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2

What activates platelets

adhesion with vWF, binding thrombin, ADP, TxA2

3

Molecule stored in platelet granules

ADP, fibrinogen, VWF, calcium

4

Glanzmann's thrombasthenia

platelets fail to expres 2 proteins for firbinogen receptor Integrin a2bb3

8

Thrombi

Thrombi

9

common location venus thrombi

around the valve in the vein

10

2 identifying features of thrombus

lines of zahn and site of attachment to vessel wall

11

postmortem clot layers

very red layer - current jelly and gelatinous yellow layer - chicken fat

13

Inherited Bleeding Disorders

Inherited Bleeding Disorders

14

factor for hemophilia A

8a

15

Factor for hemophilia B

9a

16

Glanzmann thrombasthenia clinical symptoms

easy brusing, epistaxis, Menorrhagia

17

Dual function Von Willebrand factor

platelet adhesion to endothelium. binds and carries coagulation factor 8 in plasma

18

Weibel-Palade bodies

storage granules in endothelial cells that store VWF and P-selecten

19

VWF central role in which disease

microcirculatory occlusions in thrombotic thrombocytopenic purpura

20

What proteolyzes VWF

ADAMTS13

21

VWF disorder inheritance pattern

autosomal dominant

22

VWF disorder typical bleeding

brusiing, bleeding after surgery, dental procedures

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VWF disorder locations without bleeding

No muscle or joint bleeding

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VWF disoder type 1

decreased amounts of normal

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VWF disorder type 2

decreased amounts abnormal

26

VWF disorder type 3

severely decreased concentration and activity

27

VWF disorder functional measure

Use Ristocetin co-factor activity

28

VWF disorder multimer analysis

Type 1 has normal gel with less of everything. Type 2 has abnormal gel bc actual protein is messed up

29

PT and aPTT in VWF disorder

PT normal. aPTT can be abnormal if factor 8 levels are affected

30

VWF disorder treatment DDAVP

this causes release of vWF from endothelial storage sites.

31

VWF disorder treatment plasma

Plasma from factor 8 concentrates with vWF activity

32

VWF disorder treatment alternatives

provide anti-fibrolytic agents and simple pressure, ice etc.

33

hemophilia delayed bleeding

happens because platelets are functioning normally but can't produce fibrin well so clot dissolves

34

Hemophilia common bleed sites

Joints, knees, elbows, shoulders, ankles, hips

35

Hemophilia PT aPTT

Prolonged aPTT

36

Why can't you measure factor 9 at birth

Factor 9 always low at birth so cannot diagnose neonatal Hemophilia B

37

Primary vs Secondary Prophylaxis Hemophilia

Provide factor infusion before or after first joint bleeds

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3 Treatment options Hemophilia

Plasma from factor concentrates, recombinant factor, Factor 7 recombinant to bypass the problems

40

Acquired Disorders

Acquired disorders

41

Which factor used to compare liver vs vitamin K problems

Factor 5 bc it is not vitamin K dependent. Helps diagnose long PT

42

Factor 8 response in liver disease

not affected the same. Often elevated bc not made by hepatocytes

43

thrombophlebitis

thrombosis and inflammation in veins near the skin. Can happen w thrombosis from adenocarcinomas

44

DIC initiation hypothesis

exposure of blood to tissue factor

45

lupus anticoagulant effect

causes artificial elongation of aPTT in vitro bc binding to phospholipids.

46

DIC bleeding vs thrombosis

Bleeding normally in acutely ill patients. Thrombosis classic with cancer

47

DIC PT aPTT

both elongated. aPTT less sensitive than PT

48

DIC significant lab

platelet counts are low. prsenece of fibrin degredation (D-dimers).

49

DIC cell pathology

RBC fragments (schistocytes) and thrombocytopenia bc mciroangiopathic hemolytic anemia.

50

Schistocytes

RBC fragments

51

Factor 13 function

cross-links fibrin. Need this before you get D dimers

53

DIC w cancer treatment

heparin to inhibit coagulation

54

DIC bleeding treatment

provide FFP, fibrinogen cryoprecipitate and platelet transfusion

55

antiphospholipid antibodies

includes lupus. some bind to phospholipids, others bind to phospholipid assocated proteins

56

Antiphospholipid antibody syndrome requirements

presence of antibodies at least 2 occasions w Thrombosis, pregnancy morbidity, or thrombocytopenia

57

5 Hereditary Thrombophilias

Factor 5 leiden, prothrombin mutation, protein c deficiency, protein s deficiency, antithrombin deficiency

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Most important risk of hereditary thrombophilias

increased risk of venous thromboembolism or VTE

59

heparin mechanism

imrpoves anticoagulant activity of AT

60

Antithrombin deficiency genetics

autosomal dominant

61

antithrombin deficiency Type 2 groups

Thrombin binding site defects, heparin binding site defects, defects affecting thrombin and heparain binding

62

AT deficiency assays

antigen assay measure AT levels. Functional assays measure ability to neutralize thrombin and FXa

63

AT function

forms complexes and inhibits thrombin and FXa

64

Protein C activation

Pro form activated by thrombin that is bound to thrombomodulin on endothelial surface

65

Protein S function

Protein S improves function of activated protein C

66

Protein C function

lyses coagulation factors Va and VIIIa

67

Protein C type 1 and type 2 deficiency

Again has to do with total amount and then total function

68

Protein S, 3 Types

Type 1 = amount, type 2 = functional abnormal, type 3 = normal total levels but reduced functional

69

Protein S carrier

half unbound and half bount to C4-binding protein

70

Neonatal Purpura fulminans

severe homozygous protein C deficiency. Purpura and necrosis

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Neonatal purpura fulminans treatment

anticoagulation and protein C

72

Warfarin induced skin necrosis

Half life of different factors causes initial increased clotting

73

Vitamin K protiens

2,7,9,10 and Protein C adn Protein S

74

Vitamin K protein degredation rate

Protein C,S and factor 7 decline slower than the 2,9,10

75

Warfarin induced skin necrosis mechanism

thrombotic imbalance leads to cutaneous vessel thrombosis = purpuric and necrtoic skin lesions

76

Factor V leiden mechanism

point mutation making factor 5 unaffected by Activated protein C

77

Factor 5 leidin genetics

autosomal dominant

78

Prothrombin mutation mechanism

change in a non-coding region making mRNA more stable and higher levels of prothrombin

79

prothrombin mutation effect

increased levels of prothrombin and significant increase risk of clot

80

post VTE treatment length

3-6 months of anticoagulation

81

best indicator of risk for VTE

having a previous VTE. tips balance away from testing for Hereditary thromphilias

83

Anticoagulant and Antiplatelet agents

anticoagulant and antiplatelet agents

84

Anticoagulants

inhibit thrombin or 10a or decrease levels of prothrombin and other zymogens

85

fibrinolytic agents

degrade existing clots

86

antiplatelet agents

inhibit platelet plug formation

87

Anticoagulant list

unfractionated heparin, lmw heparin, direct inhibitors of thrombin/factor10a, coumadin

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proteins inactivated by unfractionated heparin

2a, 10a, 9a, 11a, 12a

89

Large heparain useful because

have the long pentasaccharide sequence to help inhibit thrombin and factor 10a

90

Unfractionated heparin usage issues

short half-life that is variable. Have peaks and troughs in administration. Only IV leads to steady state levels

91

Unfractionated Heparin uses

acute thromboembolism, prevent thromboembolism, maintain a coronary artery bypass graft

92

unfractionated heparin significant toxicity

osteoporosis, and HIT

93

Heparin induced thrombocytopenia with thrombosis

heparin/PF4 complex binds to platelet Fc. Causes platelet aggregation and destruction. So get thrombocytopenia with thrombosis of platelets being aggregated

94

Test used to monitor unfractionated heparin

use aPTT - want 1.5-2x baseline

95

LMW heparin target

affects 10a more than 2a. Does not affect aPTT as much

96

LMW heparin benefits

half-life longer. less beleding and thrombocytopenia

97

Direct thrombin inhibitors

Lepirudin and Argatroban

98

Lepirudin

recombinant hirudin. for HIT and thrombi prevention after surgery. Renal excretion. comes from active ingredient used by leeches. IV USE

99

Argatroban

active site inhibitor, hepatic excretion IV USE

100

Factor 10a inhibitors

Rivaroxiban, Apixaban, Fondaparinux (indirect)

101

Thrombin 2a inhibitors

Dabigatran (direct) renal excretion

102

Rivaroxiban

Factor 10a inhibitor

103

Apixaban

Factor 10a inhibitor

104

Fondaparinux

Indirect factor 10a inhibitor

105

Dabigatran

Direct 2a inhibitor

106

Warfarin mechanism

inhibits re-use of vitamin K

107

Vitamin K purpose

Vitamin K carboxylation of glutamate

108

Warfarin in the body

bound to albumin

109

Warfarin degraded by

P450

111

International normalized ratio

(Patient PT/average control PT)^ISI

112

Coumadin in first trimester

causes an embryopathy

113

Limitation of oral factor 10 and 2 inhibitors

no quick reversing mechanism currently

114

Fibrinolytic agents

Fibrinolytic Agents

115

Plasmin function

cleaves fibrinogen and fibrin

116

Plasminogen activators

Streptokinase, urokinase, recombinant t-PA

117

Plasminogen activator contradiction

some trauma or surgery that puts you at risk of bleeding or massive hemorrhage

118

Antiplatelet agents

ADP, thrombin receptor antagonists, aspirin, dipyridamole, integrin blockers

119

Platelet receptor blockers

Clopidogrel (plavex) nad Vorapaxar (SCH530348)

120

Platelet receptor blocked

AD P2y12

121

ADP p2y12 receptor antagonists requiring metabolism

Ticlopidine, clopidogrel, prasugrel

122

ADP p2y12 receptor antagonist direct

Cangrelor

123

Platelet signal blockers

Aspirin and dipyridamole

124

Platelet integrin blockers

ReoPro (abiciximab), Integrilin (Epifibatide), Tirofiban (Aggrastat)

125

dipyridamole

increase cAMP and block signal in platelet aggregation

127

hemodynamic disorders

hemodynamic disorders

128

Hyperemia vs congestion

Hyperemia is an active process

129

Hyperemia causes

erythema

130

Congestion causes

cyanosis

131

Liver congestion where does blood back up

in regions such as sinusoids around the central vein. spares periportal regions

132

nutmeg liver

chronic passive congestion of liver.

133

nutmeg liver discoloration

dark red is centriolbular congestion. Periportal fatty change is yellow

134

Direction of clot formation

always towards the heart.

135

Virchow's triad

endothelial injury, hypercoagulability, abnormal blood flow

136

white thrombi

arterial thrombi. more platelets and fibrin w less RBC. Prominent lines of Zahn

137

mural thrombi

a thrombi that is stuck to the wall of the vessel and not really occlusive

138

small/medium artery w arterial thrombi

generally occlusive

139

red thrombi

venous thrombi, lines of zahn not as prominent. more red blood cells bc more about stasis and sitting blood

140

paradoxical embolus

venous thrombus passes to systemic circulation through patent foramen ovale or vsd or patent ductus arteriosus

141

thrombus organization

ingrowth of granulation tissue and smooth muscle cells into thrombus. convert to fibrous tissue

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pulmonary web

indicates that a prior thrombus had existed

143

white infarct

arterial infarct when solid organ has one blood supply

144

red infarct

hemorrhagic infarct or venous infarct, organ with 2 blood supplies. Or white infarct w/ reperfusion

145

dual blood supply w infarct

if one is blocked and second compromised than you can get tissue with ischemia and blood supply that is not enough to prevent the ischemia

147

Anemia

Anemia

148

Microcytic anemia differential

iron deficiency, anemia of chronic inflammation/chronic disease, thalassemia, sideroblastic anemia

149

iron deficiency anemia presentation

low hemoglobincMicrocytic, hypochromic anemia

150

iron deficiency anemia pathology

pencil cells, , low MCV, high RDW

151

Prussian blue stain

stain when assessing iron. Wil stain iron blue

152

Thalassemia trait unique

have microcytosis without anemia

153

thalassemia presentation

microcytic, hypochromic anemia. Very low MCV

154

Thalassemia pathology

target cells

155

Normocytic anemia differential

hemolytic anemia, hemorrhage/blood loss, sicke cell disease, anemia of chronic inflammation/disease, aplastic anemia

156

hemolytic anemia cause

hereditary spherocytosis

157

hereditary spherocytosis

defect in proteins making RBC cytoskeleton. shortened lifespan RBC

158

Hemolytic anemia presentation

normocytic, normochromic anemia with high reticulocyte count

159

spherocyte

cells that have lost membrane and take spherical shape. Lack central pallor

160

Macrocytic differential

megablastic anemia (B12 deficiency, folate deficiency), liver disease, alcohol, yelodysplastic syndrome

161

B12/folate deficiency effect

disrupt pathway for DNA synthesis. ineffective erythropoiesis

162

megaloblastic anemia pathology

large RBCs. hypersegmented neutrophils

163

Retic count correction in anemia

corrected retic count = reticulocyte x actual Hct/ideal Hct

164

Hemolytic anemia: intravascular hemolysis minfestation

anemia, hemoglobinemia, hemoglobinuria, hemosiderinuria, jaundice

165

Intravascular hemolysis cause

mechanical injury, complement fixation ,intracellular parasites

166

Extravascular hemolysis cause

premature destruction of cells in phagocytes bc alteration akes RBC less deformable

167

megaloblastic anemia cause

impaired synchrony of nuclear and cytoplasmic maturation

168

3 B12 proteins

intrinsic factor, transcobalamin II, R protein

169

Pernicious anemia

intestines cannot properly absorb B12, get an anemia because of failure for DNA production.

170

Megaloblastic anemia signs

tiredness, pallor, jaundice, epithelial esions on gums, gastric mucosa, cervical lesions

171

B12 neurologic problems

demyleination and subacute combine systems disease, paresthesias of hand and feet, spastic ataxia, etc

172

B12 lab assessment

B12 down. Methylmalonic acid and homocystein increase

173

Folate deficiency assessment

Homocystein down more in isolation than in B12

175

Folate deficiency poor nutrition

goat milk anemia, poverty, early birth etc.

176

folate deficiency absorption

nontropical or tropical spruce. disease of small intestine

177

folate deficiency increased requireent

pregnancy, increased cell turnover from chronic hemolytic anemia, exfoliative dermatitis

178

Nitrous oxide exposure

Acute megaloblastic anemia,

179

inborn cobalamin deficiency

Imerslund-grasbeck disease, congenital deficiency of IF, transcobalamin II deficiency

180

inborn error folate metabolism

congenital malabsorption, dyhydrofolate reductase deficiency, N .... transferase deficiency

181

increased LDH

marker of hemolysis. Leaking out of destroyed RBC's. enzyme for converting pyruvate to lactate

182

hyperbilirubinemia

marker for hemolysis from broken down heme

183

increased plasma hemoglobin

marker of intravascular hemolysis as hee leaks into circulation

184

low plasma haptoglobin

marker for intravascular hemolysis bc haptaglobin is depleated to bind hemoglobin and take to spleen

185

hemoglobinuria

sign of intravascular hemolysis bc extra hemoglobin is not picked up and instead comes out in urine

186

extravascular hemolysis causes

intrinsic RBC efects, extracorpuscular defects

187

Intravascular hemolysis causes

problems w hemoglobin, problems with RBC membrane, deficiencies of enzymes

188

hereditary spherocytosis osotic fragility test

red cells placed in hypotonic saline, %lysis measured HS RBC's lyse at greater concentration of hypotonic salinethan normal RBCs

189

G6PD deficiency mechanism

withotu G6PD, hemoglobin more succeptible to oxidative damage.

190

heinz bodies

damaged hemoglobin aggregate to make heinz bodies

191

bite cells

macrophages rmeove heinz bodies from RBC's causes bite cells and inducing hemolysis

192

G6PD deficiency genetics

X chromosome. more males affected

193

G6PD deficiency at risk populations

A variant = african americans. B variant = mediterranean and asian ancestry

194

Warm autoimmune hemolytic anemia

IgG bind to RBC surface at warm temp leading to microspherocytes

195

Warm AIHA test

DIrect Coombs test to see if RBC's coated with IgG

196

causes of warm AIHA

idiopathic autoimmune disorders lupus,lymphoproliferative disorders

197

Cold AIHA

IgM binding below 37 degrees. activate complement that remains and causes lysis of RBCs

198

Kuppfer cells

complement receptor expressing cells in liver that take out RBC's in Cold AIHA

199

Cold AIHA diagnosis

blood reachign room temp will agglutinate.

200

3 mechanisms of drug induced hemolytic anemia

hapten mediated - drug binds RBC and serves as IgG target. neoantigen - drug binds membrane gets new conformation for IgG. Drug alters membrane causing new antigen