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HemOnc > 28 - Thrombophilic Disorders > Flashcards

28 - Thrombophilic Disorders Flashcards

1
Q

Hypercoagulable state

A

▪ A state where thrombosis happens more often than normal; or imbalance between procoagulants and anticoagulants
▪ Recurrent thrombotic events in life-time; usually in younger age
▪ Family history of clots
▪ Unusual locations (abdominal, sagittal sinus, etc.)

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2
Q

Thrombosis

A

▪ Fibrin, platelets and entrapped cells
▪ Leads to tissue ischemia and eventual necrosis
▪ Arterial (white thrombus) vs Venous (red thrombus)

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3
Q

Embolus

A

▪ When a piece of thrombus breaks off and travels via circulatory system to a distant site
▪ DVT in lower extremity travelling to lungs causing PE (>90%)
▪ Risk of embolization lowers, the more distal you get in the extremity

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4
Q

Virchow’s Triad

A
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5
Q

How Significant is Venous Thromboembolic (VTE) Disease?

A
  • Annual US death rate
    – Influenza 51,537
    – Cancer 598,038
    – Highway 42,000
    – VTE 60,000-100,000
  • Incidence: 2-3 per 1000
  • 300,000-600,000 DVT/PE per year
  • 33% are recurrence of venous thromboembolism (VTE)
  • Age >70: 2-7 per 1000
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6
Q

Precipitating events for DVT

A
  • ~49% of hypercoagulable events in thrombophilic individuals have a precipitating event
  • Precipitating events
    – Venous stasis
    – Travel
    – Bedrest (immobilization; usually >2-3 days)
    – Surgery (post-operative period)
    – Pregnancy (post-partum)
    – Estrogen
    – Drugs
    – Advancing age
    – Inflammation
    – Trauma
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7
Q

Acquired Causes of VTE

A

▪ DIC
▪ TTP
▪ HIT
▪ PNH
▪ MPD (JAK2+)
▪ IBD
▪ OCPs/Estrogen
▪ Pregnancy
▪ Malignancies
(Trousseau syndrome)

▪ Products (ie. r-VIIa)
▪ Nephrotic Syndrome (ATIII def)
▪ Vasculitis (SLE)
▪ Intravascular Catheters
▪ Surgery
▪ Obesity
▪ Immobility
▪ Vascular anomalies
▪ COVID
▪ VITT

VITT=Vaccine-induced immune thrombotic thrombocytopenia

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8
Q

Site of Thrombosis is Important for determining the cause

A
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9
Q

Venous Thrombosis
“Unusual Sites”

A
  • Unusual Sites
    – Hepatic Vein
    – Mesenteric Vein
    – Portal Vein
    – Cerebral/Retinal Vein
  • Recurrent despite therapeutic anticoagulation

Think!!!
* Paroxysmal Nocturnal Hematuria (PNH)
* Antiphospholipid syndrome (APLS)
* Myeloproliferative disorders (MPD) with JAK2 mutation
* Malignancy

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10
Q

Incidence of Common Thrombophilia Disorders

A
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11
Q

Activated Protein C (APC)

A

Activated Protein C Resistance (APCR):
Decreased anticoagulant activity of APC resulting in more fibrin formation.

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12
Q

Activated Protein C Resistance

A

Factor V Leiden (90-95% of APCR cases)

▪ Resistant VIIIa
▪ Increased factor VIII
▪ Dysfunctional protein S
▪ Anti-APC antibodies
▪ Antiphospholipid antibodies
▪ Anti-protein S antibodies
▪ Factor V Cambridge
▪ Factor V Liverpool

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13
Q

Factor V Leiden: Facts

A

▪ 90-95% of APCR
▪ Factor V Arg 506Gln
▪ Mutant FVa resistant to APC inactivation
▪ Normal clotting function (normal PT & PTT), but 10x slower inactivation by APC

▪ 4-7x increased risk of VTE
▪ Not independent risk factor for arterial thrombosis
▪ Risk is life long

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14
Q

Factor V Leiden: Genetics

A

▪ Founder mutation 30,000 years ago
▪ Incidence
▪ Caucasians 6 - 8%
▪ Hispanic 2%
▪ Indian/Pakistani 1- 2%
▪ Native American 1%
▪ African American 0 - 1.5%

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15
Q

Relative Risk of VTE

A

Homozygotes higher thrombotic risk than heterozygotes

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16
Q

Risk of Initial DVT
Leiden Thrombophilia Study

A
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17
Q

Factor V Leiden: Diagnosis

A

▪ Coagulation studies normal: PT, aPTT, TT

▪ APCR Screening Test:

aPTT ratio: (aPTT + APC)/aPTT

Results:
> 2.0 = Normal
<2.0 = APCR
▪ Does not necessary conclude FVL mutation

▪ Confirming Diagnosis: FVL PCR (genetic testing)

▪ Test in first degree relatives after puberty and only in high risk VTE setting
(ie. planned for OCP, pregnancy, etc.) only if strong family history present

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18
Q

Factor V Leiden: Treatment

A

▪ Anticoagulation (VKA, heparin, LMWH, DOAC)
▪ Risk of recurrent VTE
▪ Heterozygote (OR 1.56, 95% CI (1.14-2.12))
▪ Homozygote (OR 2.65 (95% CI (1.2-6))

▪ Do not treat asymptomatic carriers
▪ Avoid OCPs mostly if strong family or personal history of clot
▪ DVT ppx in high-risk situations (ie. abdominal surgery, post-partum, etc.)

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19
Q

Prothrombin 20210
(a.k.a Factor II Mutation)
cause and effect

A

G → A substitution at 3’ untranslated region of nucleotide 20210

▪ Mutation causes:
▪ Increased promoter activity
▪ Prothrombin activity >125% of normal
▪ Increased thrombin generation

▪ Other variants:
▪ Prothrombin Yukuhashi
▪ C20209T
▪ A19911G

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20
Q

Prothrombin 20210: Genetics

A

▪ Autosomal dominant inheritance
▪ Incidence:
▪ Caucasian 2-3%
▪ Israel 4%
▪ Southern European 3%
▪ Northern European 1.7%
▪ African –American 0.4%
▪ Asian 0.4%
▪ Native-Americans 0%

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21
Q

Prothrombin 20210: Facts

A

▪ Increased risk:
▪ Venous thrombosis
▪ DVT/PE
▪ Cerebral sinus
▪ ? Recurrent fetal loss (conflicting studies)
▪ No role of anticoagulation to prevent fetal loss

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22
Q

Prothrombin 20210: Diagnosis

A

▪ Coagulation studies normal: PT, PTT, TT

▪ Factor II activity (assay and antigen) unreliable if serologically tested

▪ Diagnosis: PCR (genetic testing)

▪ Test in first degree relatives after puberty and only in high risk VTE setting (ie. planned for OCP, pregnancy, etc.) only if strong family history present

23
Q

Prothrombin 20210: Treatment

A

▪ Anticoagulation (VKA, heparin, LMWH, DOAC)
▪ Duration based on provoked vs unprovoked CHEST guidelines
▪ Avoid OCPs
▪ DVT ppx in high-risk settings

▪ Duration of AC should not be based on heterozygote status
▪ Risk of recurrent VTE
▪ Heterozygosity did not result in risk of recurrent VTE

▪ Population data for homozygote not available with recurrent VTE
▪ Some studies suggest increased risk of MI/CVA, but meta-analysis studies has not found association

24
Q

Protein C Deficiency

A

▪ Vitamin K dependent serine protease:
▪ [APC/PS/thrombomodulin] degrade FV and FVIII
▪ Reduce plasma PC levels by 50% → VTE

▪ Chromosome 2 (2q13-q14)
▪ Incidence 3 out 1000
▪ Autosomal dominant with partial penetrance
▪ >180 mutations
▪ Type I: variable mutations
▪ Type II: missense mutations

25
Q

Protein C Levels

A

▪ T1/2: 8-10 hours
▪ Newborn (25-45%) and increases until adolescence
▪ Adults (70-140% normal range)
▪ Then increase by 4% per decade

▪ Acquired deficiency throughout lifetime
▪ Vitamin K deficiency (nutritional)
▪ Warfarin
▪ Liver disease
▪ DIC/Sepsis, particularly meningococcemia
▪ Acute thrombosis
▪ Malignancy
▪ Lupus anticoagulant

26
Q

Protein C Deficiency - Clinical Manifestations

A

▪ Manifestations
▪ DVT/PE
▪ Mesenteric vein thrombosis
▪ **Purpura fulminans **(homozygotes particularly)
▪ PC activity < 5%
▪ Heterozygotes treated with warfarin

▪ Homozygotes > Heterozygotes for increased risk of
thrombosis
▪ 40-50% of heterozygotes experience VTE by age 50

27
Q

Protein C Deficiency: Diagnosis

A

▪ Levels should not be checked when patients on oral anticoagulants or in setting of acute thrombosis, because it will be falsely low
▪ Distinction between the two, not clinically relevant

28
Q

Protein C Deficiency: Treatment

A

▪ Anticoagulation (VKA, heparin, LMWH, DOAC)
▪ Human Protein C Concentrate

▪ Virally inactivated pooled plasma product (FFP)
▪ Indications:
▪ Prophylaxis and/or treatment of VTE or purpura fulminans in protein C deficiency

29
Q

Protein S Deficiency

A

▪ Vitamin K dependent serine protease

▪ Chromosome 3 (3p11.1-3p11.2)
▪ Incidence: 2 out of 1,000
▪ Autosomal dominant with partial penetrance

30
Q

Protein S Levels

A

▪ T1/2: 40-60 hours
▪ Levels increase with age

▪ Acquired deficiency:
▪ Pregnancy
▪ OCP/estrogen
▪ Vitamin K deficiency/warfarin/liver disease
▪ Acute thrombosis
▪ DIC
▪ Malignancy
▪ Sepsis/infection/inflammation
▪ Drugs (ie. Asparaginase)

31
Q

Protein S Deficiency
Clinical Manifestations

A

▪ Manifestations
▪ DVT, PE
▪ Purpura fulminans (particularly homozygotes)
▪ When PS <1%

▪ Homozygotes > Heterozygotes for increased
risk of thrombosis

32
Q

Protein S Deficiency
Diagnosis/Treatment

A

▪ PS circulates in 2 forms:
▪ Inactive form bound to C4BP (~60% total PS)
▪ Free form (~40% total PS)

▪ Treatment:
▪ Anticoagulation (VKA, heparin, LMWH, DOAC)

33
Q

Antithrombin III Deficiency

A

▪ Serine protease (t1/2: 2.5-5 days)
▪ Inactivates IIa, IXa, Xa, XIa, XIIa, plasmin, kallikrein
▪ ~50% reduction in AT levels → VTE
▪ Activity increased 1,000x by glycosoaminoglycans (heparin)

34
Q

Antithrombin Deficiency: Genetics

A

▪ Chromosome 1 (1q23-25)
▪ Incidence: 1 out of 1,000
▪ Autosomal dominant
▪ Point mutations > Gene deletions
▪ >250 mutations in ATIII

35
Q

Antithrombin Deficiency

A

▪ Acquired deficiency:
▪ OCP
▪ Liver disease
▪ Burns
▪ DIC
▪ Malignancy
▪ Drugs/Chemotherapy (ie. Asparaginase)
▪ Nephrotic syndrome

36
Q

Anti-thrombin Deficiency
Clinical Manifestations

A

▪ DVT, PE
▪ Mesenteric vein thrombosis
▪ Heparin Resistance: inability to anticoagulated
patients with heparin (ie. ECMO, CABG)
▪ Thrombosis is more severe compared to FVL,
prothrombin, PS and PC deficiency
▪ High risk of VTE in pregnant patients
▪ Presents usually in younger age after puberty
▪ Risk of VTE increases with age afterwards

37
Q

Anti-thrombin Deficiency
Diagnosis/Treatment

A

▪ Diagnosis:
▪ Decreased AT activity (<50%)

▪ Treatment:
▪ Heparin if enough AT activity is present (>50%)
▪ If not enough AT activity
▪ AT concentrate
▪ Use alternative anticoagulant (DOAC, DTI)
▪ Because of increased risk recurrent VTE, usually life-long
anticoagulation is needed

38
Q

Antiphospholipid Antibody Syndrome (APLS)

A

▪ Autoimmune/hypercoagulable disorder where antiphospholipid antibodies (aPL; autoantibodies) develop against phospholipid and phospholipid binding proteins causing arterial/venous thrombotic events +/- miscarriages

▪ Can be found in 5% of general population
▪ APLAs found in 50% of patients with SLE
▪ 30% of these meet the diagnostic criteria of APLS

▪ aPL antibodies:
▪ Lupus anticoagulant (LA)
▪ Anticardiolipin antibodies (aCL)
▪ β2-glycoprotein-1 antibodies (B2GP)

39
Q

Antiphospholipid Antibody Syndrome
Clinical Manifestations

A

▪ Venous Thromboembolism (DVT/PE)
▪ Arterial thrombosis
▪ Strange site thrombosis
▪ Recurrent thrombosis
▪ Recurrent miscarriage

▪ Livedo reticularis rash
▪ Sneddon Syndrome
▪ LR rash + cognitive deficits

▪ Cognitive dysfunction

▪ Catastrophic antiphospholipid syndrome (CAPS) or Asherson’s Syndrome
▪ Multiple thrombotic events affecting small vessel circulation to organs – 50% chance of mortality

▪ Valvular heart thickening, Libman-Sacks endocarditis
▪ Splenic infarcts
▪ Amaurosis Fugax
▪ Avascular necrosis

40
Q

Antiphospholipid Antibodies

A

▪ Coagulation Assays
▪ PTT with mixing study does not correct = inhibitor
▪ Lupus anticoagulant +
▪ Hexagonal phase confirmation
▪ Determining if antibody is phospholipid dependent
▪ Dilute Russell Viper Venom Test (DRVVT)
▪ Venom from Vipera russelli that activates directly FV and FX,
bypassing FVII, FVIII, IX, XI, XII
▪ Sensitive to presence of beta 2 glycoprotein antibodies
▪ Detecting other LA that do no raise PTT

▪ Serologic (ELISA)
▪ Anticardiolipin antibodies
▪ B2-glycoprotein-1 antibodies

41
Q

Lupus Anticoagulant

A

▪ Hexagonal phase
▪ Baseline PTT
▪ Incubate plasma with hexagonal phase phospholipid which will bind antiphospholipid antibodies
▪ Centrifuge to remove hexagonal phospholipid
▪ Repeat PTT
▪ Report difference in times or ratio of times
▪ >8 sec is positive

42
Q

APLS Serologic Antibodies

A

▪ B2-glycoprotein and anti-cardiolipin antibodies
▪ Different antibodies from LA
▪ Do not affect coagulation cascade
▪ ELISA Testing
▪ Repeat in 3 months to demonstrate persistence
▪ Transient, infection-related anti-cardiolipin Ab are not a thrombotic risk
▪ B2-glycoprotein Ab not associated with infection

43
Q

When To Think About
Lupus Anticoagulant?

A

▪ Any thrombotic event
▪ With Prolonged aPTT + PT
▪ Prolonged aPTT + PT with no bleeding history
▪ Other causes of thrombocytopenia

44
Q

Lupus Anticoagulant
Etiology

A

▪ Idiopathic
▪ Connective tissue disease
▪ Malignancy

▪ Drugs:
▪ phenothiazine
▪ quinidine
▪ hydralazine
▪ procainamide

▪ Infections

45
Q

Diagnosis Criteria for APLS:
Sydney Criteria

A

▪ Clinical Criteria
▪ Venous / arterial thrombosis
▪ Miscarriages: 3x <10 weeks or 1x >10 weeks

▪ Laboratory Criteria
▪ LA +
▪ IgG/IgM aCL antibodies
▪ IgG/IgM B2GP antibodies
▪ Present 12 weeks apart

46
Q

APLS Treatment

A

▪ Anticoagulation long-term if thrombosis+
▪ ~30% per year; 50-70% recurrence risk

▪ If asymptomatic patient without thrombosis and has lupus anticoagulant, no anticoagulation is needed unless patient having surgery or pregnancy, where DVT prophylaxis is recommended

47
Q

APLS Treatment

A

▪ Warfarin vs ASA Recurrent Stroke Study (WARSS)
▪ Mean age: 62.5 years
▪ Secondary ppx: Warfarin vs ASA 325mg
▪ No difference

▪ INR goal 2-3; high intensity regimens not proven beneficial (ie. INR 3-4)

▪ TRAPS Trial
▪ Rivaroxaban vs warfarin in 120 “high-risk” APS pts
▪ 1.5 years follow up; 12% vs 0%
▪ Support use of warfarin in APLS

48
Q

APLS Mortality

A

▪ Increased morbidity/mortality
▪ Mean age 59, SD 14 years (n=1000)
▪ Decreased Overall survival (90.7% at 10 years)

Causes of death
▪ VTE 31%
▪ Sepsis 27%
▪ Malignancy 14%
▪ Hemorrhage 11%
▪ SLE 8%
▪ CAPS 5%

49
Q

Catastrophic APLS (CAPS) - diagnostic criteria

A
50
Q

Catastrophic APLS (CAPS)
organ involvement and lab findings

A
51
Q

CAPS Treatment

A

▪ High dose steroids
▪ Plasma exchange
▪ Anticoagulation

52
Q

Other Thrombophilias

A

▪ Lipoprotein (a)
▪ Impairs plasminogen activation and fibrinolysis
▪ Increase MI/CVA – atherosclerotic plaques

▪ FVIII elevation
▪ Independent risk factor for VTE (FVIII >150%, ~5x)
▪ Controversial

53
Q

Congenital Vascular Anomalies
(Somewhat Hereditary)

A

▪ Varicose veins

▪ Absence of inferior vena cava
▪ 0.5% incidence
▪ 5% of DVT under age 20-40

▪ Paget-Schroetter syndrome (spontaneous upper extremity DVT)
▪ Anomaly at thoracic outlet w compression of vein between either 1st rib and hypertrophied scalene or subclavius tendon

▪ May-Thurner syndrome
▪ Compression of left common iliac vein by overlying right common iliac artery

▪ Klippel-Trénaunay-Weber or hemangiectatic hypertrophy
▪ port wine stain
▪ venous malformations
▪ lymphatic hypoplasia
▪ soft tissue/bone hypertrophy

HemOnc (29 decks)

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