14. RBCs & Bleeding Disorders Flashcards
Extravascular vs. intravascular hemolysis
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
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
Hereditary spherocytosis
Inheritance pattern and clinical features of hereditary spherocytosis
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)
_______ 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
G6PD
Inheritance pattern of G6PD deficiency
X-linked recessive
G6PD is associated with episodic hemolysis d/t exposures that generate oxidant stress. What are the most common triggers of these episodes?
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
Autosomal recessive mutation in beta chain of Hb resulting in polymerization of deoxygenated Hb —> RBC destruction, hemolytic anemia, microvascular obstruction, and ischemic tissue damage
Sickle cell disease
What changes in MCHC and intracellular pH lead to increased sickling in SCD?
Intracellular dehydration —> increased MCHC —> increased sickling
Reduced pH —> reduced oxygen affinity for Hb —> increased sickling
What types of “crises” are associated with sickle cell disease?
Vaso-occlusive crises: dactylitis, acute chest syndrome
Autosplenectomy
Pain crisis
Aplastic crisis
Renal papillary necrosis
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
Thalassemias
Alpha thalassemia is usually d/t a gene deletion (up to 4 genes). What are the variable clinical presentations?
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
Beta-thalassemia is usually due to a gene mutation vs. a deletion. What is the difference between B-thalassemia minor and B-thalassemia major?
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
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
Paroxysmal nocturnal hemoglobinuria (PNH)
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?
- Warm Ab type = MOST COMMON; IgG, extravascular hemolysis, Abs to Rh
- Cold Agglutinin type = IgM Abs cause vascular obstruction in extremities with pallor/cyanosis/raynauds
- Cold hemolysin type = IgG Abs bind P blood group Ag in cool extremities, intravascular hemolysis
Primary vs. secondary causes of warm Ab type immunohemolytic anemia
Primary — idiopathic
Secondary — autoimmune (SLE), drugs (PCN, cephalosporins, quinidine), tolerance breaking drugs like alpha methyldopa, lymphoid neoplasms
Acute vs. chronic causes of cold agglutinin type immunohemolytic anemia
Acute — mycoplasma infection, infectious mono, CMV, influenza, HIV
Chronic — idiopathic, lymphoid neoplasms
Most common cause of microangiopathic hemolytic anemia
DIC
Also caused by TTP, HUS, malignant HTN, SLE, and disseminated cancer
Etiology of pernicious anemia
Autoimmune gastritis (autoreactive T cells) that impairs production of IF from parietal cells of fundus
[often hx of autoimmune thyroiditis or adrenalitis]
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
Pernicious anemia
Microcytic hypochromic anemia + esophageal webs + atrophic glossitis
Plummer vinson syndrome
anemia associated with koilonychia, alopecia, atrophic glossitis, pica, low ferritin, low hepcidin, elevated TIBC
Iron deficiency anemia
Lab findings with anemia of chronic disease (ferritin and TIBC)
High ferritin, reduced TIBC
Chronic illnesses associated with anemia of chronic disease
Osteomyelitis, bacterial endocarditis, lung abscess
Rheumatoid arthritis, regional enteritis
Carcinomas of lung and breast, HL
Systemic immune d/o characterized by purpuric rash, colicky abdominal pain, polyarthralgia, and acute glomerulonephritis
Henoch-Schonlein Purpura
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
Hereditary hemorrhagic teleangiectasia (Weber-Osler-Rendu)
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
Chronic immune thrombocytopenic purpura
Pathogenesis of HIV-associated thrombocytopenia
CD4 and CXCR4 are found on megakaryocytes, allowing them to be infected —> apoptosis
HIV-induced B cell hyperplasia —> autoantibody formation to GPIIb-IIIa complexes
Pentad of fever, thrombocytopenia, microangiopathic hemolytic anemia, transient neuro defects, and renal failure
TTP
TTP = inherited or acquired deficiency in plasma enzyme ____
ADAMSTS13 — normally degradees vWF multimers
Typical vs. atypical HUS
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
Autosomal recessive deficiency of platelet membrane glycoprotein Ib-IX, causing variable often severe bleeding
Bernard-Soulier syndrome
AR deficiency/dysfunction of GPIIb-IIIa —> platelets fail to aggregate —> severe bleeding
Glanzmann thrombasthenia
Inheritance of von willebrand disease
Autosomal dominant (usually)
X-linked recessive mutation in factor VIII —> easy bruising, massive hemorrhage after trauma or surgery, spontaneous hemarthrosis, prolonged PTT, normal PT
Hemophilia A
[note petechiae are characteristically absent]
X-linked recessive mutations in factor IX
Hemophilia B
Disease processes associated with DIC
Obstetric complications
Sepsis
Major trauma
Cancer — acute promyelocytic leukemia; adenocarcinomas
Most common transfusion reaction
Febrile nonhemolytic reaction — presents w/ fever, chills, mild dyspnea; self-resolves
Allergic transfusion reactions are most likely to occur in what pt population?
Those with IgA deficiency
Severe, frequently fatal transfusion complication in which factors in transfused product (usually FFP or platelets) trigger activation of neutrophils in the lung microvasculature
TRALI
What is the Hb threshold above which you do not transfuse?
Hb <7
[aka DON’T transfuse unless Hb is less than 7]
If a pt presents with difficulty breathing and urticarial reaction following a transfusion, what type of transfusion did they most likely receive?
FFP
If a pt presents with jaundice and hematuria after a transfusion, what type of transfusion did they most likely receive?
PRBCs
