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Coagulation > Thrombophilia- Lab Assessment CH 14 & CH 9&19 (algorithmic) > Flashcards

Thrombophilia- Lab Assessment CH 14 & CH 9&19 (algorithmic) Flashcards

1
Q

What are some common things to

know about thrombophilia?

A
  • hereditary thrombophilias only marginally increase the risk of VTE and recurrence
  • there is no evidence that a negative lab thrombophilia panel is associated with lower risk of recurrence
  • clinical risk factors typically outweigh genetic ones in management
  • recurrent VTE is common after the initial unprovoaked VTE
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2
Q

What recurrence risk of VTE is

used to weight the benefits vs. risks of anticoagulation?

A
  • recurrence risk of >5% in the first year would outweigh the risk of long term anticoagulation
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3
Q

What are the 2 main lab findings

that could portend a clinically significant increased

risk of recurrent VTE if anticoagulation is stopped ?

A
  • antiphospholipid antibodies
  • antithrombin III deficiency
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4
Q

What is associated with VTE formation

in family members ?

A
  • unprovoked VTE at a young age (<45 years)
    • assocaited with increased risk of VTE in family members
    • the risk is further increased if it occurs in multiple family members

Note: Factor V Leiden and PT gene mutations are rather weak predictors

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5
Q

What is the relationship between

estrogen supplementation and thrombosis ?

A
  • dose dependent increased risk of thrombosis
  • thought to be related to altered levels of clotting factors
  • synergistic effect with hereditary causes, particularly Factor V leiden
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6
Q

What is key to know about Antithrombin III ?

A
  • also called Heparin cofactor I
  • synthesized in the liver
  • half life is 2.8-4.8 days
  • Inhibits
    • thrombin (factor II)
    • IXa, Xa, XIa, and XIIa
  • accelerated 1000x by Heparin
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7
Q

What is the inheritance pattern of

Antithrombin III ?

A
  • autosomal dominant with variable penetrance
    • Type I deficiency
      • quantitative
      • homozygous deficiency is lethal
    • Type II deficiency
      • qualitative
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8
Q

What are the three types of

type II defects in Antithrombin III ?

A
  • Type II reactive site (RS), defect in the thrombin binding site
  • Type II heparin binding site (HBS)
    • most common
    • least thrombophilic mutation
      • exception is the homozygous type that develops thrombosis early on in life
  • Type II PE
    • produces a conformational change that affects binding to heparin and thrombin
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9
Q

How is testing for antithrombin III deficiency performed ?

A
  • first line testing
    • functional assay - Heparin cofactor activity
      • chromogenic assay
    • detects all types of antithrombin III defects
    • performed by adding heparin to patient plasma which will bind to patient’s antithrombin III
      • then exogenous thrombin and/or factor Xa is added
      • once the antithrombin III activity is exceded there is light emittance
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10
Q

What is a pitfall in treatment with heparin

derivatives when evaluating Antithrombin III ?

A
  • derivative of heparin reduce antithrombin III levels
  • other anticoagulants may cause increases in levels
    • lead to false positive
  • direct factor Xa inhibitors may lead to an overestimation of ATIII IF using a Xa based assay
    • direct thrombin inhibitors may lead to overestimation of ATIII in thrombin based assays
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11
Q

What are causes of acquired antithrombin III

deficiencies ?

A
  • acute thrombosis
    • transiently reduces Antithrombin III
  • cirrhosis
    • leads to reduced synthesis of both procoagulant and anticoagulant proteins
  • nephrotic syndrome
    • reduces ATIII levels in the absence of clotting
  • protein losing enteropathies
  • ECMO
    • due to heparin, consumption, and dilutional defects
    • may lead to heparin resistance
  • heparin therapy
    • reduces ATIII by 30%
    • likely due to increased clearance of heparin:ATIII complexes
  • burns- levels correlate with the extent of thermal injury
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12
Q

How does aspariginase therapy (frequently seen in

treatment for B-ALL) affect ATIII levels ?

A
  • asparaginase impairs the synthesis of proteins that contain asparagine
    • ATIII is one of them
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13
Q

What is the odds ratio and clinical

presentation of ATIII deficiency ?

A
  • first VTE OR is 16
  • at risk of recurrent VTEs if they stop anticoagulation
  • low levels of ATIII
    • lead to heparin resistance, where you need higher levels to reach anticoagulation
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14
Q

Which medications do not require

antithrombin III levels in order to work ?

A
  • direct Xa inhibitors and direct thrombin inhibitors
  • their actions are not affected by low ATIII levels
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15
Q

Can people with ATIII deficiency develop

arterial thrombosis ?

A
  • arterial thrombosis has been documented but is uncomon and may not actually be associated with this
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16
Q

What is the mechanism of action of

Protein C ?

A
  • synthesized in the liver and is vitamin K dependent
  • Protein C when activated is a serine protease
    • primary function is to prevent clot extension into areas of intact endothelium
    • thrombomodulin
      • found on intact endothelium
      • thrombomodulin binds thrombin and alters it’s function
        • promotes cleavage of protein C into a functional protein C
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17
Q

Where is protein C located and

what is it’s function ?

A
  • localized to the area of thrombomodulin
    • connected by endothelial cell C protein
  • activated C
    • cleaves factor Va and VIIIa
    • thus slowing clot formation
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18
Q

What are the protein C deficiencies?

A
  • Type I deficiency (most common type)
    • quantitative
    • decreased protein with full function
  • Type II deficiency
    • qualitative
    • dysfunctional
  • Protein C deficiency is autosomal dominant
    • rare homozygotes may present with neonatal purpura fulminans

Note: acquired protein C deficiency is much more common

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19
Q

What testing is performed to evaluate for

Protein C deficiency ?

A
  • functional assays detect most types of Protein C deficiency
    • 2 types of assays: clot based and chromogenic
    • both use venom from the southern copperhead snake which activates protein C
      • clot based tests (use either a PTT or Russell viper venom clotting time) suffer from lots of interference
        • DOACs or lupus anticoagulants can cause false increases in protein C
      • elevations of VIII and factor V leiden can falsely decrease protein C activity
    • chromogenic assays are preferred due to the interferences
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20
Q

How does the chromogenic assay work

for the Protein C functional assay ?

A
  • southern copperhead snake venom is added to the patient’s plasma
    • this activates protein C
  • a chromogenic protein C substrate is added and when cleaved emits a light detected by spectrophotometry
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21
Q

How do protein C levels vary in

certain normal conditions ?

A
  • levels are significantly lower in neonates
  • levels increase throughout childhood and may not reach final levels until age 30
  • increase in normal pregnancy and postpartum
    • in contrast to protein S which decreases
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22
Q

If low levels of protein C are found

on the chromogenic assay, what subsequent

test is performed ?

A
  • immunoassay to determine levels
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23
Q

What can cause an

acquired protein C deficiency ?

A
  • acute thrombosis
  • cirrhosis cause reduced production
  • DIC, with severe purpura fulminans in meningococcal disease
  • Vitamin K or Warfarin
  • Nephrotic syndrome
  • L-asparaginase therapy
24
Q

What types of VTE can

occur in protein C deficiency ?

A
  • cerebral venous thrombosis
  • splanchnic vein thrombosis
25
Q

What are some important facts

about protein S ?

A
  • synthesized in the liver, vitamin K dependent
  • does not have direct enzymatic activity
    • is a cofactor for protein C
  • approximately 70% is bound in a 1:1 ratio to the complement regulatory protein C4b-binding protein
    • 30% free protein S is responsible for most of the activity
  • 3 types of deficiencies
    • Type I- quantitative
    • Type II- qualitative
    • Type III- decreased free protein S antigen but normal total protein levels
26
Q

How is protein S deficiency inherited ?

A
  • autosomal dominant
  • rare homozygotes get neonatal purpura fulminans
27
Q

How is testing for protein S deficiency conducted?

A
  • functional assay NOT recommended up front
    • technically difficult
    • functional protein S deficiencies are rare (type II)
    • clot based assay technique
      • DOACs and Lupus anticoagulants falsely increase protein S levels
      • increased Factor VIIIa and Factor V leiden falsely decrease protein S levels
      • also SUPER sensitive to pre-analytical variables (~10% of cases)
  • preferred test is the quantitative test
28
Q

How is the quantitative protein S test performed ?

A
  • preferred initial evaluation
  • both total protein S levels and free protein S levels are important
    • total protein S levels should not be ordered in isolation because there is poor correlation with thrombosis
  • IMP
    • free protein S levels of < 33% correlate with VTE
      • many patients have mutations in protein S
29
Q

What are causes of acquired protein S

deficiency ?

A
  • acute thrombosis
  • cirrhosis
  • pregnancy
  • oral contraceptives
  • DIC
  • Vitamin K deficiency or Warfarin therapy
  • nephrotic syndrome
  • newborns (healthy) have 15-30% of adult levels of total protein S
    • but C4b binding is also less so free protein levels are about the same
30
Q

What are the most common presentations

of patients with protein S deficiency ?

A
  • DVT and PE
  • splanchnic vein thrombosis
31
Q

What is the cause of Factor V Leiden?

A
  • caused by a single nucleotide polymorphism in the factor V gene that changes arginine 506 to glutamine
  • arginine 506 is the normal cleavage site for activated protein C
    • mutation here leads to slower inactivation of Va
    • thus there is more thrombin generation
32
Q

What is the testing for Factor V leiden ?

A
  • genetic testing for the mutation is standard
  • can do a functional assay but not necessary because most cases are caused by the single mutation
33
Q

What ethnicity is factor V Leiden most common ?

A
  • European ancestry
    • 4-5% of white individuals
    • many are heterozygous for the mutation
  • most patients never experience a VTE and of those that do fatal VTE is very rare
34
Q

What clinical manifestations are seen

with Factor V leiden ?

A
  • DVT and PE
  • cerebral vein thrombosis
  • portal/hepatic vein thrombosis
35
Q

What is the prothrombotic mechanism

of the prothrombin mutation ?

what is the mutation ?

A
  • mutation: G20210
  • there is an increase in the prothrombin plasma levels
    • increases PT mRNA and ultimately protein
    • leads to increased thrombin formation
    • enhanced tendency to clot
  • test for by genetics
36
Q

Why is testing for plasma PT

levels not recommended ?

A
  • becuase the levels fluctuate throughout the day normally
37
Q

Are patients with the PT gene mutation

at risk for recurrent VTE ?

A
  • No
38
Q

Which coagulation test do Lupus

anticoagulants affect more ?

A
  • PTT more often affected
  • PT less often affected because there is a higher amount of excess phospholipid in the test
39
Q

What is the source of extra phospholipid

for determining lupus anticoagulantS?

A
  • frozen washed platelets
    • aka platelet neutralization procedure (PNP)
  • purified hexagonal phase array phospholipids
  • LA-insensitive phospholipid

Note: all of these are clot based assays

40
Q

What factors can confound

LA testing ?

A
  • anticoagulant medication
  • factor deficiency
  • specific factor inhibitor
41
Q

What is the association between

increased factor VIII levels and VTE ?

A
  • appear to increase VTE risk in a dose-dependent manner
  • no definite cutoff that defines the disorder for how high the levels need to be
  • independent risk factor for first unprovoaked DVT
42
Q

What are common things that can

elevate factor VIII?

A
  • aging
  • acute phsyiologic stress (epinephrine)
  • liver disease
  • pregnancy
  • possibly warfarin
43
Q

Where is factor VIII produced ?

A
  • made in specialized hepatic sinusoids
  • IMP:
    • most other factors are made in the hepatocytes themselves
  • most factor VIII circulates noncovalently bound to von Willebrand factor (vWF)
  • lots of variability in levels in different people
    • 50% of variability may be related to blood type
    • type O blood has lower levels of FVIII and vWF (due to faster clearance)
44
Q

What are acquired causes of elevated

factor VIII ?

A
  • acute thrombosis
    • levels may remain high for up to 6 months
  • Warfarin therapy
  • cirrhosis
  • normal aging
  • pregnancy
  • African American race
45
Q

please see pg. 254 for a list of

minimal or null increase in thrombophilia

A
46
Q

When should testing for protein C

deficiency occur ?

A
  • delay testing for 4 weeks after discontinuing Warfarin
  • delay testing for several days after factor Xa inhibitors

Note: elevated protein C levels are of no significance

47
Q

How does heparin affect the clot-based

functional assay for Protein C activity ?

A
  • it will overestimate protein C activity
    • also seen with direct thrombin inhibitors or factor Xa anticoagulants
    • a specific factor inhibitor
    • or lupus anticoagulant
48
Q

What is the type I protein S

deficiency?

A
  • accounts for 80% of inherited forms
  • concordant reductions of total protein S antigen, free protein S antigen and protein S activity
49
Q

What is the type II protein S

deficiency ?

A
  • due to protein S mutations that lead to a dysfunctional protein
  • decreased protein S activity
  • normal free protein
  • normal total protein S antigen
50
Q

What is type III protein S

deficiency ?

A
  • debateable if this even exists
  • low activity
  • normal total S protein
  • low free protein S antigen

Note:

  • attributed to an increased binding affinity of protein S for C4bBP
  • but it could just be seen due to age related increases in C4bBP

IMP: acquired protein S deficiency is much more common

51
Q

Why do protein S activity and free protein S

antigen decrease with some combined

hormone OCPs and/or pregnancy ?

A
  • usually do to increased hepatic synthesis of C4b binding protein
52
Q

Where is antithrombin produced

and what is it’s function ?

A
  • produced in the liver
  • inactivates factor Xa and thrombin (factor IIa)
  • accelarated by Heparin
  • Type I mutation
    • hyposynthesis
    • antigen=activity
  • Type II mutation
    • dysnfunctional protein
    • antigen > activity
    • there are 3 subtypes
53
Q

How is antithrombin affected by

hemodilution ?

A
  • hemodilution from cardiopulmonary bypass reduces the response of antithrombin to heparin
54
Q

How is antithrombin measured ?

A
  • chromogenic assay
    • in the presence of heparin (heparin cofactor activity)
    • or absence of heparin (progressive antithrombin activity)
    • use of bovine thrombin or human factor Xa is needed
      • because they are not inactivated by Heparin cofactor II, which is another plasma protein with inhibitor activity
55
Q

What are the advantages of the

heparin cofactor activity antithrombin assay ?

A
  • sensitive for all types of antithrombin deficiency
  • superior precision and accuracy
  • lack of interference from all types of coagulation factor activities, lupus anticoagulants, or heparin

Because it is a measure of optical density things that interfere include:

  • high concentrations of hemoglobin, bilirubin, and triglycerides
56
Q

What has homocysteine been implicated as a

risk factor for?

A
  • implicated as a risk factor for venous thrombosis, coronary artery disease, MI and stroke
  • no mitigation in thrombosis risk by treating elevated homocysteine levels with vitamin B12 and B6

Coagulation (17 decks)

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