Pathoma Flashcards
1
Q
primary hemostasis
A
- transient vasoconstriction of damaged vessel by reflex neural stimulation and endothelin release
- platelet adhesion: vWF (derived from Weibel-Palade bodies of endothelial cells and a-grandules of platelets) binds exposed subendothelial collagen
- platelet degranulation→ ADP release promotes exposure of GPIIb/IIIa receptor on plaeteles; TXA2 synthesized by platelet COX
- platelet aggregation via GPIIb/IIIa using fibrinogen linker molecule
2
Q
disorders of primary hemostasis
A
- abnormalities in platelets → mucosal and skin bleeding (MC: epistaxis; petechiae, purpura, ecchymoses)
- immune thrombocytopenic purpura (ITP): IgG against platelet antigens (GPIIb/IIIa)
- microangiopathic hemolytic anemia: pathologic formation of platelet microthrombi in small vessels
- qualitative platelet disorders: bernard soulier; glanzmann thrombasthenia
3
Q
immune thrombocytopenic purpura (ITP)
A
- IgG against platelet antigens (GPIIb/IIIa)
- antibody bound platelets consumed by splenic macrophages→ MC cause of thrombocytopenia
- acute: children weeks after viral infection or immunization
- chronic: women of childbearing age, primary or secondary, antiplatelet IgG can cross the placenta
- labs: low platelet (<50), normal PT/PTT, high megakaryocytes on bone marrow biopsy
- treatment: corticosteroids, IVIG to raise platelet count, splenectomy (in refractory cases)
4
Q
microangiopathic hemolytic anemia
A
- platelet microthrombi in small vessels→ sheared→ hemolytic anemia with schistocytes
- TTP: decreased ADAMATS13 due to autoantibody (enzyme that normally cleaves vWF)→ abnormal platelet adhesion and microthrombi; CNS abnormalities
- HUS: endothelial damage by drugs or infection, classical e.coli O157:H7 dysentery (verotoxin damages endothelium); renal insufficiency
- Labs: thrombocytopenia with increased bleeding time, normal PT/PTT, anemia with schistocytes
- treatment: plasmapheresis, corticosteroids
5
Q
qualitative platelet disorders
A
- bernard-soulier: genetic GPIb deficiency→ imparied platelet adhesion; mild thrombocytopenia with enlarged platelets
- glanzmann thrombasthenia: genetic GPIIb/IIIa defieincy→ impaired platelet aggregation
- aspirin: irreversibly inactivates COX→ lack of TXA2 which impairs aggregation
- uremia: N builds up→ imparied aggregation and adhesion
6
Q
secondary hemostasis
A
- stabilizes weak platelet plug: coagulation cascade generates thrombin which converts fibrogen→ fibrin
- factors of coagulation cascade are made in liver in inactive state; activation requires
- exposire to activating substance
- intrinsic: damaged surface (subendothelial collagen)
- extrinsic: trauma (tissue thromboplastin)
- phospholipid surface of platelets
- Ca2+ (derived from platelet dense granules)
- exposire to activating substance
7
Q
disorders of secondary hemostasis
A
- usually due to factor abnormalities
- clinical features: deep tissue bleeding into muscle and joinrs and rebleeding after surgical procedure
- PT: measures extrinsic (VII) and common (II, V, X, fibrinogen) factors
- PTT: measures intrinsic (XII, XI, IX, VIII) and common (II, V, X, fibrinogen) factors
- hemophilia A: factor VIII deficiency
- hemophilia B: factor IX deficiency
- coagulation factor inhibitor: anti-VIII MC
- von willebrand disease: vWF deficiency
- vitamin K deficiency
8
Q
hemophilia A
A
- X-linked recessive FVIII deficiency; can arise de novo
- labs: high PTT, normal PT, low FVIII
- normal platelet count and bleeding time
- treat: recombinant FVIII
9
Q
hemophilia B
A
- FIX deficiency
- labs: high PTT, normal PT, low FIX
- normal platelet count and bleeding time
10
Q
von willebrand disease
A
- MC inherited coagulation disorder; multiple subtypes, MC is AD with decreased vWF
- presentation: milk mucosal and skin bleeding
- labs: increased bleeding time, high PTT, normal PT (vWF normally stabilized FVIII), abnormal ristocetin test (ristocetin induces platelet agglutination by causing vWF to ind platelet GPIb)
- treatment: desmopressin (ADH analog) which increased vWF release from weibel-palade bodies
11
Q
vitamin K deficiency
A
- disrupts function of multiple coagulation factors
- Vitamin K is activated by epoxide reductase in liver→ gamma carboxylates FII, VII, IX, X and proteins C and S
- newborns: lack of GI flora that normally synthesizes K (prophylaxis to all newborns to prevent HDFN)
- long-term antibiotic therapy: disrupts GI flora
- malabsorption: leads to deficiency of fat soluble vitamins
12
Q
other causes of abnormal secondary hemostasis
A
- liver failure→ decreased production of coagulation factors and decreased activation of K by epoxide reductase; follow with PT
- large volume transfusion: dilutes coagulation factors→ relative deficiency
13
Q
heparin induced thrombocytopenia
A
- platelet destruction secondary to heparin therapy
- 4 Ts
- Thrombocytopenia without bleeding
- Timing 5-14 days
- Thrombosis
- oTher causes ruled out
14
Q
disseminated intravascular coagulation (DIC)
A
- pathologic activation of coagulation cascade→ widespread microthrombi→ ischemia and infarction; consumption of platelets and factors→ bleeding
- usually secondary to another process
- OB complications: activated by tissue thromboplastin in amniotic fluid
- sepsis: activated by toxins (esp. e. coli or n. meningitidis)
- adenocarcinoma: activated by mucin
- APL: activated by primary granules
- rattlesnake bite: activated by venom
- low platelet, high PT/PTT, low fibrinogen, elevated fibrin split products esp. D-dimer (best screening test)
- treat underlying cause; transfusion with blood products and cryoprecipitate
15
Q
disorders of fibrinolysis
A
- normally
- tPA converts plasminogen→ plasmin which cleaves fibrin and serum fibrinogen, destroys coagulation factors and blocks platelet aggregation
- a2-antiplasmin inactivates plasmin
- disorders are due to plasmin overactivity→ excessive cleavage
- radical prostatectomy: urokinase activates plasmin
- cirrhosis: reduced a2-antiplasmin
- looks like DIC (high PT/PTT, high bleeding time) BUT normal platelet count and increased fibrogen split products without D-dimers
- treat: aminocaproic acid (blocks activation of plasminogen)
16
Q
thrombosis
A
- pathologic formation of intravascular blood clots (thrombus)
- MC in DVT of leg below knee
- caracteried by lines of zahn (alternating layers of platelets/fibrin and RBS) and attachment to vessel wall
- virchow’s triad of 3 risk factors: disruption in blood flow, endothelial cell damage (caused by atherosclerosis, vasculitis, and high levels of homocysteine), hypercoagulable state
17
Q
how does endothelial cell damage predispose thrombus formation?
A
normally endothelial cells prevent thrombosis by:
- blocking exposure to subendothelial collagen and underlying tissue factor
- producing PGI2 and NO→ vasodilation and inhibition of platelet aggregation
- secreting heparin-like molecules that august antithrombin III
- secreting tPA
- secreting thrombomodulin: redirects thrombin to activate protein C (instead of converting fibrinogen to fibrin)→ inactivation of FV and VIII
18
Q
hypercoagulable state
A
- classically presents as recurrent DCTs or DVT at young age
-
Protein C or S deficiency: AD, decreases negative feedback on coagulation cascade (normally inhibit FV, VIII)
- increased risk for warfarin skin necrosis (initially warfarin leads to temporary deficiency of proteins C and S due to shorter half life relative to FII, VII, IX, X); use heparin at same time until all coagulation factors become depleated
- FV Leiden mutated FV that lacks cleavage site for deactivation by proteins C and S
- Prothrombin 20210A: inherited point mutation in prothrombin→ increased gene expression
- ATIII deficiency: decreases protect effect of heparin-like molecules produced by endothelium (PTT does not rise with standard heparin dosing)
- OCPs: estrogen→ increased production of coagulation factors
19
Q
anemia
A
-
reduction in circulating RBC mass
- Hb, Hct, and RBC used as surrgoates for RBC mass (hard to measure)
- Hb<13.5 in men; Hb<12.5 in females
- presents with signs of hypoxia (weakness, fatigue, dyspnea, pale conjunctiva and skin)
20
Q
microcytic anemias
A
- MCV<80 due to decreased production of Hb (RBCs divide multiple times to maintain concentration of Hb/cell)
- types
- Fe deficiency anemia (decreased heme)
- ACD (Fe sequestered in macrophages)
- sideroblasic anemia (decrease in protoporphyrin)
- thalassemia (decrease in globin chain)
21
Q
iron deficiency anemia
A
- low Fe→ low heme→ low Hb→ microcytic anemia
- MCC of anemia; dietary lack or blood loss
- stages
- Fe depleated (low ferritin, high TIBC)
- Serum Fe depleated (low serum Fe, low % sat); high free erythrocyte protoporphyrin
- normocytic anemia: bone marrow makes fewer, normal sized RBCs
- microcytic hypochromic anemia: bone marrow smaller and fewer RBCs (high RDW)
- clinical features: anemia, koilonychia (spoon nails), pica
- treat with supplemental ferrous sulfate
22
Q
Fe transport/storage and measurements
A
- absorption in duodenum (heme is more readily absorbed by enterocyte)→ Fe transport into blood via ferroportin→ transferrin transports Fe in blood to liver and bone marrow macrophages→ stored intracellularly bound to ferritin (prevents free radical formation)
- serum Fe: Fe in blood
- TIBC: mesausre of transferrin in blood
- % sat: percentage of transferrin bound by Fe (33% is normal)
- serum ferritin: iron stores in macrophages and liver
23
Q
plummer-vinson syndrome
A
iron deficiency anemia with esophageal wed and atrophic glossitis; presents as anemia, dysphagia, and beefy-red tongue
24
Q
anemia of chronic disease
A
- chronic disease→ acute phase reactants including hepcidin
- hepcidin: prevent bacteria from accessing Fe (necessary for survival); sequesters Fe in storage sites by limiting Fe transfer from macrophages to erythroid precursons and suppressing EPO production
- low available Fe→ low heme→ low Hb→ microcytic anemia
- high ferritin, low TIBC, low serum Fe, low % sat
- high free erythrocyte protoporphyrin
- treat underlying cause
25
Q
sideroblastic anemia
A
- defective protoporphyrin synthesis
- succinyl CoA→ ALA via ALAS and B6 cofactor (rate limiting)
- ALA→ porpho B→ proto+Fe→ heme (ferrochelatase attaches proto to Fe in mitochondria)
- if no proto, Fe trapped in mitochondria→ Fe ring around nucleus (ringed sideroblasts)
- congential: ALAS defects
- acquired: alcoholism (mitochondrial poison), Pb poisoning (inhibits ALAD and ferrochelatase); B6 deficiency (ALAS cofactor; side effect of isoniazid)
- iron overload: high ferritin, low TIBC, high serum Fe, high % sat
26
Q
a-thalassemia
A
gene deletion on chromosome 16
- 1 deletion: asymptomatic
- 2 deletions: mild anemia with high RBC (cis deletion in Asians, trans in African/African Americans)
- 3 deletions: severe anemia, ß tetramers (HbH) damage RBCs
- 4 deletions: lethal in utero y tetramers (Hb Barts) damage RBCs
27
Q
ß thalassemia
A
gene mutation on on chromosome 11
-
minor (ß/ß+): mildest form, asymptomatic with increased RBCs→ microcytic hypochromic RBCs and target cells
- decreased HbA, increased HbA2 and HbF
-
major (ß0/ß0): severe anemia after birth (high HbF is protective); unpaired a chains precipitate and damage RBCs→ ineffective erythropoeisis and extravascular hemolysis→ massive erythroid hyperpasmia→ microcytic hypochromic RBCs with target cells and nucleated RBCs
- chronic transfusions necessary, risk for secondary hemochromatosis
28
Q
macrocytic anemia
A
- anemia with MCV>100
-
MC due to folate or B12 deficiency (megaloblastic anemia)
- impaired synthesis of DNA precursors→ pancytopenia, imparied division/enlargement of RBC precursors, imparied divison of granulocytic precursors leading to hypersegmented neurophils
29
Q
folate deficiency anemia
A
- folate from green veggies absorbed in jejunum
- deficiency develops in months; caused by poor diet, increased demand, and folate antagonists
- macrocytic RBCs, hypersegmented neutrophils
- gossitis (cells of tongue aren’t turning over)
- low serum and RBC folate
- high serum homocysteine (increases risk for thrombosis)
- normal methylmalonic acid (rules out B12 deficiency)
30
Q
vitamin B12 deficiency
A
- B12 is complexed to animal protein, amylase liberates, binds to R-binder, cleaved by pancreatic proteases, B12 binds IF (from gastric parietal cells) and is absorbed in ileum
- takes years to develop (large hepatic stores)
- MCC is pernicious anemia: autoimmune destruction of parietal cells leads to IF deficiency and risk of gastric cancer
- macrocytic RBCs, hypersegmented neutrophils
- glossitis
- subacute combined degeneration of spinal cord (B12 is cofactor for methylmalonic acid→ succinyl CoA, causes demyelination)
- low serum B12, high serum homocysteine, high methylmalon acid
31
Q
normocytic anemia
A
- MCV 80-100
- due to increased peripheral destruction or underproduction
- reticulocyte count helps distinguish (young RBCs, blue due to residual RNA)
-
properly functioning marrow responds to anemia by increased corrected retic count >3%
- (corrected= count x Hct/45)
- peripheral destruction is either extravascular (macrophages) or intravascular (destruction within vessels)
32
Q
extravascular hemolysis
A
- RBC destruction by macrophages of spleen, liver, and lymph nodes
- globin→ amino acids
- heme→ Fe (recycled) and proto→ unconjugated BR
- findings: splenomegaly, jaundice, increased risk for BR gallstones
- marrow hyperplasia with corrected reticulocyte count >3%
33
Q
intravascular hemolysis
A
- destruction of RBCs within vessels
- inititally low serum haptoglobin (binds up Hb that leaks out into blood)
- hemoglobinemia
- hemoglobinuria
- hemosiderinuria (renal tubular cells pick up Hb that is filtered in urine and break it into Fe which accumulates as hemosiderin, tubular cells are eventually shed)
34
Q
normocytic anemias with predominant extravascular hemolysis
A
- hereditary spherocytosis
- sickle cell anemia
- HbC
35
Q
hereditary spherocytosis
A
- inherited defect of RBC cytoskeleton-membrane tethering proteins (ankyrin, spectrin, or band 3.1)
- membrane blebs are formed→ round cells (with loss of central pallor) less able to maneuver through spleen→ consumed by macrophages
- high RDW and high MCHC
- splenomegaly, jaudice, increased risk for BR gallstones
- diagnosis: osmotic fragility test in hypotonic solution
- treatment: splenectomy→ spherocytes and howell-jolly bodies
