14. RBCs & Bleeding Disorders

Question 1

Extravascular vs. intravascular hemolysis

Answer 1

Extravascular = premature destruction of red cells occurring in phagocytes; associated features include splenomegaly, jaundice, anemia, decreased plasma haptoglobin

Intravascular = mechanical injury, complement fixation, intracellular parasites, or exogenous toxic factors; associated features include anemia, hemoglobinemia, hemoglobinuria, hemosiderinuria, jaundice, decreased serum haptoglobin

Question 2

Intrinsic defects in RBC membrane skeleton (ankyrin, band 3, spectrin, brand 4.2) that make them more round, less deformable, and vulnerable to splenic sequestration and destruction, resulting in a normocytic anemia with predominantly extravascular hemolysis

Answer 2

Hereditary spherocytosis

Question 3

Inheritance pattern and clinical features of hereditary spherocytosis

Answer 3

75% Autosomal dominant

May see osmotic lysis, increased MCHC, anemia, splenomegaly, and jaundice

Complications: aplastic crisis (usually triggered by parvovirus B19 infxn), hemolytic crises produced by intercurrent infection (usually EBV—infectious mono)

Question 4

_______ normally reduces NADP to NADPH, which then provides reducing equivalents needed to convert oxidized glutathione to reduced glutathione, which protects against oxidant injury by acting as a cofactor to neutralize ROS

Thus, a deficiency in this enzyme leads to a normocytic anemia with predominantly intravascular hemolysis

Answer 4

G6PD

Question 5

Inheritance pattern of G6PD deficiency

Answer 5

X-linked recessive

Question 6

G6PD is associated with episodic hemolysis d/t exposures that generate oxidant stress. What are the most common triggers of these episodes?

Answer 6

Infections in which oxygen-derived free radicals are produced by leukocytes (most commonly viral hepatitis, pneumonia, and typhoid fever)

Other triggers: antimalarials (primaquin), sulfonamides, nitrofurantoins, fava beans

Question 7

Autosomal recessive mutation in beta chain of Hb resulting in polymerization of deoxygenated Hb —> RBC destruction, hemolytic anemia, microvascular obstruction, and ischemic tissue damage

Answer 7

Sickle cell disease

Question 8

What changes in MCHC and intracellular pH lead to increased sickling in SCD?

Answer 8

Intracellular dehydration —> increased MCHC —> increased sickling

Reduced pH —> reduced oxygen affinity for Hb —> increased sickling

Question 9

What types of “crises” are associated with sickle cell disease?

Answer 9

Vaso-occlusive crises: dactylitis, acute chest syndrome

Autosplenectomy

Pain crisis

Aplastic crisis

Renal papillary necrosis

Question 10

Inherited mutations that decrease synthesis of either alpha-globin or beta-globin chains that compose adult HbA, leading to anemia, tissue hypoxia, and red cell hemolysis

Answer 10

Thalassemias

Question 11

Alpha thalassemia is usually d/t a gene deletion (up to 4 genes). What are the variable clinical presentations?

Answer 11

1 gene deleted — asymptomatic

2 genes deleted — mild anemia w/ slightly increased RBC count

3 genes deleted — severe anemia; beta-chains form tetramers (HbH) that damage RBCs

4 genes deleted — lethal in utero (hydrops fetalis); gamma chains form tetramers (Hb Barts) that damage RBCs

Question 12

Beta-thalassemia is usually due to a gene mutation vs. a deletion. What is the difference between B-thalassemia minor and B-thalassemia major?

Answer 12

Minor (B/B+) — usually asymptomatic w/increased RBCs; microcytic hypochromic RBCs and target cells + basophilic stippling on PB smear. Increase in HbF and HbA2

Major (B^0/B^0) — severe anemia several months after birth; alpha tetramers aggregate and damage RBCs, massive erythroid hyperplasia. Little or no normal HbA present

Question 13

Condition caused by acquired mutations in X-linked gene for enzyme essential for synthesis of GPI-linked proteins (DAF/CD55, CD59, or C8) which manifests as intravascular hemolysis by C5b-C9 MAC

Answer 13

Paroxysmal nocturnal hemoglobinuria (PNH)

Question 14

Immunohemolytic anemia is caused by Abs that bind RBCs causing premature destruction and is dx by direct Coombs anti-globulin test. What are the 3 classifications of immunohemolytic anemia?

Answer 14

1. Warm Ab type = MOST COMMON; IgG, extravascular hemolysis, Abs to Rh
2. Cold Agglutinin type = IgM Abs cause vascular obstruction in extremities with pallor/cyanosis/raynauds
3. Cold hemolysin type = IgG Abs bind P blood group Ag in cool extremities, intravascular hemolysis

Question 15

Primary vs. secondary causes of warm Ab type immunohemolytic anemia

Answer 15

Primary — idiopathic

Secondary — autoimmune (SLE), drugs (PCN, cephalosporins, quinidine), tolerance breaking drugs like alpha methyldopa, lymphoid neoplasms

Question 16

Acute vs. chronic causes of cold agglutinin type immunohemolytic anemia

Answer 16

Acute — mycoplasma infection, infectious mono, CMV, influenza, HIV

Chronic — idiopathic, lymphoid neoplasms

Question 17

Most common cause of microangiopathic hemolytic anemia

Answer 17

DIC

Also caused by TTP, HUS, malignant HTN, SLE, and disseminated cancer

Question 18

Etiology of pernicious anemia

Answer 18

Autoimmune gastritis (autoreactive T cells) that impairs production of IF from parietal cells of fundus

[often hx of autoimmune thyroiditis or adrenalitis]

Question 19

Atrophic glossitis, CNS involvement w/demyelination of dorsal and lateral spinal tracts, moderate to severe megaloblastic anemia, leukopenia w/hypersegmented granulocytes, elevated homocysteine and methylmalonic acid

Answer 19

Pernicious anemia

Question 20

Microcytic hypochromic anemia + esophageal webs + atrophic glossitis

Answer 20

Plummer vinson syndrome

Question 21

anemia associated with koilonychia, alopecia, atrophic glossitis, pica, low ferritin, low hepcidin, elevated TIBC

Answer 21

Iron deficiency anemia

Question 22

Lab findings with anemia of chronic disease (ferritin and TIBC)

Answer 22

High ferritin, reduced TIBC

Question 23

Chronic illnesses associated with anemia of chronic disease

Answer 23

Osteomyelitis, bacterial endocarditis, lung abscess

Rheumatoid arthritis, regional enteritis

Carcinomas of lung and breast, HL

Question 24

Systemic immune d/o characterized by purpuric rash, colicky abdominal pain, polyarthralgia, and acute glomerulonephritis

Answer 24

Henoch-Schonlein Purpura

Question 25

Autosomal dominant condition caused by mutations in genes that modulate TGF-beta signaling; characterized by dilated tortuous blood vessels w/thin walls that bleed readily. Usually manifests as epistaxis

Answer 25

Hereditary hemorrhagic teleangiectasia (Weber-Osler-Rendu)

Question 26

Autoantibody-mediated destruction of platelets (usually against IIb-IIIa or Ib-IX); may be primary/idiopathic or secondary (SLE, HIV, CLL); most commonly affecting adult women w/ bleeding into skin and mucosal surfaces; may present with excessive menstrual flow, PT and PTT usually normal

Answer 26

Chronic immune thrombocytopenic purpura

Question 27

Pathogenesis of HIV-associated thrombocytopenia

Answer 27

CD4 and CXCR4 are found on megakaryocytes, allowing them to be infected —> apoptosis

HIV-induced B cell hyperplasia —> autoantibody formation to GPIIb-IIIa complexes

Question 28

Pentad of fever, thrombocytopenia, microangiopathic hemolytic anemia, transient neuro defects, and renal failure

Answer 28

TTP

Question 29

TTP = inherited or acquired deficiency in plasma enzyme ____

Answer 29

ADAMSTS13 — normally degradees vWF multimers

Question 30

Typical vs. atypical HUS

Answer 30

Typical — E.coli O157:H7 w/ shiga-like toxin that activates platelets

Atypical — defects in complement factor H, membrane cofactor protein (CD46) or factor I —> excess complement activation

Question 31

Autosomal recessive deficiency of platelet membrane glycoprotein Ib-IX, causing variable often severe bleeding

Answer 31

Bernard-Soulier syndrome

Question 32

AR deficiency/dysfunction of GPIIb-IIIa —> platelets fail to aggregate —> severe bleeding

Answer 32

Glanzmann thrombasthenia

Question 33

Inheritance of von willebrand disease

Answer 33

Autosomal dominant (usually)

Question 34

X-linked recessive mutation in factor VIII —> easy bruising, massive hemorrhage after trauma or surgery, spontaneous hemarthrosis, prolonged PTT, normal PT

Answer 34

Hemophilia A

[note petechiae are characteristically absent]

Question 35

X-linked recessive mutations in factor IX

Answer 35

Hemophilia B

Question 36

Disease processes associated with DIC

Answer 36

Obstetric complications
Sepsis
Major trauma
Cancer — acute promyelocytic leukemia; adenocarcinomas

Question 37

Most common transfusion reaction

Answer 37

Febrile nonhemolytic reaction — presents w/ fever, chills, mild dyspnea; self-resolves

Question 38

Allergic transfusion reactions are most likely to occur in what pt population?

Answer 38

Those with IgA deficiency

Question 39

Severe, frequently fatal transfusion complication in which factors in transfused product (usually FFP or platelets) trigger activation of neutrophils in the lung microvasculature

Answer 39

TRALI

Question 40

What is the Hb threshold above which you do not transfuse?

Answer 40

Hb <7

[aka DON’T transfuse unless Hb is less than 7]

Question 41

If a pt presents with difficulty breathing and urticarial reaction following a transfusion, what type of transfusion did they most likely receive?

Answer 41

FFP

Question 42

If a pt presents with jaundice and hematuria after a transfusion, what type of transfusion did they most likely receive?

Answer 42

PRBCs