Pathoma Ch 4 - Hemostasis Flashcards
1
Q
what are the steps of primary hemostasis?
A
- transient vasoconstriction 2. platelet adhesion (Gp1b-vWF) 3. platelet degranulation 4. platelet aggregation (GpIIb/IIIa)
2
Q
what is the first response to endothelial cell injury?
A
transient vasoconstriction -mediated by neural reflex and endothelin released by endothelial cells
3
Q
what does vWF bind initially after endothelial cell injury?
A
subendothelial collagen
4
Q
platelets bind vWF on subendothelial collagen by which receptor?
A
GP1b receptor
5
Q
vWF derived from where?
A
Weibel-Palade bodies of endothelial cells and from alpha granules of platelets
6
Q
what does Weibel-Palade bodies contain? where are they?
A
vWF and P-selectin (found in endothelial cells)
7
Q
step 3 platelet degranulation releases what mediators?
A
ADP (dense granules) TXA2 - derivative of platelet cyclooxygenase
8
Q
what does ADP and TXA2 do?
A
ADP - promotes exposure of GpIIb/IIIa on platelets TXA2 - promotes platelet aggregation
9
Q
platelet aggregation via which receptor
A
GPIIb/IIIa with fibrinogen as linker mlcl
10
Q
what links platelets together?
A
fibrinogen links platelets via GpIIb/IIIa
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
12
Q
what is the different types of skin bleeding
A
petechiae (1-2mm) 3mm) 1cm)
13
Q
petechiae are a sign of what?
A
thrombocytopenia (seen when platelet count is low)
14
Q
at what level of platelets do you get symptoms?
A
less than 50,000
15
Q
MCC of thrombocytopenia in children and adults
A
ITP - immune thrombocytopenic purpura
16
Q
what mediates the platelet destrxn in ITP?
A
anti-platelet IgG -produced by plasma cells in spleen -consumed by splenic macrophages
17
Q
acute form of ITP?
A
-seen in children -usu occurs weeks after viral infxn or immunization -self-limited, provide supportive care
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
19
Q
Lab findings in ITP?
A
-low platelet count (
20
Q
treatment of ITP
A
- corticosteroids (children respond well; adults can relapse afterwards) 2. IVIG - symptomatic treatment, but short-lived 3. splenectomy - performed in refractory cases
21
Q
what is curative of ITP?
A
splenectomy
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
23
Q
what are the 2 disorders that you see microangiopathic hemolytic anemia in?
A
- TTP - thrombotic thrombocytopenia purpura 2. HUS
24
Q
what causes TTP?
A
decreased enzyme ADAMTS13 -normally cleaves vWF multimers into smaller monomers -without enzyme, get abnormal platelet adhesion -forms microthrombi
25
what causes enzyme defect in TTP?
-decreased ADAMTS13 is due to autoantibodies destroying it -can also be genetic (but rare) -seen in adult females (autoimmune)
26
what is HUS
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)
27
what causes HUS and who gets it?
E.coli O157:H7 -usu seen in children after exposure to undercooked beef
28
what mediates the damage in HUS?
e. coli O157: H7 has a verotoxin that damages endothelium -esp in the kidney
29
what are the clinical features of TTP-HUS
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)
30
lab findings in TTP-HUS
1. thrombocytopenia (increased bleeding time) 2. normal PT/PTT 3. anemia with schistocytes 4. increased megakaryocytes on BM biopsy
31
treatment for TTP-HUS
more for TTP 1. plasmapheresis (remove autoAb) 2. corticosteroids (suppress prdxn of autoAb)
32
Bernard-Soulier Syndrome
genetic GP1b deficiency -platelet adhesion is impaired -mild thrombocytopenia with enlarged platelets
33
mild thrombocytopenia with enlarged platelets on blood smear?
Bernard-Soulier Syndrome "Big Suckers = Bernard Soulier"
34
Glanzmann thrombasthenia
genetic GPIIb/IIIa deficiency -platelet aggregation is impaired
35
aspirin inhibits what and reduces production of what mediator
-irreversibly inhibits COX -inhibits production of TXA2 - impairs plt aggregation
36
how does uremia affect platelet function?
uremia impairs both platelet adhesion and aggregation
37
coagulation factors are produced where?
liver (produced in inactive state, require activation)
38
what is the purpose of coagulation cascade?
to generate thrombin to convert fibrinogen to fibrin -stabilizes platelet plug -forms platelet-fibrin thrombus
39
what is required to activate coagulation factors?
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)
40
clinical features of problems with secondary hemostasis (coagulation cascade)?
-deep tissue bleeding into muscles/joints (hemarthrosis) -rebleeding after surgical procedures
41
what activates extrinsic pathway?
tissue thromboplastin activates factor 7
42
what activates intrinsic pathway?
subendothelial collagen activates factor 12
43
how do you monitor intrinsic pathway?
PTT -activated by SEC - subendothelial collagen -used to monitor HEP - heparin activity
44
how do you monitor extrinsic pathway?
PT -activated by TT - tissue thromboplastin -used to monitor warfarin/coumadin
45
heparin acts on what? how do you monitor?
acts on intrinsic pathway -monitor with PTT
46
warfarin acts on what? how do you monitor?
acts on extrinsic pathway -monitor with PT/INR
47
Hemophilia A affects which factor?
Factor 8 deficiency
48
Hemophilia A - inheritance pattern
X-linked recessive - more common in males -but arises de novo, don't always need family hx
49
Lab findings in hemophilia A
1. increased PTT, normal PT 2. decreased factor VIII 3. normal platelet count and bleeding time
50
treatment for hemophilia A
recombinant factor VIII
51
Hemophilia B affects which factor?
factor 9 (aka Christmas Disease) -same lab findings as hemophilia A -tx: recombinant Factor IX
52
What is coagulation factor inhibitor? what does it usu affect?
acquired antibody against coagulation factor MC - involves factor VIII (8) -clinical and lab similar to hemophilia A -must do mixing study to differentiate
53
how do you differentiate Hemophilia A and Coagulation Factor Inhibitor
Mixing Study -mix normal plasma with patient's plasma -PTT corrects in hemophilia A -DOES NOT correct in Coagulation Factor Inhibitor
54
MC inherited coagulation disorder?
von Willebrand Disease
55
most common inheritance pattern for vWF disease
autosomal dominant
56
what happens in vWF disease?
-low levels of vWF -impairs platelet adhesion
57
lab findings in vWF disease?
1. increased bleeding time 2. increased PTT, normal PT (due to decreased F8 half-life) 3. abnormal ristocetin test - platelets don't aggregate
58
vWF usu stabilizes which factor?
factor 8
59
ristocetin test
ristocetin induces platelet aggregation by causing vWF to bind Gp1b -abnormal test in vWF disease
60
treatment for vWF disease?
desmopressin - stimulates release of vWF from weibel-palade bodies in endothelial cells
61
vitamin K is activated by?
epoxide reductase in liver (warfarin inhibits) -produced in gut, goes to liver, gets activated
62
factors dependent on vitamin K?
2, 7, 9, 10, protein C and S
63
vitamin K does what to coag factors?
gamma-carboxylation of glutamic acid residue - which is necessary for factor function
64
Vitamin K deficiency - 3 causes
1. newborns (lack of GI colonization) 2. prolonged antibiotic therapy 3. malabsorption (fat-soluble vitamins)
65
why does liver failure cause abnormal coagulation?
1. decreased prdxn of coagulation factors 2. decreased activation of vitamin K by epoxide reductase -follow effect of liver failure by monitoring PT
66
how does large volume transfusion cause coagulopathy?
-dilutes coagulation factors -results in relative deficiency
67
HIT - heparin induced thrombocytopenia - heparin does what?
heparin complexes with platelet factor 4 (protein on platelets) -IgG autoantibodies against these complexes -spleen consumes
68
what kind of autoantibodies are formed in HIT and against what?
IgG autoantibodies against platelet factor 4-heparin complexes
69
what is a possible complication of HIT?
thrombosis -due to platelet fragments that embolize and activate other platelets
70
HIT what should you also avoid and why?
avoid coumadin - higher risk for tissue necrosis
71
what is DIC?
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
what causes DIC and how does it activate coag cascade?
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
lab findings in DIC?
1. low platelet count 2. high PT/PTT 3. low fibrinogen (
74
best screening test for DIC?
D-dimer - if elevated
75
what does plasmin do?
1. cleaves fibrin and serum fibrinogen 2. destroys coag factors 3. blocks platelet aggregation
76
how is plasmin made?
-plasminogen converted to plasmin by tPA -tPA - tissue plasminogen activator
77
what inactivates plasmin?
alpha-2-antiplasmin
78
what is the basic problem in disorders of fibrinolysis?
overactivation of plasmin -excessive cleavage of serum fibrinogen
79
what are some causes of overactive plasmin and what triggers it?
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
lab findings in disorder of fibrinolysis (plasmin overactivation)
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
treatment for problems with fibrinolysis (plasmin overactivation)
aminocaproic acid - blocks activation of plasminogen
82
what is the MC location of thrombosis?
deep veins of leg - DVT
83
what distinguishes thrombosis from postmortem clot?
1. Lines of Zahn (alternating layers of platelets/fibrin and RBCs) 2. attachment to vessel wall
84
what are the 3 major risk factors for thrombosis? (Virchow's Triad)
1. disruption of blood flow 2. endothelial cell damage 3. hypercoagulable state
85
how do endothelial cells prevent thrombosis?
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
what does protein C do?
when activated, inactivates factor V and factor VIII
87
what are the causes of endothelial cell damage?
1. atherosclerosis 2. vasculitis 3. high levels of homocysteine
88
PGI2 and NO has what effect on platelets?
inhibits platelet aggregation (opposite of ADP and TXA2)
89
buildup of homocysteine
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
what is homocystinuria?
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
what does protein C and protein S do?
inactivate factor V and factor VIII
92
inheritance pattern of protein C or S deficiency
autosomal dominant -leads to hypercoagulable state
93
why do you get tissue skin necrosis with protein C/S deficiency and warfarin?
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
how does Factor V Leiden cause hypercoagulable state?
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
MCC of inherited coagulable state
Factor V Leiden - mutated form of factor V -lacks cleavage site for proteins C and S
96
Prothrombin 20210A
-inherited point mutation in prothrombin -increased gene expression -increased prothrombin = increased thrombin -get thrombus formation
97
ATIII deficiency
-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
what happens when you give heparin to ATIII deficient patients?
PTT does not rise
99
heparin works by?
activating antithrombin III - ATIII -which inactivates thrombin and coag factors
100
how do you treat ATIII deficiency (how do you anticoagulate the patient)?
high doses of heparin given, to activate limited ATIII -then give coumadin to maintain anticoagulated state -once coumadin takes effect, stop heparin
101
why do OCPs cause hypercoagulable state?
estrogen promotes production of coagulation factors
102
what's the most common type of embolus?
thromboembolus -thrombus forms, then embolizes
103
what characterizes an atherosclerotic embolus?
cholesterol clefts in the embolus
104
fat embolus
-seen with bone fractures (long bones) and soft tissue trauma -dyspnea & petechiae on skin overlying chest
105
Decompression sickness
-nitrogen gas precipitates out of blood due to rapid ascent by diver -joint and muscle pain ("bends") -respiratory symptoms ("chokes")
106
Caisson disease
chronic form of decompression sickness -nitrogen gas precipitates out into bones - get infarction -multifocal ischemic necrosis of bone
107
how can you get gas embolus from surgery?
laproscopic surgery - pump gas into abdomen -can cause gas embolus
108
amniotic fluid embolus
-embolus enters maternal circulation during labor/delivery -presents with SOB, neuro symptoms, DIC char'd by squamous cells, keratin debris in embolus
109
what is histologic characteristic of amniotic fluid embolus
squamous cells and keratin debris in embolus -from fetal cells sloughing into amniotic fluid
110
why does amniotic fluid embolus cause DIC?
amniotic fluid contains tissue thromboplastin -activates coagulation
111
why are most PE's clinically silent?
1. lung has dual blood supply - pulmonary artery and bronchial artery 2. embolus is usually small (gets lysed)
112
what is required for pulmonary infarction
1. embolic obstruction in large or medium sized artery 2. pre-existing cardiopulmonary compromised
113
clinical presentation of pulmonary infarction from PE?
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
gross exam of PE shows what?
hemorrhagic, wedge-shaped infarct
115
what causes sudden death in large PE?
saddle embolus that blocks both left and right pulmonary arteries -get electromechanical dissociation
116
what is a complication of chronic pulmonary emboli?
pulmonary HTN
117
what is the MC source of systemic emboli?
left heart (MC site is lower legs)
