RBC and Bleeding Disorders PDF

RED BLOOD CELL AND BLEEDING DISORDERS Florido A. Atibagos, MD, FPSP NORMAL BLOOD DEVELOPMENT 3RD week – yolk sac (embryonic stage) 4th week – liver (hepatic stage) 4th month – bone marrow (medullary stage) Birth – BM throughout skeleton; minimal...

RED BLOOD CELL AND BLEEDING DISORDERS Florido A. Atibagos, MD, FPSP NORMAL BLOOD DEVELOPMENT 3RD week – yolk sac (embryonic stage) 4th week – liver (hepatic stage) 4th month – bone marrow (medullary stage) Birth – BM throughout skeleton; minimal hematopoiesis in the liver 18 y/o – vertebrae, ribs, sternum, skull, pelvis, proximal humerus, and femur Adults – 50% of marrow remains active *Pronormoblast – most primitive precursor *Polychromatic Erythrocyte – reticulocyte ANEMIA ANEMIA – reduction below normal limits of total circulating RBC resulting in decreased O2 transport. Signs/Symptoms - Sx: Weakness, malaise, easy fatigability Dyspnea on mild exertion - PE: Pallor (@ palpebral conjunctiva, nailbed, frenulum of tongue); Headache, dizziness; Angina, Murmur (due to hypoxemia); Oliguria and anuria (in case of bld loss); Brittle nails, koilonychia Anemia reduces the oxygen-carrying capacity of the blood, leading to tissue hypoxia. In practice, the measurement of red cell mass is not easy, and anemia is usually diagnosed based on a reduction in the hematocrit (the ratio of packed red cells to total blood volume) and the hemoglobin concentration of the blood to levels that are below the normal range. NORMAL HEMOGLOBIN HbA – α2β2 ~ 95% adult HbA1C ~ 3% adult; diabetes HbA2 – α2δ2 ~ 2% adult HbF – α2γ2 Major fetal Hgb 3rd -9th month; Inc. O2 transport from placenta; 94 macrocytic - Extramedullary hematopoiesis (liver, lymph nodes) Mean cell hemoglobin: the average content (mass) of hemoglobin per red 3. Premature destruction of RBC – Anemia cell, expressed in picograms (pg) 4. Elevated LDH - 25-34 Hemolytic anemias share the following features: - Hb / RBC count x 10 Mean cell hemoglobin concentration: the average concentration of A shortened red cell life span below the normal 120 days hemoglobin in a given volume of packed red cells, expressed in grams per Elevated erythropoietin levels and a compensatory increase in deciliter (g/dL) erythropoiesis - 32-36 (color) Accumulation of hemoglobin degradation products that are created - Hb / Hct x 100 as part of the process of red cell hemolysis - < 32 hypochromic, Ⓝ normochromic - >32 hyperchromic → seen in patients with increased reticulocyte count; recovering from blood loss INTRAVASCULAR HEMOLYSIS MORPHOLOGIC CLASSIFICATION OF ANEMIA CHARACTERISTICS: 1. Presence of free Hb: Hemoglobinemia, Hburia Normochromic normocytic 2. Methalbuminemia - ⓃMCHC, ⓃMCV, ⓃMCH 3. ↓ serum haptoglobulin Hypochromic, microcytic 4. Hemosiderinuria PLUS - ↓ MCHC, ↓ MCV, ↓ MCH 5. Jaundice and anemia - IDA, thalassemia, sideroblastic An CAUSES: Macrocytic anemia 1. Mechanical injury- artificial heart valves, thrombi (DIC) - ↑ MCV, ↑MCH, ⓃMCHC 2. Ab – transfusion mismatch, Paroxysmal nocturnal hemoglobinuria (PNH) - B12 & folic acid deficiency 3. Infection – malaria 4. G6PD INTRAVASCULAR HEMOLYSIS Intravascular hemolysis of red cells may be caused by mechanical injury, complement fixation, intracellular parasites (e.g., falciparum malaria), or exogenous toxic factors. Compared to extravascular hemolysis, it occurs less commonly; sources of mechanical injury include trauma caused by cardiac valves, narrowing of the microcirculation by thrombi, or repetitive physical trauma (e.g., marathon running and bongo drum beating). Complement fixation occurs in a variety of situations in which antibodies recognize and bind red cell antigens. Toxic injury is Middle: Normochromic, normocytic; Right: Hypochromic, microcytic; Left: exemplified by clostridial sepsis, which results in the release of Megaloblastic Anemia enzymes that digest the red cell membrane.  INTRAVASCULAR HEMOLYSIS (CONT.) Whatever the mechanism, intravascular hemolysis is manifested by anemia, hemoglobinemia, hemoglobinuria, hemosiderinuria, and jaundice. Free hemoglobin released from lysed red cells is promptly bound by haptoglobin, producing a complex that is rapidly cleared by mononuclear phagocytes. As serum haptoglobin is depleted, free hemoglobin oxidizes to methemoglobin, which is brown in color. The renal proximal tubular cells reabsorb and break down much of the filtered hemoglobin and methemoglobin, but some passes out in the urine, imparting a red- brown color. Iron released from hemoglobin can accumulate within tubular cells, giving rise to renal hemosiderosis. HEMOLYTIC ANEMIA Concomitantly, heme groups derived from hemoglobin-haptoglobin complexes are metabolized to bilirubin within mononuclear HEREDITARY SPHEROCYTOSIS phagocytes, leading to jaundice. Unlike in extravascular hemolysis, splenomegaly is not seen. Hereditary spherocytosis (HS) is an inherited disorder caused by intrinsic defects in the red cell membrane skeleton that render red cells spheroid, EXTRAVASCULAR HEMOLYSIS less deformable, and vulnerable to splenic sequestration and destruction. Pathogenesis: Abnormally of contractile membrane protein spectrin, actin, CHARACTERISTICS: ankyrin → sphere instead of discoid shape → inflexible when it passes 1. Anemia small capillaries esp. Spleen → hemolysis 2. Jaundice 3. Splenomegaly PATHOGENESIS EXTRAVASCULAR HEMOLYSIS The remarkable deformability and durability of the normal red cell are attributable to the physicochemical properties of its specialized Extravascular hemolysis is most commonly caused by alterations that membrane skeleton, which lies closely apposed to the internal make red cells less deformable. surface of the plasma membrane. Its chief protein component, Extreme changes in shape are required for red cells to navigate the spectrin, consists of two polypeptide chains, α and β, which form splenic sinusoids successfully. intertwined (helical) flexible heterodimers. Reduced deformability makes this passage difficult, leading to red cell sequestration and phagocytosis by macrophages located within the HS is caused by diverse mutations that lead to an insufficiency of splenic cords. membrane skeletal components. As a result of these alterations, the Regardless of the cause, the principal clinical features of life span of affected red cells is decreased on average to 10 to 20 extravascular hemolysis are anemia, splenomegaly, and jaundice. days from the normal 120 days. The pathogenic mutations most Some hemoglobin inevitably escapes from phagocytes, which leads commonly affect ankyrin, band 3, spectrin, or band 4.2, the proteins to variable decreases in plasma haptoglobin, an α2-globulin that involved in one of the two tethering interactions. Most mutations binds free hemoglobin and prevents its excretion in the urine. cause frameshifts or introduce premature stop codons, such that the Because much of the premature destruction of red cells occurs in the mutated allele fails to produce any protein. The resulting deficiency spleen, individuals with extravascular hemolysis often benefit from of the affected protein reduces the assembly of the skeleton as a splenectomy whole, destabilizing the overlying plasma membrane. The loss of membrane relative to cytoplasm “forces” the cells to assume the smallest possible diameter for a given volume, namely, a sphere.  GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY Abnormalities in the hexose monophosphate shunt or glutathione metabolism resulting from deficient or impaired enzyme function reduce the ability of red cells to protect themselves against oxidative injuries and lead to hemolysis. G6PD reduces nicotinamide adenine dinucleotide phosphate (NADP) to NADPH while oxidizing glucose-6-phosphate. NADPH then provides reducing equivalents needed for conversion of oxidized glutathione to reduced glutathione, which protects against oxidant injury by participating PBS: RBC is spheroidal, loss of central pallor as a cofactor in reactions that neutralize compounds such as H2O2. Main Sx: Splenomegaly & jaundice; Splenectomy corrects anemia PBS: Normochromic normocytic anemia; Inc reticulocytes, Heinz bodies, The diagnosis is based on family history, hematologic findings, and bite cells laboratory evidence. - Exposure of G6PD-deficient red cells to high levels of oxidants S/Sx : Anemia, jaundice, splenomegaly causes the cross-linking of reactive sulfhydryl groups on globin - asymptomatic (20%-30%) chains, which become denatured and form membrane-bound - chronic hemolysis precipitates known as Heinz bodies. These are seen as dark - marked Anemia & jaundice → exchange transfusion inclusions within red cells stained with crystal violet. Heinz bodies Course: stable; Aplastic crisis – parvovirus infxn; Hemolytic crisis – IM can damage the membrane sufficiently to cause intravascular - The generally stable clinical course is sometimes punctuated by hemolysis. aplastic crises, usually triggered by an acute parvovirus infection. - As inclusion-bearing red cells pass through the splenic cords, Parvovirus infects and kills red cell progenitors, causing all red cell macrophages pluck out the Heinz bodies. As a result of membrane production to cease until an immune response clears the virus, damage, some of these partially devoured cells retain an abnormal generally in 1 to 2 weeks. Because of the reduced life span of HS shape, appearing to have a bite taken out of them. red cells, cessation of erythropoiesis for even short periods leads - Other less severely damaged cells become spherocytes due to loss to sudden worsening of the anemia. of membrane surface area. Both bite cells and spherocytes are - Hemolytic crises are produced by intercurrent events leading to trapped in splenic cords and removed by phagocytes. increased splenic destruction of red cells (e.g., infectious Precipitating Factors: oxidant drugs, fava beans, infection, stress mononucleosis and its attendant increase in spleen size); these are - The episodic hemolysis that is characteristic of G6PD deficiency is clinically less significant than aplastic crises. Gallstones, found in caused by exposures that generate oxidant stress. The most many patients, may also produce symptoms. Splenectomy treats common triggers are infections, in which oxygen-derived free the anemia and its complications, but brings with it an increased radicals are produced by activated leukocytes. risk of sepsis because the spleen acts as an important filter for - Many infections can trigger hemolysis; viral hepatitis, pneumonia, blood-borne bacteria. and typhoid fever are among those most likely to do so. Other Laboratory abn: Increased Osmotic Fragility Test - The other important initiators are drugs and certain foods. The - Test to determine susceptibility of the RBC to rupture drugs implicated are numerous, including antimalarials (e.g., - Shape of RBC is the main determining factor of the test primaquine and chloroquine), sulfonamides, nitrofurantoins, and - Normally, you can expect the red cells to rupture as the NSS others. Some drugs cause hemolysis only in individuals with the solution becomes hypotonic. Do not expect hemolysis in hypertonic more severe Mediterranean variant. The most frequently cited food solution → In HS, cells start to hemolyze in hypertonic solution. is the fava bean, which generates oxidants when metabolized. “Favism” is endemic in the Mediterranean, Middle East, and parts of Africa where consumption is prevalent. - Uncommonly, G6PD deficiency presents as neonatal jaundice or a chronic low-grade hemolytic anemia in the absence of infection or known environmental triggers. Variants: G6PD- only mature RBC lack the enz.; G6PD Mediterranean – all RBC lack enz.  - G6PD deficiency is a recessive X-linked trait, placing males at much higher risk for symptomatic disease. Several hundred G6PD genetic variants exist, but most clinically significant hemolytic anemia is associated with only two variants, designated G6PD– - and G6PD Mediterranean. - G6PD variants associated with hemolysis result in misfolding of the protein, making it more susceptible to proteolytic degradation. - Because mature red cells do not synthesize new proteins, as red cells age G6PD– and G6PD Mediterranean enzyme activities quickly fall to levels that are inadequate to protect against oxidant stress. Thus, older red cells are much more prone to hemolysis than younger ones. Sickle Cell Anemia Sickle Cell Trait SSx: Intravascular / extravascular hemolysis → 2-3 days after exposure, Gen. make-up Homozygous Heterozygous self-limited; Manifestation of recovery → ↑retic count; Mild extravascular % HbS 90-100% 20-40%, the rest HbA hemolysis, No Sx of chronic hemolysis Symptom Plugging of cap → No Sx unless exposed - Acute intravascular hemolysis, marked by anemia, pain and infarction in continuously to dec. hemoglobinemia, and hemoglobinuria, usually begins 2 to 3 days different organ 02 following exposure of G6PD-deficient individuals to environmental Spleen Enlarged in infancy; Normal triggers. small adults = - Because only older red cells are at risk for lysis, the episode is self- autosplenectomy limited, as hemolysis ceases when only younger G6PD-replete red Peripheral smear Normochromic Normal cells remain (even if exposure to the trigger, e.g., an offending drug, normocytic, continues). (+) sickle cells, - The recovery phase is heralded by reticulocytosis. (+) normoblasts, - Because hemolytic episodes related to G6PD deficiency occur (+) Howell Jolly bodies intermittently, features related to chronic hemolysis (e.g., Hb identification Single large band of Small band of HbS; splenomegaly, cholelithiasis) are absent. HbS Large band of HbA Other lab abnormality Dec. osmotic fragility; None SICKLE CELL ANEMIA Dec. ESR Sickle cell disease is a common hereditary hemoglobinopathy caused by a Prognosis Fetal at 20 y/o Normal life span point mutation in β-globin that promotes the polymerization of deoxygenated hemoglobin, leading to red cell distortion, hemolytic anemia, microvascular obstruction, and ischemic tissue damage. Pathogenesis: Presence of HbS due to substitution of glutamine for valine at the 6th position of β-chain. HbS = α2β2 6val In the presence of deoxygenation → HbS will aggregate and polymerize its molecular structure → distortion → sickling of RBC → (1) chronic hemolysis in spleen & (2) small vessel occlusion → ischemia Hemoglobin (Hb) is a tetrameric protein composed of two pairs of globin chains, each with its own heme group. Normal adult red cells contain mainly HbA (α2β2 ), along with small amounts of HbA2 (α2δ2 hemoglobin (HbF; α2 ) and fetal γ2). Sickle cell disease is caused by a missense mutation in the β-globin gene that leads to the replacement of a charged glutamate residue with a hydrophobic valine residue. The abnormal physiochemical properties of the resulting sickle hemoglobin (HbS) are responsible for the disease. FACTORS AFFECTING SICKLING 1. Amt and interaction of HbS6val - HbS=HbS vs HbS=HbA (if you have a lot of HbS → there would be sickling; HbA → prevents sickling) - HbF ≠ HbS - HbC6lys → polymerization of HbS 2. Inc MCHC & intracellular dehydration 3. Dec pH 4. Length of exposure to dec O2 - > microvasculature -BM, spleen (increase in transit time) - > infection The major pathologic manifestations—chronic hemolysis, microvascular S/SX OF SICKLE CELL DISEASE occlusions, and tissue damage—all stem from the tendency of HbS molecules to stack into polymers when deoxygenated. Initially, this process 1. Infarction - capillary stasis & thrombosis converts the red cell cytosol from a freely flowing liquid into a viscous gel. 2. Spleen: splenomegaly → autosplenectomy With continued deoxygenation, HbS molecules assemble into long 3. Predisposition to infection with encapsulated org. needlelike fibers within red cells, producing a distorted sickle or holly-leaf 4. Evidences of chronic hemolysis shape. a. Inc RBC destruction - Anemia, inc. bilirubin, hemosiderin, Fe overload FACTORS THAT AFFECT THE RATE AND DEGREE OF SICKLING: b. Inc erythropoiesis - Extramedullary hematopoiesis Interaction of HbS with the other types of hemoglobin. - Skull x-ray: “crew haircut” due to hyperplastic bone marrow In heterozygotes with sickle cell trait, about 40% of the hemoglobin - Inc. retic and normoblasts on peripheral smear is HbS and the rest is HbA, which interferes with HbS polymerization. As a result, red cells in heterozygous individuals only sickle if exposed Sickle cell disease causes a moderately severe hemolytic anemia (hematocrit to prolonged, relatively severe hypoxia. 18% to 30%) associated with reticulocytosis, hyperbilirubinemia, and the HbF inhibits the polymerization of HbS even more than HbA; hence, presence of irreversibly sickled cells. infants with sickle cell disease do not become symptomatic until they reach 5 or 6 months of age, when the level of HbF normally falls. CRITICAL EPISODES THAT CAN COMPLICATE CLINICAL PICTURE: However, in some individuals HbF expression remains relatively high, a condition known as hereditary persistence of fetal hemoglobin; in Vaso occlusive crisis – multiple simultaneous painful thrombosis in these individuals, sickle cell disease is much less severe. different organs Moreover, with aging HbSC cells tend to lose salt and water and - Vaso-occlusive crises, also called pain crises, are episodes of become dehydrated, an effect that increases the intracellular hypoxic injury and infarction that cause severe pain in the affected concentration of HbS. These factors increase the tendency for HbS to region. Although infection, dehydration, and acidosis (all of which polymerize, and as a result compound HbSC heterozygotes have a favor sickling) may act as triggers, in most instances no symptomatic sickling disorder termed HbSC disease that is predisposing cause is identified. somewhat milder than sickle cell disease. - The most commonly involved sites are the bones, lungs, liver, brain, spleen, and penis. Mean cell hemoglobin concentration (MCHC). - In children, painful bone crises are extremely common and often difficult to distinguish from acute osteomyelitis. These frequently Higher HbS concentrations increase the probability that aggregation manifest as the hand-foot syndrome or dactylitis of the bones of and polymerization will occur during any given period of the hands and feet. deoxygenation. Thus, intracellular dehydration, which increases the - Acute chest syndrome is a particularly dangerous type of vaso- MCHC, facilitates sickling. occlusive crisis involving the lungs that typically presents with Conversely, conditions that decrease the MCHC reduce disease fever, cough, chest pain, and pulmonary infiltrates. severity. This occurs when an individual who is homozygous for HbS - Pulmonary inflammation (such as may be induced by an infection) also has coexistent α-thalassemia, which reduces Hb synthesis and may cause blood flow to become sluggish and “spleenlike,” leading leads to milder disease. to sickling and vaso-occlusion. This compromises pulmonary Intracellular pH. function, creating a potentially fatal cycle of worsening pulmonary and systemic hypoxemia, sickling, and vaso-occlusion. A decrease in pH reduces the oxygen affinity of hemoglobin, thereby Aplastic crisis – sudden failure of BM to increase RBC production despite increasing the fraction of deoxygenated HbS at any given oxygen anemia tension and augmenting the tendency for sickling. - Aplastic crises stem from the infection of red cell progenitors by parvovirus B19, which causes a transient cessation of Transit time of red cells through microvascular beds. erythropoiesis and a sudden worsening of the anemia. As will be discussed, much of the pathology of sickle cell disease is Sequestration crisis – massive destruction of RBC passing through spleen related to vascular occlusion caused by sickling within microvascular → sudden splenomegaly → hypovolemia → shock beds. Transit times in most normal microvascular beds are too short - Sequestration crises occur in children with intact spleens. Massive for significant aggregation of deoxygenated HbS to occur, and as a entrapment of sickled red cells leads to rapid splenic enlargement, result sickling is confined to microvascular beds with slow transit hypovolemia, and sometimes shock. Both sequestration crises and times. the acute chest syndrome may be fatal and sometimes require Blood flow is sluggish in the normal spleen and bone marrow, which prompt treatment with exchange transfusions. are prominently affected in sickle cell disease, and also in vascular THALASSEMIA beds that are inflamed. The movement of blood through inflamed tissues is slowed because Thalassemia is a genetically heterogeneous disorder caused by germline of the adhesion of leukocytes to activated endothelial cells and the mutations that decrease the synthesis of either α-globin or β-globin, transudation of fluid through leaky vessels. leading to anemia, tissue hypoxia, and red cell hemolysis related to the As a result, inflamed vascular beds are prone to sickling and imbalance in globin chain synthesis. occlusion. Pathology: Defective globin synthesis  - The two α chains in HbA are encoded by an identical pair of α- LABORATORY DIAGNOSIS: THALASSEMIA globin genes on chromosome 16, and the two β chains are encoded by a single β-globin gene on chromosome 11. 1. Hb electrophoresis - β-thalassemia is caused by deficient synthesis of β chains, whereas - β-Thal maj – No HbA, marked ↑ in HbF/HbA2 α-thalassemia is caused by deficient synthesis of α chains. - β-Thal minor – ↓ HbA, slight ↑ HbA2 (4-8%) - The hematologic consequences of diminished synthesis of one - α-Thal – HbH or Barts Hb globin chain stem not only from hemoglobin deficiency but also 2. Peripheral smear from a relative excess of the other globin chain, particularly in β- - Hypochromic, microcytic anemia thalassemia - Target cells, basophilic stippling Classification: 3. Evidences of bone marrow hyperplasia 1. β-Thalassemia: defective β-globin chain - Inc. reticulocyte and normoblasts a. β Thal minor = Cooleys trait; β+/β or β0/β (heterozygous) 4. Fe overload b. β Thal intermedia = β+/β0, mild β+/β+ - Marked inc. siderocytes and sideroblasts, hemochromatosis c. β Thal major = Cooleys An; β+/β+ or β0/β0 2. α-Thalassemia: defective α-globin chain COD: Cardiac hemochromatosis (overloading of iron into the heart) a. Silent carrier – no Sx, no RBC abn PBS CHANGES IN THALASSEMIA b. α-Thal trait – no Sx, w/ mild anemia c. HbH - 4 β-chains (adults) d. Hydrops fetalis – Barts Hb = 4 γ chains (fetus) PATHOGENESIS OF ANEMIA IN THALASSEMIA 1. Decrease rate of globin synthesis → Dec. HbA → hypochromic microcytic β-THALASSEMIA anemia 2. Aggregation and precipitation of unpaired globin → The causative mutations fall into two categories: a. Abn erythropoiesis → death of young RBC - β0 mutations- associated with absent β-globin synthesis b. RBC with inclusions → destroyed by spleen - β+ mutations- characterized by reduced (but detectable) βglobin The result of early cell death → severe Anemia + transfusions → as a result synthesis of transfusion, the patient may present with iron overload → Point mutations fall into three major classes: hemosiderosis (@ liver, pancreas, and heart) - Splicing mutations- most common cause of β+ -thalassemia - Promoter region mutations- reduce transcription by 75% to 80%, S/SX: THALASSEMIA associated with β+ -thalassemia - Chain terminator mutations- consist of either non-sense mutations 1. Massive erythroid hyperplasia → expansion of red marrow or small insertion/deletions, most common cause of β0 – a. Skull x-ray – “crew haircut” appearance thalassemia b. Facial alteration: enlargement of the face with small jaw Impaired β-globin synthesis results in anemia by 2 mechanisms: 2. Hemosiderosis/ hemochromatosis - Deficit in HbA synthesis produces “underhemoglobinized” 3. Massive Hepatosplenomegaly hypochromic, microcytic red cells with subnormal oxygen transport 4. Jaundice capacity - Diminished survival of red cells and their precursors, which results from the imbalance in α- and β-globin synthesis PATHOGENESIS Aggregates of unpaired α-globin chains- hallmark of the disease, are not visible in routinely stained blood smears Blood transfusions are a double-edged sword, diminishing the anemia and its attendant complications, but also adding to the systemic iron overload Unpaired α chains precipitate within red cell precursors → insoluble inclusions → membrane damage undergo apoptosis - 70% to 85% of red cell precursors ineffective erythropoiesis - Those red cells that are released from the marrow also contain inclusions and have membrane damage splenic sequestration and extravascular hemolysis  Erythropoietic drive in the setting of severe uncompensated anemia leads Small red cells (microcytosis), minimal or no to: anemia, and no abnormal physical signs - Massive erythroid hyperplasia in the marrow- erosion of bony HbA2 levels are normal or low cortex → impairs bone growth → skeletal abnormalities Hemoglobin H (HbH) Caused by deletion of three α-globin genes - Extensive extramedullary hematopoiesis- metabolically active Disease HbH has an extremely high affinity for erythroid progenitors steal nutrients from other tissues that are oxygen → not useful for oxygen delivery → already oxygen-starved, causing severe cachexia tissue hypoxia disproportionate to the level Excessive absorption of dietary iron- another serious complication of of Hgb ineffective erythropoiesis HbH is prone to oxidation → intracellular - Erythroid precursors secrete erythroferrone that inhibits production inclusions → red cell sequestration and of hepcidin (negative regulator of iron uptake in the gut) phagocytosis in the spleen - In thalassemia: marked expansion of erythroid precursors → Moderately severe anemia resembling increased absorption of iron from the gut + repeated blood βthalassemia intermedia transfusions → secondary hemochromatosis Hydrops Fetalis Most severe form of α-thalassemia Caused by deletion of all four α-globin genes β-THALASSEMIA MAJOR In the fetus: excess γ-globin chains form Most common in Mediterranean countries, parts of Africa, and Southeast tetramers (hemoglobin Barts) hypoxia Asia Signs of fetal distress usually become Microscopic findings: evident by the third trimester of pregnancy o Peripheral blood smear: S/Sx: Severe pallor, generalized edema, and - Anisocytosis and poikilocytosis, microcytosis, and massive hepatosplenomegaly similar to that hypochromia seen in hemolytic disease of the newborn - Target cells, basophilic stippling, and fragmented red cells Tx: dependence on blood transfusions, - Reticulocytosis but is lower than expected for the severity of associated w/ increased iron overload anemia because of ineffective erythropoiesis - Normoblasts are seen as a result of “stress” erythropoiesis and extramedullary hematopoiesis PAROXYSMAL NOCTURNAL HEMOGLOBINURIA o Other major alterations involve the bone marrow and spleen Paroxysmal chronic intravascular hemolysis. - Untransfused patients: expansion of bone marrow Paroxysmal nocturnal hemoglobinuria (PNH) is a disease that results from - Crewcut appearance on radiographic studies acquired mutations in the phosphatidylinositol glycan complementation - Enlargement of the spleen (1500 g) group A gene (PIGA), an enzyme that is essential for the synthesis of - Liver and the lymph nodes also may be enlarged by certain membrane-associated complement regulatory proteins. extramedullary hematopoiesis Phosphatidylinositol glycan complementation group A gene (PIGA) o - Enzyme that is essential for the synthesis of certain membrane- β-THALASSEMIA MINOR associated complement regulatory proteins. Usually asymptomatic - (PNH) is a disease that results from acquired mutations in the PIGA Mild anemia, if present, It is the only hemolytic anemia caused by an acquired genetic defect PBS: hypochromia, microcytosis, basophilic stippling, and target cells Pathology: Abn PIGA gene → Def of a stem cell protein: CD59 (lysis Mild erythroid hyperplasia is seen in the bone marrow inhibitor), CD55 (DAF), C8 protein → susceptible to lysis by complement Recognition of β-thalassemia trait is important for two reasons: PNH blood cells are deficient in three GPI-linked proteins that regulate - It may be mistaken for iron deficiency complement activity: - It has implications for genetic counseling - Decay-accelerating factor, or CD55 - Membrane inhibitor of reactive lysis, or CD59- most important, it is α-THALASSEMIA a potent inhibitor of C3 convertase that prevents the spontaneous In newborns with α-thalassemia: excess unpaired γ-globin chains form activation of the alternative complement pathway γ4 tetramers known as hemoglobin Barts - C8-binding protein Older children and adults: excess β-globin chains form β4 tetramers SSx: intravascular hemolysis → mild hemoglobinuria, IDA known as HbH COD: Episodic venous thrombosis Because free β and γ chains are more soluble than free α chains and form Clinical features: fairly stable homotetramers → hemolysis and ineffective erythropoiesis - Hemosiderinuria eventually leads to iron deficiency, which can are less severe than in β-thalassemia exacerbate the anemia if untreated Gene deletion- most common cause of reduced α-chain synthesis - Thrombosis- leading cause of death in individuals with PNH - 5-10% of patients eventually develop AML or myelodysplastic CLINICAL SYNDROMES syndrome Silent Carrier State Associated with the deletion of a single Laboratory Diagnosis αglobin gene barely detectable reduction in - PNH is diagnosed by flow cytometry α-globin chain synthesis - Detects RBCs that are deficient in GPI-linked proteins (CD59) Individuals are completely asymptomatic but - Flow cytogram of blood from a patient with PNH shows a population have slight microcytosis. of RBCs that is deficient in both CD55 and CD59 α-Thalassemia Trait Identical to β-thalassemia minor  IMMUNE HEMOLYTIC ANEMIA antibodies rarely induce clinically important hemolysis. Chronic cold Pathology: Hemolysis is due to the appearance of Ab against RBC Loss of substances needed for nuclear maturation and division. Nucleus Major Diagnostic criterion: Coomb’s antiglobulin test remains immature thus are abnormally large.agglutinin Classification: immunohemolytic anemia occurs in association with certain B-cell - Warm Ab neoplasms or as an idiopathic condition. - Cold agglutinin Most common cause: mycoplasma pneumonia & infectious - Cold hemolysin mononucleosis Clinical symptoms result from binding of IgM to red cells in vascular CLASSIFICATION OF IHA beds where the temperature may fall below 30°C, such as in exposed fingers, toes, and ears. IgM binding agglutinates red cells and fixes 1. Warm Ab IHA complement rapidly. It is caused by antibodies that bind stably to red cells at 37°C. As the blood recirculates and warms, IgM is released, usually before Does not fix complement complement-mediated hemolysis can occur; therefore, intravascular IgG-coated RBC binds to monocytes & spleenic macrophage → hemolysis is usually not seen. However, the transient interaction with splenomegaly IgM is sufficient to deposit sublytic quantities of C3b, an excellent Most causative antibodies are of the IgG class; less commonly, IgA opsonin, which leads to the removal of red cells by phagocytes in the antibodies are the culprits. The red cell hemolysis is mostly spleen, liver, and bone marrow (extravascular hemolysis). extravascular. IgG-coated red cells bind to Fc receptors on phagocytes, The hemolysis is of variable severity. Vascular obstruction caused by which remove red cell membrane during “partial” phagocytosis. agglutinated red cells may produce pallor, cyanosis, and Raynaud As in hereditary spherocytosis, the loss of membrane converts the red phenomenon in parts of the body that are exposed to cold temperatures. cells to spherocytes, which are sequestered and destroyed in the spleen. Chronic cold agglutinin immunohemolytic anemia caused by IgM Moderate splenomegaly due to hyperplasia of splenic phagocytes is antibodies may be difficult to treat. The best approach, when possible, usually seen. is avoidance of cold temperatures. Mostly idiopathic 3. Cold hemolysin IHA = paroxysmal cold hemoglobinuria - In cases that are idiopathic, the antibodies are directed against IgG Ab binds to RBC and complement at low temp, activation and red cell surface proteins, often components of the Rh blood hemolysis starts as temp starts to rise group complex. Characterized by acute massive IV hemolysis following exposure to cold Secondary causes that lead to warm Ab AHA Common causes: mycoplasma pneumonia, measles, mumps, & other - Drugs (Abx) viral flu like syndrome - Lymphomas & leukemias/ neoplasia This rare disorder may cause substantial, sometimes fatal, intravascular - Autoimmune disorders (SLE) hemolysis and hemoglobinuria. In drug-induced cases, two mechanisms have been described. The autoantibodies are IgGs that bind to the P blood group antigen on - Antigenic drugs. In this setting hemolysis usually follows large, the red cell surface in cool, peripheral regions of the body. Complement- intravenous doses of the offending drug and occurs 1 to 2 weeks mediated lysis occurs when the cells recirculate to the body’s warm after therapy is initiated. These drugs, exemplified by penicillin core, where the complement cascade functions more efficiently. and cephalosporins, bind to the red cell membrane and create a Most cases are seen in children following viral infections; in this setting new antigenic determinant that is recognized by antibodies. The the disorder is transient, and most of those affected recover within 1 responsible antibodies sometimes fix complement and cause month. intravascular hemolysis, but more often they act as opsonins that promote extravascular hemolysis within phagocytes. MICROANGIOPATHIC HEMOLYTIC ANEMIA - Tolerance-breaking drugs. These drugs, of which the antihypertensive agent α-methyldopa is the prototype, break Hemolytic Anemia resulting from trauma to RBC from narrowing or tolerance in some unknown manner that leads to the production obstruction in the microvasculature e.g.: DIC, TTP, SLE, malignant HPN, of antibodies against red cell antigens, particularly the Rh blood patients with prosthetic valves group antigens. About 10% of patients taking α-methyldopa The common pathogenic feature in these disorders is microvascular develop autoantibodies, as assessed by the direct Coombs test, lesions that result in luminal narrowing, often due to the deposition of and roughly 1% develop clinically significant hemolysis. thrombi, producing shear stresses that mechanically injure passing red Treatment of warm antibody immunohemolytic anemia centers on the cells. removal of initiating factors (i.e., drugs); when this is not feasible, The most significant hemolysis caused by trauma to red cells is seen in immunosuppressive drugs and splenectomy are the mainstays. individuals with cardiac valve prostheses and microangiopathic disorders. 2. Cold agglutinin IHA Artificial mechanical cardiac valves are more frequently implicated than are This type of immunohemolytic anemia is caused by IgM antibodies that bioprosthetic porcine or bovine valves. The hemolysis stems from shear bind to red cells avidly at low temperatures (0°C to 4°C) but not at 37°C. forces produced by turbulent blood flow and pressure gradients across An IgM Ab binds to RBC at 0-4°C, activates complement at a slightly damaged valves. higher temp. and dissociates at 30°C Regardless of the cause, traumatic damage leads to intravascular Cold agglutinin antibodies sometimes appear transiently following hemolysis and the appearance of red cell fragments (schistocytes), “burr certain infections, such as with Mycoplasma pneumoniae, Epstein-Barr cells,” “helmet cells,” and “triangle cells” in blood smears virus, cytomegalovirus, influenza virus, and human immunodeficiency virus (HIV). In these settings, the disorder is self-limited and the  ANEMIA DUE TO DIMINISHED PRODUCTION MEGALOBLASTIC ANEMIA Due to B12 & folic acid def The common theme among the various causes of megaloblastic anemia is an impairment of DNA synthesis that leads to ineffective hematopoiesis and distinctive morphologic changes, including abnormally large erythroid precursors and red cells. Pathology: Loss of substances needed for nuclear maturation and division. Nucleus remains immature thus are abnormally large. Absorption: - Mouth: B12 breakdown by pepsin. - Transport: salivary protein - Stomach: cleaved by pancreatic enz B12+ IF - Ileum: absorption LABORATORY DIAGNOSIS Peripheral smear a. Megaloblastic Anemia - Macrocytic “hyperchromic” RBC - Large nucleated RBC in PBS “megaloblasts” b. Leukopenia with hypersegmented neutro or “macropolys” (six- lobed nucleus) c. ↓ platelets (thrombocytopenia) RBC indices: ↑MCV, high to normal MCHC Retic count: decreased In the absence of your tetrahydrofolate, there will be no remethylation to - Striking reticulocytosis seen at least 5days after IV administration methionine. On the other hand, in the presence of methylmalonic acid, it is of B12/Folic Acid converted to succinyl-CoA. In the absence of vit B12 and tetrahydrofolate, toxic Bone marrow hyperplasia substances can accumulate. - Hypercellular - Erythroid: myeloid ratio 1:1 CAUSES OF MEGALOBLASTIC ANEMIA - “Megaloblasts” - All stages of myeloid development are large B12 Deficiency Folic Acid Deficiency - Asynchronism or dissociation in the nucleus and cytoplasm of the Vegetarian diet Alcoholics RBCs Impaired absorption: Folic acid antagonists: Others: Malabsorption, ileitis, Methotrexate a. Decreased serum B12 gastrectomy, intestinal Increased requirement: b. Inc. homocysteine & methylmalonic acid (bec the are not resection, lymphoma pregnancy, infancy, converted) Fish tapeworm thyrotoxicosis, hemolysis (Diphyllobothrium latum) Inc. losses - dialysis  PERNICIOUS ANEMIA Cow’s milk contains about twice as much iron, but its bioavailability is poor. Type of Megaloblastic Anemia caused by autoimmune destruction of - The impoverished, who can have suboptimal diets for gastric mucosa → loss of parietal cells and intrinsic factor (IF) socioeconomic reasons at any age - Pernicious anemia is believed to result from an autoimmune attack - Older adults, who often have restricted diets with little meat because on the gastric mucosa. Histologically, there is a chronic atrophic of limited income or poor dentition gastritis marked by a loss of parietal cells, a prominent infiltrate of - Teenagers who subsist on “junk” food lymphocytes and plasma cells, and megaloblastic changes in IRON METABOLISM mucosal cells similar to those found in erythroid precursors. Iron absorbed from the gut is bound to plasma transferrin and transported Pathology to the bone marrow, where it is delivered to developing red cells and 1. Autoantibody to IF (70%) incorporated into haemoglobin - Type I blocks attachment of B12 to IF Mature red cells are released into the circulation After 120 days, are - Type II blocks B12-IF complex to ileal receptor ingested by macrophages, primarily in the spleen, liver, and bone marrow 2. Autoantibody to gastric parietal cells (90%) Here iron is extracted from hemoglobin and recycled to plasma transferrin - Directed against the parietal cell At equilibrium, iron absorbed from the gut is balanced by losses in shed - Leads to decline in # of parietal cells & IF keratinocytes, enterocytes, and (in women) endometrium - Leads to chronic atrophic gastritis & gastric atrophy Iron absorption in the duodenum is regulated by hepcidin, a small Three types of autoantibodies are present in many, but not all, patients. circulating peptide that is synthesized and released from the liver in About 75% of patients have a type I antibody that blocks the binding of response to increases in intrahepatic iron levels vitamin B12 to intrinsic factor. Type I antibodies are found in both plasma Alterations in hepcidin have a central role in diseases involving and gastric juice. Type II antibodies prevent binding of the intrinsic factor– disturbances of iron metabolism vitamin B12 complex and also present in a large proportion of patients - Anemia of chronic inflammation with pernicious anemia. Both type I and type II antibodies are found in - Rare form of microcytic anemia is caused by mutations that disable plasma and gastric juice. Type III antibodies are present in 85% to 90% of TMPRSS6 → high hepcidin levels, resulting in reduced iron patients and recognize the α and β subunits of the gastric proton pump, a absorption and failure to respond to iron therapy component of the microvilli of the canalicular system of the gastric parietal - Hepcidin activity is inappropriately low in both primary and cell. Type III antibodies are not specific, as they are found in as many as secondary hemochromatosis 50% of older adults with idiopathic chronic gastritis. Autoantibodies are of diagnostic utility, but are not thought to be the primary cause of the gastric pathology; rather, it seems that an autoreactive T-cell response initiates gastric mucosal injury and triggers the formation of autoantibodies Laboratory Diagnosis: 1. Achlorhydria 2. Positive serum antibodies Morphology: - GIT: Atrophic glossitis (Beefy tongue); Atrophic gastritis → inc. risk for cancer (gastric carcinoma) LABORATORY DX OF IDA: 1. PBS: hypochromic microcytic IRON DEFICIENCY ANEMIA (IDA) - Normal retic or normoblasts - Normal platelets, WBC Deficiency of iron is the most common nutritional disorder in the world 2. Bone marrow: Dec. sideroblasts and results in clinical signs and symptoms that are mostly related to 3. Fe indices: inadequate hemoglobin synthesis. - Low serum Fe Causes: - Low serum ferritin - Low dietary intake - elderly, infants, poor - High Total Iron Binding Capacity (TIBC) - Poor absorption 4. Elevated RDW - Excessive demand - pregnancy, children - Chronic blood loss Response to Tx: Reticulocytosis w/in 3-5 days Dietary iron inadequacy occurs in even high income societies in the following groups: Both the hemoglobin and hematocrit are depressed, usually to a moderate - Infants, who are at high risk due to the very small amounts of iron degree, in association with hypochromia, microcytosis, and modest in milk. Human breast milk provides only about 0.3 mg/L of iron. poikilocytosis.  The serum iron and ferritin are low, and the total plasma iron-binding ANEMIAS OF MARROW FAILURE capacity (reflecting elevated transferrin levels) is high. Low serum iron with increased iron-binding capacity results in a reduction of transferrin APLASTIC ANEMIA saturation to below 15%. Reduced iron stores inhibit hepcidin synthesis, and its serum levels fall. Aplastic anemia refers to a syndrome of chronic primary hematopoietic In uncomplicated cases, oral iron supplementation produces an increase failure and attendant pancytopenia in reticulocytes in about 5 to 7 days that is followed by a steady increase Pathogenesis: Marrow failure due to suppression of hematopoesis in blood counts and the normalization of red cell indices. Diagnosis: - BM: hypocellular with no response to SIGNS AND SYMPTOMS - PBS: pancytopenia - Retic count: decreased Koilonychia, alopecia Tx: transplant / immunosuppressive therapy Pica - Depletion of iron from the central nervous system may lead to the CAUSES OF APLSATIC ANEMIA appearance of pica, in which affected individuals have a craving for non-foodstuffs such as clay or food ingredients such as flour, and 2 major etiologies have been invoked: periodically move their limbs during sleep. - Extrinsic- immune-mediated suppression of marrow progenitors - Pica is also seen in association with developmental disorders such - Intrinsic abnormality of stem cells as autism (in the absence of iron deficiency) Hereditary = Fanconi’s Anemia Atrophy of tongue and stomach o Fanconi anemia is a rare autosomal recessive disorder caused by Plummer Vinson Syndrome: esophageal webs + atrophic glossitis + Fe defects in a multiprotein complex that is required for DNA repair. deficiency Anemia Marrow hypofunction becomes evident early in life and is often - Esophageal webs may appear together with microcytic accompanied by multiple congenital anomalies, such as hypoplasia hypochromic anemia and atrophic glossitis to complete the triad of of the kidney and spleen, and bone anomalies, commonly involving findings in the rare Plummer-Vinson syndrome the thumbs or radii. Idiopathic – stem cell defect Acquired: - Drugs idiosyncratic – chloramphenicol (antibiotiC); carbamazepine & phenytoin (anticonvulsants) - Chemicals – benzene compounds & alkylating agents (insectisides) - Infections – CMV, parvovirus, hepatitis, EBV ANEMIA OF CHRONIC DISEASE Pathogenesis : 1. Impaired Fe absorption – Inc. hepcidin 2. Reduced erythroid progenitors 3. Impaired Fe utilization Conditions: OTHER FORMS OF MARROW FAILURE 1. Chronic microbial infection 2. Chronic immune disorders 1. Myelophthisic Anemia § 3. Neoplasms - Pathogenesis: space occupying lesions that destroy significant HYPOCHROMIC MICROCYTIC ANEMIA amount of marrow Chronic Disease IDA Thalassemia - Diagnosis: Serum Fe ↓ ↓ ↑ o BM: presence of SOL e.g. metastatic CA, MM, Serum Ferritin ↑ ↓ ↑ o PBS: pancytopenia; tear drop shaped RBC → deformed TIBC ↓ ↑ ↓ during their tortuous escape from the fibrotic marrow Morphology N/N OR H/M H/M H/M 2. Chronic renal failure - Associated with an anemia that tends to be roughly proportional to the severity of the uremia - Diminished synthesis of EPO by the damaged kidneys - Uremia also reduces red cell lifespan and impairs platelet function - Administration of EPO and iron replacement therapy significantly improves the anemia 3. Diffuse liver disease - Associated with anemia attributed to decreased marrow function  - Erythroid progenitors are preferentially affected o - Anemia is often slightly macrocytic due to lipid abnormalities associated with liver failure 4. Neoplasia 5. Hypothyroid disease - Associated with mild normochromic, normocytic anemia S/Sx: - Plethoric, cyanotic - Pruritus, peptic ulcer - Headache, dizziness, Hpn Complications: - Bleeding or thromotic episodes - Hyperuricemia EVALUATION OF ANEMIA BY RBC INDICES Prognosis: - Regular phlembotomy can extend life MCHC MCV MCH - Myelofibrosis (20%) in 10 years IDA/THALASSEMIA ↓ ↓ ↓ - AML (2%) CHRONIC N/↓ N/↓ N/↓ INFLAMMATION/ BLEEDING DISORDERS DISEASE SHPEROCYTOSIS sl↑ ↓/N Variable Causes of Bleeding Disorders Lab Parameter Affected PERNICIOUS ANEMIA Hi N ↑ Hi N Blood vessel (primary) All parameters normal B12/ FOLIC ACID Hi N ↑ Hi N Platelet (primary) HEMOLYTIC/APLASTIC N N N Number Dec plt ct, inc Bleeding Time (BT) POLYCYTHEMIA N N N Function Ⓝ plt ct, inc BT Clotting factors (secondary) Inc clotting time (CT) POLYCYTHEMIA Extrinsic factors Inc prothrombin time Intrinsic factors Inc APTT Increase in red cell mass Polycythemia denotes an abnormally high number of circulating red cells, VESSEL WALL ABNORMALITY usually with a corresponding increase in the hemoglobin level. It may be relative (when there is hemoconcentration due to decreased plasma Small hemorrhages in skin or mucous membranes → Non- volume) or absolute (when there is an increase in the total red cell mass). thrombocytopenic purpura Types: All bleeding parameters normal - Relative Causes o Hemoconcentration due to decreased plasma volume - Infection – meningococcemia, measles, infective endocarditis o Dehydration o Infections often induce petechial and purpuric hemorrhages, - Absolute particularly meningococcemia, other forms of septicemia, o Primary: Polycythemia Vera - results from an intrinsic infective endocarditis, and several of the rickettsioses. The abnormality of hematopoietic precursors involved mechanisms include microbial damage to the o Secondary: Inc. erythropoetin secretion; compensatory or microvasculature (vasculitis) and disseminated intravscular paraneoplastic; stems from the response of red cell coagulation. progenitors to elevated levels of erythropoietin - Scurvy, Ehlers Danlos - Stress polycythemia (Gaisböck syndrome) o Scurvy and the Ehlers-Danlos syndrome are associated with Increased marrow production of myeloid progenitors microvascular bleeding due to collagen defects that weaken Pathogenesis: Mutation of tyrosine kinase JAK2 → erythropoetin vessel walls. Acquired vascular fragility accounts for the receptors spontaneous purpura that are commonly seen in older adults Laboratory Dx: and the skin hemorrhages that are seen with Cushing - PBS – panmyelosis (all of the myeloid series are affected) syndrome, in which the protein-wasting effects of excessive - RBC = > 6M corticosteroid production cause loss of perivascular - Platelets = >500T extracellular matrix. - WBC = 12-50T - Drugs – penicillin, sulfa - Hct = >60% o Drug reactions sometimes take the form of cutaneous Incidence: Males, middle aged – elderly petechiae and purpura without causing thrombocytopenia. In many instances the vascular injury is mediated by the  deposition of drug-induced immune complexes in vessel - ADAMTS13 degrades very high-molecular-weight multimers of walls, leading to hypersensitivity (leukocytoclastic) vasculitis vWF. In its absence, large multimers accumulate in plasma and tend - Henoch Schönlein Purpura to promote spontaneous platelet activation and aggregation. o Henoch-Schönlein purpura is a systemic immune disorder Superimposition of endothelial cell injury (caused by some other characterized by purpura, colicky abdominal pain, condition) may further promote the formation of platelet polyarthralgia, and acute glomerulonephritis (Chapter 20). aggregates, thus initiating or exacerbating clinically evident TTP. These changes result from the deposition of circulating - ADAMTS13 deficiency may be inherited or acquired. In the acquired immune complexes within vessels throughout the body and form, an autoantibody that inhibits the metalloprotease activity of within the glomerular mesangial regions. ADAMTS13 is present. Less commonly, patients inherit an - Hemorrhagic Telangiectasia = Weber Osler Rendu Syndrome inactivating mutation in ADAMTS13. In those with hereditary o Hereditary hemorrhagic telangiectasia (also known as ADAMTS13 deficiency, the onset is often delayed until adolescence, WeberOsler-Rendu syndrome) is an autosomal dominant and the symptoms are episodic. Thus, factors other than disorder that can be caused by mutations in at least five ADAMTS13 deficiency (e.g., a superimposed vascular injury or different genes, most of which modulate TGF-β signaling. It prothrombotic state) must be involved in triggering full-blown TTP. is characterized by dilated, tortuous blood vessels with thin Tx: plasma exchange walls that bleed readily. Bleeding can occur anywhere, but it DDx: Hemolytic Uremic Syndrome (HUS) is most common under the mucous membranes of the nose (epistaxis), tongue, mouth, and eyes, and throughout the gastrointestinal tract. QUANTITATIVE PLATELET ABNORMALITY Dec platelet # (NV 150T-450T) 20T - Spontaneous bleeding 20T-50T – postraumatic bleeding Bleeding characteristic - Petechial Hges in skin & mucous membranes - Easy bruisability - GI, GUT bleed : melena, hematuria, inc menstrual flow HEMOLYTIC UREMIC SYNDROME Complication: Threat of Intracranial bleeding Same manifestations as TTP minus the neurologic manifestations CAUSES OF THROMBOCYTOPENIA - Renal manifestation prominent - S/Sx of hemolysis present 1. BM diseases – aplastice anemia, myelopthisic anemia Morphology: widespread hyaline microthombi 2. Ineffective megakaryopoiesis – B12 def Pathogenesis: excessive activation of platelets by bacterial toxin (E.coli) 3. Inc. destruction – infection, immuno (ex. SLE), drugs “Typical” HUS 4. Massive transfusion - Strongly associated with infectious gastroenteritis caused by 5. Sequestration Escherichia coli strain O157:H7, which elaborates a Shiga-like toxin. This toxin is absorbed from the inflamed gastrointestinal HIT - heparin induced thrombocytopenia mucosa into the circulation, where it is believed to directly or - I – 1-2 days after treatment, no clinical importance, continue indirectly alter endothelial cell function in some manner that treatment provokes platelet activation and aggregation. - II – 4-14 days after Tx, life threatening, stop Tx - Children and older adults are at highest risk. Those affected present with bloody diarrhea, and a few days later HUS makes its ABNORMALITIES IN PLATELET NUMBER appearance. - Typical HUS is treated supportively. Patients who survive the acute IDIOPATHIC THROMBOCYTOPENIC PURPURA (ITP) insult usually recover, but some have permanent renal damage and Autoimmune dis producing Ab against platelets require dialysis or renal transplantation. BM normal or w/ inc. megakaryocytes “Atypical” HUS is Acute ITP - Often associated with defects in complement factor H, membrane - Self-limited disorder in children ff viral infection cofactor protein (CD46), or factor I, proteins that act to prevent Chronic ITP excessive activation of the alternative complement pathway. - Seen in adults esp reproductive females with autoimmune disorders - Deficiencies of these proteins may be caused by inherited defects or lymphoproliferative dis or acquired inhibitory autoantibodies and are associated with a remitting, relapsing clinical course. THROMBOTIC THROMBOCYTOPENIC PURPURA ABNORMALITIES IN PLATELET FUNCTION Characterized by microangiopathic hemolytic anemia, fever, transient 1. Inborn neurologic deficits, renal failure usually in females, 4th decade of life. a. Von Willebrands Dis. – defective adhesion deficient von Willebrands Morphology: widespread hyaline microthombi factor Pathogenesis: excessive activation of platelets due to def of enz (ADAMTS b. Bernard Soulier – defective adhesion (no GpIb) 13)  - Bernard-Soulier syndrome illustrates the consequences of disease is associated with a spectrum of mutations, including point defective adhesion of platelets to subendothelial matrix. It is an substitutions that interfere with maturation of the vWF protein or autosomal recessive disorder caused by an inherited deficiency that result in rapid clearance from the plasma. of the platelet membrane glycoprotein complex Ib–IX. This - Type 3 disease is an autosomal disorder usually caused by deletions glycoprotein is a receptor for vWF and is essential for normal or frameshift mutations involving both alleles, resulting in little to platelet adhesion to the subendothelial extracellular matrix. no vWF synthesis. Because vWF stabilizes factor VIII in the - Affected patients have a variable, often severe, bleeding circulation, factor VIII levels are also reduced in type 3 disease and tendency. the associated bleeding disorder is often severe. c. Glanzmann Thrombasthenia – defective aggregation (no GpIIb/IIIa) Type 2 von Willebrand disease is characterized by qualitative defects in - Glanzmann thrombasthenia exemplifies bleeding due to vWF; there are several subtypes, of which type 2A is the most common. It defective platelet aggregation. It is transmitted as an autosomal is inherited as an autosomal dominant disorder. vWF is expressed in recessive trait. normal amounts, but missense mutations are present that lead to defective - Thrombasthenic platelets fail to aggregate in response to multimer assembly. As a result, large- and intermediatesized multimers, adenosine diphosphate (ADP), collagen, epinephrine, or the most active forms of vWF, are missing from plasma. Type 2 von thrombin because of deficiency or dysfunction of glycoprotein Willebrand disease accounts for 25% of all cases and is associated with IIb–IIIa, an integrin that participates in “bridge formation” mild to moderate bleeding between platelets by binding fibrinogen. The associated S/SX – spontaneous bleeding from mucous membrane, excessive bleeding tendency is often severe. bleeding from wounds, menorrhagia, hemarthrosis 2. Aquired Laboratory diagnosis: a. Aspirin/NSAIDS – inhibit cyclooxygenase → suppress - Ⓝ platelet count prostaglandins (specifically, prostacyclin which is a potent platelet - Elevated BT aggregator) - Elevated APTT b. Uremia (suppresses the function of factor III) - Reduced ristocetin aggregation test HEMOPHILIA Hemophilia A, the most common hereditary disease associated with life- threatening bleeding, is caused by mutations in factor VIII, an essential cofactor for factor IX in the coagulation cascade. Hemophilia A is inherited as an X-linked recessive trait and thus affects mainly males and homozygous females. Rarely, excessive bleeding occurs in heterozygous females, presumably as a result of inactivation of the X chromosome bearing the normal factor VIII allele by chance in most cells (unfavorable lyonization). About 30% of patients have no family history;