Chapter 14: Red Blood Cells Flashcards
What are the Mean Cell Volume, Mean Cell Hemoglobin, Mean Cell Hemoglobin Concentration, and Red Cell Distribution Width values?
MCV: average volume of red blood cells
- normal = 80-100
MCH: average mass of hemoglobin per RBC
- changes RBCs color
MCHC: average hemoglobin concentration in a given volume of RBCs
RDW: coefficient of variation of red blood cell volume
- elevation –> reactive phenomenon in anemia
- have FUNCTIONING marrow
What is hematocrit?
ratio of packed RBCs to total blood volume
approximately 3x the hemoglobin concentration
If a male or postmenopausal women is found to be chronically bleeding, what should it be assumed that patient has until proven otherwise?
Colon Cancer
What is Hemolytic Anemia and what does it look like morphologically? (3)
RBC lifespan less than 120 days, with inc. in EPO and accumulation of hemoglobin degradation products
Morph: inc. normoblast in marrow, reticulocytosis in peripheral blood, hemosiderosis
What is the difference between Extravascular and Intravascular Hematopoiesis?
EH: occurs in macrophages of spleen (predisposed by RBC injury)
- anemia, splenomegaly, jaundice
- splenectomy is often beneficial
IH: RBC rupture due to mechanical injury, complement, parasites, or toxins
- hemoglobinuria, hemosiderinuria (NO splenomega)
- markedly reduced serum haptoglobin (a2 globulin)
- renal hemosiderosis
haptoglobin normally prevents hemoglobin excretion in urine
Hereditary Spherocytosis:
What is it, how is it inherited, and what is its pathogenesis?
- defects of RBC membrane skeleton causing cells to become spheroid and less deformable
- 75% autosomal dominant, mostly prevelant in Northern Europe
- mutations of ankyrin, band 3, band 4.2, and spectrin (RBCs destroyed by spleen in 10-20 days)
Hereditary Spherocytosis:
What does it look like (3) and how is it diagnosed?
M: small, dark RBCs w/o central pallor zone, reticulocytosis, and cholelithiasis (pigment stones in 40-50% of pts)
D: history, hematology findings, and labs
- osmotic fragility test, inc. MCHC
Hereditary Spherocytosis:
How does it present clinically (4) and how is it treated?
C: variable anemia, splenomegaly, jaundice, gallstones
- inc. risk of aplastic crisis due to Parovirus B19
- stops hematopoiesis for a couple of weeks
T: splenectomy (corrects anemia but Howell-jolly bodies remain)
- inc. risk of sepsis (encapsulated bacteria)
G6PD Deficiency:
What are the two types, what are their genetics, and what is happening?
G6PD- (African Americans, less severe) and G6PD Mediterranean (more severe, shorter enzyme 1/2 life)
X-linked recessive
- oxidants cause crosslinking of globin chains causes precipitates (Heinz bodies) which are removed by macrophages, creating “bite cells”
older RBCs more prone to hemolysis; younger RBCs not affected
What causes oxidative stress on G6PD? (FASN)
fava beans, antimalarial drugs (quines), sulfonamides, nitrofurantoins
Sickle Cell Anemia:
What mutation is it caused by and what four things are likely to decrease the rate of sickling?
- hereditary hemoglobinopathy via glutamate –> valine mutation in beta-globulin (microvascular obstruction most serious feature)
- Hb forms RBC polymers when deoxygenated, forming long needlelike fibers
Dec. sickling: inc. HbA, dec. MCHC/hydration, inc. pH, inc. microvascular transit
What are HbSC (Sickle Cell Disease) and Fetal Sickle Cell Anemia?
HbSC - compound heterozygotes (HbS and HbC genes) –> milder than sickle cell anemia
- glutamic acid –> lysine (crystals on smear)
- causes extravascular hemolysis
Fetal SC - have more HbF (protective), so problems often present at 6 months old
- hydroxyurea enhances HbF expression
What is the process of Sickle Cell Stasis?
- inc. adhesion molecules (inflammation) cause cells to arrest while moving through microvasculature
- inc. sickling and obstruction lead to hypoxia
- free hemoglobin binds and inactivates NO = inc. vascular tone and inc. platelet aggregation
Sickle Cell Anemia:
What is Autosplenectomy, Vasoocclusive Crises, Sequestration Crisis, Aplasic Crisis, and what bone problems are seen?
AS: chronic erythrostasis causes splenic infact and fibrosis
VC: MOST IMPORTANT COMPLICATION
- hypoxic injury/infarction episodes cause pain
- manifests as dactylitis or acute chest syndrome
- hard to differentiate from Acute Osteomyelitis
SC: massive entrapment of RBCs in kids spleen
- rapid enlargment, hypovolemia, shock
AC: Parovirus B19 infection dec. hematopoiesis
bones: marrow expansion = remodeling
- “Chipmunk” cheeks, prominent cheek bones
- skull changes resembling “crew cut”
Sickle Cell Anemia:
What is Dactylitis and Acute Chest Syndrome?
- manifestations of Vasoocclusive Crisis
D: hand-foot syndrome
- vasoocclusive infarcts = swollen hands/feet
- seen in African America infants
ACS: vasooclusive crisis of lungs
- most common cause of death in adult pts
- often precipitated by pneumonia
What is the most common cause of death in children with Sickle Cell Anemia?
H. influenzae
- causes septicemia and meningitis
What 4 pathogens are pts with Sickle Cell Anemia more at risk for?
S. pneumoniae, H. influenzae, neisseria (encaspsulated)
- inc. risk of S. Typhi osteomyelitis
How is Sickle Cell Anemia diagnosed, what is its prognosis, and how can it be treated (2)?
D: clinical signs/symptoms, lab testing of hemoglobin
- metabisulfite screen (+)
- elecrophoresis
P: 90% survive to 20, 50% survive to 50+
T: hydroxyurea (inc. HbF) and HSC transplant
What is the difference between Beta0 and Beta+ in Beta Thalassemia?
What is the pathogenesis of Beta Thalassemia?
Beta0 - absent beta globin chain synthesis
- most common mutation is premature STOP codon
Beta+ - reduced but detectable bet globin synthesis
- most common mutation is splicing
P: unpaired alpha chain preceiptates, creating insoluble inclusions = membrane damage = APOPTOSIS of precursors
What are manifestations that occur in severe cases of Beta Thalassemia? (4)
- massive erythroid hyperplasia; extramed. hematoe
- “crew cut” and “chipmunk” facies
- severe cachexia, iron overloading causing SECONDARY hemachromatosis
What cell changes are seen on peripheral smear of Beta Thalassemia? (4)
anisocytosis (variable size), poikilocytosis (variable shape), target cells (hemoglobin in center), and basophilic stippling
Beta Thalassemia Major:
Who is it most common in (3) and what Hb type is most prominent?
- individuals have transfusion dependent anemia beginning at 6-9 months
- Mediterranean, Africa, Southeast Asia
- HbF hemoglobin is predominant
Beta Thalassemia Major:
What are 4 clinical impacts of disease and what are two major treatment options?
- hepatosplenomegaly (hematopoiesis), massive erythroid hyperplasia, possible aplastic crisis
T: chronic transfusions (3rd decade survival)
- predisposed to 2nd hemachromatosis - HSC transplant may occur
Beta Thalassemia Minor:
What is it, what does it cause (4), and what Hb type is most prominent?
What anemia must be ruled out if you believe your pt. has Beta Thalassemia Minor?
- individuals with heterozygous alleles (MORE COMMON)
- mild microcytic, hypochromic anemia, basophilic stippling, target cells, and erythroid hyperplasia
- HbA2 hemoglobin is predominant
confirm diagnosis to rule out IRON DEFICIENCY ANEMIA
Alpha Thalassemia:
What is it, how does it differ from Beta Thalassemia clinically, and what are its 4 types?
- inherited gene deletion causing absent or reduced alpha-globin chains
- beta and gamma chains are more soluble, meaning less severe hemolysis and ineffective erythropoiesis
types: Silent Carrier, a-thalassemia trait, Hemoglobin H disease, Hydrops Fetalis
Alpha Thalassemia:
What is the Silent Carrier Type?
- deletion of single gene causing barely detectable reduction in synthesis
- asymptomatic
Alpha Thalassemia:
What are the two alpha-thalassemia deletions and what disease is it clinically similar to?
- Cis deletion: two genes deleted on 1 chromosome
- common in Asians, offspring at inc. risk of disease
- Trans deletion: one gene deleted from both chromo
- common in African Americans
- microcytosis w/minimal anemia
clinically similar to B-thalassemia Minor
Alpha Thalassemia:
What is the Hemoglobin H Disease and what disease is it clinically similar to?
- 3 gene deletion common in Asians, creates HbH
- Beta tetramers form w/inc. oxygen affinity, causing tissue hypoxia disproportionate to lvl of Hb
- does NOT require transfusions
resembles B-thalassemia Intermedia
Alpha Thalassemia:
What is Hydrops Fetalis and what does it cause?
- deletion of all 4 genes, creates Hemoglobin Barts (gamma globin tetramer w/greatly inc. oxygen affinity)
- causes Fetal Distress Syndrome beginning 3rd trimester (requires lifelong transfusions)
HSC is curative
Paroxysmal Nocturnal Hemoglobinuria (PNH)
What is it, what 3 proteins is it deficient for, and how does it present clinically (4)?
- acquired PIGA gene (GIP protein) mutation (subject to lyonization since its X-linked, so one mutation will fuck it up)
- proteins: CD55 (DAF), CD59 (MIRL –> most important), and C8 binding protein
C: shallow nighttime breathing (respiratory acidosis inc. complement), mild anemia (chronic), hemosiduria –> iron deficiency
only hemolytic anemia caused by acquired genetic defect
Paroxysmal Nocturnal Hemoglobinuria (PNH):
What is the leading cause of death, how is it diagnosed, and what are 2 major treatment options?
- Venous Thrombosis of hepatic, portal, or cerebral veins (5-10% develop AML)
- Flow Cytometry to see GPI deficient RBCs
T: Eculizumab (prevents C5 conversion) or HSC transplant
What are Immunohemolytic Anemias and how are Direct and Indirect Coombs Tests used?
- antibodies bind to RBCs causing their premature anemias
Direct Coomb’s Test - mix pt. RBCs mixed w/abs for human immunoglobins
(+) - if agglutenation occurs (Abs to Abs on RBCs)
Indirect Coomb’s Test - RBCs w/defined Ags are mixed with pt. serum
(+) - if pts. serum has Abs against Ags on RBCs
Warm Antibody Type of Immunohemolytic Anemia:
What is it, how does it work, and what does it lead to?
- most COMMON type of immunohemolytic anemia caused by IgG abs
- leads to extravascular hemolysis (phagocytes Fc receptor binding) and sequestering of spherocytes in spleen (splenomegaly)
How do Antigenic (2 examples) and Tolerance Breaking Drugs (1 example) cause immunohemolytic anemia?
A: agent binds to RBCs after IV infusion
- hemolysis occurs after 1-2 wks
- phagocytes eat –> extravascular hemolysis
- penicillins and cephalosporins
TB: agent stims Abs against RBC antigens, usually Rh antigens
- alpha-methyldopa
Cold Agglutinin Type of Immunohemolytic Anemia:
What is it, what are its two types (A/C), and what does it lead to clinically (4)?
- IgM Abs bind RBCs at low temperatures, usually in extremity vascular beds
Acute: self-limited, appearing after infection (EBV, CMB, flu, HIV)
Chronic: symptomatic (idiopathic or B cell neoplasms)
- more difficult to treat
- leads to Raynaud’s, cyanosis, pallor; opsonized cells phagocytosed w/minimal complement hemolysis
Immunohemolytic Anemias:
Cold Hemolysin and RBC Trauma (What are they, what are they caused by, and what do they lead to?)
CH: IgG auto-Abs bind to P Ag on RBC in peripheral (cold) regions and cause paroxysmal cold hemoglobinuria when they return to central (warm) areas –> complement more effective here
RT: commonly caused by prosthetic cardiac valves and microangiopathic disorders (LUMINAL NARROWING)
- fibrin/platelets inc shear stress –> injure RBCs
- schistocytes –> helmet, triangle, burr cells
What is Microangiopathic Hemolytic Anemia most commonly seen with and what other blood disorders (2) is it also commonly seen in?
most associated with DIC (disseminated intravascular coagulation)
- also seen in thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS)
Megaloblastic Anemias:
What are they, what does the peripheral blood look like, and what does the bone marrow look like?
- impairment of DNA synthesis leading to abnormally large RBC precursors due to ineffective hematopoiesis
- usually B12 or folate deficiencies
P: large, oval RBCs (macro-ovalocytes)
- appear hyperchromic and MCHC not changed
- hypersegmented neutrophils
M: hypercellular with inc. blast forms
- giant metamyelocytes/band forms
- pancytopenia due to ineffective synthesis
Pernicious Anemia
What is it and who does it commonly affect?
- autoimmune gastritis impairs Intrinsic Factor required for B12 uptake in gut (autoreactive T cell response; auto-Abs do not cause pathology)
- median age 60 and especially effects Scandinavians
Vitamin B12 Deficiency:
How does the morphology of the GI and CNS change in patients with deficiency? What are 3 common consequences of having the disease?
GI: beefy red tongue, fundic gland atrophy, intestinalization (parietal cells –> goblet cells)
CNS: dorsal/lateral spinal tract demyelination = sensory ataxia, lower limb parasthesias
CC: inc. risk of gastric carcinoma, neuro disease (methylmalonic acid build-up), and atherosclerosis/thrombosis (inc. homocysteine)
Vitamin B12 Deficiency:
How is it diagnosed (2) and how can it be treated?
D: inc. homocysteine and methylmalonic acid (meth. NOT inc. in Folic Acid deficiency), serum Abs to IF (pernicious anemia)
B12 challenge: hematocrit inc. in 5 days after B12 administration (CONFIRMED after seeing response)
T: high dose or parenteral B12/folate administration
What are two ways that Folate Deficiency differs from Vitamin B12 Deficiency?
- folate def. has NO neurological problems (CNS problems w/B12 deficiency)
- methylmalonic acid within NORMAL limits (inc. methylmalonic acid w/B12 deficiency)
What tapeworm is a potential cause of B12 deficiency and what is it found in?
Diphyllobothrium latum
- found in fish
Anemia of Folate Deficiency:
What are 3 causes of it, where can it normally be acquired, and what are 3 groups it is commonly associated with?
How is it treated?
C: dec. intake, inc. requirements, or impaired utilization
- similar pathologic features to B12 deficiencyI
Sources: green veggies/animal organ meat
- absorbed in proximal jejunum
seen in:
- old, poor, alcoholics
- people using phenytoin/oral contraceptives
- methotrexate or other chemo drugs
Treat: folic acid administration
What is the most common nutritional disorder in the world and how can it be diagnosed?
Iron Deficiency (most commonly due to CHRONIC blood loss in the Western world)
D: Prussian Blue Stain for hemosiderin granules (no stained iron in macrophages = diagnostically significant finding of iron deficiency)
- normally turns blue-black
What is Ferritin and Hemosiderin?
F: storage form of iron found in liver, spleen, bones, muscles
H: partially degraded protein-shell granules of Ferritin
- most iron stored as hemosiderin in Iron Overload
What is hepcidin and why is it important?
- released from liver cells in response to inc. in intra-hepatic iron levels
- regulates iron absorption in proximal duodenum by binding FERROPORTIN (blocks iron release from enterocyte to plasma and from macrophage storage pools)
- hepcidin levels are directly related to total body iron stores (enterocytes slough off, allowing the body to excrete iron)
Hepcidin and infection (what are two microbes that require iron to survive?)
- hepcidin is structurally related to defensins (anti-bacterial), so iron sequestration enhances ability to fight off certain infections
EX: H. influenza and Yersinia enterocolitica (pseudo-appendicitis)
What is iron deficiency in men or postmenopausal women diagnosed as until proven otherwise?
GI bleed! –> cancer or occult
think colon cancer
Iron Deficiency Anemia:
What is its morphology (3) and what clinical findings does it cause (4)? What syndrome can it lead to?
M: microcytic, hypochromic anemia (started normocytic, normochromic) –> enlarged RBC central pallor
- Poikilocytosis (pencil cells)
C: koilonychia (spoon nails), hair loss, atropic changes (tongue and gastric mucosa), Pica
- can lead to Plummer-Vinson Syndrome (late iron deficiency anemia causing atrophic glottitis and esophageal webbing)
Iron Deficiency Anemia:
What are laboratory findings of disease? (4)
- HCT/Hgb decreased
- serum iron low
- plasma ferritin low (iron storage form)
- inversely related to Total Iron Binding Capacity
- serum hepcidin is low
Anemia of Chronic Disease:
Who is it most commonly seen in, what are 3 things that can cause it, and what is its pathogenesis?
- most common cause of anemia in hospital pts. (microcytic, hypochromic anemia)
C: chronic infections, immune disorders, or neoplasms
P: systemic inflammation (IL-6 inc. hepcidin production)
- low serum iron, dec. TIBC, abundant iron stores
TREAT UNDERLYING CONDITION
What is Apastic Anemia? What are its two models of pathogenesis?
- syndrome of primary hematopoietic failure and attendant pancytopenia
- autoimmune is most common cause and idiopathic causes are seen in 65% of cases
Extrinsic: immune-mediated progenitor suppression
- Th1 causes IFNy and TNF (SUPPRESSORS)
- antithymocyte globulin suppress T-cells
Intrinsic: stem cell abnormality
- antigenically altered via drug/infectious agents
- Hepatitis D/E?
What is Fanconi Anemia and what two telomerase problems are seen in aplastic pts?
FA: auto recessive due to defective DNA repair protein complex (see w/congenital anomalies)
- kidney/spleen hypoplasia and thumb abnormality
Telomerase:
- Mutations (5-10% of adults)
- premature HSC exhaustion and marrow aplasia
- Short Telomeres (50% of pts)
- undiscovered defects or excessive SC replication
Aplastic Anemia:
Wht does it look like, what does it cause clinically, and how is it treated?
- hypocellular bone marrow (fat, fibrous stroma); do “dry-tap” on marrow since biopsy necessary for diagnosis
- mucocutaneous bacterial infection, abnormal bleeding, systemic hemosiderosis (mutiple transfusions) –> PANCYTOPENIA
T: bone marrow transplant (5 year survival in 75%+) or immunosuppresion in older pts
What is Pure Red Cell Aplasia?
- primary marrow disorder that ONLY suppresses RBC progenitors (THYMOMA and Parovirus B19 associated)
PB19 –> infects RBC precursors and can lead to aplastic crisis in pts w/hemolytic anemias (HIV inc. infection)
T: with thymoma resection (50% have improvement) or immunosuppression if NO thymoma
What is Myelophthisic Anemia?
What is it most commonly caused by?
- space occupying lesions replace normal marrow elements
- causes Leukoerythroblastosis (abnormal blast/immature cell release), “Teardrop RBCs” from having to escape fibrotic marrow
caused by: metastatic breast/lung/prostate cancer
Chronic Renal Failure leading to anemia and treatment
- anemia is proportional to uremia severity (kidneys produce less EPO causing inadequate RBC production)
T: recombinant EPO +/- Iron therapy
hepatocellular liver disease can also cause anemia due to toxins/infections/cirrhosis
Polycythemia:
What is the difference between Relative and Absolute (P/S) versions?
- abnormally high RBC count (usually w/inc. Hb lvls)
Relative: inc. hemoconc. due to dec. plasma vol.
- usually from dehydration
- Gaisbock Syndrome: stress version (HTN/anxious)
Absolute: inc. in total red cell mass
- Primary: instrinsic abnormality in RBC precursors
- Secondary: RBC precursors respond to inc. EPO
Renal Cell carcinomas are known to secrete erythropoietin
What is Polycythemia Vera?
- most common cause of primary polycythemia
- myeloproliferative disorder associated w/mutations leading to EPO-independent RBC progenitor growth
HIF-1a - hypoxia-inducing factor; stimulates EPO gene transcription
What is the difference between Prothrombin and Partial Thromboplastin Time?
PT: assesses EXTRINSIC coagulation pathway
- plasma clot after thromboplastin/Ca addition
- prolonged due to Factor VII deficiency
- measured in pts taking WARFARIN (coumadin)
PTT: assesses INTRINSIC coagulation pathway
- plasma clot - kaolin, cephalin, Ca addition
- prolonged due to Factor VIII, IX, XI, XII defic.
- measured in pts taking heparin
do PTT testing if you thing HEMOPHILIA
Vessel Wall Abnormalities:
What do they lead to, what infections (3) are potential causes of them, and what does lab testing reveal about them?
- relatively common, causing petechiae and purpura w/o serious bleeding
- infections of meningococcemia (can be catastrophic), rickettsioses, and Neisseria can lead to it
Labs: platelet count normal, PT/PTT are normal
What is Henoch-Schonlein Purpura? What are 4 classic symptoms of it?
- systemic hypersensitivity due to immune complex deposition (IgA), usually in the glomerular mesangial region
- causes purpuric rash, colicky abdominal pain, polyarthralgia, and acute glomerulonephritis
deposition of immune complexes within vascular walls
Hereditary Hemorrhagic Telangiectasia (WOR Syndrome):
What is it and what is it caused by, how does it present, and how is it treated?
- dilated, tortuous, thin-walled vessels due to TGF-B signaling dysregulation (AutoDominant inheritance of CD105 gene endoglin)
- causes bleeding under mucous membranes of NOSE (recurrent EPISTAXIS most common symptom), tongue, mouth, eyes, GI tract (Vermillion border of lip and on tongue)
T: mostly benign, surgery/photoablation in select pts
What is Thrombocytopenia and what are its 4 major categories?
- platelet count BELOW 100,000 (counts of 20,000-50,000 can exacerbate posttraumatic hemorrhage)
Categories:
- Dec. Production - marrow output suppressed
- Dec. Survival - inc. consumption/activation
- mechanical injury, DIC/thrombotic microangiopathy
- Sequestration
- Dilution - see in prolonged storage for transfusion
Chronic Immune Thrombocytopenic Purpura (ITP):
What is it, who does it commonly affect, and what lab values does it produce (3)?
- primary/secondary auto-Abs (IgG) destroying platelets (secondary associated with SLE, HIV, CLL)
- no splenomegaly noted even though platelets are removed there
- seen in women < 40 yo, and is 3x more likely in F’s
Labs: normal PT/PTT, low platelet counts with large ones seen on smear, inc. megakaryocytes
Chronic Immune Thrombocytopenic Purpura (ITP):
How is it diagnosed, how does it present clinically, and how can it be treated (3)?
D: diagnosis of exclusion due to no reliable Ab tests
C: bleeding into skin/mucousal surfaces
- epistaxis, easy bruising, gum bleeding
- no splenomegaly or lymphadenopathy (B cell neos)
T: splenectomy (normalizes platelet count, IVIG or Rituximab, TPO mimetics to stimulate production
Acute Immune Thrombocytopenic Purpura (ITP):
What is it and who does it commonly affect? How is it treated?
- childhood disease appearing 1-2 wks after self-limited viral infection
- auto-Abs to platelets develop but are self-limited with resolution in 6 months
- 20% of pts can persist to a chronic form resembling CHRONIC ITP
What are 3 common drugs that cause Drug-induced Thrombocytopenia and how do they cause the disease?
quinine, quinidine (malarial drugs), and vancomycin
- bind platelet glycoproteins and create antigenic determinants that are recognized by Abs
- Abs bind to them, allowing for macrophage ingestion and platelet removal
What is Type II Heparin-induced Thrombocytopenia (HIT)?
- Abs form to Heparin-Platelet Factor 4 complexes (occurs 5-14 days after therapy begins)
- causes DVT that can become pulmonary embolisms (setting of thrombocytopenia) and can clot large arteries leading to limb loss
DISCONTINUE THERAPY and find another anti-clotting drug
What is one of the most common hematological manifestations of HIV infection and how does it infect?
THROMBOCYTOPENIA
- through CD4 receptors and CXCR4 coreceptors on megakaryocytes
What are two common examples of Thrombotic Microangiopathies?
How can they be separated from DIC?
- Thrombotic Thrombocytopenic Purpura
- Hemolytic Uremic Syndromes
- both examples have NORMAL PT/PTT times because mode of action is DIRECT platelet activation
- DIC would follow coagulation cascade and has abnormal PT/PTT times
Thrombotic Thrombocytopenic Purpura (TTP):
What is it, who does it commonly affect, and what is its classic pentad of symptoms?
What do labs show and how can it be treated?
- hyaline thrombi occlude capillaries of organs (dec. ADAMSTs13 - normally degrades vWF either by auto-Abs or hereditary mutation)
- commonly affects females
Pentad: fever, mental changes, renal failure, thrombocytopenia, and microangiopathic hemolytic anemia
Labs: PT/PTT normal in early disease, late suggest DIC
Treatment: plasma exchange/plasmapheresis
- untreated = 100% MORTALITY
Hemolytic Uremic Syndrome:
Why is the difference between its Typical and Atypical form?
How can it be differentiated from TTP?
Typical: drug/infection endothelial damage
- children/elderly w/E. coli dysentery (uncooked beef)
- Shiga-like toxin leads to bloody diarrhea
- irreversible renal damage, supportive treatment
Atypical: acquired/inherited Factor H (CD46) or I defect
- normally prevent excess Alt. Complement pathway activation
- immunosuppresion for pts. with auto-Abs
different from TTP due to LACK of NEUROLOGICAL changes
Bernard-Soulier Syndrome:
What is it and what will it not aggregate to?
- defective platelet adhesion to subendothelial matrix due to deficiency of complex Ib-IX (receptor for vWF)
- severe bleeding tendencies and giant platelets on smear
no aggregation - ADP, collagen, epinephrine, thrombin
- ABSENT aggregation to RISTOCETIN
Glanzmann Thrombasthenia:
What is it and what will it not aggregate to?
- defective platelet aggregation due to auto recessive dysfunction of IIb/IIIa (binds fibrinogen for platelet agg)
- severe bleeding tendencies, normal platelets
no aggregation - ADP, collagen, epinephrine, thrombin
- WILL aggregate to RISTOCETIN
How does Aspirin and other NSAIDS affect platelets?
- aspirin is a potent, irreversible inhibitor of COX, which is required for synthesis of TxA2 and PGs (platelet activators)
- acquired defect in platelet aggregation
What disease is hemarthrosis after minor stress a sign of?
Hemophilia A or B, but not vWF related
i.e. coagulation factor deficiencies
Vitamin K Deficiency:
What is it, what causes it (3), and what does it lead to clinically?
How is it treated?
- vitamin K activated by epoxide reductase (liver); leads to impaired synthesis of Factors II, VII, IX, X, Protein C (“1972 and C)
- Warfarin impairs vitamin K; also due to chronic antibiotics (mess up GI bacteria), severe liver disease
C: prolonged PT –> bleeding and hemorrhage
T: replacement of deficiency (12-18 hr correction)
How do Clotting Factor abnormalities clinically manifest? (3)
- large ecchamoses/hematomas after injury, or prolonged bleeding after laceration/surgery
- can bleed into GI/GU tracts or weight-bearing joints (Hemarthrosis)
Von Willebrand Disease:
What is it and how does it look on labs?
- most common inherited bleeding disorder of humans; usually unnoticed till surgery or dental procedure
- autosomal DOMINANT disorder
Labs: factor VIII is reduced (plasma protein lvl low), prolonged PTT time (Hemophilia A and B also have prolonged PTT, so need to differentiate)
Von Willebrand Disease:
What is the difference between Type 1, Type 3, and Type 2?
T1: AD quantitative defect; most common subtype (70%) w/mild-moderate deficiency
- PTT may be prolonged
- point mutation
T3: AR quantitative defect; very low levels with SEVERE CLINICAL manifestations
- Factor VIII stability affected, PTT may be prolonged
- frameshift/deletion of BOTH alleles
- hemarthrosis may be seen
T2: AD qualitative with normal protein expression
- missense mutation = defective multimer assembly
- 25% of cases have mild-moderate bleeding
Hemophilia A:
What is it, how does it present clinically, and how can it be treated?
- Factor VIII deficiency (most common hereditary disease associated with life-threatening bleeding)
- x-linked recessive trait; X chromosome inversion is most severe form, leading to NO synthesis of F VIII
C: no petechiae, tendency to bleed at particular sites (joints, muscles, CNS); prolonged PTT, normal PT
T: recombinant factor VIII infusions (replace what is missing) and prophylaxis before surgery
Hemophilia B (Christmas Disease):
What is it, how is it diagnosed, and what is its treatment?
Factor IX deficiency that is X-linked recessive (clinically identical to Hemophilia A)
D: assay of factor levels, prolonged PTT, normal PT
T: recombinant Factor IX (replace what is missing)
Disseminated Intravascular Coagulation:
What is it, what are 3 common signs of it, and how is it caused?
- acute, subacute, or chronic thrombo-hemorrhagic disease due to excessive activation of coagulation and thrombi formation in microvasculature
signs: tissue hypoxia, infaction, hemorrhage
triggered by the release of tissue factor or procoagulants, or widespread injury to the endothelial cells
caused by: sepsis, major trauma, certain cancers (33% of pts), or obstetric complications (50% of pts)
Disseminated Intravascular Coagulation:
What is the difference between Acute and Chronic presentation, what are common clinical complications, and what is the treatment?
Acute: obstetric complications/trauma: bleeding diasthes
Chronic: carinomatosis w/thrombotic complications
C: microangiopathic hemolytic anemia, respiratory (cyanosis, dyspnea, failure), neuro signs
T: remove or treat underlying cause quickly since DIC is well-established as a DEATH SENTENCE
Transfusion Complications:
Febrile non-hemolytic and Allergic Reactions
FNH: fever/chills +/- dyspnea (6 hrs after transfusion)
- inflammation from donor leukocytes
Allergic: most common in pts. w/IgA deficiency
- life-threatening in pts. who have been sensitized
- mild, most pts. respond to antihistamines
- IgG recognizes IgA in blood
Transfusion Complications:
Acute vs Delayed Hemolytic Reactions
Acute: due to preformed IgM Abs against donor RBCs
- ABO compatibility (fix complement)
- rapid onset (fever/chills/shaking)
- (+) direct Coomb’s test
Delayed: due to IgG Abs against RBC Ags (sensitized)
- Abs to Rh, Kell, Kidd activate compliment
- Abs can also opsonize = spherocytosis
- (+) direct Coomb’s, dec. haptoglobin, inc. LDH
Transfusion Complications due to Infection
- bacterial infections due to skin contamination at time of donation
- more likely with platelet transfusion since they must be stored at ROOM temperature
- frequent donors or IV drug users who get past screening = LAB ERROR
Transfusion-related Acute Lung Injury (TRALI)
- activated neutrophils in lung microvasculature (more frequent in pts with lung disease)
- transfused Abs attack neutrophils, leading to rapid/diffuse respiratory failure and diffuse bilateral pulmonary infiltrates
- treatment is support since it is unresponsive to diuretics
TRALI “2 Hit” hypothesis
First hit: priming event that leads to sequestration and sensitization of neutrophils in microvasculature of the lung
Second hit: primed neutrophils are activated by factor present in transfused blood product
most common Abs are those that bind MHC proteins, especially MHC1
