Blood Flashcards
Mediators of increased vascular permeability
histamine and serotonin
C3a and C5a
leukotriene C4, D4, E4
Mediators of vasodilation
histamine
prostaglandins
Mediators of chemotaxis, leukocyte recruitment and activation
TNF, IL-1
chemokines
C3a, C5a
leukotriene B4
Macrophage activator
interferon-gamma
macrophages are responsible for development of ceseating granuloma in TB infections
Mediators of fever
IL-1, TNF
prostaglandins
Mediators of pain
prostaglandins
bradykinin
Mediators of tissue damage
lysosomal enzymes of leukocytes,
reactive oxygen species (ROS)
Acute vs chronic inflammation
histology
Acute:
- neutrophils
- fibrin
Chronic:
- lymphocytes
- plasma cells
- macrophages
Types of necrosis and the organs typically involved
Liquefaction necrosis: brain
- tissue is completely digested and transformed into viscous liquid
Fat necrosis: pancreas
- release of pancreatic enzymes
Coagulative necrosis: liver, spleen, intestine
- underlying architecture of organ is preserved
Granulation tissue
- fibroblasts
- endothelial cells
- may be inflammatory cells in the background as well
Hypersensitivity reactions 1-4
ACID:
Type I: Allergy
Type II: Cytotoxic
- where it binds
Type III: Immune Complex
- where it lands
Type IV: CD4 effector or Delayed
- everywhere it meets
Type I hypersensitivity
Immediate hypersensitivity:
- Th2, IgE antibody, mast cells, eosinophils
- mast cell-derived mediators (granulation) = immediate hypersensitivity reaction (minutes)
- rapid reaction: IgE antibodies are already bound to Fc-epsilon receptor on surface of mast cells
- cytokine-mediated inflammation = late phase reaction (2-24hr after repeat exposure)
- eosinophil recruitment = chronic allergic inflammation, major cause of tissue damage
Type II hypersensitivity
Antibody-mediated hypersensitivity:
- own cells (cell surface or extracellular matrix antigens) treated as encapsulated bacteria; get tagged with antibodies (IgG mostly) to be attacked by complement system (lysis) or leukocytes (phagocytosis)
- complement- and Fc receptor-mediated recruitment
- activation of leukocytes (neutrophils, macrophages) ==> opsonization and phagocytosis of cells
- abnormalities in cellular function (hormone/NT receptor signaling)
- usually tissue-specific <- issue is on what type of cell the binding event occurs (ex: hemolytic anemia)
Type III hypersensitivity
Immune complex-mediated hypersensitivity:
- immune complexes of circulating soluble antigens and IgG/IgM antibodies deposited in vascular basement membrane
- complexes are unable to be cleared; that is where inflammation occurs
- complement- and Fc receptor-mediated recruitment and activation of leukocytes
- tissue damage secondary to impaired blood flow
- vasculitis, nephritis, arthritis
Serum sickness:
- Deposition in the vasculature of the skin can produce hives through the production of C3a and C5a of the complement system which then activate local mast cells.
- A fever response is caused by release of IL-1 and IL-6 from blood monocytes that have taken up the immune complexes.
Type IV hypersensitivity
Delayed, T cell-mediated hypersensitivity:
- sensitization stage of 1-2 weeks
- takes 1-3 days to develop after re-exposure
- CD4+ (Th1, Th17) T-cells (cytokine-mediated inflammation) activate macrophages ==> inflammation
- CD8+ T-cells (T cell mediated cytolysis) direct target cell lysis and inflammation
TNF-a
IL-1
inflammatory cytokines that induce gene expression of adhesion molecules on endothelial cells, thereby recruiting leukocytes
tryptase
protease that causes tissue damage
leukotrienes C4, D4, E4
slow reacting substances of anaphylaxis; cause bronchoconstriction
leukotriene B4
chemotactic for neutrophils
bradykinin
pain
prostaglandin D2
promotes vasodilation and vascular leakage
also bronchoconstriction?
late phase response of allergy
T-cell response mediated by cytokines
- treat with glucocorticoid (Prednisone)
C3, C4, C5
complement proteins, but also anaphylatoxins that drive mast cell involvement
Erythropoietin (EPO)
- produced in kidneys
- major hormone regulator of erythropoiesis
- promotes the proliferation, differentiation, survival of erythroid precursors
Iron deficiency anemia vs. anemia of chronic disease
Iron deficiency anemia:
- microcytic, hypochromic anemia
- low serum ferritin and iron
- can be due to loss of blood through GI bleeds
Anemia of chronic disease:
- can be normocytic or microcytic
- high serum ferritin
- chronic inflammation => increase in cytokines and hepcidin => reduced iron release from macrophages, reduced RBC synthesis from low erthropoietin levels, reduced RBC survival
Heme synthesis pathway
Occurs in liver and erythroid progenitor cells of bone marrow
First and rate-limiting step: ALA synthase
- glycine + succinyl CoA ⇒ ALA
- requires PLP (vit B6) cofactor
- regulated via: feedback inhibition (heme/hemin), repression of ALA synthase gene, inhibition of ALA synthase transport from cytosol to mitochondria
Last step: ferrochelatase
- last reaction ⇒ heme
- regulated by iron availability in bone marrow
Heme synthesis deficiencies
Vitamin B6 deficiency:
- Vit B6 (PLP) cofactor is requred for ALA synthase
Lead-induced anemia:
- lead binds to sulfhydryl groups in ALA dehydratase and ferrochelatase
Porphyrias: occur when body has problems making heme
1. AIP: acute intermittent porphyria
2. PCT: porphyria cutanea tarda
3. EPP: erythropoietic protoporphyria
Acute intermittent porphyria (AIP)
Pathology:
- defect in porphobilinogen (PBG) deaminase (3rd reaction in pathway)
- porphobilinogen ==> hydroxymethylbilane
Symptoms:
- neurocognitive: fever, muscle weakness, intellectual disability, limb/head/neck/chest pain
- visceral: abdominal pain, vomiting/constipation
- second most common porphyria
Labs:
- PBG and 5-ALA accumulate in plasma and urine
- urine turns red after being left out
Treatment:
- IV hemin and glucose (negative feedback on ALA synthase)
“An Insane Person Peed Blue Dye”
Porphyria cutanea tarda (PCT)
Pathology:
- deficiency in uroporphyrinogen decarboxylase (UDC) (5th reaction)
- uroporphyrinogen III ==> coproporphyrinogen III
- hepatic
- autosomal dominant
- precipitated by: alcohol, hepatic iron overload, sunlight exposure
Symptoms:
- photosensitivity due to porphyrin accumulation
- light-sensitive blistering, rash, increased hair growth
- most common porphyria
Labs:
- uroporphyrinogen III accumulates in urine
Treatment:
- sun avoidance, sunscreen
- decrease iron load
- chloroquine or hydroxychloroquine treat underlying cause
“People Can Tell U Drink Constantly”
Erythropoietic protoporphyria (EPP)
Pathology:
- deficiency in ferrochelatase (last step)
- protoporphyrin IX ==> heme
- autosomal dominant
Symptoms:
- hemolytic anemia
- extreme photosensitivity w or w/o blistering
Labs:
- accumulation of protoporphyrin IX in RBC, plasma, feces (NOT urine)
Treatment:
- physical sun blocks
- exchange transfusion
- hematin
“Easily Produces Pebbly Fingers”
Heme degradation syndromes
- Neonatal jaundice
- Gilberts syndrome
- Crigler-Najjar syndrome
- Dubin-Johnson syndrome
Neonatal jaundice
Pathology:
- Deficiency in bilirubin glucuronyl-transferase ==> increased unconjugated (indirect) bilirubin
- UDP glucuronyl transferase (UGT) activity is low at birth
- Rate of bilirubin production is increased due to shorter lifespan of RBCs
- Decreased bacteria in intestine ⇒ increased enterohepatic circulation
Symptoms:
- yellow skin
- toxic encephalopathy (kernicterus)
Treatment:
- phototherapy with blue light: converts unconjugated bilirubin into water soluble isomer
- phenobarbital: induces bilirubin metabolizing enzymes
- blood transfusion to prevent brain damage
Gilberts syndrome
Pathology:
- glucuronosyltransferase deficiency
- mild increase in unconjugated (indirect) bilirubin
Symptoms:
- generally benign, very mild jaundice during illnesses
- 5-10% of population
Crigler-Najjar syndrome
Pathology:
- glucuronosyltransferase deficiency
- very high unconjugated bilirubin
- autosomal recessive
Symptoms:
- profound jaundice
- brain damage in infants
Treatment:
- Type I (more severe): phototherapy, liver transplantation
- Type II (still severe but less so): phenobarbital to increase expression of UGT1A1
Dubin-Johnson syndrome
Pathology:
- mutation in MRP2 gene
- autosomal recessive
- inability of hepatocytes to secrete conjugated bilirubin out of ER after it’s formed ==> mildly increased conjugated bilirubin
Symptoms:
- usually asymptomatic
- moderate jaundice
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Platelet disorders
- Bernard-Soulier disease
- Glanzmann thrombasthenia
- Gray platelet syndrome
- idiopathic thrombocytopenia purpura (ITP)
- thrombotic thrombocytopenia purpura (TTP)
Bernard-Soulier syndrome
Pathology:
- autosomal recessive
- deficiency of GPIb receptor for vWF ==> impaired platelet adhesion to vWF
Symptoms:
- epistaxis, mucosal bleeding, easy bruising
Labs:
- thrombocytopenia
- giant platelets on smear
- prolonged bleeding time
- normal PT and PTT
- decreased platelet aggregation to ristocetin (induces binding of vWF and GPIb)
- ADP aggregation, epinephrine aggregation, collagen aggregation
Treatment:
- supportive
- platelet transfusion
Glanzmann Thrombasthenia
Pathology:
- autosomal recessive
- deficiency/abnormality of platelet GIIb/IIIa (fibrinogen receptor) ==> platelets unable to aggregate
Symptoms:
- mucocutaneous microhemorrhages, epistaxis, petechiae/purpura
Labs:
- normal platelet morphology on smear
- absent platelet aggregation to ADP, collagen, epinephrine
- normal aggregation to ristocetin
Treatment:
- platelet transfusions
Platelet Storage Pool Disease (Gray Platelet Syndrome)
Pathology:
- autosomal recessive
- deficient platelet granule contents: alpha, delta, or both
- decreased platelet secretion
- decreased secondary wave of platelet aggregation
Symptoms:
- mild, lifelong bleeding symptoms
Labs:
- gray appearing platelets in smear due to absence of alpha granules
- prolonged bleeding time
- normal PT and PTT
- normal ristocetin
- no second wave in ADP and epinephrine aggregation; impaired collagen aggregation
Treatment:
- anticipating and preventing risks of bleeding
Idiopathic/Immune thrombocytopenic purpura (ITP)
Pathology:
- autoantibodies (usually IgG) directed against GpIIb/IIIa or GpIb bind to platelet surface
- platelets being destroyed
Symptoms:
- easy bleeding, petechiae, epistaxis
- acute ITP: self limited, seen in children after viral infections
- chronic ITP: tends to affect women between 20-40
Labs:
- large platelets on smear <- megakaryotes stimulated due to platelets being destroyed
- increased bleeding time
- normal PT and PTT
- coagulation factors unaffected
Treatment:
- Prednisone (immune suppressant)
- splenectomy
Thrombotic thrombocytopenic purpura (TTP)
Pathology:
- ADAMTS13 (protease) deficiency ==> abnormally large vWF multimers that activate platelets
- vWF multimers remain attached to endothelial cells ==> platelet adhesion, aggregation, microvascular thrombosis
- usually due to acquired antibodies
Symptoms:
- occurs primarily in adults
- skin and mucosal bleeding
- classic pentad: thrombocytopenia, microangiopathic hemolytic anemia, neurologic impairment, fever, renal dysfunction
Labs:
- erythroid progenitors (nucleated RBCs) and schistocytes, thrombocytopenia
- increased bleeding time
- normal PT and PTT
- coagulation factors unaffected
Treatment:
- plasma exchange using FFP
- corticosteroids
ITP vs. TTP
ITP: disorder of platelet destruction governed by platelet autoantibodies
TTP: disorder of platelet consumption and microthrombi formation resulting in organ ischemia
Aspirin
- irreversibly inhibits platelet cyclooxygenase (normally induces platelet activation)
- normal platelet count
- Low dose aspirin is good: it irreversibly inhibits platelet and endothelial cell TXA2 synthesis
- Endothelial cells can synthesize new enzyme and produce PGI, but platelets cannot recover
Hypocoagulation (bleeding) disorders
- von Willbrand deficiency
- Disseminated intravascular coagulation (DIC)
- Hemophilia A & B
- Vitamin K deficiency
von Willebrand deficiency
Pathology:
- Types 1-3 vWF deficiency: 1 = slight decrease, 2 = qualitative, 3 = absent
- vWF binds to exposed collagen at site of injury => GpIb receptors on platelets bind to vWF => activation of GpIIb/IIIa => platelets crosslink
- vWF is carrier protein for FVIII
Symptoms:
- primary hemostasis impairment
- secondary hemostasis impairment (prolonged PTT that may not see mixing correction)
- mucosal bleeding, superficial bleeding
Treatment:
- Desmopressin (vasopressin)
Disseminated intravascular coagulation (DIC)
Pathology:
- Systemic activation of clotting cascade ⇒ increased consumption of clotting factors and platelets ⇒ exhaustion of clotting factors
- syndrome secondary to sepsis, obstetric disasters, malignancies, leukemia, snake bites, heat stroke, brain injury, transfusion reaction, etc.
Symptoms:
- clotting and bleeding can dominate
- prolonged PT and PTT
- D-dimer positive (fibrin degradation product)
- low factors V & VIII, low platelets, low fibrinogen (clot)
Treatment:
- treat underlying cause
Hemophilia A & B
Pathology:
- X-linked deficiencies
- Hemophilia A = factor VIII deficiency
- Hemophilia B = factor IX deficiency
- inhibitors can develop after previous exposure (mixing study would be positive)
Symptoms:
- prolonged PTT, mixed study negative (corrects)
- hemarthrosis (hemophilia of joint spaces, deep tissue)
Treatment:
- replacement of deficient factor
- prophylaxis, on demand therapy
Vitamin K deficiency
Pathology:
- malnutrition, alcohol use disorder
- vitamin K-dependent factors are deficient: factors II, VII, IX, X
Symptoms:
- PT affected more than PTT
Hypercoagulation (clotting) disorders
- Factor V Leiden mutation
- prothrombin mutation
- protein C & S deficiency
- antithrombin III deficiency
Factor V Leiden mutation
- autosomal dominant
- point mutation abolishes binding site for protein C => factor V resistant to degradation => increased risk for venous thrombosis
- common (> 1%)
Prothrombin mutation
- autosomal dominant
- G20210A mutation causes increased prothrombin (factor II) expression => hypercoagulation
- common
Protein C & S deficiency
- normally, protein C complexes with protein S to inhibit factors V and VIII => degradation of thrombus
- both vitamin K-dependent <- would expect protein C/S levels to be low in a patient on warfarin
- if pt with low protein C is started on warfarin, increased risk of clotting => superficial necrosis of skin (breasts)
- rare
Antithrombin III deficiency
- too little or abnormal antithrombin III produced => decreased inhibition of coagulation
- rare
Type and screen test vs Type and crossmatch test
Used prior to blood transfusions
Type and screen: performed when blood may be needed
- front type: using reagent anti-A/anti-B Abs to type for antigens on RBC
- back type: using reagent A and B RBC type for matching Ab in plasma
Type and crossmatch: performed with blood is definitely needed
- blood units are reserved and tested for ABO and Rh compatibility
Hemolytic Disease of Newborn (HDN)
Pathology:
- Rh(D) negative mom is exposed to Rh(D) positive fetal cells, stimulating mom to make anti-Rh(D) IgG antibodies
- first pregnancy is stimulus for immunization; often not affected
Symptoms:
- fetal RBCs attacked by mom’s anti-Rh(D) antibodies ==> fetal anemia
- baby can be born with jaundice (high bilirubin) and anemia
Treatment:
- Rh(D) negative mom should receive pooled IgG anti-Rh(D) at 28wks and within 72hr postpartum
- if fetal anemia develops: transfusion of washed group O RBC intrauterine to baby
- if fetus born with anemia and jaundice: neonatal exchange transfusion (removal of whole blood and replacement with group O Rh- RBC and AB plasma)
Coombs test
Direct antiglobulin test:
- detects antibodies already bound to blood RBCs
- pt’s blood sample is directly used and washed, then incubated with Coomb’s reagent (C3, antihuman Ab) ==> RBCs agglutinate
- positive DAT = pt’s RBCs have auto IgG antibodies and/or C3 on them
- ex: to detect hemolytic anemia
Indirect antiglobulin test:
- detects serum antibodies that might bind to RBCs
- recipient serum is combined with donor blood sample ==> recipient Igs form complexes with donor RBCs ==> C3 added to agglutinate targeted RBCs
- cross-match testing, maternal serum testing
Mixed lymphocyte reaction (blood test)
To ensure bone marrow donor is a match with recipient:
- mix blood mononuclear cells from 2 persons (donor and recipient) in tissue culture
- bone marrow recipient APC presents MHC I/II, which is recognized by donor T lymphocytes
- MHC I would stimulate CD8+ CTL proliferation
- MHC II would stimulate CD4+ helper T cell proliferation
- measure lymphocyte proliferation in vitro ==> less proliferation of T cells is good
List the
Transfusion reactions:
- acute hemolytic transfusion reaction (AHTR)
- delayed hemolytic transfusion reaction (DHTR)
- febrile non-hemolytic transfusion reaction (FNHTR)
- allergic and anaphylactic transfusion reaction
- septic transfusion reaction
- transfusion-associated circulatory overload (TACO)
- transfusion-related acute lung injury (TRALI)
- post-transfusion purpura (PTP)
- transfusion-associated graft vs. host disease (TA-GVHD)
Acute hemolytic transfusion reaction (AHTR)
Pathology:
- preformed RBC antibody (pt has hx of transfusions) reacts with donor RBC
- complement activation => membrane lysis => release of free Hb, IgM
Symptoms:
- intravascular hemolysis < 24hr after transfusion
- fever, hypotension, shock, pink/red urine
- 40% mortality
- negative DAT (direct antibody test) due to all incompatible cells hemolyzed; positive urine hemoglobinuria, schistocytes
Treatment:
- stop transfusion, support BP
- protect kidneys: IV fluids, diuretics
Delayed hemolytic transfusion reaction (DHTR)
Pathology:
- new alloantigen develops in pt post-transfusion
- no complement activation; instead, cells destroyed via phagocytosis (reticuloendothelial system) ==> extravascular hemolysis
Symptoms:
- progressive anemia 3 days-3wk after transfusion
- may present with fever, jaundice, dark urine
- positive DAT, positive new antibody
Treatment:
- transfusion of antigen-free RBCs
Febrile non-hemolytic transfusion reaction (FNHTR)
Pathology:
- cytokines released from donor lymphocytes accumulate in bag during storage ==> antibodies in recipient plasma react
Symptoms:
- temperature increase of >1C (fever may be only symptom)
- often accompaniesd by chills / rigors
Treatment:
- increased risk due to previous alloimmunization to HLA
- prevention: leukoreduction (remove WBCs), premedicate with acetaminophen
Allergic and anaphylactic transfusion reaction
Allergic:
- pts develop urticaria (hives), flushing, pruritus (itching)
- due to recipient IgE reacting to donor plasma proteins
- Tx: stop transfusion, give antihistamine, may restart once symptoms resolve
Anaphylactic:
- pts develop urticaria, wheezing low BP
- due to recipient IgA reacting to donor plasma proteins
- Tx: stop transfusion, start epinephrine, antihistamines, corticosteroids
- Prevention: wash donated RBCs/platelets
Septic transfusion reaction
Pathology:
- bacteria in donor blood
- higher risk in platelet transfusions (platelets stored in room temp)
Symptoms:
- fevers, rigors, drop in BP, increase in HR
Treatment:
- broad spectrum abx until organism identified
Transfusion-associated circulatory overload (TACO
Pathology:
- transfusion ==> expansion of intravascular volume ==> pulmonary edema
- increased risk in those with heart failure, renal insufficiency
Symptoms:
- acute hypertension (increase in blood volume)
- jugular venous distension (backup of blood from heart into veins)
- elevated brain natriuretic peptide
- usually NO fever
- CXR: pulmonary edema
Treatment:
Prevention: decrease rate of transfusion (slowly over 4hr)
Transfusion-related acute lung injury (TRALI)
Pathology:
- donor anti-HLA antibodies and/or anti-neutrophil antibodies passed onto recipient ==> recipient granulocytes release proinflammatory mediators ==> increased vascular permeability ==> pulmonary endothelium damage, fluid extravasion into lungs
- usually FFP or platelets
Symptoms:
- within 6hr of transfusion: fever, tachycardia, hypotension, hypoxemia (low blood O2)
- CXR: new bilateral infiltrate
Treatment:
- supportive
- prevention: no FFP from any female donors
Post-transfusion purpura (PTP)
Pathology:
- previously sensitized recipients (hx of transfusion, pregnancy) produce platelet-specific alloantibodies which may be autoreactive ==> thrombocytopenia
- within 2wks of transfusion
Symptoms:
- purpura (bruising)
- thrombocytopenia (10,000 platlets/uL)
- mucosal bleeding (GI bleeding) common
Transfusion-associated graft versus host disease (TA-GVHD)
Pathology:
- different HLA antigens between donor (graft) and recipient (host)
- functionally active immune cells must be present in donor blood product
- host incapable of rejecting donor immune cells
- high risk for immunocompromised recipients
Symptoms:
- onset 3-30 days after transfusion
- rash (trunk => extremities), fever, watery diarrhea, elevated LFT (liver enzymes), pancytopenia
- bone marrow failure
- > 90% mortality within 1-3wk of symptom onset
Treatment:
- prevention: irradiation of products (inactivates donor lymphocytes)
