and endoscopy despite a single negative FOBT, especially if no other obvious source of chronic blood loss is identified.
Bone Marrow biopsy is usually NOT required in the workup of IDA.
Tx: Iron [Oral] (ferrous sulfate) 324 mg TID
stool softener
Parenteral iron, either intramuscular iron dextran or intravenous iron sucrose, is reserved for patients receiving dialysis or for patients who cannot absorb or tolerate oral iron replacement.
α-Thalassemia
Normal hemoglobin is a heterotetramer composed of 4 chains:
- 2 alpha and 2 beta chains in children and adults (adult hemoglobin), or
- 2 alpha and 2 gamma chains in fetuses and infants (fetal hemoglobin)
In patients with alpha-thalassemia, ≥1 alpha genes are deleted.
Alpha-thalassemia minima (asymptomatic silent carrier)
Alpha-thalassemia minor
Hx: Asymptomatic mild microcytic anemia with normal RDW due to homozygous single α-globin gene deletion or heterozygous double α-globin gene deletion.
Seen in persons of African, Mediterranean, Middle Eastern, or Southeast Asian ancestry.
Tx: not needed
Hemoglobin H disease
When 3 genes are lost (α-/–). The nonalpha chains accumulate into homotetramers; in children and adults, these homotetrameters are composed of beta chains (hemoglobin H) whereas, in fetuses and infants, they are composed of gamma chains (hemoglobin Barts).
Hemoglobin H disease usually presents in infancy with chronic hemolysis due to a shorter red blood cell (RBC) lifespan and increased splenic sequestration. Elevated erythrocyte count and reticulocytosis occur as the bone marrow attempts to replenish hemolyzed RBCs. However, RBCs are microcytic (mean corpuscular volume <80 µm3) and hypochromic because hemoglobin accounts for the majority of RBC volume. Characteristic findings on peripheral smear include abundant target cells as a result of the reduced RBC volume.
Hydrops fetalis
- High-output cardiac failure, anasarca, death in utero
The presence of gamma tetramers (hemoglobin Barts) on hemoglobin electrophoresis should raise suspicion for alpha-thalassemia; it is classically associated with hydrops fetalis, the most severe form of alpha-thalassemia, which is due to 4 alpha gene loss (–/–) and typically leads to death in utero.
Dx: Serum Iron, ferritin and TIBC are normal
Hgb electrophoresis is normal❗❗❗
Blood smear shows target cells 🎯 and teardrop cells
Normal RDW
β-Thalassemia
Beta-thalassemia is the most common thalassemia in patients of Mediterranean descent. Normal adult hemoglobin (hemoglobin A) contains 2 alpha chains and 2 beta chains (α2β2) in combination with heme.
β-Thalassemia minor (trait) are heterozygotes with 1 normal β-globin allele and 1 abnormal β-globin allele. α-thalassemia minor patients are missing 2 of the 4 α-globin genes. The majority of patients with α- or β-thalassemia minor are asymptomatic; have varying degrees of anemia, microcytosis, and target cells on peripheral smear; mean corpuscular volume <75 µm3; and normal RBC distribution width (as all cells are the same shape and size).
Hx: Mild, asymptomatic anemia with normal RDW due to reduced expression of one β-globin gene. Seen in persons of African, Mediterranean, Middle Eastern, or Southeast Asian ancestry. Serum ferritin concentration and transferrin saturation are generally normal. Hgb electrophoresis shows an increased percentage of Hgb A2 and a normal to slightly increased percentage of Hgb F.
Tx: Treatment not needed
β-Thalassemia intermedia
Moderate, asymptomatic to symptomatic anemia due to reduced but not absent expression of one or both β-globin genes.
Dx: Typically, there is evidence of ineffective erythropoiesis, with a low serum haptoglobin and increased levels of indirect bilirubin and LDH in the setting of a normal reticulocyte count and increased iron stores. Serum ferritin concentration and transferrin saturation are increased. Hgb electrophoresis shows an increased percentage of Hgb A2 and Hgb F. Intermittent transfusion and risk of iron overload requiring iron chelation therapy.
Normal RDW
β-Thalassemia major is due to impaired production of BOTH β-globin chains, leading to an excess of α-globin chains. These chains are unstable and lead to chronic hemolysis and transfusion-dependent anemia. Instead of the two alpha and two beta chains that typically compose hemoglobin A, patients have increased hemoglobin F (two alpha and two gamma chains) and hemoglobin A2 (two alpha and two delta chains).
Since fetal hemoglobin (HbF) predominates in the first few months of life until adult hemoglobin (HbA) is synthesized, beta thalassemia major is generally asymptomatic in the newborn period. Patients around age 6-12 months develop fatigue and pallor due to microcytic anemia. Splenic hemolysis of red blood cells (RBCs) can cause jaundice, dark urine, and splenomegaly. If left untreated, patients can develop skeletal abnormalities due to extramedullary hematopoiesis.
There is evidence of ineffective erythropoiesis, with a low serum haptoglobin and increased levels of indirect bilirubin and LDH in the setting of a normal reticulocyte count and increased iron stores. Serum ferritin concentration and transferrin saturation are increased. Hgb electrophoresis shows an increased percentage of Hgb A2 Hgb F.
Tx: Beta-thalassemia major is transfusion-dependent. The additional iron from transfused RBCs increases the risk for iron overload. Chelation therapy is required to avoid damage to the liver, kidneys, and endocrine glands and improve survival. Splenectomy may enhance RBC survival and reduce transfusion need. HSCT is an option to consider
Lead poisoning
Lead poisoning can cause a microcytic hypochromic anemia.
In addition to his clinical presentation consisting of nonspecific general manifestations (eg, fatigue), other features include:
- Neuropsychiatric manifestations (eg, short-term memory loss, sensorimotor neuropathy, headaches, ataxia)
- Gastrointestinal manifestations (eg, abdominal pain, constipation)
- Hypertension and possible nephrotoxicity (eg, elevated creatinine)
Inhibition of enzymes responsible for heme and RNA synthesis in both bone marrow and mature erythrocytes can lead to microcytic anemia with basophilic stippling or target cells, and impaired purine metabolism can result in hyperuricemia.
Once absorbed (in adults, predominantly via the lungs), lead distributes throughout the blood, bones, and other organs, affecting cell function throughout. Lead is predominantly stored in the skeleton and is released slowly, potentially exerting its pathologic effects over decades. Diagnosis depends on establishing a history of lead exposure accompanied by corroborating physical examination findings (eg, neurologic manifestations) and elevated blood lead levels. Removal from the lead source and chelation therapy is the treatment for those with symptoms and/or markedly elevated levels.
✨Anemia of Chronic Disease
Cytokines produced by inflammation cause a block in the normal recirculation of iron from reticuloendothelial cells (which pick up the iron from senescent red blood cells) to the red cell precursors (normoblasts). The peptide hepcidin is felt to be the main mediator of the effect. This defect in iron reutilization causes a drop in the serum iron concentration and a normocytic OR mildly microcytic anemia.
Hx: Chronic Inflammatory state (SLE, RA); neoplastic disease; generally aymptomatic
Dx: Low Iron
Ferritin Increased [acute phase reactant] (In patients with rheumatoid arthritis, serum ferritin levels are expected to rise by as much as threefold as a result of the effects of inflammatory cytokines)
TIBC Decreased
Tx: EPO in severe cases
Hemoglobin H disease
Moderate to severe anemia with splenomegaly. Intermittent transfusions may be needed with risk of iron overload. Hgb H = tetramers of β-globin chains.
Hemoglobin Barts
Usually lethal in utero, unless salvage is obtained with in utero transfusions. Hgb Barts = tetramers of γ globin chains
Sideroblastic Anemia
This condition results from defective heme synthesis, most commonly due to pyridoxine-dependent impairment in early steps of protoporphyrin synthesis.
Isoniazid, a well-known pyridoxine antagonist can be responsible for this condition. Acquired sideroblastic anemia frequently manifests as microcytic hypochromic anemia simulating iron-deficiency anemia.
Usually two groups of RBC can be demonstrated on microscopy - hypochromic and normochromic (“dimorphic” RBC population). Besides that, iron studies typically reveal increased serum iron concentration and decreased total iron binding capacity (TIBC), which helps to differentiate sideroblastic anemia from iron-deficiency anemia
🔴 MACROCYTIC ANEMIA:
Folate deficiency
Vitamin B12 deficiency
Drug-induced changes in erythrocytes
Myelodysplastic syndromes
B12 deficiency
Vegetarians are at risk of developing vitamin B12 deficiency, particularly if dairy product consumption is limited; vegans are also at increased risk as they do not consume any dairy products [3-10 yrs storage]
Gastric resection, malabsorbtion and vegan diet (B12 is contained in all animal products).
The presentation is usually with anemia or orthostatic lightheadedness but may also be neurologic.
🧦Peripheral neuropathy: Distal paresthesias, gait ataxia, a bandlike sensation of tightness around the trunk or limbs, and ⚡Lhermitte sign (an electric shock–like sensation along the spine precipitated by neck flexion) may be present. May lead to loss of tendon reflexes in the legs and urinary retention.
Degeneration (demyelination) of the posterior and pyramidal tracts of the spinal cord which causes impaired vibratory and joint position sense, sensory gait ataxia, and spastic paraparesis with extensor plantar responses.
Less frequently, optic atrophy or cerebral symptoms.
Dx:
BOTH methylmalonic acid (MMA) AND homocysteine levels are increased.
An elevated methylmalonic acid (MMA) level is more sensitive and specific for diagnosing cobalamin deficiency than a low serum vitamin B12 level because serum vitamin B12 levels do NOT adequately assess tissue vitamin B12 stores, especially in patients with serum vitamin B12 levels in the low-normal range.
Hematologic abnormalities include macrocytic anemia, leukopenia with hypersegmented neutrophils, and thrombocytopenia with giant platelets. Because folate deficiency can produce identical changes, the diagnosis must be confirmed by measuring the serum vitamin B12 level. MMA elevated; schilling’s test
Tx: Treatment of neurologic manifestations is by prompt intramuscular administration of cyanocobalamin (1,000 μg), as soon as blood is drawn to determine the serum vitamin B12 level. Daily injections are continued for 1 week, and further testing is performed to determine the cause of deficiency.
Cx: Pernicious anemia, an autoimmune disorder where the body makes anti-intrinsic factor antibodies, is the leading cause of B12 deficiency. It is associated with atrophic gastritis, anti-parietal cell antibodies, and achlorhydria, [inadequate absorbtion] which is most common in those of northern European ancestry. First, anti-intrinsic factor antibodies decrease the amount of functional intrinsic factor available to facilitate B12 absorption. Second, patients develop a chronic atrophic gastritis with decreased production of intrinsic factor by gastric parietal cells. This atrophic gastritis increases the risk of intestinal-type 🦀gastric cancer and gastric carcinoid tumors by 2-3 times over the general population. Thus, patients with pernicious anemia need to be monitored for the development of gastric cancer (periodic stool testing for the presence of blood).
Folate deficiency anemia
🍺 Alcohol abuse is the most common cause of nutritional folic acid deficiency in the United States, leading to a megaloblastic anemia. Alcohol abuse causes folate deficiency by impairing its enterohepatic cycle and inhibiting its absorption. Alcoholics can develop megaloblastic anemia within 5 to 10 weeks, as body stores of folate are limited.
Etiology
- Chronic hemolysis (eg, sickle cell disease)
- Poor dietary intake (tea and toast)
- Malabsorption (eg, gastric bypass)
- Medications (eg, methotrexate)
- Trimethoprim: It inhibits dihydrofolate reductase and in high doses can cause megaloblastic pancytopenia.
- Methotrexate: Also inhibits dihydrofolate reductase. Folinic acid (leucovorin) is indicated to reverse the chemotherapeutic anti-folate effect of methotrexate.
- Phenytoin: Some anti-epileptic drugs including phenytoin, primidone and phenobarbital can cause megaloblastic anemia that is usually mild. The pathophysiology of this condition involves impaired absorption of folic acid in the small intestine.
Clinical features
- Dyspnea, fatigue, pallor, weakness
Laboratory findings
- Macrocytic anemia
- Poor reticulocyte response (low to normal)
- Hypersegmented neutrophils
- Low serum folate
Treatment
- Folic acid supplementation
SCD is a chronic hemolytic anemia in which red blood cells are typically normocytic and normochromic with a compensatory elevated reticulocyte count. Without adequate folic acid supplementation or intake, chronic hemolysis can lead to folate deficiency, as the bone marrow uses folate in an attempt to produce red blood cells. Folate deficiency results in laboratory findings of macrocytic anemia and hypersegmented neutrophils. Due to ineffective erythropoiesis, the expected reticulocytosis is absent and an inappropriately low reticulocyte count is seen (ie, low corrected reticulocyte count).
Dx: MMA normal; NO neurologic findings
Tx: Adequate folic acid intake via diet or supplementation is recommended to correct the underlying folate deficiency.
Drug-induced changes in erythrocytes (nonmegaloblastic)
Liver Disease, ETOH, Drugs: 5-FU, HAART (AZT), psoriasis, SLE, rheumatoid arthritis, and posttransplantation immunosuppression cause macrocytic and sometimes megaloblastic changes in erythrocytes. History should be revealing
Myelodysplastic syndromes
Myelodysplastic syndromes are a spectrum of primary hematopoietic disorders characterized by hypercellular bone marrow and peripheral blood cytopenias due to ineffective myelopoiesis, abnormal maturation (including idiopathic acquired megaloblastic maturation of erythroid cells), and intramedullary apoptosis of myeloid cells
⚪ NORMOCYTIC ANEMIA DDX
- Acute blood loss
- Chronic kidney disease (see Chronic Kidney Disease)
- Pure red cell aplasia
- Malignancy (solid tumor, lymphoma, myelofibrosis)
- Hemolytic Anemia (Ddx)
Acute blood loss
Most iron-deficiency anemia is explained by blood loss.
Anemia with variation in erythrocyte size (increased RDW) if iron deficiency is present. Reticulocyte count is usually increased; leukocyte count and platelet count may be slightly increased, depending on the rapidity of bleeding.
Dx: Colonoscopy
Pure red cell aplasia
Anemia with severe reticulocytopenia. Diagnosis is made by examination of a bone marrow aspirate, in which erythroblasts will be absent or severely diminished. Red cell aplasia can be idiopathic or secondary to a thymoma, solid tumor, hematologic malignancy, collagen vascular disease, viral infection (particularly human parvovirus B19 infection, which is common in immunosuppressed patients), or drug (eg, phenytoin, azathioprine, isoniazid, chloramphenicol, mycophenolate mofetil). Red cell aplasia may also occur in patients with hemolytic anemia from any cause
Malignancy (solid tumor, lymphoma, myelofibrosis)
Anemia with a low reticulocyte count. With bone marrow involvement by tumor, leukoerythroblastosis and extramedullary hematopoiesis occur, and nucleated erythrocytes and myelocytes are seen in the peripheral blood. Peripheral blood smear may show rouleaux formation (if a plasma cell dyscrasia is present) or teardrop-shaped erythrocytes (if splenomegaly is present)
💥HEMOLYTIC ANEMIA DDX
Type (spherocytic or nonspherocytic), site (intramedullary or extramedullary, intravascular or extravascular), and mechanism (immune-mediated or nonimmune-mediated, intrinsic vs extrinsic to the erythrocyte).
Extravascular:
Membrane defect (hereditary spherocytosis, hereditary elliptocytosis)
Intrinsic RBC enzyme deeficiency/enzymopathy (G6PD deficiency, pyruvate kinase deficiency)
Hemoglobinopathy (hemoglobin S, hemoglobin C, thalassemia, sickle cell)
Autoimmune hemolytic anemia (warm or cold- agglutinin)
Erythrocyte fragmentation
Infection (malaria, babesiosis, bartonella)
Hypersplenism (see Cirrhosis)
Intravascular:
Microangiopathic hemolytic anemia
Transfusion reactions
Infections (clostridia species)
Paroxysmal nocturnal hemoglobinuria
Intravenous Rho(D) immune globulin infusion
Hereditary spherocytosis (HS) [Membrane defect]
Epidemiology
- Usually autosomal dominant
- Northern European descent
Clinical presentation
- Hemolytic anemia
- Jaundice
- Splenomegaly
Laboratory findings
- ↑ MCHC
- Negative Coombs test
- Spherocytes on peripheral smear
- ↑ Osmotic fragility on acidified glycerol lysis test
- Abnormal eosin-5-maleimide binding test
Treatment
- Folic acid supplementation
- Blood transfusion
- Splenectomy
HS is an inherited deficiency of red blood cell (RBC) scaffolding proteins (eg, spectrin, ankyrin). Sphere-shaped RBCs are more fragile and get trapped in splenic fenestrations.
Hx: The anemia is generally normocytic with associated reticulocytosis in response to hemolysis. Increased mean corpuscular hemoglobin concentration (MCHC) occurs due to membrane loss and RBC dehydration. In addition, spherocytes burst easily due to their decreased surface-area-to-volume ratio, and diagnosis can be confirmed by assessing RBC fragility with either the eosin-5-maleimide (EMA) binding test (flow cytometry) or acidified glycerol lysis test.
Chronic hemolysis causes high hemoglobin turnover and excess bilirubin that overwhelms conjugation and elimination from the body. The resulting hyperbilirubinemia manifests as jaundice, dark urine, and pigment (calcium bilirubinate) gallstones. [Classic symptoms of acute cholecystitis (fever, right upper quadrant pain, positive Murphy sign, leukocytosis)]
Px: splenomegaly
Dx: Confirmed by osmotic fragility (best) and negative direct antiglobulin (Coombs) test; Spherocytes or elliptocytes on blood smear.
Tx: Splenectomy
Hypoproliferative anemia
Patients with CKD frequently develop a hypoproliferative anemia due to inadequate production of erythropoietin by the kidneys. Erythropoiesis-stimulating agents (ESAs), such as recombinant erythropoietin and darbepoetin, stimulate red blood cell production and are the treatment of choice in CKD-related anemia. All patients with significant renal failure and a hemoglobin <10 g/dL are candidates for ESAs after iron deficiency has been ruled out.
Anemia with a low reticulocyte count due to impaired erythropoietin production. Renal endocrine function does not correlate with renal exocrine function
Tx: involves correcting underlying causes (chronic infection, iron deficiency, vitamin deficiencies) and supplementation with erythropoiesis-stimulating agents (ESAs) (darbepoetin or recombinant erythropoietin) to maintain hemoglobin levels >10 g/dL (100 g/L). Iron deficiency is typically corrected with oral supplementation, but intravenous infusions may be necessary if the patient is refractory to oral therapy. Correction of hemoglobin to normal physiologic levels (>13 g/dL) is associated with an increased mortality rate and cardiovascular events and is NOTrecommended.
Cx: Up to 30% of patients on erythropoietin therapy develop new or worsening hypertension, which typically occurs 2-8 weeks after treatment initiation. Hypertension is generally mild but can be severe, leading to end-organ damage (eg, encephalopathy, seizures). Large doses of erythropoietin or rapidly rising hemoglobin soon after administration increase the risk of hypertension. Therefore, patients started on erythropoietin require close blood pressure monitoring.
Autoimmune hemolytic anemia
Autoimmune hemolytic anemia may be idiopathic or result from drugs, lymphoproliferative disorders, collagen vascular diseases, or malignancies. The disorder occurs when IgG, IgM, or, rarely IgA, autoantibodies bind to erythrocyte antigens.
These antiglobulins, also referred to as “agglutinins,” may be detected when bound to the surface of red blood cells (direct Coombs test) or circulating in serum (indirect Coombs test).
♨ “Warm antibody–mediated”. In this condition, IgG antibodies bind to Rh-type antigens on the erythrocyte surface at 37.0 °C (98.6 °F) . Although these antibodies may fix complement, they more commonly bind to the cell surface and facilitate Fc-receptor–mediated erythrocyte destruction by splenic macrophages. Hx: Most cases of warm antibody disease are drug induced or associated with an underlying disorder (eg, SLE, lymphoproliferative disorder, cancer).
❄ Cold agglutinin disease is also frequently associated with underlying disorders (eg, SLE). Immune-mediated IgM antibodies which may follow Mycoplasma infections. These antibodies are also called cold-reacting antibodies as they react at temperatures less than 37°C (98°F).
Dx:
Examination of the peripheral blood smear is the first step in evaluation of hemolytic anemia. Peripheral smear typically shows spherocytes, microspherocytes, elliptocytes, or increased numbers of polychromatophilic cells (eg, reticulocytes). The young red cells (which would show up as reticulocytes when properly stained) are much larger than mature RBCs, accounting for the macrocytosis (the MCV can be as high as 140 with vigorous reticulocytosis). The presence of microspherocytes suggests immune-mediated hemolysis, while the presence of fragmented RBCs or schistocytes suggest a mechanical cause of hemolysis, as seen in the microangiopathic hemolytic anemias (MAHA).
Normocytic anemia with evidence of hemolysis (jaundice, elevated 🔰indirect bilirubin, increased serum LDH, decreased serum haptoglobin)[see next card]
Direct and indirect antiglobulin (Coombs) tests and cold (IgM) agglutinin titer (Mycoplasma and Mono); [positive for C3 in cold agglutinin disease].
Splenomegaly (due to erythrocyte entrapment) commonly develops. The bone marrow response appears as reticulocytosis.
Tx:
Cold: Avoid Cold
Warm - streoids (glucodorticoids), rituximab, splenectomy
Extramedullary hemolysis
Extravascular hemolysis: The RBCs are predominantly destroyed by phagocytes in the reticuloendothelial system (eg, lymph nodes, spleen). As a result, there is less hemoglobin release than in intravascular hemolysis, so laboratory results usually show normal to slightly low haptoglobin, slightly elevated LDH, and elevated indirect bilirubin.
Intravascular hemolysis: Due to significant RBC structural damage resulting in RBC destruction within the intravascular space (eg, paroxysmal nocturnal hemoglobinuria, disseminated intravascular coagulation). The hemoglobin released from hemolyzed RBCs binds to haptoglobin, and the hemoglobin-haptoglobin complex is cleared by the liver. This leads to markedly reduced serum haptoglobin (to undetectable levels). RBC hemolysis also results in elevated indirect bilirubin levels (from heme breakdown) and raised serum lactate dehydrogenase (LDH) levels (released from RBCs). (eg, hemolysis associated with cold agglutinin disease or thrombotic microangiopathy).
Sickle cell trait
Clinical features
- Usually asymptomatic
- No change in overall life expectancy
Laboratory findings
- Normal hemoglobin, reticulocyte count, RBC indices & morphology
- Hemoglobin electrophoresis: Hb A > Hb S
❗ Complications
- Hematuria/papillary necrosis, hyposthenuria
- Splenic infarction (especially at higher altitudes🗻), venous thromboembolism, priapism
- Exertional rhabdomyolysis
Hyposthenuria (inability of the kidneys to concentrate urine) is common in patients with SCD and may also develop in those with SCT. In response to hypoxic, hyperosmolar conditions of the renal medulla, red blood cells sickle in the vasa recta, impairing free water reabsorption and countercurrent exchange. Patients typically have polyuria and nocturia despite fluid restriction. Urine osmolality is low; however, normal serum sodium is maintained due to intact antidiuretic hormone (ADH). Urinary diluting capacity is also intact as it is a function of the superficial loop of Henle, which is not supplied by the vasa recta.
Typically, mild hyposthenuria due to SCT requires no treatment. In patients with SCD, red blood cell transfusions often improve urine-concentrating ability and provide relief of symptoms.
Papillary necrosis can occur with massive hematuria, but the episodes are usually mild and resolve spontaneously. The urinalysis usually shows normal-appearing RBCs.
Sickle cell Disease
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.
Enzymopathy (G6PD deficiency, pyruvate kinase deficiency)
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
Hemoglobinopathy (hemoglobin S, hemoglobin C, thalassemia, hereditary unstable)
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
Erythrocyte fragmentation
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
Infection (malaria, babesiosis)
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
Hypersplenism (see Cirrhosis)
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)
Intramedullary hemolysis
Seen in various disorders associated with ineffective erythropoiesis, including thalassemia.
Paroxysmal Nocturnal Hemoglobinuria (PNH)
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.
Hemochromatosis
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.
💦 Bleeding
Von Willebrand disease
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.
🔽 Thrombocytopenia: Decreased Platelet Production:
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.
Hemophilia
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.
Pseudothrombocytopenia
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.
Heparin-induced thrombocytopenia (HIT)
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:
Timing Thrombosis - 5-10 days (+2), >10 days (+1), <5 days (0)
Thrombosis - New, progressive or recurrent, None
Thrombocytopenia - >50%, 30-50%, <30%
alTernative, 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.
Immune thrombocytopenic purpura (ITP) [Immune thrombocytopenia]
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 second-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.
Idiopathic thrombocytopenia purpura (ITP)
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.
Thrombotic thrombocytopenic purpura (TTP)
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
- Fever
- Anemia (Microangiopathic hemolytic anemia)[MAHA]
- Thrombocytopenia (nonimmune)
- Renal Failure
- Neurologic 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.
HELLP syndrome
Late pregnancy complication of thrombocytopenia associated with microangiopathic hemolytic anemia, and elevated liver enzymes, and hypertension.
(Hemolysis, Elevated Liver enzymes, Low Platelets)
Disseminated intravascular coagulation (DIC)
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
Henoch-Schönlein purpura
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.
Ddx: Thrombophilia
Risk Factors for Inherited Thrombophilia:
Thrombosis in ages <50 years, especially in the absence of acquired risk factors (idiopathic)
History of recurrent thrombosis, especially if idiopathic
First-degree relative(s) with thrombosis, especially if first VTE occurs at age <50 years
Unusual site of thrombosis (mesenteric, splenic, portal, hepatic, cerebral sinus, upper extremity in the absence of central lines)
Thrombotic event during pregnancy or postpartum
Thrombotic event while taking oral contraceptives
History of recurrent pregnancy loss
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
Factor V Leiden
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%)].
[APS] Antiphospholipid syndrome
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.
Protein C deficiency
⛑ 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.
