Pathoma Ch 4 - Hemostasis Flashcards

1
Q

what are the steps of primary hemostasis?

A
  1. transient vasoconstriction 2. platelet adhesion (Gp1b-vWF) 3. platelet degranulation 4. platelet aggregation (GpIIb/IIIa)
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2
Q

what is the first response to endothelial cell injury?

A

transient vasoconstriction -mediated by neural reflex and endothelin released by endothelial cells

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3
Q

what does vWF bind initially after endothelial cell injury?

A

subendothelial collagen

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4
Q

platelets bind vWF on subendothelial collagen by which receptor?

A

GP1b receptor

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5
Q

vWF derived from where?

A

Weibel-Palade bodies of endothelial cells and from alpha granules of platelets

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6
Q

what does Weibel-Palade bodies contain? where are they?

A

vWF and P-selectin (found in endothelial cells)

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7
Q

step 3 platelet degranulation releases what mediators?

A

ADP (dense granules) TXA2 - derivative of platelet cyclooxygenase

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8
Q

what does ADP and TXA2 do?

A

ADP - promotes exposure of GpIIb/IIIa on platelets TXA2 - promotes platelet aggregation

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9
Q

platelet aggregation via which receptor

A

GPIIb/IIIa with fibrinogen as linker mlcl

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10
Q

what links platelets together?

A

fibrinogen links platelets via GpIIb/IIIa

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11
Q

clinical features of disorders of primary hemostasis (platelet disorders)

A

mucosal and skin bleeding -epistaxis (MC), hemoptysis, GI bleeding, hematuria, menorrhagia -intracranial bleeding if severe thrombocytopenia

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12
Q

what is the different types of skin bleeding

A

petechiae (1-2mm) 3mm) 1cm)

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13
Q

petechiae are a sign of what?

A

thrombocytopenia (seen when platelet count is low)

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14
Q

at what level of platelets do you get symptoms?

A

less than 50,000

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15
Q

MCC of thrombocytopenia in children and adults

A

ITP - immune thrombocytopenic purpura

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16
Q

what mediates the platelet destrxn in ITP?

A

anti-platelet IgG -produced by plasma cells in spleen -consumed by splenic macrophages

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17
Q

acute form of ITP?

A

-seen in children -usu occurs weeks after viral infxn or immunization -self-limited, provide supportive care

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18
Q

chronic form of ITP

A

-seen in women 20-50 yo -primary (idiopathic) or secondary (SLE) -can see transient thrombocytopenia in fetus, since IgG can cross placenta

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19
Q

Lab findings in ITP?

A

-low platelet count (

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20
Q

treatment of ITP

A
  1. corticosteroids (children respond well; adults can relapse afterwards) 2. IVIG - symptomatic treatment, but short-lived 3. splenectomy - performed in refractory cases
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21
Q

what is curative of ITP?

A

splenectomy

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22
Q

what is the basic mechanism in microangiopathic hemolytic anemia?

A

-formation of platelet microthrombi (platelets get consumed) -shearing of RBCs when trying to cross platelet microthrombi -get schistocytes and hemolysis

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23
Q

what are the 2 disorders that you see microangiopathic hemolytic anemia in?

A
  1. TTP - thrombotic thrombocytopenia purpura 2. HUS
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24
Q

what causes TTP?

A

decreased enzyme ADAMTS13 -normally cleaves vWF multimers into smaller monomers -without enzyme, get abnormal platelet adhesion -forms microthrombi

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25
Q

what causes enzyme defect in TTP?

A

-decreased ADAMTS13 is due to autoantibodies destroying it -can also be genetic (but rare) -seen in adult females (autoimmune)

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26
Q

what is HUS

A

hemolytic uremic syndrome -get endothelial damage from drugs or infxn -results in platelet microthrombi - shears rbc’s -microangiopathic hemolytic anemia -esp in the kidney (and brain)

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27
Q

what causes HUS and who gets it?

A

E.coli O157:H7 -usu seen in children after exposure to undercooked beef

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28
Q

what mediates the damage in HUS?

A

e. coli O157: H7 has a verotoxin that damages endothelium -esp in the kidney

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29
Q

what are the clinical features of TTP-HUS

A
  1. skin and mucosal bleeding 2. microangiopathic hemolytic anemia 3. fever 4. renal insufficiency (more common in HUS) 5. CNS abnormalities (more common in TTP)
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30
Q

lab findings in TTP-HUS

A
  1. thrombocytopenia (increased bleeding time) 2. normal PT/PTT 3. anemia with schistocytes 4. increased megakaryocytes on BM biopsy
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31
Q

treatment for TTP-HUS

A

more for TTP 1. plasmapheresis (remove autoAb) 2. corticosteroids (suppress prdxn of autoAb)

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32
Q

Bernard-Soulier Syndrome

A

genetic GP1b deficiency -platelet adhesion is impaired -mild thrombocytopenia with enlarged platelets

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33
Q

mild thrombocytopenia with enlarged platelets on blood smear?

A

Bernard-Soulier Syndrome “Big Suckers = Bernard Soulier”

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34
Q

Glanzmann thrombasthenia

A

genetic GPIIb/IIIa deficiency -platelet aggregation is impaired

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35
Q

aspirin inhibits what and reduces production of what mediator

A

-irreversibly inhibits COX -inhibits production of TXA2 - impairs plt aggregation

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36
Q

how does uremia affect platelet function?

A

uremia impairs both platelet adhesion and aggregation

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37
Q

coagulation factors are produced where?

A

liver (produced in inactive state, require activation)

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38
Q

what is the purpose of coagulation cascade?

A

to generate thrombin to convert fibrinogen to fibrin -stabilizes platelet plug -forms platelet-fibrin thrombus

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39
Q

what is required to activate coagulation factors?

A
  1. exposure to activating substance -tissue thromboplastin activates FVII (extrinsic) -subendothelial collagen activates FXII (intrinsic) 2. phospholipid surface (of platelets) 3. calcium (platelet dense granules)
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40
Q

clinical features of problems with secondary hemostasis (coagulation cascade)?

A

-deep tissue bleeding into muscles/joints (hemarthrosis) -rebleeding after surgical procedures

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41
Q

what activates extrinsic pathway?

A

tissue thromboplastin activates factor 7

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42
Q

what activates intrinsic pathway?

A

subendothelial collagen activates factor 12

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43
Q

how do you monitor intrinsic pathway?

A

PTT -activated by SEC - subendothelial collagen -used to monitor HEP - heparin activity

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44
Q

how do you monitor extrinsic pathway?

A

PT -activated by TT - tissue thromboplastin -used to monitor warfarin/coumadin

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45
Q

heparin acts on what? how do you monitor?

A

acts on intrinsic pathway -monitor with PTT

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46
Q

warfarin acts on what? how do you monitor?

A

acts on extrinsic pathway -monitor with PT/INR

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47
Q

Hemophilia A affects which factor?

A

Factor 8 deficiency

48
Q

Hemophilia A - inheritance pattern

A

X-linked recessive - more common in males -but arises de novo, don’t always need family hx

49
Q

Lab findings in hemophilia A

A
  1. increased PTT, normal PT 2. decreased factor VIII 3. normal platelet count and bleeding time
50
Q

treatment for hemophilia A

A

recombinant factor VIII

51
Q

Hemophilia B affects which factor?

A

factor 9 (aka Christmas Disease) -same lab findings as hemophilia A -tx: recombinant Factor IX

52
Q

What is coagulation factor inhibitor? what does it usu affect?

A

acquired antibody against coagulation factor MC - involves factor VIII (8) -clinical and lab similar to hemophilia A -must do mixing study to differentiate

53
Q

how do you differentiate Hemophilia A and Coagulation Factor Inhibitor

A

Mixing Study -mix normal plasma with patient’s plasma -PTT corrects in hemophilia A -DOES NOT correct in Coagulation Factor Inhibitor

54
Q

MC inherited coagulation disorder?

A

von Willebrand Disease

55
Q

most common inheritance pattern for vWF disease

A

autosomal dominant

56
Q

what happens in vWF disease?

A

-low levels of vWF -impairs platelet adhesion

57
Q

lab findings in vWF disease?

A
  1. increased bleeding time 2. increased PTT, normal PT (due to decreased F8 half-life) 3. abnormal ristocetin test - platelets don’t aggregate
58
Q

vWF usu stabilizes which factor?

A

factor 8

59
Q

ristocetin test

A

ristocetin induces platelet aggregation by causing vWF to bind Gp1b -abnormal test in vWF disease

60
Q

treatment for vWF disease?

A

desmopressin - stimulates release of vWF from weibel-palade bodies in endothelial cells

61
Q

vitamin K is activated by?

A

epoxide reductase in liver (warfarin inhibits) -produced in gut, goes to liver, gets activated

62
Q

factors dependent on vitamin K?

A

2, 7, 9, 10, protein C and S

63
Q

vitamin K does what to coag factors?

A

gamma-carboxylation of glutamic acid residue - which is necessary for factor function

64
Q

Vitamin K deficiency - 3 causes

A
  1. newborns (lack of GI colonization) 2. prolonged antibiotic therapy 3. malabsorption (fat-soluble vitamins)
65
Q

why does liver failure cause abnormal coagulation?

A
  1. decreased prdxn of coagulation factors 2. decreased activation of vitamin K by epoxide reductase -follow effect of liver failure by monitoring PT
66
Q

how does large volume transfusion cause coagulopathy?

A

-dilutes coagulation factors -results in relative deficiency

67
Q

HIT - heparin induced thrombocytopenia - heparin does what?

A

heparin complexes with platelet factor 4 (protein on platelets) -IgG autoantibodies against these complexes -spleen consumes

68
Q

what kind of autoantibodies are formed in HIT and against what?

A

IgG autoantibodies against platelet factor 4-heparin complexes

69
Q

what is a possible complication of HIT?

A

thrombosis -due to platelet fragments that embolize and activate other platelets

70
Q

HIT what should you also avoid and why?

A

avoid coumadin - higher risk for tissue necrosis

71
Q

what is DIC?

A

disseminated intravascular coagulation -pathologic activation of coag cascade -widespread microthrombi - ischemia and infarction -consumption of platelets and factors - bleeding from IV sites, mucosal surfaces, body orifices

72
Q

what causes DIC and how does it activate coag cascade?

A
  1. OB complxns - tissue thromboplastin in amniotic fluid 2. sepsis (e. coli/n.mening) - endotoxin from bacterial wall -also cytokines (TNF and IL-1) secreted by macrophages 3. adenocarcinoma (mucin) 4. acute promyelocytic leukemia (primary granules) 5. rattlesnake bite (venom)
73
Q

lab findings in DIC?

A
  1. low platelet count 2. high PT/PTT 3. low fibrinogen (
74
Q

best screening test for DIC?

A

D-dimer - if elevated

75
Q

what does plasmin do?

A
  1. cleaves fibrin and serum fibrinogen 2. destroys coag factors 3. blocks platelet aggregation
76
Q

how is plasmin made?

A

-plasminogen converted to plasmin by tPA -tPA - tissue plasminogen activator

77
Q

what inactivates plasmin?

A

alpha-2-antiplasmin

78
Q

what is the basic problem in disorders of fibrinolysis?

A

overactivation of plasmin -excessive cleavage of serum fibrinogen

79
Q

what are some causes of overactive plasmin and what triggers it?

A
  1. radical prostatectomy - release of urokinase activates plasmin 2. cirrhosis of liver - decreased prdxn of alpha-2-antiplasmin presents as increased bleeding (resembling DIC)
80
Q

lab findings in disorder of fibrinolysis (plasmin overactivation)

A
  1. increased PT/PTT (destroys coag factors) 2. increased bleeding time, normal platelet count - blocks platelet aggregation 3. increased fibrinogen split product (without D-dimer) - due to absent fibrin thrombi
81
Q

treatment for problems with fibrinolysis (plasmin overactivation)

A

aminocaproic acid - blocks activation of plasminogen

82
Q

what is the MC location of thrombosis?

A

deep veins of leg - DVT

83
Q

what distinguishes thrombosis from postmortem clot?

A
  1. Lines of Zahn (alternating layers of platelets/fibrin and RBCs) 2. attachment to vessel wall
84
Q

what are the 3 major risk factors for thrombosis? (Virchow’s Triad)

A
  1. disruption of blood flow 2. endothelial cell damage 3. hypercoagulable state
85
Q

how do endothelial cells prevent thrombosis?

A
  1. block exposure to subendothelial collagen & tissue factor 2. produces prostacyclin (PGI2) and NO - cause vasodilation and inhibit plt aggregation 3. secrete heparin-like mlcl (HLM) - augments anti-thrombin III (ATIII) - inactivates thrombin and coag factors 4. secretes tissue plasminogen activator (tPA) 5. secrete thrombomodulin - redirects thrombin to activate protein C (which inactivates FV and FVIII)
86
Q

what does protein C do?

A

when activated, inactivates factor V and factor VIII

87
Q

what are the causes of endothelial cell damage?

A
  1. atherosclerosis 2. vasculitis 3. high levels of homocysteine
88
Q

PGI2 and NO has what effect on platelets?

A

inhibits platelet aggregation (opposite of ADP and TXA2)

89
Q

buildup of homocysteine

A

seen in B12 and folate deficiency THF hands methyl off to B12, which then hands it off to homocysteine forming methionine -without B12 or folate - get buildup of homocysteine

90
Q

what is homocystinuria?

A

cystathione beta synthase (CBS) deficiency -results in high levels of homocysteine -unable to convert homocysteine to cystathione -s/s - vessel thrombosis, mental retardation, lens dislocation, long slender fingers

91
Q

what does protein C and protein S do?

A

inactivate factor V and factor VIII

92
Q

inheritance pattern of protein C or S deficiency

A

autosomal dominant -leads to hypercoagulable state

93
Q

why do you get tissue skin necrosis with protein C/S deficiency and warfarin?

A

warfarin - knocks out vitamin K - affecting F 2, 7, 9, 10, C and S -initial stage of warfarin tx - knocks out C and S first, due to shorter half life - causes transient hypercoagulable state (which is why we use heparin bridge) -if prexisiting deficiency of C or S, severe deficiency at onset of therapy - can result in thrombosis, esp in skin

94
Q

how does Factor V Leiden cause hypercoagulable state?

A

Factor V - normally inactivated by proteins C or S -Proteins C or S cleave Factor V at specific site -in FV Leiden - patients have mutation that prevents cleavage by protein C or S -results in overactive F V - hypercoagulable

95
Q

MCC of inherited coagulable state

A

Factor V Leiden - mutated form of factor V -lacks cleavage site for proteins C and S

96
Q

Prothrombin 20210A

A

-inherited point mutation in prothrombin -increased gene expression -increased prothrombin = increased thrombin -get thrombus formation

97
Q

ATIII deficiency

A

-decreases protective effect of heparin-like mlcls released by endothelial cells -increases risk for thrombus (NOTE if you give heparin in ATIII deficiency, PTT does not rise) HLM - normally activate ATIII - which inactivate thrombin and coag factors

98
Q

what happens when you give heparin to ATIII deficient patients?

A

PTT does not rise

99
Q

heparin works by?

A

activating antithrombin III - ATIII -which inactivates thrombin and coag factors

100
Q

how do you treat ATIII deficiency (how do you anticoagulate the patient)?

A

high doses of heparin given, to activate limited ATIII -then give coumadin to maintain anticoagulated state -once coumadin takes effect, stop heparin

101
Q

why do OCPs cause hypercoagulable state?

A

estrogen promotes production of coagulation factors

102
Q

what’s the most common type of embolus?

A

thromboembolus -thrombus forms, then embolizes

103
Q

what characterizes an atherosclerotic embolus?

A

cholesterol clefts in the embolus

104
Q

fat embolus

A

-seen with bone fractures (long bones) and soft tissue trauma -dyspnea & petechiae on skin overlying chest

105
Q

Decompression sickness

A

-nitrogen gas precipitates out of blood due to rapid ascent by diver -joint and muscle pain (“bends”) -respiratory symptoms (“chokes”)

106
Q

Caisson disease

A

chronic form of decompression sickness -nitrogen gas precipitates out into bones - get infarction -multifocal ischemic necrosis of bone

107
Q

how can you get gas embolus from surgery?

A

laproscopic surgery - pump gas into abdomen -can cause gas embolus

108
Q

amniotic fluid embolus

A

-embolus enters maternal circulation during labor/delivery -presents with SOB, neuro symptoms, DIC char’d by squamous cells, keratin debris in embolus

109
Q

what is histologic characteristic of amniotic fluid embolus

A

squamous cells and keratin debris in embolus -from fetal cells sloughing into amniotic fluid

110
Q

why does amniotic fluid embolus cause DIC?

A

amniotic fluid contains tissue thromboplastin -activates coagulation

111
Q

why are most PE’s clinically silent?

A
  1. lung has dual blood supply - pulmonary artery and bronchial artery 2. embolus is usually small (gets lysed)
112
Q

what is required for pulmonary infarction

A
  1. embolic obstruction in large or medium sized artery 2. pre-existing cardiopulmonary compromised
113
Q

clinical presentation of pulmonary infarction from PE?

A

SOB, hemoptysis, pleuritic chest pain, pleural effusion -V/Q mistmatch - perfusion is abnormal -spiral CT - shows vascular filling defect -LE doppler US - can detect DVT -D-dimer is elevated

114
Q

gross exam of PE shows what?

A

hemorrhagic, wedge-shaped infarct

115
Q

what causes sudden death in large PE?

A

saddle embolus that blocks both left and right pulmonary arteries -get electromechanical dissociation

116
Q

what is a complication of chronic pulmonary emboli?

A

pulmonary HTN

117
Q

what is the MC source of systemic emboli?

A

left heart (MC site is lower legs)