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SBL Test 2 > Hubbard: Thrombosis and Hemostasis > Flashcards

Hubbard: Thrombosis and Hemostasis Flashcards

1
Q

Hemostasis = process of stopping bleeding at a vascular site by formation of a thrombus.

What is primary hemostasis?

A

Primary hemostasis = Formation of a platelet plug via platelet adhesion and aggregation

  1. Initiation: endothelial injury results in transient vasoconstriction. → exposure of of subendothelial collagen → von Willebrand factor (vWF) binds to exposed collagen. vWF is a glycoprotein made and stored in Weibel-Palade bodies of endothelial cells and α-granules of platelets.
  2. Adhesion (hemostasis):
    - Gp1B-R on platelets bind to vWF => platelets adhere to endothelium.
  3. . Activation: Activated platelets release ADP, thromboxane, Ca2+, and platelet activating factor (PAF), which assist in platelet aggregation, vasoconstriction and degranulation
  4. Aggregation (hemostasis): platelets aggregate w one another via GpIIb/IIIa-receptor and fibrinogen → formation of a white thrombus composed of platelets and fibrin
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2
Q

Hemostasis = process of stopping bleeding at a vascular site by formation of a thrombus.

What is secondary hemostasis?

A

2’ hemostasis = formation of a stable clot via the interaction of the coagulation cascade

  1. Injury to endothelium → (+) of the extrinsic pathway (hemostasis)
  • Tissue factor (factor III), which is present under the endothelium on fibroblasts, binds to and thus activates factor 7 =>
  • Factor 7a and tissue factor form a complex (TF-FVIIa)* that activates factor 10 and factor 9.
  1. (+) of intrinsic pathway (hemostasis), especially through thrombin.
  • Thrombin activates factors 11 and factor 8.
  • Factor 11a activates factor 9.
  • Factors 8a and IXa form a complex* that activates factor 10..
  • This causes a positive feedback loop of factor X and thrombin activation via the intrinsic pathway
  1. The common pathway (hemostasis) of the extrinsic and intrinsic pathways then follows:
    - Factor 10a and factor 5a form a complex* that cleaves prothrombin to thrombin (= factor 2).
    - Thrombin cleaves fibrinogen (factor I) into insoluble fibrin (factor Ia) monomers.
    - Cross links of the fibrin network are stabilized by factor XIIIa → formation of a fibrin network → fibrin closely binds to the platelet plug, forming a stable fibrin clot (secondary or red thrombus)
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3
Q

Which pathway does the prothrombin time (PT) assess; deficiencies of which factors and drugs cause prolongation?

A
  • Monitors extrinsic pathway and warfarin/dicoumaro

- Prolonged in deficiencies of Factors 2, 5, 7, and 10 (vit K) as well as fibrinogen

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4
Q

Which pathway does the partial thromboplastin time (PTT) assess; deficiencies of which factors and drugs cause prolongation?

A

Monitors the intrinsic system and heparin

  • Prolonged in deficiencies of factors VIII, IX, XI, XII (8, 9, 11, 12)
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5
Q

What is the NL PT and PTT?

A

NL PT = 10-13 seconds

NL PTT = 25-40 seconds

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6
Q

What does thrombin time (TT) assess?

A

Deficiency/abnormality of fibrinogen

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7
Q

What is important background information to get in a patient with a clotting/bleeding disorder?

A
  1. Hx (PMH and FHx = never unremarkable; PSH, ALL meds, SocHx (ETOh, recreational meds, occupational), ROS))
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8
Q

What affects do tonic water have on blood counts?

A

Tonic water (Quinine) = decreases platelet counts

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9
Q

Classes of hemorrhagic disorders

A
  1. Platelet disorders (thrombocytopenia or qualitative platelet disorders)
  2. Factor deficiencies
  3. Endothelial deficiencies
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10
Q

Platelet aggregation studies are important in determining what defects?

A

Qualitative platelet defects: perform when platelets are NL in numbers

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11
Q

What is the most common cause of abnormal platelet function?

A

Meds (ASA or NSAIDS due to impaired arachidonate metabolism)

  • Very important to make sure pt has not taken these drugs for at least 7 days prior to doing a platelet aggregation study
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12
Q

What is the utility of using a 1:1 mixing study in pt with bleeding abnormality?

A
  • Differentiates factor deficiency from presence of a factor inhibitor by mixing the pt plasma w/ normal plasma
  • Factor deficiencies will correct and PTT will correct with mixing
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13
Q

What is the diagnostic testing utilized for Von Willebrand Disease (wWD)?

A
  • Platelet function analysis (PFA) –> may be normal in mild cases
  • vWF antigen level, vWF activity assay, factor VIII level
  • Platelet aggregation tests are abnormal –> especially to ristocetin
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14
Q

What is first-line tx for Von Willebrand Disease (wWD); what else can be given?

A
  • Desmopressin; administered IV or intranasally
  • Can give intermediate-purity factor 8 concentrates, which contain vWF
  • Cryoprecipitate replaces wWF but carries risk of transfusion-transmitted infection!
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15
Q

What are the “big 4” drugs associated with thrombocytopenia?

A
  1. Heparin
  2. H2 blockers
  3. ABX (Cephalosporin and penicillins)
  4. Digoxin
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16
Q

What is DIC (Disseminated Intravascular Coagulation)?

A

Medical/surgical/obstetrical complication that cause activation of coagulation cascade => escape of thrombin into circulation and resulting formation of thrombi, platelet consumption and exhaustion of all clotting factors. As platelets and clotting factors are depleted, bleeding occurs.

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17
Q

Diagnosis of DIC is based on which PT, PTT, thrombine time, D-dimer titer, fibrinogen and platelet level?

A
  • Prolonged PT, PTT and thrombin time.
  • ↑ D-dimer titer
  • ↓ serum fibrinogen and platelet count (thrombocytopenia)
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18
Q

Treatment of DIC

A
  1. Correct underlying disorder (sepsis, bowel obstruction)
  2. If overt thrombosis occurs => heparin.
  3. Supportive care (platelet and factor replacement)
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19
Q

When would giving heparin be useful for DIC?

A

Only given if overt thrombosis is recognized, unfortunately thrombosis is often masked

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20
Q

Thrombotic Thrombocytopenic Purpura (TTP) quartad

A
  1. MAHA (microangiopathic hemolytic anemia)
  2. Thrombocytopenia (<50,000)
  3. Fever
  4. Neurological symptoms
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21
Q

Hemolytic Uremic Syndrome (HUS) pentad

A
  1. 4 TTP symptoms

2. + renal failure

22
Q

Histological findings of TTP

A
  1. Microangiopathic anemia - Schistocytes/helmet cells; “Waring blender effect”
  2. Hyaline thrombi, which occlude the capillaries of virtually every organ in body.
23
Q

What is TTP?

A

Disorder that causes thrombosis formation in small vessels, which consumes platelets and leads to thrombocytopenia due to

  • Hereditary mutation of ADAMTS13 (aka “vWF metalloprotease”/ eznyme that cleaves vWF)
  • Acquired via autoAB directed at ADAMTS13.
  • Normally, ADAMTS13 breaks down vWF multimers
  • With disease = large vWF multimers => abnormal platelet adhesion and microthrombi
24
Q

TTP typically occurs in _____

HUS typically occurs in _____.

A

TTP = Females

HUS = children

25
Q

Treatment of TTP

A
  1. Treat causative disorder

2. Plasmapheresis = life saving in 100% of cases. 100% mortality if not treated.

26
Q

What is vonWillebrand diseases?

A

Large group of diseases whose hallmark feature is decreased platelet adhesion to the endothelium due to decreased or absent vWF.

27
Q

Defects in platelet function may be seen in what conditions?

A
  1. Uremia = impaired platelet adhesion
  2. Dysproteinemias = interference with platelet membrane function
  3. AI disorders
28
Q

What is Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu)?

A

AD disorder caused by mutation in TGF-B signaling => defect in gene encoding endolin (CD105), a membrane glycoprotein on endothelial cell that causes dilated tortuous BV with thin walls that bleed easily => serious bleeding.

29
Q

Hereditary hemorrhagic telangiectasia is due to a defect in gene coding what?

A

Endoglin (CD105) a membrane glycoprotein strongly expressed on endothelial cells

30
Q

Clinical features of Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu)?

A
  1. Telangiectasias: appear gradually on skin, mucuous membranes, visceral tissue
  2. Bleeding: epistaxis is most common symptom
31
Q

Course and treatment of Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu)?

A

Benign clinical course: frequent bleeds but death is rare

Surgery and laser photoablation

32
Q

What are the 6 thrombotic disorders

A
  1. Anti-thrombin 3 deficiency
  2. Protein C and S deficiency
  3. Factor 5 Leidin Syndrome
  4. Prothrombin 20210
  5. Antiphospholipid Syndrome
  6. Superficial Venous Thrombosis
33
Q

Which acquired thrombotic disorder is often characterized by recurrent LE thrombophlebitis, DVT/PE, venous insufficiency and chronic leg ulcers?

A

Antithrombin III deficiency => ↓ of a serine protease that inhibits thrombin activation

Thus, ↑ conversion of prothrombin => thrombin (hypercoagulable state)

34
Q

Antithrombin III deficiency is associated with a significantly increased risk of DVT in whom?

A

Pregnant pt’s - due in part to pregnancy causing induced hypercoagulability

35
Q

Diagnosis of antithrombin III deficiency requires what?

A

↓ levels of AT-III in serum (<50% of normal activity)

36
Q

What is the treatment approach for AT-III deficiency, prophylactically and those with DVT; what about pt’s who do not respond?

A
  • Prophylactic anticoagulants for life

- If DVT, give high-dose heparin. If don’t respond => AT-III replacement therapy

37
Q

Protein C and S are dependent on ________.

What do protein C and S do?

A

Vitamin K.

Protein C = inactivates factor 5 and 8

Protein S = cofactor for protein C

38
Q

Which inherited deficiency is the cause of Warfarin-induced skin necrosis in some patients?

A

Protein C deficiency

39
Q

Which therapy is used to decrease the risk of thromboembolic disease in patients with Protein C and S deficiency; why must you be careful?

A
  • Warfarin
  • These proteins are depleted prior to other coagulation factors so there is a temporary increase in coagulation (as they are anticoagulant molecules)!!
  • Must be careful because the most common cause of hypercoagulable state from deficiency of these proteins is the initiation of warfarin therapy!!!
  • Pt needs to be on heparin first, and therapeutically anticoagulated before starting warfarin
40
Q

What is Factor V Leidin mutation?

A

Mutation of Factor 5 Leidin at the binding site for protein C => ↑ hypercoagulable/ thrombolic state

41
Q

Treatment of Factor V Leidin?

A

If no prior episodes, monitor.

Prior episodes: lifelong coagulation

42
Q

What is Prothrombin 20210?

Treatment?

A

G-A mutation resulting in ↑ activity of prothrombin and inability to deactivate prothrombin => ↑↑↑ risk of thrombosis

Treatment = same as Factor V Leidin

43
Q

What is anti-phospholipid syndrome?

A

AI disease that increases the risk of thrombosis as due to AB to phospholipid, such as anti-cardiolipin AB and lupus anticoagulant.

44
Q

What test do patients with APS test (+) for?

A

VDRL or RPR = false (+) because due to anticardiolipin AB.

45
Q

What are some of the common clinical presentations of someone with antiphospholipid syndrome?

A
  1. Thromboembolism
  2. Miscarriage
  3. Pre-mature births
  4. Cerebral ischemia and reccurent stroke (especially in young pt’s)
46
Q

What tests ID lupus anticoagulant in Anti-phospholipid syndrome?

A
  1. Prolonged PTT

2. Prolonged dilute Russell viper venom time (DRVVT) test

47
Q

What are associated features seen in Antiphospholipid syndrome?

A
  1. CT disease (>50% of cases)
  2. Valvular heart disease
  3. Coronary artery disease
48
Q

Diagnosis of APS

A
  1. Prolonged PTT
  2. Lack of correction in 1:1 mixing study (NL plasma + pts plasma)
  3. Neutralize inhibitor wit excess phospholipid to correct ABNLity
49
Q

What is the recommended tx for pt with antiphospholipid syndrome and no hx of thromboembolic disease vs. pt with a hx?

A
  • No hx: Observation: Current recommendation suggests no benefit for anticoagulation;
  • Prior hx: lifelong anticoagulation (warfarin) - don’t base off a single test! Multiple positive tests over a 3-12 month period are required for dx
50
Q

Which drugs can be used for Antiphospholipid Syndrome during pregnancy and pt’s with concurrent SLE?

A
  • Pregnancy: you can anticoagulate with SC heparin

- Hydroxychloroquine: may help ↓ thromboembolism in pt’s with APS and SLE

51
Q

Levels of what should be routinely monitored in pt’s with anticardiolipin antibodies or lupus anticoagulant?

A

Platelet levels since these can cause thrombocytopenia

SBL Test 2 (11 decks)

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