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1

What is hemostatsis?

Damage to the wall is repaired by hemostasis,

2

Hemostasis involves the formation of?

a thrombus (clot) at the site of vessel injury

3

Hemostasis stages?

primary and secondary.

4

Primary hemostasis?

forms a weak platelet plug

5

Primary hemostasis is mediated by?

interaction between platelets and the vessel wall

6

Secondary hemostasis?

stabilizes the platelet plug

7

Secondary hemostasis is mediated by?

the coagulation cascade.

8

What is Step 1 in secondary hemostasis?

Transient vasoconstriction of damaged vessel

9

How is Step 1 in secondary hemostasis mediated?

by reflex neural stimulation and endothelin release from endothelial cells

10

What is Step 2 in secondary hemostasis?

Platelet adhesion to the surface of disrupted vessel

11

In step 2 of secondary hemostasis, how does platelet adhesion occur?

Von Willebrand factor (vWF) binds exposed subendothelial collagen,

12

How do platelets bind to vWF?

via the GPIb receptor

13

vWF is derived from?

the Weibel-Palade bodies of endothelial cells and a-granules of platelets.

14

What is Step 3 in secondary hemostasis?

Platelet degranulation

15

In step 3 of secondary hemostasis what does Adhesion induce?

shape change in platelets and degranulation with release of multiple mediators

16

What are the mediators released in step 3 of secondary hemostasis?

ADP and TXA

17

What is the role of ADP in step 3 of secondary hemostasis?

it is released from platelet dense granules; promotes exposure of GPIIb/IIIa receptor on platelets.

18

What is the role of TXA in step 3 of secondary hemostasis?

it is synthesized by platelet cyclooxygenase (COX) and released; promotes platelet aggregation

19

What is step 4 in secondary hemostasis?

Step 4?Platelet aggregation

20

Where and how do Platelets aggregate in step 4 of secondary hemostasis?

at the site of injury via GPIIb/IIIa using fibrinogen (from plasma) as a linking molecule;

21

What does platelet aggregation result in?

formation of platelet plug

22

Platelet plug?

It is weak; coagulation cascade (secondary hemostasis) stabilizes it.

23

What are disorders of primary hemostasis usually due to?

Usually due to abnormalities in platelets;

24

Disorders of primary hemostasis are divided into?

quantitative or qualitative disorders

25

What are some Clinical features for disorders of primary hemostasis?

mucosal and skin bleeding.

26

What is the most common overall symptom in mucosal bleeding?

epistaxis

27

What are symptoms of mucosal bleeding?

epistaxis, hemoptysis, GI bleeding, hematuria, and menorrhagia. Intracranial bleeding occurs with severe thrombocytopenia.

28

What are the symptoms of skin bleeding?

include petechiae (1-2 mm), ecchymoses (> 3 mm), purpura (> 1 cm), and easy bruising;

29

Petechiae are a sign of what?

thrombocytopenia and are not usually seen with qualitative disorders.

30

What are some useful laboratory studies for disorders of primary hemostasis?

platelet count, bleeding time, blood smear, bone marrow biopsy

31

Platelet count

normal 150-400 K/pL; < 50 K/pL leads to symptoms,

32

Bleeding time

normal 2-7 minutes; prolonged with quantitative and qualitative platelet disorders

33

Blood smear

used to assess number and size of platelets

34

Bone marrow biopsy

used to assess megakaryocytes, which produce platelets

35

What is immune thrombocytopenic purpura?

(ITP) is an autoimmune production of IgG against platelet antigens (GPIIb/IIIa)

36

What is the most common cause of thrombocytopenia in children and adults?

immune thrombocytopenic purpura

37

In ITP what results in thrombocytopenia?

Antibody-bound platelets are consumed by splenic macrophages

38

ITP is divided into?

acute and chronic forms

39

Acute form of ITP?

arises in children weeks after a viral infection or immunization;selflimited, usually resolving within weeks of presentation

40

Chronic form of ITP?

arises in adults, usually women of chilbearing age. May be primary or secondary (e.g SLE).

41

What is the risk involved in chronic ITP?

May cause short-lived thrombocytopenia in offspring since antiplatelet IgG can cross the placenta.

42

laboratory findings for ITP include

decreased platelet count, often < 50 K/pL, Normal PT/FTT, Coagulation factors are not affected. increased megakaryocytes on bone marrow biopsy

43

What is the Initial treatment for ITP?

corticosteroids.

44

How will children and adults respond to the initial treatment for ITP?

Children respond well; adults may show early response, but often relapse.

45

In addition to corticosteroids what else is used in the treatment of ITP?

IVIG is used to raise the platelet count in symptomatic bleeding, but its effect is short-lived,

46

What is a permenant solution for patients with ITP?

Splenectomy eliminates the primary source of antibody and the site of platelet destruction (performed in refractory cases).

47

What is microangiopathic hemolytic anemia?

Pathologic formation of plateletmicrothrombin small vessels

48

How are plateletmicrothrombin formed and what is the result?

Platelets are consumed in the formation of microthrombi sheering the RBCs as they cross microthrombi, resulting in hemolytic anemiawith schistocytes

49

What is microangiopathic hemolytic anemia seen in?

thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS)

50

What is TTP due to?

decreased ADAMTS13 which is an enzyme that normally cleaves vWF multimers into smaller monomers for eventual degradation.

51

How does TTP lead to microangiopathic hemolytic anemia?

1. Large, uncleaved multimers lead to abnormal platelet adhesion, resulting in microthrombi.

52

Decreased ADAMTS13 is usually due what?

an acquired autoantibody;

53

TTP is most commonly seen in?

adult females

54

HUS is due to?

Hemolytic uremic syndrome is due to endothelial damage by drugs or infection.

55

HUS is classically seen in?

children with E coli G157;H7 dysentery, which results from exposure to undercooked beef

56

How is E Coli related to microangiopathic hemolytic anemia?

E coli verotoxin damages endothelial cells resulting in platelet microthrombi

57

The clinical findings for HUS and TTP include

Skin and mucosal bleeding, Microangiopathic hemolytic anemia, Fever, Renal insufficiency, CNS abnormalities

58

Renal insufficiency is more common in HUS or TTP?

HUS ? thrombi involve vessels of the kidney

59

CNS abnormalities are more common in HUS or TTP?

TTP ? Thrombi involve vessels of the CNS

60

Laboratory findings for microangiopathic hemolytic anemia include?

Thrombocytopenia with increased bleeding time Normal PT/PTT (coagulation cascade is not activated), anemia with schistocytes, increased megakaryocytes on bone marrow biopsy

61

Treatment for microangiopathic hemolytic anemia?

involves plasmapheresis and corticosteroids, particularly in TTP.

62

What are the qualitative platelet disorders?

bernard-soulier, Glanzmann thrombasthenia, asprin, uremia

63

Bernard-Soulier syndrome

is due to a genetic GPIb deficiency; platelet adhesion is impaired.

64

In Bernard-Soulier what lab test are you interested in?

Blood smear which shows mild thrombocytopenia with enlarged platelets.

65

Glanzmann thrombasthenia is due to?

a genetic GPIIb/IIIa deficiency; platelet aggregation is impaired.

66

Aspirin and microangiopathic hemolytic anemia?

it irreversibly inactivates cyclooxygenase; lack of TXA, impairs aggregation.

67

Uremia and microangiopathic hemolytic anemia

disrupts platelet function; both adhesion and aggregation are impaired.

68

What does secondary hemostasis do?

Stabilizes the weak platelet plug via the coagulation cascade

69

In secondary hemostasis the coagulation cascade generates?

thrombin, which converts fibrinogen in the platelet plug to fibrin.

70

In secondary hemostasis what happens to fibrin?

It is cross-linked, yielding a stable platelet-fibrin thrombus.

71

Where are the factors of the coagulation cascade produced?

In the liver in an inactive state.

72

What does activation of the factors of the coagulation cascade require?

exposure to an activating substance, Phospholipid surface of platelets, calcium

73

What are the activating substances involved in the activation of the factors of the coagulation cascade?

Tissue thromboplastin activates factor VII (extrinsic pathway). Subendothelial collagen activates factor XII (intrinsic pathway).

74

Where does the Calcium involved in the activation of the factors of the coagulation cascade come from?

derived from platelet dense granules

75

Disorders of secondary hemostasis are usually due to?

factor abnormalities

76

What are the clinical features of disorders of secondary hemostasis?

they include deep tissue bleeding into muscles and joints (hemarthrosis) and rebleeding after surgical procedures (e.g circumcision and wisdom tooth extraction).

77

Laboratory studies for Disorders of secondary hemostasis include?

PT (prothrombin time) and PTT (partial thromboplastin time)

78

Prothrombin time (PT)

measures extrinsic (factor VII) and common (factors II, V, X, and fibrinogen) pathways of the coagulation cascade

79

Extrinsic pathway of the coagulation cascade

factor VII

80

Common pathway of the coagulation cascade

factors II, V, X, and fibrinogen

81

Partial thromboplastin time (PTT) measures

intrinsic (factors XII, XI, IX, VIII) and common (factors II, V, X, and fibrinogen) pathways of the coagulation cascade

82

What is involved in Hemophilia A?

Genetic factor VIII (FVIII) deficiency, X-linked recessive (predominantly affects males)

83

Does Hemophilia A require a family history of it?

Can arise from a new mutation (de novo) without any family history

84

Hemphilia A presents with?

deep tissue, joint, and postsurgical bleeding

85

Clinical severity of hemophilia A depends on?

the degree of deficiency

86

Laboratory findings of hemophilia A include

1. increased PTT; normal PT 2. decreased FVIII 3. Normal platelet count and bleeding time

87

What does treatment of hemophilia A involve?

recombinant FVIII.

88

What is christmas disease?

Hemophilia B - Genetic factor IX deficiency, Resembles hemophilia A, except FIX levels are decreased instead of FVIII

89

What is coagulation factor inhibitor?

Acquired antibody against a coagulation factor resulting in impaired factor function; anti-FVIII is most common,

90

Clinical and lab findings for hemophilia B?

its similar to hemophilia A, PTT does not correct upon mixing normal plasma with patient's plasma (mixing study) due to inhibitor; PTT does correct in hemophilia A.

91

How can you tell the difference between hemophilia A and B?

mixing study

92

von Willebrand Disease

Genetic vWF deficiency

93

What is the most common inherited coagulation disorder?

von Willebrand disease

94

Does von Willebrand Disease result in qualitative or quantitative disorders?

Multiple subtypes exist, causing quantitative and qualitative defects;

95

What is the most common type of von Willebrand Disease?

is autosomal dominant with decreased vWF levels

96

von Willebrand Disease presents with?

mild mucosal and skin bleeding; low vWF impairs platelet adhesion.

97

Laboratory findings for von Willebrand Disease include

1. increased bleeding time 2. increased PTT: normal PT ? Decreased FVIII half-life (vWF normally stabilizes FVIII); 3. Abnormal ristocetin test

98

What is usually not seen with von Willebrand Disease that is unusual

deep tissue, joint, and postsurgical bleeding are usually not seen.

99

Why is there an Abnormal ristocetin test in von Willebrand disease

Ristocetin induces platelet aggregation by causing vWF to bind platelet GPIb; lack ofvWF ?> impaired aggregation ?> abnormal test.

100

What is the treatment for von willebrand disease?

desmopressin (ADH analog), which increases vWF release from Weibel-Palade bodies of endothelial cells

101

How does vitamin K deficiency relate to hemostasis?

Disrupts function of multiple coagulation factors

102

What is involved in Vitamin K activation?

Vitamin K is activated by epoxide reductase in the liver

103

What does Activated vitamin K do?

it gamma carboxvlates factors II, VII, IX, X, and proteins C and S; gamma carboxylation is necessary for factor function.

104

Vitamin K deficiency occurs in?

1. Newborns 2. Long-term antibiotic therapy 3. Malabsorption

105

Why is there vitamin K deficiency in newborns?

its due to lack of GI colonization by bacteria that normally synthesize vitamin K; vitamin K injection is given prophylactic ally to all newborns at birth to prevent hemorrhagic disease of the newborn

106

How does Long-term antibiotic therapy elad to Vitamin K deficiency?

disrupts vitamin K-producing bacteria in the GI tract

107

How does Malabsorption lead to Vitamin K deficincy?

leads to deficiency of fat-soluble vitamins, including vitamin K

108

What are some other causes of secondary hemostasis?

liver failure, large volume transfusion,

109

How does liver failure lead to secondary hemostasis?

decreased production of coagulation factors and decreased activation of vitamin K by epoxide reductase;

110

How is the effect of liver failure on coagulation followed?

followed using PT.

111

How does Large-volume transfusion lead to secondary hemostasis?

it dilutes coagulation factors, resulting in a relative deficiency

112

What is Heparin induced thrombocytopenia?

Platelet destruction that arises secondary to heparin therapy

113

How does Heparin induced thrombocytopenia lead to thrombosis?

Fragments of destroyed platelets may activate remaining platelets, leading to thrombosis

114

What is disseminated intravascular coagulation?

Pathologic activation of the coagulation cascade

115

What does disseminated intravascular coagulation result in?

1. Widespread microthrombi result in ischemia and infarction, 2. Consumption of platelets and factors results in bleeding, especially from IV sites and mucosal surfaces (bleeding from body orifices).

116

Is disseminated intravascular coagulation usually primary or secondary?

Almost always secondary to another disease process

117

What are some situations that may result in disseminated intravascular coagulation?

Obstetric complications, sepsis, adenocarcinoma, Acute promyelocytic leukemia, Rattlesnake bite

118

Obstetric complications and disseminated intravascular coagulation

Tissue thromboplastin in the amniotic fluid activates coagulation

119

Sepsis and disseminated intravascular coagulation

(especially with E. coli or Neisseria meningitidis) ? Endotoxins from the bacterial wall and cytokines (e.g TNF and IL-1) induce endothelial cells to make tissue factor.

120

Adenocarcinoma and disseminated intravascular coagulation

Mucin activates coagulation.

121

Acute promyelocytic leukemia and disseminated intravascular coagulation

Primary granules activate coagulation.

122

Rattlesnake bite and and disseminated intravascular coagulation

Venom activates coagulation

123

Laboratory findings for disseminated intravascular coagulation include?

decreased platelet count, increased PT/PTT, decreased fibrinogen, Microangiopathic hemolytic anemia, Elevated fibrin split products, particularly D-dimer

124

What is the best screening test for DIC?

Elevated D-dimer

125

D dimer is derived from?

splitting of cross-linked fibrin; D-dimer is not produced from splitting of fibrinogen.

126

Treatment of DIC involves?

addressing the underlying cause and transfusing blood products and cryoprecipitate (comains coagulation factors), as necessary.

127

What does normal fibrinolysis do?

Normal fibrinolysis removes thrombus after damaged vessel heals

128

Tissue plasminogen activator (tPA)

converts plasminogen to plasmin

129

Plasmin

cleaves fibrin and serum fibrinogen, destroys coagulation factors, and blocks platelet aggregation.

130

a2-antiplasmin

inactivates plasmin.

131

What are the disorders of fibrinolysis due to? What does this result in?

plasmin overactivity resulting in excessive cleavage of serum fibrinogen.

132

What are some examples of disorders of fibrinolysis?

radical prostatectomy, cirrohsis of the liver

133

How does radical prostatectomy lead to a disorder of fibrinolysis?

Release of urokinase activates plasmin

134

How does cirrhosis of the liver lead to a disorder of fibrinolysis?

reduced production of a2-antiplasmin

135

How does disorders of fibrinolysis present?

with increased bleeding (resembles DIC)

136

Laboratory findings for disorders of fibrinolysis include

Increased PT/PTT, increased bleeding time with normal platelet count, Increased fibrinogen split products without D-dimers

137

Why is there increased fibrinogen split products without D-dimers in disorders of fibrinolysis?

Serum fibrinogen is lysed; however, D-dimers are not formed because fibrin thrombi are absent

138

Why is there increased bleeding time with disorders of fibrinolysis?

Plasmin blocks platelet aggregation

139

Why is there increased PT/PTT with disorders of fibrinolysis?

Plasmin destroys coagulation factors.

140

What is the treatment for disorders of fibrinolysis?

it is aminocaproic acid, which blocks activation of plasminogen.

141

What is thrombosis?

Pathologic formation of an intravascular blood clot (thrombus), Can occur in an artery or vein,

142

What is the most common location for thrombosis?

it is the deep veins (DVT) of the leg below the knee

143

What is thrombosis characterized by?

lines of Zahn and attachment to vessel wall

144

What are the lines of Zahn?

alternating layers of platelets/fibrin and RBCs

145

What distinguishes thrombus from a postmortem clot?

lines of Zahn and attachment to vessel wall

146

What are three major risk factors for thrombosis?

disruption in blood flow, endothelial cell damage, and hypercoagulable state (Virchow triad)

147

What is normal blood flow?

blood flow is normally continuous and laminar; keeps platelets and factors dispersed and inactivated

148

What happens to blood flow that causes an increase in the risk for thrombosis?

Stasis and turbulence of blood flow increases risk for thrombosis

149

What are some examples of disruption of normal blood flow?

Immobilization?increased risk for deep venous thrombosis 2. Cardiac wall dysfunction (e.g arrhythmia or myocardial infarction) 3. Aneurysm

150

How does endothelial cell damage increase the risk for thrombosis?

Endothelial damage disrupts the protective function of endothelial cells, increasing the risk for thrombosis

151

How do endothelial cells prevent thrombosis?

1. Block exposure to subendothelial collagen and underlying tissue factor 2. Produce prostacyclin (PGI2) and NO, 3. Secrete heparin-like molecules, 4. Secrete tissue plasminogen activator (tPA) 5. Secrete thrombomodulin

152

How does endothelial cells use the secretion of tPA to prevent thrombosis?

converts plasminogen to plasmin, which (1) cleaves fibrin and serum fibrinogen, (2) destroys coagulation factors, and (3) blocks platelet aggregation

153

How does the secretion of thrombomodulin from endothelial cells prevent thrombosis?

redirects thrombin to activate protein C, which inactivates factors V and VIII

154

How do endothelial cells use the secretion of heparin-like molecules to prevent thrombosis?

augment antithrombin III (ATIII) which inactivates thrombin and coagulation factors

155

How does endothelial cells use the production of prostacyclin (PGI2) and NO to prevent thrombosis?

vasodilation and inhibition of platelet aggregation

156

What are the causes of endothelial cell damage?

atherosclerosis, vasculitis, and high levels of homocysteine

157

Vitamin B12 and folate deficiency result in?

mildly elevated homocysteine levels, increasing the risk for thrombosis.

158

What does folic acid circulate as?

methyl-THF (tetrahydrofolate, THF) in the serum,

159

How does THF participate in the synthesis of DNA precursors?

Methyl is transferred to cobalamin (vitamin B12) which transfers methyl to homocysteine resulting in methionine

160

What does a lack of vitamin B12 or folate lead to?

decreased conversion of homocysteine to methionine resulting in buildup of homocysteine

161

Cystathionine beta synthase (CBS) deficiency results in what?

high homocysteine levels with homocystinuria,

162

What does CBS do?

CBS converts homocysteine to cystathionine

163

CBS deficiency leads to?

homocysteine buildup

164

CBS deficiency is characterized by?

vessel thrombosis, mental retardation, lens dislocation, and long slender fingers

165

what is a hypercoagulabe state due to?

excessive procoagulant proteins or defective anticoagulant proteins; may be inherited or acquired

166

What is the classic presentation for a hypercoagulable state?

recurrent DVTs or DVT at a young age, usually occurs in the deep veins of the leg; other sites include hepatic and cerebral veins

167

What are some causes of a hypercoagulable state?

protein C and S deficiency, factor V Liden deficiency, prothrombin 20210A, ATIII deficiency, oral contraceptives

168

protein C or S deficiency

(autosomal dominant) decreases negative feedback on the coagulation cascade (hypercoagulable state)

169

Proteins C and S normally do what?

inactivate factors V and VIII

170

Protein C and S deficiency increases the risk for what?

warfarin skin necrosis

171

What does the initial stage of warfarin therapy result in?

a temporary deficiency of proteins C and S (due to shorter half-life) relative to factors II, VII, IX, and X

172

In preexisting C or S deficiency, what danger does the initial stage of warfarin therapy present?

a severe deficiency is seen at the onset of warfarin therapy increasing the risk for thrombosis, especially in the skin

173

What is Factor V Leiden?

a mutated form of factor V that lacks the cleavage site for deactivation by proteins C and S

174

What is the most common inherited cause of hypercoagulable state?

Factor V Leiden

175

What is Prothrombin 20210A?

it is an inherited point mutation in prothrombin that results in increased gene expression,

176

Increased prothrombin (prothrombin 20210A) results in what?

increased thrombin, promoting thrombus formation.

177

What does ATIII deficiency result in?

decreases the protective effect of heparin-like molecules produced by the endothelium, increasing the risk for thrombus

178

What do heparin-like molecules normally do?

activate ATIII, which inactivates thrombin and coagulation factors

179

What happens in ATIII deficiency?

PTT does not rise with standard heparin dosing.

180

Pharmacologic heparin works by doing what?

binding and activating ATIII

181

High doses of heparin in someone with ATIII deficiency results in what?

activate limited ATIII; Coumadin is then given to maintain an anticoagulated state.

182

How are oral contraceptives associated with a hypercoagulable state?

Estrogen induces increased production of coagulation factors, thereby increasing the risk for thrombosis

183

What is an embolism?

Intravascular mass that travels and occludes downstream vessels; symptoms depend on the vessel involved

184

What is a thromboembolus due to?

a thrombus that dislodges;

185

What is the most common type of embolus?

thromboembolus (>95%)

186

Atherosclerotic embolus is due what?

to an atherosclerotic plaque that dislodges.

187

Atherosclerotic embolus is characterized by what?

the presence of cholesterol clefts in the embolus

188

Fat embolus is associated with what?

bone fractures, particularly long bones, and soft tissue trauma

189

When does a fat embolus develop?

while fracture is still present or shortly after repair

190

What is fat embolus characterized by?

dyspnea (fat, often with bone marrow elements, is seen in pulmonary vessels and petechiae on the skin overlying the chest

191

Gas embolus is classically seen in what?

decompression sickness.

192

Decompression sickness

Nitrogen gas precipitates out of blood due to rapid ascent by a diver (gas embolus)

193

What does gas embolus presents with?

joint and muscle pain (bends) and respiratory symptoms (chokes)

194

Caisson disease

Chronic form of gas embolus that is characterized by multifocal ischemic necrosis of bone

195

Gas embolus and laproscopic surgery?

may also occur during laparoscopic surgery (air is pumped into the abdomen)

196

Amniotic fluid embolus

enters maternal circulation during labor or delivery

197

How does amniotic fluid embolus present?

with shortness of breath, neurologic symptoms, and DIC (due to the thrombogenic nature of amniotic fluid)

198

How is amniotic fluid embolus characterized?

by squamous cells and keratin debris, from fetal skin, in the embolus

199

pulmonary embolism is usually due to?

thromboembolus;

200

What is the most common source of thromboembolus?

deep venous thrombus (DVT) of the lower extremity usually involving the femoral, iliac, or popliteal veins

201

Pulmonary embolism is most often clinically silent because?

the lung has a dual blood supply via pulmonary and bronchial arteries and the embolus is usually small (self-resolves)

202

When does pulmonary infarction occur?

if a large- or medium-sized artery is obstructed in patients with pre-existing cardiopulmonary compromise; only 10% of PEs cause infarction

203

How does pulmonary infarction present?

with shortness of breath, hemoptysis, pleuritic chest pain, and pleural effusion

204

In pulmonary infarction what does the V/Q lung scan show?

a mismatch; perfusion is abnormal.

205

In pulmonary infarction what does the spiral CT show?

a vascular filling defect in the lung

206

What is useful in determining DVT?

lower extremity Doppler ultrasound is useful to detect DVT

207

In pulmonary infarction what happens the the D-dimer

it is elevated

208

In pulmonary infarction what does gross examination reveal?

a hemorrhagic, wedge-shaped infarct

209

In pulmonary infarction sudden death occurs with?

a large saddle embolus that blocks both left and right pulmonary arteries or with significant occlusion of a large pulmonary artery

210

In pulmonary infarction sudden death with a large saddle embolus, death is due to?

electromechanical dissociation

211

Pulmonary hypertension may arise with what?

chronic emboli that are reorganized over time.

212

Systemic embolism is usually due to?

thromboembolus

213

Where does systemic embolism most commonly arise?

in the left heart and travels down systemic circulation to occlude flow to organs, most commonly lower extremities