Coagulation Flashcards
1
Q
Main actor in primary hemostasis
A
platelets
2
Q
Main actor in primary hemostasis
A
platelets
3
Q
Main actor in secondary hemostasis
A
fibrin
4
Q
First phenomenon observable at damaged vessel
A
transient vasoconstriction, mediated by:
1) reflex neural stimulation
2) endothelin release
5
Q
How does platelet adhesion occur (3 steps)
A
1) vWF is released from Weibel-Palade bodies and PLT α-granules
2) vWF binds exposed subendothelial collagen
3) PLT GP1b binds vWF
6
Q
How does platelet activation occur? (3 steps)
A
1) Adhesion induces PLT shape-change
2) PLTs release ADP from dense granules, promoting GPIIb/IIIa expression
3) PLTs produce TXA2 with COX, promoting aggregation
4) PLTs release Ca+2, enabling coagulation cascade
7
Q
How does platelet aggregation occur?
A
GPIIb/IIIa binds fibrinogen, crosslinking PLTs
8
Q
Aspirin in primary hemostasis
A
Inhibits COX → ↓TXA2
9
Q
Drugs that inhibit ADP-signaling in PLTs
A
Clopidogrel, prasugrel, ticlopidine (inhibits GPIIb/IIIa expression)
10
Q
Drugs that directly inhibit GPIIb/IIIa
A
Abciximab, eptifibatide, tirofaban
11
Q
Ristocetin mechanism
A
Causes vWF to bind GPIIb/IIIa
12
Q
Failure to aggregate in ristocetin assay occurs in
A
von Willebrand disease and Bernard-Soulier syndrome
13
Q
Clinical features in disorders of primary hemostasis (8)
A
Mucosal bleeding:
1) Intracranial bleeding (most important)
2) Epistaxis (most common)
3) Others: menorrhagia, hematuria, GI bleeds, hemoptysis
Skin bleeding:
1) petechiae, purpura, ecchymosis
2) easy bruising
14
Q
petechiae are usually seen in ______ PLT disorders
A
Quantitative
15
Q
PLT count at which Sxs are seen
A
16
Q
Most common cause of thrombocytopenia in children and adults?
A
ITP
17
Q
Pathogenesis of ITP
A
Anti-GPIIb/IIIa antibodies cause PLT destruction in spleen
18
Q
Causes of ITP?
A
Acute: viral infection, immunization
Chronic: SLE or idiopathic in women of childbearing age
19
Q
Complication associated with ITP in pregnancy
A
Transient thrombocytopenia in newborn (IgG crosses placenta)
20
Q
Tx of ITP
A
1) Corticosteroids (less long term effectiveness in adults)
2) IVIG
3) Splenectomy (refractory)
21
Q
Tx of ITP
A
1) Corticosteroids (less long term effectiveness in adults)
2) IVIG
3) Splenectomy (refractory)
22
Q
Main actor in secondary hemostasis
A
fibrin
23
Q
First phenomenon observable at damaged vessel
A
transient vasoconstriction, mediated by:
1) reflex neural stimulation
2) endothelin release
24
Q
How does platelet adhesion occur (3 steps)
A
1) vWF is released from Weibel-Palade bodies and PLT α-granules
2) vWF binds exposed subendothelial collagen
3) PLT GP1b binds vWF
25
How does platelet activation occur? (3 steps)
1) Adhesion induces PLT shape-change
2) PLTs release ADP from dense granules, promoting GPIIb/IIIa expression
3) PLTs produce TXA2 with COX, promoting aggregation
4) PLTs release Ca+2, enabling coagulation cascade
26
How does platelet aggregation occur?
GPIIb/IIIa binds fibrinogen, crosslinking PLTs
27
Aspirin in primary hemostasis
Inhibits COX → ↓TXA2
28
Drugs that inhibit ADP-signaling in PLTs
Clopidogrel, prasugrel, ticlopidine (inhibits GPIIb/IIIa expression)
29
Drugs that directly inhibit GPIIb/IIIa
Abciximab, eptifibatide, tirofaban
30
Ristocetin mechanism
Causes vWF to bind GPIIb/IIIa
31
Failure to aggregate in ristocetin assay occurs in
von Willebrand disease and Bernard-Soulier syndrome
32
Clinical features in disorders of primary hemostasis (8)
Mucosal bleeding:
1) Intracranial bleeding (most important)
2) Epistaxis (most common)
3) Others: menorrhagia, hematuria, GI bleeds, hemoptysis
Skin bleeding:
1) petechiae, purpura, ecchymosis
2) easy bruising
33
petechiae are usually seen in ______ PLT disorders
Quantitative
34
PLT count at which Sxs are seen
Less than 50
35
Most common cause of thrombocytopenia in children and adults?
ITP
36
Pathogenesis of ITP
Anti-GPIIb/IIIa antibodies cause PLT destruction in spleen
37
Causes of ITP?
Acute: viral infection, immunization
Chronic: SLE or idiopathic in women of childbearing age
38
Complication associated with ITP in pregnancy
Transient thrombocytopenia in newborn (IgG crosses placenta)
39
Lab findings in ITP (4)
1) ↓ PLT
2) NL PT/PTT
3) ↑ BT
4) ↑ Megakaryocytes in marrow
40
Tx of ITP
1) Corticosteroids (less long term effectiveness in adults)
2) IVIG
3) Splenectomy (refractory)
41
Schistocytes on smear imply
microangiopathic hemolytic anemia
42
Cause of thrombocytopenia in Microangiopathic Hemolytic Anemia
Consumption of platelets in microthrombus formation
43
Anti-ADAMTS13 antibodies are seen in
Thrombotic Thrombocytopenic Purpura
44
Pathogenesis of TTP
Acquired anti-ADAMTS13 antibody prevents cleavage of vWF multimers → hypercoagulability
45
Pathogenesis of HUS
EHEC expresses shiga-like toxin → glomerular endothelial damage → microthrombus formation
46
Labs in TTP (6)
1) ↓PLT
2) NL PT/PTT
3) ↑LDH
4) ↑BT
5) Schistocytes
6) ↑Megakaryocytes in marrow
47
Labs in HUS (6)
1) ↓PLT
2) NL PT/PTT
3) ↑LDH
4) ↑BT
5) Schistocytes
6) ↑Megakaryocytes in marrow
48
Clinical findings in HUS and TTP
1) Skin and mucosal bleeding
2) Hemolytic anemia
3) Fever
4) Renal insufficiency (more in HUS)
5) CNS abnormalities (more in TTP)
49
Complications in FV Leiden
1) DVT
2) cerebral vein thrombosis
3) recurrent pregnancy loss
50
Pathogenesis in Bernard-Soulier syndrome
Congenital GPIb deficiency → defect in primary hemostasis
51
Smear findings in Bernard-Soulier syndrome
Enlarged platelets: splenic destruction of dysfunction platelets → compensatory marrow hyperplasticity → immature platelets in circulation
52
Lab findings in Bernard-Soulier syndrome
1) ↓/NL PLT
2) ↑BT
3) No aggregation in Ristocetin assay
53
Tx in TTP
plasmapheresis, steroids
54
Pathogenesis in Glanzmann thrombasthenia
Genetic GPIIb/IIIa deficiency → defective platelet aggregation
55
Labs in Glanzmann thrombasthenia
1) NL PLT
2) ↑BT
3) Aggregation on Ristocetin assay
56
Chemical agents causing defective primary hemostasis
Aspirin (aggreagation)
| Uremia (aggregation and adhesion)
57
Activation of extrinsic pathway requires
1) TF and FVII
2) Platelet phospholipid surface
3) Calcium (dense granules)
58
Activation of intrinsic pathway requires
1) Subendothelial collagen and FXII
2) Platelet phospholipid surface
3) Calcium (dense granules)
59
Extrinsic pathway
1) TF:FVIIa
2) → FVa:FXa
3) → Thrombin (FII)
4) → FVIIIa:FIXa
5) → ↑ FVa:FXa
6) → ↑↑ Thrombin
7) → fibrin
8) Fibrin crosslinking via FXIII
60
Intrinsic pathway
1) Subendothelial collagen → XIIa
2) → XIa
3) → FVIIIa:FIXa
4) → FVa:FXa
5) → Thrombin (FII)
6) → fibrin
7) Fibrin crosslinking via FXIII
61
Vitamin K dependent coagulation factors
II, VII, IX, X, C, S
62
t(1/2) of FVIII is dependent on
binding to vWF
63
Protein C pathway
1) Activated by thrombin:thrombomodulin complex
2) complexes with protein S
3) Inactivates FVa, VIIIa
64
Activation of vit K dependent coagulation factors
1) VitK -[epoxide reductase]→ Reduced VitK
| 2) Precursors -[Reduced VitK, γ-glutamyl transferase]→ mature factors
65
Mechanism of Warfarin action
Inhibits epoxide reductase
66
Cause of heparin induced thrombocytopenia
Heparin binds PF-4 on PLT surface → antibodies bind complex → splenic destruction of PLTs
PLT fragments may activate coagulation and cause thrombosis
67
Cause of hypocoagulability in newborns
Lack enteric flora, which produce vit K
68
Lab findings in DIC
1) ↑ D-dimers
2) Schistocytes
3) ↓PLTs
4) ↑PT/PTT
5) ↓ fibrinogen, FV, FVIII
69
Tx in DIC
Frozen plasma
70
Causes of antithrombin deficiency
1) inherited
| 2) Renal failure (loss to urine)
71
Labs in antithrombin deficiency
1) PT/PTT NL
| 2) PTT following thrombin less increased than expected
72
Thrombotic skin necrosis and hemorrhage after Warfarin administration may be observed in
Protein C or S deficiency
73
Deficiency in Hemophilia A
FVIII; X-linked
74
Deficiency in Hemophilia B
FIX; X-linked
75
Deficiency in Hemophilia C
FXI; autosomal recessive
76
PT measures
Extrinsic pathway
77
PTT measures
Intrinsic pathway
78
Lab findings in hemophilia
1) ↑PTT, NL PT
| 2) NL PLT
79
Tx in hemophilia
1) Desmopressin
| 2) Deficient factor concentrate
80
Hemophilia presentation
1) Easy bruising
2) Bleeding after surgery
3) Hemarthrosis
81
Autoimmune disease with similar findings to Hemophilia A
Anti-FVIII antibody
82
Lab distinguishing FVIII inhibitor from Hemophilia A
1) Inhibitor: Mixing normal plasma with patient plasma does not correct PTT
2) Hemophilia A: mixing study corrects PTT
83
von Willebrand Disease defect
vWF deficiency; most commonly autosomal dominant
84
Labs in von Willebrand disease
1) NL PT/↑PTT (due to ↓FVIII)
| 2) No aggregation on ristocetin screen
85
Tx in von Willebrand disease
Desmopressin
86
Cause of heparin induced thrombocytopenia
Heparin binds PF-4 on PLT surface → antibodies bind complex → splenic destruction of PLTs
PLT fragments may activate coagulation and cause thrombosis
87
Common causes of DIC (7)
1) Obstetric complications (amniotic TF)
2) Sepsis (esp. E Coli/N meningitidis)
3) Adenocarcinoma (Mucin)
4) APL (abnormal primary granules)
5) Rattlesnake bite
6) Nephrotic syndrome (loss of ATIII)
7) Pancreatitis
88
Lab findings in DIC
1) ↑ D-dimers
2) Schistocytes
3) ↓PLTs
4) ↑PT/PTT
5) ↓ fibrinogen, FV, FVIII
89
Tx in DIC
Frozen plasma
90
Plasmin pathway
1) Activated by tPA
2) cleaves fibrin and fibrinogen, destroys coag factors, blocks PLT aggregation
3) inactivated by α2-antiplasmin
91
Causes of plasmin overactivity
1) Radical prostatectomy (uPA release)
| 2) Liver cirrhosis (↓ α2-antiplasmin)
92
Labs in plasmin overactivity
1) ↑ PT/PTT (loss of plasma factors)
2) ↑ BT
3) NL PLT
4) 0 D dimers
93
Tx in plasmin overactivity
aminocaproic acid
94
Features distinguishing postmortem clot from thrombus
1) Lines of Zahn
| 2) Attachement to vessel wall
95
Mechanisms by which endothelial cells prevent clotting (5)
1) Conceal subendothelial collagen and TF
2) Production of PGI2 and NO
3) Secretion of heparin-like molecules
4) Secretion of tPA
5) Secretion of thrombomodulin
96
Mechanism of ↑ thrombosis risk in B12/folate deficiency
Elevated homocysteine damages endothelial cells
97
Findings in Cystathione β Synthase deficiency
CBS deficiency inhibits conversion of homocysteine into cystathione, →
1) Homocysteinuria
2) Vessel thrombosis
3) mental retardation
4) lens dislocation
5) long, slender fingers
98
Prothrombin 20210A
Point mutation increasing expression of prothrombin → hypercoagulable state
99
Effects of oral contraceptives on coagulation
Estrogen increases coagulation factor production → hypercoagulable state
100
Histological finding in atherosclerotic embolus
cholesterol clefts
101
Dyspnea and petechiae on skin overlying the chest following trauma
Fat embolus
102
Caisson disease
Chronic decompression sickness, characterized by multifocal ischemic necrosis of the bone
103
Histological findings in amniotic fluid embolus
squamous cells and keratin debris
104
Cause of sudden death in PE
R heart pumping against complete occlusion
105
Packed RBCs: effect
↑ Hb and O2 carrying capacity
106
Packed RBCs: use
acute blood loss, severe anemia
107
Platelet transfusion: use
Stop bleeding in thrombocytopenia/PLT defects
108
Fresh frozen plasma: effect
↑ Coagulation factor levels
109
Fresh frozen plasma: use
DIC, cirrhosis, warfarin reversal
110
Cryoprecipitate: contains
Fibrinogen
FVIII, FXIII
vWF
Fibronectin
111
Electrolyte imbalances caused by blood transfusion
Hypocalcemia (chelated by citrate, anticoagulant)
Hyperkalemia (lysed RBCs)
iron overload
112
Conditions causing appropriate absolute polycythemia (3)
Lung Dz
Congenital heart disease
High altitude
113
Unfractionated heparin mechanism
Binds ATIII, increasing irreversible inhibition of clotting factors, esp. FII and FX
114
Heparin clinical use (4)
1) DVT prophylaxis
2) PE prophylaxis and acute Tx
3) Acute MI
4) Pregnancy (doesn't cross placenta)
115
Heparin adverse affects (4)
1) Bleeding
2) HIT
3) Osteoporosis
4) Hyperkalemia (aldosterone suppression)
116
Pathogenesis of heparin induced thrombocytopenia
IgG antibodies against heparin-PF4 complex → PLT destruction and hypercoagulability
117
Reversal of heparin
Protamine sulfate (unfractionated only)
118
Heparin monitoring is done via
PTT
119
Differences between LMWH and unfractionated heparin (6)
1) Action at FX only
2) Longer half-life
3) Renal elimination
4) Cannot be monitored via PTT
5) Lower HIT risk
6) Not reversible by protamine sulfate
120
Tx in HIT
DC heparin, start direct thrombin inhibitors (e.g. bivalirudin, argatroban/dabigatran)
121
Direct thrombin inhibitors
Bivalirudin
| Argatroban/Dabigatran
122
Direct FXa inhibitors
Apixaban, rivaroxaban
123
Clinical use of Direct FXa Inhibitors
Tx/prophylaxis for DVT and PE
| Prophylaxis in A-fib
124
Warfarin MOA
inhibits vitamin K epoxide reductase →↓ production of FII, VII, IX, X, C, S
125
Warfarin monitoring is done via
PT/INR
126
First factors affected by Warfarin
C, S, VII
127
INR goal in most warfarin therapy
2 - 3
128
Warfarin use
Chronic anticoagulation (esp. DVT and A-Fib prophylaxis)
129
Rxn inhibited by warfarin
γ-carboxylation
130
Pathogenesis and Tx of warfarin induced skin necrosis
Transient hypercoagulable state caused by loss of Protein C/S
Prevent w/heparin bridge
131
time to onset of Warfarin effects
8-12 hours
132
Warfarin reversal
```
Vit K (delayed)
FFP (immediate)
```
133
Warfarin in pregnancy
Teratogenic
134
Warfarin elimination
Hepatic - CyP450
135
Warfarin route of administration
oral
136
Heparin route of administration
IV/SC
137
Site of warfarin action
Liver
138
ADP receptor inhibitors (4)
1) Clopidogrel
2) prasugrel
3) ticagrelor
4) ticlopidine
139
Ticagrelor: difference from other ADP receptor inhibitors
Allosteric binding site; reversible inhibition
140
ADP receptor inhibitors MOA
Irreversibly (or reversibly - ticagrelor) inhibits P2Y12 → ↓GPIIb/IIIa expression
141
Adverse effects of ADPr inhibitors (2)
Neutropenia (ticlopidine)
| TTP
142
Use of ASA/ADPr inhibitor therapy (3)
1) Prophylaxis in PAD/CAD/Cerebrovascular disease
2) Prophylaxis for coronary stent thrombosis (dual therapy)
3) Acute MI (chewable aspirin)
143
ASA mechanism
irreversibly inhibits COX-1 and COX-2 by acetylation → ↓TXA2
144
Substances released in PLT degranulation (3)
TXA2, ADP, 5-HT
145
ASA adverse effects
"Pseudo-allergy" due to ↑LT synthesis
146
Phosphodiesterase inhibitors (2)
cilostazol, dipyridamole
147
Phosphodiesterase inhibitor MOA
↑cAMP in PLTs → inhibition of PLT aggregation; vasodilation
148
Phosphodiesterase inhibitor Use (4)
1) Intermittent claudication
2) Coronary vasodilation
3) Angina prophylaxis
4) Stroke/TIA prophylaxis
149
Phosphodiesterase inhibitor adverse effects (3)
1) Coronary steal
2) Flushing, hypotension
3) Abdominal pain
150
GPIIb/IIIa inhibitors (3)
ABCiximab
eptiFIBatide
tiroFIBan
151
GPIIb/IIIa inhibitor MOA
bind GPIIb/IIIa, preventing aggregation
152
GPIIb/IIIa inhibitor use (2)
1) Unstable angina
| 2) Percutaneous transluminal angioplasty
153
GPIIb/IIIa inhibitor adverse effects (2)
Thrombocytopenia, bleeding
154
Fibrinolytics (4)
tPA (alteplase)
rPA (reteplase)
TKA-tPA (tenecteplase)
Streptokinase
155
Fibrinolytic MOA
Aid conversion of plasminogen to plasmin
156
Fibrinolytics clinical use (3)
1) Ischemic stroke (3 - 4.5 hrs after Sxs appear)
2) Acute MI (if PCI not available w/in 2 hours)
3) Severe PE/DVT
157
Fibrinolytics: contraindications (4)
1) Severe HTN
2) Head trauma or intracranial bleeding
3) Recent surgery
4) Hypocoagulability disorders
158
Tx of bleeding as a result of fibrinolytic therapy
1) Aminocaproic acid
2) Tranexamic acid
3) Cryoprecipitate
4) FFP
159
Labs in fibrinolytic therapy
1) ↑ D-dimers
| 2) ↑ PT/PTT
160
Adverse effects in fibrinolytic therapy
1) Bleeding (esp intracranial)
| 2) Anaphylaxis (streptokinase)
