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General Pathology > Hemostasis > Flashcards

Hemostasis Flashcards

1
Q

what are the 4 general steps of hemostasis that occur after injury?

A
  1. reflex arteriolar vasoconstriction (transient)
  2. primary hemostasis → formation of platelet plug
  3. secondary hemostasis → stabilization of platelet plug
  4. negative feedback → stops clotting process (antithrombosis)
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2
Q

where does hemostasis occur?

A

at the site of injury

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3
Q

immediately after injury, reflex vessel vasoconstriction occurs, exposing what 2 things to the subendothelial ECM? what does this trigger?

A

-von Willebrand factor (vWF) & collagen

-triggers formation of the primary hemostatic plug

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4
Q

how is the primary hemostatic plug formed?

A
  1. vessel injury –> reflex vasoconstriction
  2. vWF and collagen are exposed to the subendothelial ECM
  3. platelets adhere to vWF on the subendothelial matrix and become activated (change shape)
  4. activated platelets release ADP and produce TXA2
  5. ADP and TXA2 cause platelet recruitment and aggregation = primary hemostatic plug
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5
Q

how do platelets adhere to vWF, and thus the subendothelial matrix?

A

platelet receptor GpIb binds to vWF = complex is now attached to sub-endothelial matrix

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6
Q

Platelet activation causes conformational change of what in primary hemostasis? Why does this happen?

A
  • GpIIb-IIIa
  • so it can bind fibrinogen, linking platelets together (platelet aggregation)
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7
Q

disc-shaped, anucleate cell fragments that are shed from megakaryocytes in the bone marrow into the bloodstream

A

platelets

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8
Q

Where do platelets originate from?

A

megakaryocytes in bone marrow

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9
Q

what are the components of platelets? (3)

A

-Contractile cytoskeleton (actin)
-α-Granules
-Dense (δ) granules

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10
Q

what is contained within platelet α-Granules? what is the function?

A

-multiple proteins: P-selectin (adhesion), fibrinogen, PDGF
-involved in coagulation and wound healing

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11
Q

what is contained within platelet dense (δ) Granules?

A

ADP, Ca2+, other molecules

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12
Q

what is the purpose of the shape change in platelets after activation?

A

spikes increase SA for attachment

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13
Q

What is platelet half life?

A

10-14 days

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14
Q

what is the shape of inactive platelets compared to that of activated platelets?

A
  • inactive: round discs
  • active: flat, spiky plates
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15
Q

T/F
TXA2 is present in its activated form before injury occurs.

A

false – TXA2 is produced after platelet activation (i.e. after injury)

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16
Q

what initiates the coagulation cascade of secondary hemostasis?

A

exposure of tissue factor (factor III or thromboplastin)

(this is for extrinsic pathway)

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17
Q

what are 2 other names for tissue factor?

A

factor III or thromboplastin

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18
Q

what is tissue factor? (factor III or thromboplastin)

A

a cell surface glycoprotein that is normally found on SM cells and fibroblasts (CT cells)

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19
Q

what 3 things are needed in order for clotting factors to be able to bind during secondary hemostasis? (what is needed for coagulation cascade?)

A

-negatively charged surface
-Ca2+ (cofactor)
-phospholipids

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20
Q

during secondary hemostasis, activated platelets increase surface expression of ______, which become a binding site for Ca2+ and coagulation factors.

A

negatively charged phospholipids

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21
Q

what is the overall goal/end result of the coagulation cascade during secondary hemostasis?

A

produce Thrombin (factor II)

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22
Q

what is another name for thrombin?

A

factor II

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23
Q

what are the 2 main functions of thrombin (factor II)?

A

-adhere to platelets (increases aggregation)
-converts fibrinogen to fibrin

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24
Q

during secondary hemostasis, Platelets ______ while fibrin strands _____ holding platelets and entrapped RBCs and WBCs together

A

contract

polymerize

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25
Q

put it all together: what are all of the events that occur during secondary hemostasis?

A
  1. Exposure of Tissue Factor (factor III or thromboplastin) –> initiates the coagulation cascade
  2. Activated platelets increase surface expression of negatively charged phospholipids which become a binding site for Ca2+ and coagulation factors
  3. Coagulation cascade culminates in production of Thrombin (factor II) –> adheres to platelets

(increasing aggregation) and converts fibrinogen to fibrin

  1. Platelets contract while fibrin strands polymerize, holding platelets and entrapped RBCs and WBCs together
  2. a stable secondary hemostatic plug is formed
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26
Q

this process stops clotting/platelet aggregation in order to avoid infarcation via negative feedback

A

antithrombosis

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27
Q

Platelet aggregation is limited to what?

A

activated platelet surfaces

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28
Q

where does antithrombosis initiate?

A

endothelial cells adjacent to activated platelet surfaces

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29
Q

what do the endothelial cells adjacent to activated platelet surfaces do to promote antithrombosis?

A

-express membrane-bound, antithrombotic molecules: Heparin-like molecules and thrombomodulin

-release tissue plasminogen activator (t-PA)

-in response to thrombin, produce: prostacyclin (PGI2) and nitric oxide (NO)

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30
Q

what do Heparin-like molecules do?

A

act with antithrombin III to inactivate thrombin

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31
Q

what does thrombomodulin do?

A

binds directly to thrombin –> stimulates protein C with protein S = lysis of coagulation factors

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32
Q

what does tissue plasminogen activator (t-PA) do?

A

converts plasminogen into plasmin

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33
Q

what does plasmin do?

A

lysis fibrin

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34
Q

what do prostacyclin (PGI2) and nitric oxide do?

A

prevent platelet aggregation and are potent vasodilators

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35
Q

why is vasodilation from PGI2 and NO necessary during antithrombosis?

A

it allows blood to still flow past the platelet plug so no blockage/infarction occurs

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36
Q

timing-wise when does the platelet plug form/when is primary hemostasis complete?

A

1-3 min after injury

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37
Q

timing-wise when does fibrin stabilization occur/when is secondary hemostasis complete?

A

5-10 min after injury

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38
Q

the amplifying series of events of proteolytic cleavage of an inactive proenzyme into an active enzyme, all leading to thrombin formation

A

coagulation cascade

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39
Q

What is required to initiate the coagulation cascade?

A

Requires phospholipids, calcium and a negatively charged surface (glass beads in the lab or tissue factor)

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40
Q

what are the 2 pathways of the coagulation cascade and what are they stimulated by?

A
  • Extrinsic pathway (in vivo): stimulated by tissue factor (factor III/thromboplastin)
  • intrinsic pathway (in laboratory): stimulated by factor XII (Hageman factor)
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41
Q

what is another name for factor XII?

A

Hageman factor

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42
Q

compare the different things that are needed for the following clotting pathways to occur:
-intrinsic pathway
-extrinsic pathway
-common pathway

A

-intrinsic pathway: patient plasma, Ca2+, negatively charged surface phospholipids

-extrinsic pathway: patient plasma, Ca2+, tissue factor

-common pathway: patient plasma, thrombin

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43
Q

what are the steps of the intrinsic pathway of the Coagulation Cascade?

A
  1. surface activation → activates Hageman factor (factor XII)
  2. XIIa → activates factor XI
  3. XIa → activates factor IX
  4. IXa → activates factor VIII
  5. VIIIa and IXa bind → common pathway

(12, 11, 9, 8, 10, 5, 2, fibrin)

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44
Q

what are the steps of the extrinsic pathway of the Coagulation Cascade?

A
  1. vascular damage → exposure of tissue factor (factor III/thromboplastin)
  2. TF → activates factor VII → intrinsic pathway (no Hageman) → common pathway

(TF, 7, 10, 5, 2, fibrin)

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45
Q

what are the steps of the common pathway of the coagulation cascade?

A
  1. factor X activated (either by IXa/VIIIa or VIIa/TF)
  2. Xa → activates and binds factor V
  3. Va → activates prothrombin to thrombin (factor II)
  4. IIa → converts fibrinogen to fibrin

(10, 5, 2, fibrin)

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46
Q

what clotting factors are part of the intrinsic pathway Coagulation Cascade?

A

factors XII (hageman factor), XI, IX, VIII

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47
Q

what clotting factors are part of the extrinsic pathway Coagulation Cascade?

A

factor VII

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48
Q

what clotting factors are part of the common pathway Coagulation Cascade?

A

factors X, V, II (thrombin), and fibrinogen

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49
Q

what does Partial thromboplastin time (PTT) measure?

A

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

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50
Q

what is normal PTT?

A

28-35 sec (~30 sec)

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51
Q

what is PTT used to monitor?

A

Heparin therapy

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52
Q

what is heparin therapy used for?

A

treatment of acute thrombosis or embolism

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53
Q

how does Heparin therapy work?

A

heparin binds and activates antithrombin III to inactivate thrombin

54
Q

what does Prothrombin Time (PT) measure?

A

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

55
Q

how is PT standardized so that it can analyzed and compared to the rest of the population?

A

International normalized ratio (INR):

patient’s PT value / mean PT or normal patients (11-13 sec)

56
Q

what is normal PT?

A

11-13 sec (~12 sec)

57
Q

what is PT used to monitor and why?

A

levels of anticoagulation because it is sensitive to Coumadin (warfarin)

58
Q

what is a good INR to aim for in patients who take Coumadin (warfarin)?

A

2-3

(2-3x more “liquidy blood” than normal patients to prevent clot formation)

59
Q

how does Coumadin (warfarin) work to cause anticoagulation?

A

inhibits vitamin K function (influences factors II, VII, IX, X)

60
Q

how does the lab check for a clotting factor deficiency or dysfunction?

A

Once the PTT or PT is shown to be abnormal, factor- specific assays can be run to check for which factor is deficient or dysfunctional

61
Q

what does thrombin time measure and what does it help to determine?

A

-how long it takes for fibrinogen to convert to fibrin
-helps determine if there is a problem with fibrinogen or if there is a thrombin inhibitor issue

62
Q

what are the 5 key regulatory actions of thrombin?

A

-Converts fibrinogen into cross-linked fibrin

-Amplifies coagulation by activating multiple factors

-Induces platelet activation and aggregation

-Promotes inflammation, angiogenesis and repair

-Upon encountering normal endothelium- changes from procoagulant to anti-coagulant (helps contain the clotting process)

63
Q

what are 5 major causes of bleeding disorders?

A
  1. Disseminated intravascular coagulation (DIC)
  2. Defect in platelet number (quantitative) or

function (qualitative)

  1. Defect or deficiency in a coagulation factor
  2. Defect in adhesive interactions between platelets and the vessel wall
  3. Systemic condition that damages endothelial cells
64
Q

in general, what is Disseminated intravascular coagulation (DIC)?

A

clotting in vessels all over the body

65
Q

what can trigger Disseminated intravascular coagulation (DIC)?

A

Tissue damage, sepsis, cancer cells, or obstetric complications → all trigger release of tissue factor

66
Q

describe what all happens during intravascular coagulation (DIC)

A
  1. trauma/stress –> tissue factor release
  2. Formation of wide-spread thrombi in the systemic circulation
  3. Vascular occlusion, leading to RBC hemolysis (hemolytic anemia) and Consumption of platelets and activation of plasmin, leading to bleeding

(initially clots but then uses up all potential to form clots so they bleed excessively)

67
Q

acute and chronic DIC vary between clotting and bleeding tendency. which is more predisposed to clotting and which is bleeding? when can each type be seen?

A

-Acute DIC: bleeding (i.e. postpartum)

-Chronic DIC: thrombosis (i.e. cancer)

68
Q

T/F DIC causes severe problems in brain, lungs, heart and kidneys but any organ can be affected

A

true

69
Q

how does DIC onset appear? (2)

A

-cutaneous petechiae/ecchymoses (bruises)
-prolonged post-partum bleeding

70
Q

what lab values would be seen in DIC?

A

-thrombocytopenia (<150,000 platelets/μl)
-prolonged PT and PTT

71
Q

T/F the prognosis of DIC depends on cause and managing that cause

A

true

72
Q

what is the prognosis for chronic DIC?

A

may only be discovered on lab findings

73
Q

what is the prognosis for acute DIC?

A

can be life-threatening- requires aggressive tx

74
Q

what value shows Thrombocytopenia?

A

<150,000 platelets/μl

75
Q

what Thrombocytopenia value can cause spontaneous bleeding?

A

<5,000 platelets/μl

76
Q

during Thrombocytopenia of

<5,000 platelets/μl, where does most of the spontaneous bleeding occur in the body?

A

from small, superficial vessels (skin, mucous membranes)

77
Q

what Thrombocytopenia value presents posttraumatic bleeding risk?

A

<50,000 platelets/μl

78
Q

what are Petechiae are sign of?

A

thrombocytopenia and things it may cause (i.e. DIC, leukemia, etc)

79
Q

what is normal platelet count?

A

150,000-450,000 platelets/μl

80
Q

what lab tests are there for testing platelet function?

A

-Bleeding time (not used much anymore)

-Platelet function analyzer (PFA) (can show abnormal results in some platelet disorders but not great for screening for platelet disorders)

81
Q

T/F there is a really great overall test for platelet function

A

false

82
Q

in general, what can cause Thrombocytopenia?

A

-Decreased platelet production
-Increased platelet destruction
-Other causes like hypersplenism, multiple transfusions

83
Q

what are the 2 categories of diseases that cause thrombocytopenia due to decreased platelet production?

A

-Generalized marrow dysfunction
-Platelet specific diseases

84
Q

what are examples of Generalized marrow dysfunction that cause decreased platelet production and thus, thrombocytopenia? (2)

A

aplastic anemia, marrow infiltration (cancer)

85
Q

what are examples of Platelet specific diseases that cause decreased platelet production and thus, thrombocytopenia? (2)

A

drug-related (alcohol, chemotherapeutics), HIV infection

86
Q

what are the 2 categories of diseases that cause thrombocytopenia due to increased platelet destruction?

A

-autoimmune
-non-immunologic

87
Q

what are examples of autoimmune diseases that cause increased platelet destruction and thus, thrombocytopenia? (4)

A

-immune thrombocytopenic purpura (ITP)
-systemic lupus erythematosus (SLE),
-drug-related
-infections like HIV

88
Q

what are examples of non-immunologic diseases that cause increased platelet destruction and thus, thrombocytopenia? (2)

A

-DIC
-thrombotic thrombocytopenia purpura (TTP)

89
Q

what are the 2 types pf Immune Thrombocytopenic Purpura (ITP) and who are they seen in?

A

-Acute: self-limited form in children after viral infection

-Chronic: women 20-40yrs

90
Q

physiologically, what can be seen occurring in most cases of chronic ITP?

A

auto-antibodies to
platelet membrane glycoproteins IIb/IIIa or Ib/IX

91
Q

what are the clinical features seen in patients with chronic ITP? (4)

A

petechiae, easy bruising, epistaxis, gum bleeding

92
Q

how is chronic ITP treated?

A

immunosuppressive agents + splenectomy

93
Q

why is a splenectomy needed to treat chronic ITP?

A

the spleen is the site of formation of the Abs and where IgG-coated platelets are destroyed

94
Q

what are Thrombotic microangiopathies?

A

Clinical syndromes that share the following characteristics:
-microangiopathic hemolytic anemia
-thrombocytopenia
-renal failure

95
Q

what are examples of diseases where Thrombotic microangiopathies can be seen? (2)

A

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

96
Q

in addition to Thrombotic microangiopathies, what other symptoms are seen in patients with thrombotic thrombocytopenic purpura (TTP)?

A

fever & neurologic symptoms

97
Q

when is hemolytic uremic syndrome (HUS) seen to occur?

A

occurs in children –> Most commonly occurs following infection with Shiga toxin-producing E. Coli (i.e. contaminated meat)

98
Q

describe the overall Pathogenesis of Thrombotic microangiopathies

A

Diverse causes leading to endothelial cell injury and platelet activation and aggregation

99
Q

how do lab values for Thrombotic microangiopathies differ from DIC?

A

they do not show strong activation of the coagulation cascade (just platelet clots) –> normal PT and PTT with thrombocytopenia

100
Q

what can be the cause of a coagulation factor deficiency or defect? (4)

A

-True deficiency (congenital or more often acquired)
-An abnormal protein (defect)
-Inhibitor to the active site of the protein
-Enhanced clearance of a protein (often due to antigen/antibody complex formation)

101
Q

what are the most common defects/ deficiencies that can cause coagulation disorders?

A

vitamin K, vWF, factor VIII, factor IX

102
Q

what are the fat-soluble vitamins?

A

A, D, E, K

103
Q

what is a good source of vitamin K? (2)

A

-leafy green vegetables
-created by gut bacteria, then it is activated in the liver

104
Q

how is activated vitamin K involved in coagulation?

A

it gamma carboxylates factor II, VII, IX, X, protein C and S –> creates binding sites for Ca2+ and is necessary for factor function

105
Q

why do people who take warfarin (Coumadin) need to watch their vitamin K intake?

A

too much vitamin K can override warfarin and cause coagulation

106
Q

Any condition that disrupts intestinal flora so that Vit. K absorption is reduced will all lower active coagulation factor levels. what are some example of these type of conditions? (3)

A

-biliary tract obstruction
-malabsorption syndrome (celiac ds, Crohn ds, pancreatitis)
-excessive broad-spectrum antibiotics

107
Q

how does liver disease affect vitamin K?

A

-reduces amount of
coagulation factors and their function (can’t be
activated bc of lack of active Vit. K)
-also can cause hypersplenism –> reduces platelet numbers

108
Q

what are 3 Hereditary Coagulation Disorders?

A

-von Willebrand disease
-Hemophilia A (factor VIII deficiency)
-Hemophilia B (Christmas disease/deficiency of factor IX)

109
Q

what is Hemophilia A a deficiency in?

A

factor VIII

110
Q

what is Hemophilia B a deficiency in?

A

Factor IX

111
Q

what is a shared cause of both Hemophilia A and von Willebrand disease?

A

qualitative or quantitative defects of the factor VIII-vWF complex

112
Q

vWF is mostly made by endothelial cells. where is it found in the body? (4)

A

-In subendothelium bound to collagen

-in platelet granules

-in endothelial cell vesicles (Weibel-Palade) bodies

-bound to factor VIII in plasma

113
Q

describe the bond between factor VIII-vWF complex

A

non-covalent, can separate easily

114
Q

what is the most common inherited (autosomal dominant) mild to moderate bleeding disorder (1% in U.S.)?

A

von Willibrand disease

115
Q

what is the inheritance pattern for
von Willibrand disease?

A

autosomal dominant

116
Q

what 2 defects are seen in
von Willibrand disease? which is clinically evident?

A

-Defect in both platelets and coagulation factor (factor VIII)
-only the platelet problem is clinically evident

117
Q

what are symptoms of von Willibrand disease?

A

mild to moderate bleeding (spontaneous or excessive) from mucous membranes resembling thrombocytopenia (with normal platelet count)

118
Q

how is von Willibrand disease tested for?

A

Ristocetin platelet agglutination test –> evaluates vWF binding to platelets

119
Q

what is the most common hereditary cause of serious bleeding?

A

Hemophilia A (Factor VIII deficiency)

120
Q

what is the inheritance pattern for Hemophilia A (Factor VIII deficiency)?

A

X-linked recessive (primarily affects males)

121
Q

what are symptoms of Hemophilia A (Factor VIII deficiency)?

A

-Spontaneous hemorrhage in joints (hemarthroses, leading to progressive deformity
-Easy bruising/hemorrhage after trauma or surgery.

122
Q

are Petechiae seen in Hemophilia A (Factor VIII deficiency)?

A

no

123
Q

when is bruising/hemorrhage after trauma or surgery severe in Hemophilia A (Factor VIII deficiency) patients?

A

when <1% factor activity level (veryy low)

124
Q

what labs are taken to diagnose Hemophilia A (Factor VIII deficiency)?

A

-prolonged PTT
-then specific factor assays show deficiency

125
Q

how is Hemophilia A (Factor VIII deficiency) treated?

A

recombinant factor VIII infusions 2-3x/wk

126
Q

what is the main challenge in Hemophilia A (Factor VIII deficiency) treatment?

A

Development of autoantibodies (inhibitors) (~15% of patients)

127
Q

what is the inheritance pattern for Hemophilia B (Factor IX deficiency/Christmas disease)?

A

X-linked

128
Q

how do Hemophilia A and B compare in clinical findings?

A

clinically indistinguishable but B is much less common

129
Q

what labs will be seen in Hemophilia B patients?

A

prolonged PTT

130
Q

how is Hemophilia B (Factor IX deficiency/Christmas disease) treated?

A

recombinant Factor IX infusions

131
Q

what are 2 bleeding disorders that cause systemic damage to vessel walls

A

-scurvy
-vasculitis

132
Q

what is scurvy?

A

Vit C deficiency leading to weak collagen and vascular fragility –> damage to vessel walls –> bleeding

General Pathology (32 decks)

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