1. Anemia -reduction in total circulating red blood cell mass below normal limits--> reduced oxygen carrying capacity and tissue hypoxia-pale, weak and easily fatigued

2. Acute Blood loss -clinical effects due mainly to the loss of intravascular volume; shock and/or death can occur-if pt. survives, fluid shifts from the interstitium rapidly restore the blood volume but with hemodilution andlowering of hematocrit--> ERYTHROPOIETIN PRODUCTION, with increased proliferation of committed erythroid progenitors-release of new RBCs begins at day 5 (increased numbers of reticulocytes -large, immature RBCs) peaking at 10-15% of the peripheral RBC count by day 7-also an adrenergic response --> leukocytosis-thrombocytosis also occurs due to increased platelet production

3. Chronic Blood loss *anemia will occur only if the rate of loss exceeds the marrow regenerative capacity, or when iron reserves aredepleted

4. Hemolytic anemia -premature RBC destruction-elevated erythropoietin with increased erythropoiesis-increased hemoglobin catabolites

5. Extravascularhemolysis

*occurs in MACROPHAGES of the spleen (and other organs)-predisposing factors include RBC membrane injury, reduced deformability, or opsonization

*Clinical:-anemia, splenomegaly, and jaundice-modest reductions in HAPTOGLOBIN (a serum protein that binds hemoglobin) also occur

6. Intravascularhemolysis

-RBC rupture by mechanical injury, complement fixation, intracellular parasites, or extracellular toxins

-anemia, hemoglobinemia, hemoglobinuria, hemosiderinuria, and jaundice-MARKEDLY reduced HAPTOGLOBIN-free hemoglobin can be oxidized to methemoglobin - both forms of the protein are excreted un the urine(imparting a BROWN color) or are reabsorbed by renal proximal tubules-iron released from hemoglobin can accumulate in tubular cells (renal hemosiderosis)

7. Hereditaryspherocytosis (HS)

-due to cytoskeletal or membrane protein defects that RENDER RBCs SPHEROIDAL and LESS DEFORMABLE,and thus vulnerable to splenic sequestration and destruction*AUTOSOMAL DOMINANT in 75% of patients

8. Pathogenesis -EXTRAVASCULAR HEMOLYSIS

-insufficiency in several different proteins (spectrin, ANKYRIN, band 3, or band 4.2) can cause HS--> all lead to reduced density of the membrane skeletal components --> reduced stability of the lipid bilayer andloss of membrane fragments as RBC age*reduction in surface area causes RBC to assume a spheroidal shape with diminished deformability and apropensity for being trapped and destroyed by splenic macrophages

9. Morphology -spherical, small and LACK CENTRAL PALLOR-reticulocytosis and marrow erythroid hyperplasia-marked splenic congestion is seen with prominent erythrophagocytosis

640-675Study online at quizlet.com/_8ci63

10. Clinicalfeatures

*Diagnosis:-family hx-hematologic findings-increased RBC osmotic fragility (lyse in moderately hypotonic solutions)-mean RBC hemoglobin [ ] is increased due to cellular dehydration-anemia-moderate splenomegaly-jaundice

*APLASTIC CRISIS - occurs when PAROVIRUS induces transient suppression of erythropoiesis-events that trigger splenic RBC destruction (e.g. infectious mononucleosis) trigger HEMOLYTIC CRISIS

-half of adults dev. gallstones fro chronic hyperbilirubinemia

11. G6PDdeficiency

-G6PD is an enzyme in the hexose monophosphate shunt that reduces NADP to NADPH-NADPH reduces RBC glutathione, providing protection against RBC oxidative injury

**In G6PD-deficient cells, oxidant stress causes HEMOBLOBIN SULFHYDRYL CROSS-LINKING and PROTEINDENATURATION

%%The altered hemoglobin precipitates as HEINZ BODIES that can cause direct hemolysis or attach to inner membrane,reduce deformability, and increase susceptibility to splenic macrophage destruction

-X-linked disorder: G6PD- (present in 10% of african americans; usually self-limited episodes b/c only affects older cells)and G6PD Mediterranean (more severe episodes) --> clinically sig. hemolysis

12. Sickle CellDisease

-Normal adult red cells mainly contain HbA (a2b2) with smaller amounts of HbA2 (a2S2) and fetal hemoglobin HbF(a2y2)

*hereditary hemoglobinopathy (autosomal recessive) resulting from sub of VALINE FOR GLUTAMIC ACID at the 6thposition of the B-globin chain = HbS

-8-10% of AA's are heterozygous for the abnormal allele (sickle cell trait, which is largely asymptomatic). while 70,000indv. in the U.S. are homozygous and have sickle cell DISEASE

13. Pathogenesis -when DEOXYGENATED, HbS polymerizes into long, stiff chains that deform (sickle) RBCs--> this in turn, causes chronic hemolysis, microvascular occlusion, and tissue damage

*Factors affecting rate and degree of sickling1) Interaction of HbS with other types of hemoglobin within RBCs-if HbA present, as in with heterozygotes (40% HbS), it interferes with HbS polymerization and sickling only occursduring extreme hypoxia-HbF does the same thing - why newborns don't manifest until 5-6 months of age when RBC HbF content is reduced toadult levels-HbSC disease - HbC is another variant of hemoglobin; in patients with both the B-globin C and S alleles (HbSC) HbSconstitutes 50%. these cells tend to get dehydrated --> increased [ ] of HbS and sickling (albeit milder)

2) Mean corpuscular hemoglobin concentrations (MCHC)-increases probability of interaction b/w HbS molecules-thus DEHYDRATION, which increases MCHC, facilitates sickling

3) Intracellular pH-reduced pH reduces hemoglobin oxygen affinity, thereby increasing the proportion of deoxygenated HbS and thepropensity to polymerize

4) Microvascular transit time-sickling is usually confined to tissues with intrinsically sluggish blood flow (significant deoxygenation can occur

14. HbS damage -polymerized HbS herniates through the membrane skeleton-Ca2+ influx-protein cross linking-potassium and water efflux-dehydration and become rigid and non-defromable-uptake by splenic macrophages

*Macrovascular occlusion--> tissue hypoxia and infarction-propensity to occlude small vessels is a function of RBC STICKINESS (sickled RBCs express increased levels ofadhesion molecules)-also free hemoglobin released binds and inactivates NO -increasing vascular tone and enhancing platelet aggregation

15. Morphology *Peripheral blood - variable numbers of irreversibly sickled cells, reticulocytosis, and target cells

*in Childhood: splenomegaly due to sickled cell trapping in splenic cords-by adulthood --> autosplenectomy due to repeat vaso-occlusion$$ Howell-Jolly Bodies in RBCs are a sign of SPLENIC DYSFUNCTION

*Bone marrow:-shows normoblastic hyperplasia-when hyperplasia is severe, expansion of the marrow can cause bone resorption -extramedullary hematopoiesis can occur

*Microvascular occlusions-produce damage and infarction in various tissues

16. Clinicalfeatures

-chronic hyperbilirubinemia and propensity for GALLSTONES

-chronic hypoxia - stunts growth and dev.

-Vaso-occlusive crises - painful episodes of ischemic necrosis, most commonly involving bones, lung, liver, brain,penis, and spleen*Acute Chest Syndrome - serious vaso-occlusive crisis caused by pulmonary inflammation that impedes lung vascularflow (most common cause of death in adults)

-Aplastic crisis -triggered by parovirus = transient suppression of erythropoiesis -Sequestration crisis occurs in CHILDREN with intact spleens; massive entrapment of sickled RBCs --> rapid splenicenlargement, hypovolemia, and occasionally shock

-Progressive splenic fibrosis and impairment of the alternate complement pathway predispose to infections, particularlyinvolving encapsulated organisms such as Strep pneumoniae and H. influenzae

17. Diagnosis -sickle cells in peripheral blood smear-detection of HbS by hemoglobin electrophoresis-prenatal detection is possible through fetal DNA analysis**HYDROXYUREA (increases HbF and reduces WBC count/inflammation) is mainstay of treatment

18. ThalassemiaSyndromes

-caused by mutations that REDUCE a or B globin chain SYNTHESIS*B chains are encoded by a single gene on chromosome 11 (yielding 2 copies)*a chains are encoded by 2 closely linked genes on chromosome 16 (yielding 4 copies)

$$ diminished synthesis of one chain has path consequences due to low intracellular hemoglobin

19. B-Thalassemias

*deficient synthesis of B-globin-B^0 mutations abrogate B-globin chain synthesis; most commonly these involve chain termination mutations thatcreate premature STOP CODONS = milder anemia-B^+ mutations --> reduced (but detectable) B-globin synthesis; most commonly these involve aberrant RNA SPLICING,although some are promoter region mutations = severe anemia

*normal synthesis of other chains

20. Molecularpathogenesis

--> reduced HbA production-the under-hemoglobinized RBC are hypochromic and microcytic with reduced oxygen carrying capacity*excess UNBOUND a chains form highly unstable aggregates that cause cell membrane damage --> precursordestruction in the marrow (ineffective erythropoiesis) and splenic sequestration of mature RBCs

-Severe anemia --> expansion of erythropoietic marrow, ultimately encroaching on cortical bone and causing skeletalabnormalities in growing children-ineffective erythropoiesis is also associated with EXCESSIVE ABSORPTION OF DIETARY IRON --> iron overload

21. ClinicalSyndromes

1) B-thalassemia major-patients with 2 B thalassemia alleles typically have SEVERE, transfusion dependent anemia-manifestations begin 6-9 months after birth-peripheral blood - shows ANISOCYTOSIS (variability in cell size) with many microcytic, hypochromic RBCs, targetcells, and erythrocyte fragments; poorly hemoglobinized RBC precursors (normoblasts) are also common

-marked expansion of the hematopoietic marrow, with erosion of existing cortical bone and subsequent new boneformation

-without transfusions -death occurs at an early age-in multiply tranfused pts. - iron overload ensues and secondary hemochromatosis

2) B-Thalassemia minor-heterozygotes - usually asymptomatic -minor abnormalities in blood smear (microcytosis, hypochromia, basophilic stripping, and target cells$$hemoglobin electrophoresis shows increased HbA2 (a2S2 hemoglobin) due to increased ratios of S versus B-also increased HbF

3) B-Thalassemia intermedia

22. a-Thalassemias

-inherited defects that reduced a-globin synthesis-gene DELETION is the most common cause*free HbH (B chain tetramers) have extremely high oxygen affinity and thus cause tissue hypoxia disproportionate tohemoglobin levels*HbH is also prone to oxidation --> precipitation of intracellular protein aggregates that promote RBC sequestration bymacrophages

*free y chains also form tetramers (HbBarts) that have high oxygen affinity --> hypoxia

23. Subsets 1) Silent carrier state -completely asymptomatic-resulting from a SINGLE a-globin gene depletion-changes in total a-globin chain synthesis are barely detectable

2) a-Thalassemia trait-either one chromosome has both a-globin genes or each chromosome has a deletion of one gene-severe a-thalassemia (if 3 or more chains deleted)

3) Hemogloin H (HbH) disease-deletion of 3 a-globin chains causes marked suppression of a chain synthesis and formation of unstable HbHtetramers-clinically it resembles B-thalassemia intermedia

4) Hydrops fetalis-DELETION of ALL FOUR a-globin chains -early fetal dev. is permitted by embryonic S-chain synthesis; however, as S-globin ceases and the fetal S2y2tetramers are replaced by y-globin tetramers (HbBarts), the high oxygen affinity of the HbBarts prevents O2release to tissues and is not compatible with life-Intrauterine transfusions can be life saving

24. ParoxysmalNocturnalHemoglobinuria(PNH)

-rare X-linked hemolytic disease resulting from acquired mutations in PHOSPHATIDYLINOSITOL glycancomplementation group A gene (PIGA)--> deficient expression of a family of proteins normally anchored into the cell membrane viaglycosylphosphatidylinositol (GPI)

*Among the GPI-linked proteins affected are several that regulate COMPLEMENT INACTIVATION-DAF -decay accerlerating factor (CD55)* =normally destabilizes C3 and C5 convertases adhering to RBCs,platelets, and neutrophils, preventing activation of MAC-membrane inhibitor of reactive lysis (CD59)-C8-binding protein

-also affects platelets and neutrophils --> predisposition to thrombosis, particularly in portal, cerebral andhepatic veins--> PANCYTOPENIA

-Hemolysis is intravascular, but it is paroxysmal and nocturnal in only 25% of cases

-there is an association with aplastic anemia when the PNH develops due to an autoimmune response to GPI-linked proteins on hematopoietic stem cells

-5-10%, PNH --> acute myeloid leukemia

*Bone marrow transplant can be curative

25. ImmunohemolyticAnemia

*caused by antibodies that bind to RBCs and cause their premature destruction

*Diagnosis:-detection of antibodies and/or complement on RBCs-accomplished through DIRECT COOMBS TEST - the patient's RBCs are mixed with antibodies directed againsthuman immunoglobulin or complement, with RBC agglutination constituting a positive test-INDIRECT COOMBS TEST - a patient's serum is assayed for it ability to agglutinate test RBC expressing specificsurface antigens

26. Types 1) Warm antibody type-most common-half of cases are IDIOPATHIC (primary)-remainder associated with other autoimmune disease (i.e. SLE), lymphoid neoplasms, or drug hypersensitivity-most commonly IgG anti-RBC antibodies coat the RBC and act as OPSONINS-> erythrocytes become spheroidal due to partial macrophage phagocytosis and are eventually completelydestroyed in the spleen (EXTRAVASCULAR HEMOLYSIS)-splenomegaly is characteristic

*Drug induced hemolytic anemias 2 mechs.:-Antigenic drugs - penicillins, cephalosporins, quinidine) bind to the RBC surface; antibodies then interact withthe drug or an RBC-drug complex-Tolerance-breaking drugs - drugs (e.g. a-methyldopa) induce antibodies against intrinsic RBC antigens

2) Cold agglutinin type-caused by IgM antibodies that agglutinate RBCs at LOW temperatures; it accounts for 15% to 30% of immunehemolytic anemias

*Acute hemolysis - during recovery from certain infections. Usually self-limited and rarely induces sig. hemolysis

*Chronic hemolysis - can be idiopathic or occur in setting of B-cell neoplasms-clinical symptoms arise 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 readilyphagocytized in spleen, liver, and bone marrow --> HEPATOSPELNOMEGALY-variable severity-vascular obstruction in areas exposed to cold temps. --> pallor, cyanosis, and Raynaud phenomenon

3) 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 temp. is elevated, hemolysis occurs-most cases occur in children after viral infections and are transient

27. Hemolytic anemiaresulting fromtrauma to RBCs

-turbulent flow and increased shear forces cause RBC fragmentation and intravascular hemolysis-peripheral blood: reveals fragmented RBC (shistocytes)

*Causes:-Prosthetic heart valves (mechanical more than bioprosthetic valves)-microangiopathic hemolytic anemia with diffuse microvascular narrowing owing to fibrin or platelet deposition(e.g DIC, thrombotic thrombocytopenic purpura, HUS)

28. Megaloblasticanemia

-most commonly due to deficiency of vitamin B12 or folate = coenzymes required for SYNTHESIS OFTHYMIDINE (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-neurological complications of B12 deficiency are attributed to abnormal myelin degradation

29. Morphology -prominent peripheral blood anisocytosis w/ abnormally large and oval RBCs (macro-ovalocytes)-In the marrow, erythroid precursor nuclear maturation lags behind cytoplasmic maturation; ineffectiveerythropoiesis is reflected by increased apoptosis with compensatory megaloblastic hyperplasia-abnormal granulopoiesis with giant metamyelocytes in marrow and hypersegmented neutrophils in peripheralblood

30. Normal VitaminB12 metabolism

-MICROORGANISMS are the ultimate source of vit. B12-it is bound to salivary proteins called R BINDERS-Pepsin (gastric acid converts pepsinogen to pepsin) frees vit. B12 from ingested proteins-R-B12 complexes are digested in the DUODENUM by pancreatic proteases; released vit. B12 binds toINTRINSIC FACTOR (IF), a protein secreted by parietal cells of the gastric fundus-IF-B12 complexes bind to IF receptors in the distal ileum epithelium; absorbed vit. B12 complexes withTRANSCOBALAMIN II and is transported to tisues

$$ except for in strict vegans and chronic alcoholism, most diets contain adequate cobalamin*Most deficiencies in vit. B12 result from impaired absorption:-Achlorhydria (in elderly) impairs B12 release from R binders-Gastrectomy or loss of IF-Pernicious anemia-resection of the distal ileum prevents IF-B12 absorption-Malabsorption syndromes-Increased requirements (pregnancy)

31. Pernicious anemia *specific form of megaloblastic anemia caused by autoimmune gastritis and attendant loss of IF production-likely autoreactive T CELLS

*Secondary auto-antibodies:-Type I antibodies (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 (85-90%) - directed against parietal proton pump proteins affect acid secretion

32. Morphology -panmegaloblastinemia-atrophic glossitis; tongue is shiny, glazed and red-gastric fundal atrophy with virtual absence of parietal cells and replacement by mucus-secreting goblet cells("intestinalization")-CNS lesions occur in 75% of cases, characterized by demyelination of dorsal and lateral spinal cord tracts

33. Clinical features -increased incidence in Blood Group A-insidious onset with symptoms due to ANEMIA and POSTEROLATERAL SPINAL TRACT involvement (spasticparesis and sensory ataxia)-Diagnosis is based on the presence of megaloblastic anemia, leukopenia with hypersegmented neutrophils, lowserum B12 levels, and elevated homocysteine and methylmalonic acid-diagnosis is confirmed by profound RETICULOCYTOSIS after PARENTERAL B12 administration*serum anti-IF antibodies are highly specific for pernicious anemia-increased gastric cancer risk-sig. association with other autoimmune disorders of the adrenal and thyroid glands

34. Anemia of folatedeficiency

-similar changes in RBCs-no gastric atrophy and no neurological sequelae*Diagnosis of folate deficiency - requires demonstration of reduced serum or RBC folate levels.

*Deficiency occurs with:-Inadequate intake-Malabsorption syndromes (e.g. sprue) or diffuse infiltrative disease of the bowel (e.g. lymphoma)-Increased demand (e.g. preg, infancy, disseminated cancer)-Folate antagonists (e.g. methotrexate for chemo)

35. Iron deficiencyAnemia

*most common nutritional disorder in the world-15-20% of total body iron is in STORED FORM bound to hemosiderin or ferritin (good indicator of total iron stores)-80% in hemoglobin; myoglobin, catalase, and cytochromes make up the rest

$$ Iron balance is maintained by regulating the absorption of dietary iron across the duodenal epithelium $$-Heme iron enters mucosal cells directly (~20% is absorbable) -non-heme iron is first reduced to ferrous iron (via cytochrome B) before transport; only 1-2% of non-heme iron isabsorbed-Absorbed iron is transported across the basolateral membrane, where it is bound to plasma TRANSFERRINfor distribution throughout the body-this basolateral transport requires FERRIPORTIN, a membrane transporter, and hephaestin to re-oxidize thereduced iron-the remaining intracellular iron is bound to FERRITIN and subsequently lost when the epithelium is sloughedduring normal turnover

*Iron homeostasis is regulated in large part by HEPCIDIN - a hepatic peptide that blocks duodenal irontransepithelial transport by inducing the degradation of ferroportin-as hepcidin levels decrease (e.g. with reduced iron stores or increased erythropoiesis), ferroportin expression isincreased, and iron transport into the bloodstream is enhanced-conversely: as stores become replete, hepcidin levels INCREASE, ferroportin is degraded, and iron transport into thebloodstream is blocked*Hepcidin also blocks the release of iron from marrow macrophages, an important source of iron for heme synthesisin erythropoiesis-abnormalities in hepcidin levels lead to disturbances in iron metabolism ranging from some forms of anemia toHEMOCHROMATOSIS (systemic iron overload)

36. Pathogenesis -most important cause of negative iron balance in western world is chronic blood loss-blood loss occurs through the GI tract (peptic ulcers, colon cancer, hemorrhoids) or the female genital tract (e.g.menstruation)-anemia occurs when iron reserves are depleted*accompanied by low serum iron, ferritin, and transferrin saturation levels

37. Morphology -produces HYPOCHROMIC (RBCs with less than normal color and hemoglobin [ ]), MICROCYTIC ANEMIA-increased RBC central pallor and poikilocytosis-marrow exhibits a mild to moderate erythroid hyperplasia, with loss of stainable iron in marrow macrophages

38. Clinical features -fatigue and pallor-alopecia, koilonychia (abnormally thin nails (usually of the hand) which have lost their convexity, becoming flat oreven concave in shape), and atrophy of the tongue and gastric mucosa*PLUMMER VINSON TRIAD -hypochromic microcytic anemia, atrophic glossitis, and esophageal webs may occur

39. Anemia ofChronic Disease

-occurs is setting of chronic inflammation, infections, or neoplasms*elevated IL-6 increases hepatic hepcidin production and reduces iron export from duodenal epithelium andmacrophages-erythropoietin production is also low, exacerbating the anemia*serum iron is low, but ferritin levels are high (can't go out)-the anemia is normocytic/normochromic or microcytic/hypochromic -most common anemia is hospitalized patients-tx the underlying condition and in some cases giving EPO is effective

40. Aplastic anemia *syndrome of chronic primary hematopoietic failure; pancytopenia affecting all lineages results

41. Pathogenesis 1) 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 antimetabolitessuch as vincristine) or idiosyncratic, affecting only some exposed individuals in an unpredictable (frequentlyirreversible) manner (chloramphenicol, chlorpromazine, and streptomycin)

2) Viral infections-most commonly non-A, non-B, non-C, and non-G hepatitis

3) Inherited diseases-fanconi anemia, defects in telomerase activity

4) Idiopathic (65% of cases)*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

42. Morphology -hypocellular marrow (hematopoietic cells are replaced by fat cells

43. Clinicalfeatures

-insidious onset-fever (infections due to neutropenia), bleeding (thrombocytopenia), fatigue-splenomegaly is absent *withdrawal of a potential inciting agent can sometimes lead to recovery; more commonly, bone marrowtransplantation or immunosuppression is required

44. Pure Red CellAplasia

*form of marrow failure due to erythroid precursor suppression-outside of cases associated with B19 parvovirus infections, the etiology is likely AUTOIMMUNE-it can occur in association with drug exposures, autoimmune diseases, and neoplasms-in such cases the anemia may remit with IMMUNOSUPPRESSION, PLASMAPHERESIS, or following thymomaresection

45. Myelophthisicanemia

-space occupying lesions (e.g. metastatic cancer or granulomatous disease) destroy/distort the marrow architecture anddepress hematopoiesis; pancytopenia results, often with immature precursors in the peripheral blood

46. Chronic renalfailure

-insufficient ERYTHROPOIETIN PRODUCTION is most important-recombinant erythropoietin is usually efficacious

47. Diffuse liverdisease

-anemia is primarily due to bone marrow failure, often exacerbated by (variceal) bleeding, and folate and/or irondeficiency

48. Polycythemiavera (primarydisorder)

-a myeloproliferative disorder in which RBC precursors proliferate in an erythropoietin -independent fashion-clonal expansion of the myeloid stem cell-most due to mutations of JAK2 gene on short arm of chromosome 9

49. 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 or hepatocellular carcinomas)

50. Bleeding disorders caused by vesselwall abnormalities

*relatively common but usually cause only petechia and purpura without serious bleeding-platelet counts and coagulation and bleeding times are typically normal

*Causes:

1) Infections (e.g. meningococcus and rickettsia): underlying mech. are microvasculardamage (vasculitis) or DIC

2) Drug reactions-immune complex deposition -> hypersensitivity vasculitis

3) Poor vascular support-abnormal collagen synthesis (e.g. scurvy), loss of perivascular supporting tissue (e.g.Cushing syndrome), or vascular wall amyloid deposition are included

4) Henoch-Schonlein purpura-systemic hypersensitivity response due to immune complex deposition and characterized bypurpuric rash, abdominal pain, polyarthralgia, and acute glomerulonephritis

5) Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)-autosomal dominant disorder characterized by dilated, thin walled vessels (often in mucousmembranes of the nose and GI tract)

51. Bleeding related to REDUCEDPLATELET NUMBER(thrombocytopenia)

-defined as counts 100,000/uL or less, but spontaneous bleeding does not occur untilplatelet decrease to 20,000/uL or less-counts b/w 20,000 and 50,000 can exacerbate post traumatic hemorrhage*most SPONTANEOUS BLEEDS involve small vessels of the skin and mucous membranes

*Causes:

1) Decreased production due to ineffective megakaryopoiesis (e.g. HIV, myelodysplasticsyndromes) or due to generalized marrow disease

2) Decreased survival -due to increased consumption (DIC) or due to immune-mediated platelet destruction; thelatter secondary to anti-platelet antibodies or immune complex deposition on platelets

3) Sequestration-in the RED PULP of enlarged spleens

4) Dilution-due to massive transfusions;prolonged storage of whole blood results in prompt subsequentplatelet sequestration -thus while plasma volume and RBC mass are reconstituted by transfusion, the number ofcirculating platelets is relatively reduced

52. Chronic ImmuneThrombocytopeniaPurpura (ITP)

*caused by autoantibodies to platelets

Pathogenesis:-Platelet autoantibodies are usually directed toward one of two platelet antigens:1) the platelet membrane glycoprotein complexes IIb/IIIa 2) or Ib/IX

-destruction of antibody-coated platelets occurs in the spleen, and splenectomy can be beneficial

Morphology:-spleen is normal in size but shows SINUSOIDAL CONGESTION and PROMINENT GERMINAL CENTERS-bone marrow megakaryocyte numbers are increased

53. Clinical features -typically a disease of YOUNGER WOMEN (younger than 40)-often long history of easy bruising or epistaxis-cutaneous bleeding often takes form of petechiae-initial manifestation: melena (dark, sticky feces), hematuria, or heavy menses-subarachnoid hemorrhages are rare but serious-the bleeding time is prolonged, while prothrombin and partial thromboplastin times are normal-tests for antiplatelet antibodies are unreliable*most respond to glucocorticoids, but some require splenectomy or immunomodulation

54. Acute ImmuneThrombocytopenicPurpura

-seen most often in CHILDREN after a viral infection-platelet destruction is due to transient production of anti-platelet antibodies

55. Drug inducedthrombocytopenia

-occurs when drugs act as HAPTENS on platelet proteins or participate in the formation of immune complexesthat deposit on platelet surfaces --> platelet removal via macrophages

*HEPARIN-INDUCED THROMBOCYTOPENIA (HIT)-Type I thrombocytopenia - occurs rapidly after drug administration and is due to a direct platelet-aggregatingaffect of heparin; usually of little clinical sig. and usually resolves

-Type II thrombocytopenia - less common; sig adverse effects; occurs 5-14 days after therapy and is caused byautoantibodies directed against a complex of heparin and PLATELET FACTOR 4 that activates platelets --> inturn leads to thrombi in arteries and veins even in the setting of thrombocytopenia - that can be limb and lifethreatening -therapy requires heparin discontinuation and alternate anticoagulation administration

56. HIV -associatedthrombocytopenia

-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-mediated dysregulation of B cells --> anti-platelet autoantibodies that can also cause their prematuredestruction

57. Thrombotic Microangiopathies (a pathologythat results in thrombosis in capillaries andarterioles, due to an endothelial injury)-excessive platelet activation

*most of the clinical manifestations are due to WIDESPREAD HYALINEMICROTHROMBI in arterioles and capillaries composed of dense aggregates ofplatelets and fibrin

1) Thrombotic thrombocytopenic purpura (TTP)-transient neurological deficits are seen-occurs in adult females-inherited or acquired deficiencies in ADAMTS13, a serum metalloprotease thatlimits the size of von Willebrand factor multimers in plasma --> in its absence -->large amounts of platelet aggregation throughout the microcirculation-platelets are consumed owing to production of platelet thrombi IN AREAS OFINJURY (not DIC)

2) HUS-most common after GI e.coli infections-VEROTOXIN injures endothelial cells and thereby promotes dysregulated plateletactivation and aggregation-often occurs in children and the elderly

*plasma exchange or plasmapheresis is effective in both

58. Congenital defects in platelet function 1) Defective platelet adhesion-i.e. autosomal recessive Bernard-Soulier Syndrome caused by deficient plateletmembrane glycoprotein complex GpIb-IX

2) Defective platelet aggregation-i.e. Glanzmann thrombasthenia - autosomal recessive disorder caused by adeficiency of platelet membrane glycoprotein GpIIb-IIIa (involved in bindingfibrinogen)

3) Disorders of platelet secretion of prostaglandins and/or granule-bound ADPthat promote further aggregation

59. Acquired defects *Aspirin - IRREVERSIBLE inhibits cyclooxygenase and can suppress thesynthesis of thromboxane A2, necessary for platelet aggregation

*Uremia - causes defects in platelet adhesion, granule secretion, and aggregation

60. The bleeding associated with CLOTTINGFACTOR ABNORMALITIES differs from thatseen in platelet deficiencies:

-spontaneous petechiae or purpura is uncommon-more often bleeding manifests as LARGE ECCHYMOSES or HEMATOMAS afterinjury or as prolonged bleeding after laceration or surgery-bleeding into the GI and urinary tracts, and particularly into weight-bearingjoints (hemarthrosis) is common

61. The factor VIII-vWF Complex -circulating factor VIII is stabilized by binding to vWF, and DEFICIENT LEVELSOF vWF --> commensurate reductions in factor VIII**Factor VIII is an essential co-factor for factor IXa activation of factor X; factorVIII deficiency causes CLASSIC HEMOPHILIA (hemophilia A)

-vWF also mediates platelet adhesion to subendothelial matrix by bridging plateletglycoprotein Ib-IX and collagen-vWF also promotes platelet aggregation by binding to factor IIb-IIIa, particularlyunder high shear stress

62. Von WillebrandDisease

*the most common heritable bleeding disorder (1% of US population)-generally mild symptoms but can be more severe-therapy: can include DESMOPRESSIN (stimulating vWF release) or infusions of plasma concentrates containingthe missing factor(s)

*Type 1 and type 3 von Willebrand disease-associated with reduced levels of vWF-type 1 = autosomal dominant and MOST COMMON; clinically mild-type 3 is uncommon, autosomal recessive associated with marked vWF deficiency and a severe phenotype

*Type 2-autosomal dominant-QUALITATIVE defects in vWF-type 2A is most common-levels are normal but ability to form the most active high molecular weight multimers is defective-mild to moderate bleeding

63. Hemophilia A(Factor VIIIdeficiency)

-disrupts intrinsic system-increased PTT -normal PT-specific diagnosis is made by ASSAY for factor VIII

*treatment: replacement therapy with recombinant factor VIII or factor VIII concentrates

-the most common hereditary disease associated with life-threatening bleeding-X-linked recessive disorder (thus, primarily affecting males)*reduced amount and/or activity of factor VIII-severe disease = less than 1% of normal levels-moderate severe = 2-5% of normal levels-mild = 6-50% of normal

Clinically:-petechiae are absent-MASSIVE HEMORRHAGE after trauma or operative procedures-spontaneous hemorrhages in regions of the body normally subject to trauma

64. Hemophilia B(ChristmasDisease, FactorIX Deficiency)

-clinically indistinguishable from hemophilia A-requires assay of factor IX levels-X-linked recessive

65. DIC *a thrombohemorrhagic disorder characterized by excessive activation of coagulation --> formation of thrombi inthe microvasculature-symptoms arise from tissue ischemia and/or bleeding caused by the exuberant consumption of clotting factors oractivation of fibrinolytic pathways

66. Pathogenesis *2 major triggering mechanisms

1) Thromboplastic substances release into circulation-from a variety of sources (placenta, amniotic fluid in OBSTETRIC COMPLICATIONS) damaged tissues followingburns, mucus from certain adenocarcinomas, in sepsis bacterial endotoxins activate monocytes to release TNF-a,thereby increasing tissue factor expression on endothelial cell membranes while simultaneously decreasingthrombomodulin expression

2) Endothelial injury-initiates DIC by causing clotting tissue factor release from endothelial cells, by promoting platelet aggregation, andby activating the intrinsic coagulation pathway by exposing subendothelial CT*WIDESPREAD ENDOTHELIAL INJURY - can occur through antigen-antibody complex deposition (e.g. SLE),hypoxia, acidosis, temp. extremes (e.g. heatstroke, burns), or infections (e.g. meningicocci and rickettsiae)

67. Morphology -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 ARDS-in ADRENAL - massive hemorrhages due to DIC give rise to the WATERHOUSE-FRIDERICHSEN SYNDROME seenin meningococcemia-Sheehan postpartum pituitary necrosis is a form of DIC complicating labor and delivery

68. ClinicalFeatures

~50% of DIC occurs in obstetric patients with pregnancy complications (bleeding is major manifestation); morefulminant onset-33% occur in the setting of carcinomatosis (thrombosis is major manifestation) - usually insidious onset-sepsis and trauma are resp. for remaining

-Microangiopathic hemolytic anemia-resp. symptoms (dyspnea, cyanosis)-Neurologic signs and symptoms, including convulsions and coma-Oliguria and acute renal failure-Circulatory failure and shock

*Prognosis-highly variable-heavily impacted by the underlying disorder-remove inciting cause-depending on clinical picture, anticoagulants, or procoagulants can be administered