Red Blood Cells and Bleeding Disorders

clinical features of B thalassemia intermediate

Clinical consequences and severity are intermediate between the major and minor forms. These patients are genetically heterogeneous.

what is cold agglutinin type anemia?

caused by IgM antibodies that agglutinate RBCs at low temperatures; it accounts for 15% to 30% of immune hemolytic anemias

50% of dic, 33% of dic, 17% of dic, occurs in the setting of what?

About 50% of DIC occurs in obstetric patients with pregnancy complications; 33% occurs in the setting of carcinomatosis, with sepsis and trauma responsible for most of the remaining cases. In the setting of trauma or obstetric complications, bleeding is the dominant complication, while thrombosis is the major manifestation in malignancy.

TTP and HUS occurs in who

Acquired TTP typically affects women; HUS often occurs in children and the elderly during outbreaks of food poisoning.

what is Acute Immune Thrombocytopenic Purpura

Acute ITP is mainly a self-limited disorder seen most often in children after a viral infection; platelet destruction is due to transient production of anti-platelet autoantibodies.

what is anemia?

Anemia is a reduction in the total circulating red blood cell (RBC) mass below normal limits; the consequences are reduced oxygen carrying capacity and tissue hypoxia. Patients are pale, weak, and easily fatigued. Anemia is formally diagnosed based on a reduction in the hematocrit and/or hemoglobin concentration The classification of anemias is usually based on the underlying mechanism; the specifics of RBC morphology (size, shape, and hemoglobinization) can often provide etiologic clues. Thus, microcytic, hypochromic anemias suggest disorders of hemoglobin synthesis (most often iron deficiency), while macrocytic anemias suggest abnormalities in bone marrow erythroid precursor maturation; normochromic, normocytic anemias have diverse etiologies

what is anemia of chronic disease?

Anemia of chronic disease occurs in the setting of chronic inflammation, infections, or neoplasms; elevated interleukin-6 increases hepatic hepcidin production and reduces iron export from duodenal epithelium and macrophages. Erythropoietin production is also inappropriately low, exacerbating the anemia. Serum iron is low, but ferritin levels are high. The anemia is normocytic/normochromic or microcytic/hypochromic.

what is chronic blood loss?

Anemia will occur only if the rate of loss exceeds the marrow regenerative capacity, or when iron reserves are depleted.

what is acute blood loss?

Any clinical effects are due mainly to the loss of intravascular volume; shock and/or death can result. If the patient survives, fluid shifts from the interstitium rapidly restore the blood volume; however, there will be hemodilution and lowering of the hematocrit. The resulting reduction in oxygen-carrying capacity triggers renal erythropoietin production, with increased proliferation of committed erythroid progenitors. Release of new RBCs begins at day 5; it is heralded by increased numbers of reticulocytes (large, immature RBCs) peaking at 10% to 15% of the peripheral RBC count by day 7. Significant bleeding (with hypotension) also triggers an adrenergic response that mobilizes granulocytes from the intravascular marginated pool (causing leukocytosis); thrombocytosis also occurs due to increased platelet production.

what is aplastic anemia? pathogenesis of it?

Aplastic anemia is a syndrome of chronic primary hematopoietic failure; pancytopenia affecting all lineages results. Known causes fall into three broad categories: • Toxic exposures Total body irradiation Drugs or chemicals are the most common causes of secondary aplastic anemia; marrow suppression can be dose related, predictable, and reversible (benzene, alkylating agents, and antimetabolites such as vincristine) or idiosyncratic, affecting only some exposed individuals in an unpredictable manner (chloramphenicol, chlorpromazine, and streptomycin) • Viral infections (most commonly non-A, non-B, non-C, and non-G hepatitis) • Inherited diseases (e.g., Fanconi anemia, defects in telomerase activity) In idiopathic cases (65% of aplastic anemia), stem cell failure may be due to: • A primary defect in the number or function of stem cells, in some cases due to mutagen exposure; occasionally, genetically damaged stem cells transform to myeloid neoplasms • Suppression of antigenically altered stem cells by T-cell-mediated immune mechanisms

clinical features of chronic ITP

Chronic ITP is classically a disease of women younger than 40 years of age. Cutaneous bleeding often takes the form of petechiae. Initial manifestations can be melena, hematuria, or heavy menses. the bleeding time is prolonged, while prothrombin and partial thromboplastin times are normal.

what is Chronic Immune Thrombocytopenia Purpura

Chronic immune thrombocytopenia purpura (ITP) is caused by autoantibodies to platelets; these can be primary or can arise in the setting of certain exposures or pre-existing conditions (e.g., lupus, B-cell neoplasms, or HIV).

What are anemias of blood loss?

Clinical features depend on the rate of hemorrhage and whether it is external or internal; interstitial bleeding allows recapture of red cell iron, but bleeding into the gut or externally can lead to iron deficiency and hamper restoration of normal RBC counts. we have acute and chronic blood loss

Bleeding Disorders Related to Defective Platelet Functions These disorders are characterized by prolonged bleeding time in association with normal platelet count.

Congenital defects • Defective platelet adhesion, for example, autosomal-recessive Bernard-Soulier syndrome caused by deficient platelet membrane glycoprotein complex GpIb-IX (platelet receptor for von Willebrand factor, necessary for platelet-collagen adhesion). • Defective platelet aggregation, for example, Glanzmann thrombasthenia, an autosomal recessive disorder caused by a deficiency of platelet membrane glycoprotein GpIIb-IIIa, (involved in binding fibrinogen). • Disorders of platelet secretion of prostaglandins and/or granule bound ADP that promote further aggregation. Acquired defects: • Aspirin irreversibly inhibits cyclooxygenase and can suppress the synthesis of thromboxane A2, necessary for platelet aggregation. • Uremia causes defects in platelet adhesion, granule secretion, and aggregation.

What is disseminated intravascular coagulation (DIC)?

DIC is a thrombohemorrhagic disorder characterized by excessive activation of coagulation leading to formation of thrombi in the microvasculature. It is a secondary complication in a variety of diseases; DIC symptoms arise from tissue ischemia (due to the thrombosis) and/or bleeding caused by the exuberant consumption of clotting factors or activation of fibrinolytic pathways.

What is hydrops fetalis?

Deletion of all four a-globin genes. Early fetal development is permitted by embryonic z-chain synthesis; however, as z-globin ceases and the fetal z2g2 tetramers are replaced by y-globin tetramers (HbBarts), the high oxygen affinity prevents O2 release to tissues and is not compatible with life. Intrauterine (and then life-long) transfusions can be lifesaving.

drug induced thrombocytopenia bara läs

Drug-induced thrombocytopenia occurs when drugs act as haptens on platelet proteins or participate in the formation of immune complexes that deposit on platelet surfaces; antibodies to the drugs or modified platelet molecules then cause platelet removal via macrophage ingestion. Heparin-induced thrombocytopenia (HIT) has a distinctive pathogenesis. Type I thrombocytopenia occurs rapidly after drug administration and is due to a direct platelet-aggregating effect of heparin; it is usually of little clinical significance and spontaneously resolves. Type II thrombocytopenia, while less common, has significant potential for adverse clinical consequences. It occurs 5 to 14 days after therapy and is caused by autoantibodies directed against a complex of heparin and platelet factor 4 that activates platelets. This, in turn, leads to thrombi in arteries and veins— even in the setting of thrombocytopenia—that can be limb- and life-threatening (e.g., from pulmonary embolism of deep venous thromboses). Therapy requires heparin discontinuation and alternate anticoagulation administration.

What is anemia of folate deficiency and what causes it?

Folate is involved in single carbon transfers in a variety of biochemical pathways. Deficiency induces a megaloblastic anemia hematologically indistinguishable from that seen with B12 deficiency; notably, however, gastric atrophy and the neurologic sequelae of B12 deficiency do not occur. Diagnosis of folate deficiency requires demonstration of reduced serum or RBC folate levels. Deficiency occurs with: • Inadequate intake (e.g., chronic alcoholics, very elderly, or indigents) • Malabsorption syndromes (e.g., sprue) or diffuse infiltrative disease of the bowel (e.g., lymphoma) • Increased demand (e.g., pregnancy, infancy, or disseminated cancer) • Folate antagonists (e.g., methotrexate for chemotherapy)

what is Hemolytic Disease Due to Red Cell Enzyme Defects: Glucose-6-Phosphate Dehydrogenase Deficiency

Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme in the hexose monophosphate shunt that reduces nicotinamide adenine dinucleotide phosphate (NAPD) to NADPH; in turn, NADPH reduces RBC glutathione, providing protection against RBC oxidative injury. In G6PD-deficient cells, oxidant stress (e.g., due to inflammation, drugs, or foods such as fava beans) causes hemoglobin sulfhydryl cross-linking and protein denaturation. The altered hemoglobin precipitates as Heinz bodies that can cause direct hemolysis; in addition, the precipitated hemoglobin can attach to the inner cell membrane, reduce deformability, and increase susceptibility to splenic macrophage destruction. G6PD deficiency is an X-linked disorder; although there are several G6PD variants, only two—G6PD- and G6PD Mediterranean

Hiv associated thrombocytopenia bara läs

HIV-associated thrombocytopenia is due to both diminished platelet production and increased destruction. Megakaryocytes express both CXCR4 and CD4 and thus can be directly infected by HIV; infected cells are prone to apoptosis and defective platelet production. HIV-mediuated dysregulation of B cells leads to anti-platelet autoantibodies that can also cause their premature destruction.

HUS is caused by

HUS most commonly follows gastrointestinal infections with verotoxin-producing Escherichia coli. Verotoxin injures endothelial cells and thereby promotes dysregulated platelet activation and aggregation.

what is hemolytic anemias, what types are there?

Hemolytic anemias feature premature RBC destruction (i.e., less than the normal 120-day lifespan), elevated erythropoietin with increased erythropoiesis, and increased hemoglobin catabolites (e.g., bilirubin). The excess serum bilirubin is unconjugated; the ultimate levels of hyperbilirubinemia depend on liver functional capacity and the rate of hemolysis; with normal livers, jaundice is rarely severe. Hemolysis can be extravascular or intravascular:

what is Hemophilia A?

Hemophilia A is the most common hereditary disease associated with life-threatening bleeding. It is an X-linked recessive disorder (thus, primarily affecting males), characterized by a reduced amount and/or activity of factor VIII. Severe disease occurs when factor VIII levels are less than 1% of normal; Clinically, petechiae are characteristically absent; instead, symptomatic patients exhibit the following: • Massive hemorrhage after trauma or operative procedures • Spontaneous hemorrhages in regions of the body normally subject to trauma (e.g. joints); this can lead to progressive, crippling deformities The partial thromboplastin time is prolonged (intrinsic pathway defect), and specific diagnosis is made by assay for factor VIII.

What is hemophilia B(christmas disease)?

Hemophilia B is an X-linked recessive disease caused by factor IX deficiency; it is clinically indistinguishable from hemophilia A. Identification of hemophilia B requires assay of factor IX levels.

What is hereditary spherocytosis and its pathogenesis?

Hereditary spherocytosis (HS) is due to cytoskeletal or membrane protein defects that render RBCs spheroidal and less deformable, and thus vulnerable to splenic sequestration and destruction; it is autosomal dominant in 75% of patients. Insufficiency in several different proteins (spectrin, ankyrin, band 3, or band 4.2) can cause HS; all lead to reduced density of membrane skeletal components, which in turn causes reduced stability of the lipid bilayer and loss of membrane fragments as RBC age. Compound heterozygosity for two defective alleles typically causes a more severe phenotype. Reduction in surface area causes RBC to assume a spheroidal shape with diminished deformability and a propensity for being trapped and destroyed by splenic macrophages.

clinical features of B thalassemia minor

Heterozygotes are usually asymptomatic due to sufficient b-globin synthesis. Peripheral blood shows minor abnormalities, including hypochromia, microcytosis, basophilic stippling, and target cells. Hemoglobin electrophoresis shows increased HbA2 (a2d2 hemoglobin) due to increased ratios of d- versus b-globin synthesis.

Mean corpuscular hemoglobin concentration (MCHC) and intercellular ph in Sickle cell disease?

Higher HbS concentrations increase the probability of interaction between individual HbS molecules. Thus, dehydration—which increases MCHC—facilitates sickling. Conversely, concurrent diseases that reduce MCHC (e.g., a-thalassemia) lessen sickling severity. Reduced pH reduces hemoglobin oxygen affinity, thereby increasing the proportion of deoxygenated HbS and the propensity to polymerize.

morphology and clinical features of aplastic anemia?

Hypocellular marrow (hematopoietic cells are replaced by fat cells), with secondary effects due to granulocytopenia (infections) and thrombocytopenia (bleeding). Onset is insidious with symptoms related to the pancytopenia; splenomegaly is absent.

what is immunohemolytic anemia?

Immunohemolytic anemia is caused by antibodies that bind to RBCs and cause their premature destruction; classification is based on the characteristics of the responsible antibody. Diagnosis requires detection of antibodies and/or complement on RBCs. This is accomplished by the direct Coombs test and indirect Coombs test.

interaction of HbS with other types of hemoglobin within RBC

In heterozygotes, HbS constitutes only 40% of the hemoglobin with the remainder being HbA; the HbA interferes with HbS polymerization. Consequently, in heterozygotes, sickling occurs only with profound hypoxia. HbF also interferes with HbS polymerization, and newborns do not manifest disease complications until 5 to 6 months of age when RBC HbF content is reduced to adult levels. For the fortunate adult patient who has hereditary persistence of HbF, the sickle cell disease is considerably less severe. Another variant of hemoglobin is HbC (substituting lysine for the glutamic acid in the b-chain sixth position); in patients with both b-globin S and C alleles (HbSC), HbS constitutes 50% of the hemoglobin, and the HbSC cells have a tendency to lose salt and water, becoming dehydrated—which increases the intracellular HbS concentrations. Both factors increase the tendency of the HbS to polymerize and thus result in HbSC patients having a symptomatic (albeit milder) sickling disorder called HbSC disease.

What is megaloblastic anemias?

Megaloblastic anemias are most commonly due to deficiency of vitamin B12 or folate. These are coenzymes required for the synthesis of thymidine (and are also involved in normal methionine synthesis); in their absence, inadequate DNA synthesis causes defective nuclear maturation of rapidly proliferating cells. The resultant blockade in cell division leads to abnormally large RBCs and erythroid precursors (megaloblasts), and also affects granulocyte maturation. Neurologic complications of B12 deficiency are attributed to abnormal myelin degradation.

Morphology of DIC

Microthrombi, with infarctions and, in some cases, hemorrhages, are found in many organs and tissues. In lungs, alveolar capillary microthrombi may be associated with histology resembling acute respiratory distress syndrome. In the adrenals, massive hemorrhages due to DIC give rise to the Waterhouse-Friderichsen syndrome seen in meningococcemia. Similarly, Sheehan postpartum pituitary necrosis is a form of DIC complicating labor and delivery.

most important clinical aspect of sickle cell disease?

Microvascular occlusion with resultant tissue hypoxia and infarction The propensity to occlude small vessels is not strictly dependent on the percentage of irreversibly sickled cells in the blood; rather, it is a function of RBC stickiness (sickled RBCs express increased levels of adhesion molecules), local inflammation, and platelet aggegation.

pathogenesis of iron deficiency anemia

Negative iron balance can result from low dietary intake, malabsorption, excessive demand (infancy or pregnancy), or chronic blood loss. The last is the most important cause of iron deficiency anemia; blood loss occurs through the gastrointestinal tract (e.g., peptic ulcers, colon cancer, hemorrhoids) or the female genital tract (e.g., menstruation). Anemia occurs when iron reserves are depleted; it is accompanied by low serum iron, ferritin, and transferrin saturation levels.

Microvascular transit time in sickle cell disease?

Normally, the capillary transit rate is sufficiently high that significant deoxygenation (and therefore sickling) cannot occur. Consequently, sickling is usually confined to tissues with intrinsically sluggish blood flow (e.g., spleen, bone marrow) or those involved by inflammation, where transit rates are retarded.

Clinical features of pernicious anemia?

Onset is insidious, with symptoms due to anemia and posterolateral spinal tract involvement; the latter includes spastic paresis and sensory ataxia. Diagnosis is based on the presence of megaloblastic anemia, leukopenia with hypersegmented neutrophils, low serum B12 levels, and elevated homocysteine and methylmalonic acid (consequences of diminished thymidine and methionine synthesis). The diagnosis is confirmed by profound reticulocytosis after parenteral B12 administration; serum anti-IF antibodies are highly specific for pernicious anemia. There is a significant association of pernicious anemia with other autoimmune disorders of the adrenal and thyroid glands, as well as increased risk of gastric cancer.

what is Paroxysmal Nocturnal Hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare X-linked hemolytic disease resulting from acquired mutations in phosphatidylinositol glycan complementation group A gene (PIGA); PIGA mutations lead to deficient expression of a family of proteins normally anchored into the cell membrane via glycosylphosphatidylinositol (GPI). Among the GPI-linked proteins affected are several that regulate complement inactivation: decay-accelerating factor (CD55), membrane inhibitor of reactive lysis (CD59), and C8-binding protein. Their deficiency renders RBCs hypersensitive to complement, which is activated spontaneously at low rates. Granulocyte and platelet GPI-linked proteins are also affected, resulting in a predisposition to thrombosis, particularly in portal, cerebral, and hepatic veins. Hemolysis is intravascular, but it is paroxysmal and nocturnal in only 25% of cases. PNH may arise due to an autoimmune response to GPI-linked proteins on hematopoietic stem cells. In this scenario, rare clones harboring a mutated PIGA gene thus have a selective advantage and eventually "take over" the marrow. This pathogenic basis explains the association of PNH with aplastic anemia, a marrow failure syndrome with an autoimmune pathogenesis. In 5% to 10% of patients, PNH transforms to acute myeloid leukemia or myelodysplastic syndrome. Bone marrow transplantation can be curative.

What is pernicious anemia?

Pernicious anemia is a specific form of megaloblastic anemia caused by autoimmune gastritis and attendant loss of IF production. Gastric injury is likely initiated by autoreactive T cells; secondary autoantibodies against proteins involved in B12 uptake are not the primary cause of disease but can exacerbate the process: • Type I antibodies (present in 75%of patients) block B12 binding to IF • Type II antibodies block IF or IF-B12 binding to the ileal receptor • Type III antibodies (i.e., 85% to 90% of patients) directed against parietal proton pump proteins affect acid secretion

pathogenesis of chronic ITP

Platelet autoantibodies are usually directed toward one of two platelet antigens—the platelet membrane glycoprotein complexes IIb/IIIa or Ib/IX. Destruction of antibody-coated platelets occurs in the spleen, and splenectomy can be beneficial.

What is polycythemia?

Polycythemia denotes an abnormally high RBC count, usually with an associated increase in hemoglobin level. Relative increases may be caused by hemoconcentration due to dehydration (e.g., water deprivation, vomiting, or diarrhea) or due to stress polycythemia (also called Gaisböck syndrome). Absolute increases can be: • Primary due to polycythemia vera, a myeloproliferative disorder in which RBC precursors proliferate in an erythropoietin independent fashion. Mutations in the erythropoietin receptor can also render its activity erythropoietin independent. • Secondary due to increased erythropoietin, which may be physiologic (lung disease, high-altitude living, cyanotic heart disease) or pathophysiologic (erythropoietin-secreting tumors, such as renal cell or hepatocellular carcinomas).

what is pure red cell aplasia

Pure red cell aplasia is a form of marrow failure due to erythroid precursor suppression. Outside of cases associated with B19 parvovirus infections (that infect and destroy RBC precursors), the etiology is likely autoimmune; it can occur in association with drug exposures, autoimmune diseases, and neoplasms (e.g., large granular lymphocytic leukemia or thymoma). In such settings, the anemia may remit with immunosuppression, plasmapheresis, or following thymoma resection.

what is intravascular hemolysis?

RBCs can be ruptured by mechanical injury (e.g., mechanical cardiac valves), complement fixation (e.g., mismatched blood transfusion), intracellular parasites (e.g., malaria), or extracellular toxins (e.g., clostridial enzymes). Patients exhibit anemia, hemoglobinemia, hemoglobinuria, hemosiderinuria, and jaundice; there is markedly reduced serum haptoglobin. Free hemoglobin can be oxidized to methemoglobin. Both forms of the protein are excreted in the urine (imparting a brown color) or are resorbed by renal proximal tubules; iron released from hemoglobin can accumulate in tubular cells (renal hemosiderosis).

what is sickle cell disease?

Sickle cell disease is a hereditary hemoglobinopathy resulting from substitution of valine for glutamic acid at the sixth position of the b-globin chain; the resultant mutant hemoglobin substitutes for the normal b-globin to generate HbS. This is an autsomal recessive disorder; 8% to 10%of African Americans are heterozygous for the abnormal allele (sickle cell trait, which is largely asymptomatic), while 70,000 individuals in the United States are homozygous (a2bS2) and have sickle cell disease.

morphology and clinical features of hereditary spherocytosis?

Spherocytic RBCs are small and lack central pallor; there is reticulocytosis and marrow erythroid hyperplasia. Marked splenic congestion is seen with prominent erythrophagocytosis in the cords of Billroth. Diagnosis depends on family history, hematologic findings, and increased RBC osmotic fragility; the mean RBC hemoglobin concentration is increased due to cellular dehydration. Anemia, moderate splenomegaly, and jaundice are characteristic. Although the clinical course is typically stable due to compensatory increases in erythropoiesis, increased RBC turnover or diminished erythropoiesis can be problematic. Thus, aplastic crisis occurs when parvovirus induces transient suppression of erythropoiesis; events that increase splenic RBC destruction (e.g., infectious mononucleosis) trigger hemolytic crisis. Half of adults develop gallstones from chronic hyperbilirubinemia.

TTP is caused by what

TTP is associated with inherited or acquired deficiencies in ADAMTS13, a serum metalloprotease that limits the size of von Willebrand factor multimers in the plasma. In its absence, very high molecular weight multimers accumulate that are capable of promoting platelet aggregation throughout the microcirculation. In the case of acquired TTP, patients often have antibodies directed against ADAMTS13.

What are thalassemia syndromes and what is b-thalassemias?

Thalassemia syndromes are a heterogeneous group of inherited disorders caused by mutations that reduce a- or b-globin chain synthesis . b Chains are encoded by a single gene on chromosome 11 (yielding two copies); a chains are encoded by two closely linked genes on chromosome 16 (yielding four copies). Diminished synthesis of one chain has pathologic consequences due to: low intracellular hemoglobin (hypochromia) and effects related to a relative excess of the other chain. The syndromes are most common in Mediterranean countries, parts of Africa, and Southeast Asia. • b-Thalassemias are characterized by deficient synthesis of b-globin: • b0 mutations abrogate b-globin chain synthesis; most commonly these involve chain termination mutations that create premature stop codons. • b+ mutations lead to reduced (but detectable) b-globin synthesis; most commonly these involve aberrant RNA splicing, although some are promoter region mutations.

what is A thalassemia? what is the silent carrier state?

These are due to inherited defects that reduced a-globin synthesis; gene deletion is the most common genetic cause. The clinical consequences are due to imbalanced synthesis of a and non-a chains (y chains in infancy, b and d chains after 6 months of age). Free b chain tetramers (HbH) have extremely high oxygen (O2) affinity and thus cause tissue hypoxia disproportionate to hemoglobin levels. In addition, HbH is prone to oxidation, leading to precipitation of intracellular protein aggregates that promote RBC sequestration by macrophages. Free g chains form stable tetramers (HbBarts) that also bind O2 with excessive avidity, resulting in tissue hypoxia. Completely asymptomatic, resulting from a single a-globin gene deletion; changes in total a-globin chain synthesis are barely detectable.

what is Thrombotic Microangiopathies: Thrombotic Thrombocytopenic Purpura and Hemolytic-Uremic Syndrome

Thromobotic thrombocytopenic purpura (TTP) and hemolyticuremic syndrome (HUS) are related disorders within the spectrum of thrombotic microangiopathies; these are characterized by thrombocytopenia, microangiopathic hemolytic anemia, fever, transient neurologic deficits (in TTP), or renal failure (in HUS). Although clinically similar to DIC, activation of the protein clotting factors is not a prominent feature in the thrombotic microangiopathies; rather HUS and TTP are both caused by excessive platelet activation. Most of the clinical manifestations are due to widespread hyaline microthrombi in arterioles and capillaries composed of dense aggregates of platelets and fibrin.

hemolytic anemia resulting from trauma to red cells?

Turbulent flow and increased shear forces cause RBC fragmentation and intravascular hemolysis; peripheral blood reveals fragmented RBC (schistocytes). Causes include: • Prosthetic heart valves (mechanical more than bioprosthetic valves) • Microangiopathic hemolytic anemia with diffuse microvascular narrowing owing to fibrin or platelet deposition (e.g., disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome)

What is von Willebrand disease?

Von Willebrand disease is the most common heritable bleeding disorder, most are autosomal dominant. Symptoms are generally mild (epistaxis, excess bleeding from wounds, etc.), but can be more severe. Therapy can include desmopressin (stimulating vWF release) or infusions of plasma concentrates containing the missing factor(s). • Type 1 and type 3 von Willebrand disease are associated with reduced levels of vWF. Type 1 is autosomal dominant and most common; it is clinically mild. Type 3 is an uncommon autosomal recessive variant associated with marked vWF deficiency and a severe phenotype. • Type 2 is an autosomal dominant form caused by qualitative defects in vWF. Type 2A (autosomal dominant) is most common; vWF levels are normal, but the ability to form the most active high-molecular-weight multimers is defective, leading to a functional deficit. Patients have mild to moderate bleeding.

which is the most common immunohemolytic anemia and what can also lead to it?

Warm antibody type is the most common immunohemolytic anemia; half of the cases are idiopathic (primary), with the remainder being associated with other autoimmune disorders (e.g., lupus), lymphoid neoplasms, or drug hypersensitivity. Most commonly, immunoglobulin G (IgG) anti-RBC antibodies (anti-Rh in most idiopathic cases) coat the RBC and act as opsonins; erythrocytes become spheroidal due to partial macrophage phagocytosis and are eventually completely destroyed in the spleen. Splenomegaly is characteristic.

morphology and clinical features of iron deficency anemia?

Whatever the cause, iron deficiency produces a hypochromic, microcytic anemia, with increased RBC central pallor and poikilocytosis. Marrow exhibits a mild to moderate erythroid hyperplasia, with loss of stainable iron in marrow macrophages. Besides the fatigue and pallor attendant with anemia, depletion of essential iron-containing enzymes can cause alopecia, koilonychia, and atrophy of the tongue and gastric mucosa. The Plummer-Vinson triad of hypochromic microcytic anemia, atrophic glossitis, and esophageal webs may occur.

molecular pathogenesis of B thalassemia?

With decreased b-globin synthesis, there is reduced HbA production; the "under-hemoglobinized" RBC are hypochromic and microcytic with reduced oxygen carrying capacity. In addition, excess unbound a chains form highly unstable aggregates that cause cell membrane damage; this leads to precursor destruction in the marrow (ineffective erythropoiesis) and splenic sequestration of mature RBCs. Severe anemia causes marked compensatory expansion of the erythropoietic marrow, ultimately encroaching on cortical bone and causing skeletal abnormalities in growing children. Ineffective erythropoiesis is also associated with excessive absorption of dietary iron; along with repeated blood transfusions this leads to severe iron overload.

What is A-thalassemia trait and hemoglobin H (HbH) disease?

a-Thalassemia trait: Either one chromosome has both a-globin genes or each chromosome has a deletion of one gene; the clinical picture is comparable to b-thalassemia minor. Although these two genotypes are clinically identical, they differ in whether offspring are at risk for severe a-thalassemia (three or more a chains deleted). Hemoglobin H (HbH) disease: Deletion of three a-globin genes causes marked suppression of a chain synthesis and formation of unstable HbH tetramers; clinically, it resembles b-thalassemia intermedia.

Clinical features of B- thalassemia Major

b-Thalassemia major: Patients with two b-thalassemia alleles (b+/b+, b+/b0, or b0/b0) typically have severe, transfusion-dependent anemia; the manifestations begin 6 to 9 months after birth as hemoglobin synthesis switches from HbF to HbA. Peripheral blood shows marked anisocytosis (variability in cell size) with many microcytic, hypochromic RBCs, target cells, and erythrocyte fragments; poorly hemoglobinized RBC precursors (normoblasts) are also common. There is marked expansion of the hematopoietic marrow, with erosion of existing cortical bone and subsequent new bone formation. Extramedullary hemaotopoiesis is common with splenomegaly. Without transfusions, death occurs at an early age from profound anemia. Blood transfusions lessen the anemia and suppress the secondary bone deformities. In multiply transfused patients, morbidity and fatality are related to cardiac failure resulting from progressive iron overload and secondary hemochromatosis; iron chelation can slow (but not prevent) these complications. Bone marrow transplantation is the only curative therapy.

worlds most common nutritional disorder in world?

iron deficieny

what is extravascular hemolysis?

occurs in macrophages of the spleen (and other organs). Predisposing factors include RBC membrane injury, reduced deformability, or opsonization. The principal clinical features are anemia, splenomegaly, and jaundice; modest reductions in haptoglobin (a serum protein that binds hemoglobin) also occur.

what is cold hemolysin type anemia?

occurs in paroxysmal cold hemoglobinuria, capable of causing substantial (sometimes fatal) intravascular hemolysis. The autoantibodies are IgG that bind to the P blood group antigen at low temperatures and fix complement; when the temperature is elevated, hemolysis occurs. Most cases occur in children after viral infections and are transient.

Except for strict vegans or in chronic alcoholism, most diets contain adequate cobalamin. Thus, most deficiencies in vitamin B12 result from impaired absorption:

• Achlorhydria (in elderly individuals) impairs vitamin B12 release from R binders • Gastrectomy causes loss of IF • Pernicious anemia • Resection of the distal ileum prevents IF-B12 absorption • Malabsorption syndromes • Increased requirements (e.g., pregnancy)

what is acute hemolysis and chronic hemolysis in immunohemolytic anemia?

• Acute hemolysis occurs during recovery from certain infections (e.g., Mycoplasma, Epstein-Barr virus [EBV], or human immunodeficiency virus [HIV] infections). It is usually self-limited and rarely induces significant hemolysis. • Chronic hemolysis can be idiopathic or can occur in the setting of B-cell neoplasms. Clinical symptoms result from RBC agglutination and complement fixation in vascular beds cooler than 30'C; although there is minimal complement-mediated hemolysis, the complement-coated cells are readily phagocytized in spleen, liver, and bone marrow. The hemolytic anemia is of variable severity; vascular obstruction in areas exposed to cold temperatures results in pallor, cyanosis, and Raynaud phenomenon.

drug induced hemolytic anemia occurs through 2 ways?

• Antigenic drugs: Drugs (e.g., penicillin, cephalosporins, quinidine) bind to the RBC surface; antibodies then interact with the drug or an RBC-drug complex. • Tolerance-breaking drugs: Drugs (e.g., a-methyldopa) induce antibodies against intrinsic RBC antigens.

Morphology of pernicious anemia

• Bone marrow shows megaloblastic erythroid hyperplasia, giant myelocytes and metamyelocytes, hypersegmented neutrophils, and large, multilobed nuclei in megakaryocytes • Atrophic glossitis; the tongue is shiny, glazed, and red • Gastric fundal atrophy with virtual absence of parietal cells and replacement by mucus-secreting goblet cells ("intestinalization") • Central nervous system (CNS) lesions occur in 75% of cases, characterized by demyelination of dorsal and lateral spinal cord tracts

sickle cell disease clinical features

• Chronic hemolytic anemia is associated with chronic hyperbilirubinemia and a propensity for gallstones. Chronic hypoxia will cause generalized impairment of growth and development. • Vaso-occlusive crises present as painful episodes of ischemic necrosis, most commonly involving bones, lungs, liver, brain, penis, and spleen. Acute chest syndrome is a particularly serious vaso-occlusive crisis caused by pulmonary inflammation that impedes lung vascular flow. • Aplastic crisis due to transient suppression of erythropoiesis is triggered by parvovirus infections. Sequestration crises occur in children with intact spleens; massive entrapment of sickled RBCs leads to rapid splenic enlargement, hypovolemia, and occasionally shock. • Progressive splenic fibrosis and impairment of the alternate complement pathway predispose to infections, particularly involving encapsulated organisms such as Streptococcus pneumoniae and Haemophilus influenzae.

Causes of thrombocytopenia

• Decreased production due to ineffective megakaryopoiesis (e.g., HIV, myelodysplastic syndromes) or due to generalized marrow disease that also compromises megakaryocyte number (e.g., aplastic anemia, disseminated cancer). • Decreased survival due to increased consumption (e.g., DIC) or due to immune-mediated platelet destruction, the latter secondary to anti-platelet antibodies or immune complex deposition on platelets. • Sequestration in the red pulp of enlarged spleens • Dilution due to massive transfusions; prolonged storage of whole blood results in prompt subsequent platelet sequestration. Thus, while plasma volume and RBC mass are reconstituted by transfusion, the number of circulating platelets is relatively reduced.

morphology of sickle cell disease?

• In childhood, there is splenomegaly due to sickled cell trapping in splenic cords. By adulthood, repeated episodes of vaso-occlusion have caused progressive fibrosis and shrinkage (autosplenectomy). • Bone marrow shows normoblastic hyperplasia. When hyperplasia is severe, expansion of the marrow can cause bone resorption; extramedullary hematopoiesis can occur.

Bleeding Disorders Caused by Vessel Wall disorders Such disorders are relatively common but usually cause only petechia and purpura without serious bleeding. Platelet counts and coagulation and bleeding times are typically normal. Causes include:

• Infections (e.g., meningococcus and rickettsia): Underlying mechanisms are microvascular damage (vasculitis) or disseminated intravascular coagulation (DIC). • Drug reactions: These are attributed to immune complex deposition with resulting hypersensitivity vasculitis. • Poor vascular support: Abnormal collagen synthesis (e.g., scurvy or Ehlers-Danlos syndrome), loss of perivascular supporting tissue (e.g., Cushing syndrome), or vascular wall amyloid deposition are included. • Henoch-Schönlein purpura: This is a systemic hypersensitivity response due to immune complex deposition and characterized by purpuric rash, abdominal pain, polyarthralgia, and acute glomerulonephritis. • Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome): This is an autosomal dominant disorder characterized by dilated, thin-walled vessels (often in mucous membranes of the nose and gastrointestinal tract).

clinical manifestations of DIC

• Microangiopathic hemolytic anemia • Respiratory symptoms (e.g., dyspnea, cyanosis) • Neurologic signs and symptoms, including convulsions and coma • Oliguria and acute renal failure • Circulatory failure and shock

what are the other forms of marrow failure? • Myelophthisic anemia • Chronic renal failure: • Diffuse liver disease (toxic, infectious, or cirrhotic)

• Myelophthisic anemia: Space-occupying lesions (e.g., metastatic cancer or granulomatous disease) destroy/distort the marrow architecture and depress hematopoiesis; pancytopenia results, often with immature precursors in the peripheral blood. • Chronic renal failure: This is almost invariably associated with anemia. Although multifactorial, insufficient erythropoietin production is most important; recombinant erythropoietin is usually efficacious. • Diffuse liver disease (toxic, infectious, or cirrhotic): anemia is primarily due to bone marrow failure, often exacerbated by (variceal) bleeding, and folate and/or iron deficiency.

morphology of megaloblastic anemia?

• Prominent peripheral blood anisocytosis with abnormally large and oval RBCs (macro-ovalocytes) • In the marrow, erythroid precursor nuclear maturation lags behind cytoplasmic maturation; ineffective erythropoiesis is reflected by increased apoptosis with compensatory megaloblastic hyperplasia • Abnormal granulopoiesis with giant metamyelocytes in marrow and hypersegmented neutrophils in peripheral blood

DIC is triggered by two major mechanisms: (1) release of tissue factor or thromboplastic substances into the circulation or (2) widespread endothelial cell injury?

• Thromboplastic substances can be derived from a variety of sources; placenta or amniotic fluid in obstetric complications; damaged tissues following major trauma, burns, or surgery; granules of leukemic cells in acute promyelocytic leukemia; or mucus released from certain adenocarcinomas. In sepsis, bacterial endotoxins activate monocytes to release tumor necrosis factor-a, thereby increasing tissue factor expression on endothelial cell membranes while simultaneously decreasing thrombomodulin expression. This results in both activation of the clotting system and inhibition of coagulation control. • Endothelial injury initiates DIC by causing tissue factor release from endothelial cells, by promoting platelet aggregation, and by activating the intrinsic coagulation pathway by exposing subendothelial connective tissue. Widespread endothelial injury can occur through antigen-antibody complex deposition (e.g., systemic lupus erythematosus), hypoxia, acidosis, temperature extremes (e.g., heatstroke, burns), or infections (e.g., meningococci, rickettsiae)