28 - Thrombophilic Disorders Flashcards
Hypercoagulable state
▪ 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.)
Thrombosis
▪ Fibrin, platelets and entrapped cells
▪ Leads to tissue ischemia and eventual necrosis
▪ Arterial (white thrombus) vs Venous (red thrombus)
Embolus
▪ 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
Virchow’s Triad
How Significant is Venous Thromboembolic (VTE) Disease?
- 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
Precipitating events for DVT
- ~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
Acquired Causes of VTE
▪ 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
Site of Thrombosis is Important for determining the cause
Venous Thrombosis
“Unusual Sites”
- 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
Incidence of Common Thrombophilia Disorders
Activated Protein C (APC)
Activated Protein C Resistance (APCR):
Decreased anticoagulant activity of APC resulting in more fibrin formation.
Activated Protein C Resistance
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
Factor V Leiden: Facts
▪ 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
Factor V Leiden: Genetics
▪ Founder mutation 30,000 years ago
▪ Incidence
▪ Caucasians 6 - 8%
▪ Hispanic 2%
▪ Indian/Pakistani 1- 2%
▪ Native American 1%
▪ African American 0 - 1.5%
Relative Risk of VTE
Homozygotes higher thrombotic risk than heterozygotes
Risk of Initial DVT
Leiden Thrombophilia Study
Factor V Leiden: Diagnosis
▪ 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
Factor V Leiden: Treatment
▪ 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.)
Prothrombin 20210
(a.k.a Factor II Mutation)
cause and effect
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
Prothrombin 20210: Genetics
▪ 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%
Prothrombin 20210: Facts
▪ Increased risk:
▪ Venous thrombosis
▪ DVT/PE
▪ Cerebral sinus
▪ ? Recurrent fetal loss (conflicting studies)
▪ No role of anticoagulation to prevent fetal loss
Prothrombin 20210: Diagnosis
▪ 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
Prothrombin 20210: Treatment
▪ 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
Protein C Deficiency
▪ 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
Protein C Levels
▪ 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
Protein C Deficiency - Clinical Manifestations
▪ 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
Protein C Deficiency: Diagnosis
▪ 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
Protein C Deficiency: Treatment
▪ 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
Protein S Deficiency
▪ Vitamin K dependent serine protease
▪ Chromosome 3 (3p11.1-3p11.2)
▪ Incidence: 2 out of 1,000
▪ Autosomal dominant with partial penetrance
Protein S Levels
▪ 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)
Protein S Deficiency
Clinical Manifestations
▪ Manifestations
▪ DVT, PE
▪ Purpura fulminans (particularly homozygotes)
▪ When PS <1%
▪ Homozygotes > Heterozygotes for increased
risk of thrombosis
Protein S Deficiency
Diagnosis/Treatment
▪ PS circulates in 2 forms:
▪ Inactive form bound to C4BP (~60% total PS)
▪ Free form (~40% total PS)
▪ Treatment:
▪ Anticoagulation (VKA, heparin, LMWH, DOAC)
Antithrombin III Deficiency
▪ 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)
Antithrombin Deficiency: Genetics
▪ Chromosome 1 (1q23-25)
▪ Incidence: 1 out of 1,000
▪ Autosomal dominant
▪ Point mutations > Gene deletions
▪ >250 mutations in ATIII
Antithrombin Deficiency
▪ Acquired deficiency:
▪ OCP
▪ Liver disease
▪ Burns
▪ DIC
▪ Malignancy
▪ Drugs/Chemotherapy (ie. Asparaginase)
▪ Nephrotic syndrome
Anti-thrombin Deficiency
Clinical Manifestations
▪ 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
Anti-thrombin Deficiency
Diagnosis/Treatment
▪ 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
Antiphospholipid Antibody Syndrome (APLS)
▪ 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)
Antiphospholipid Antibody Syndrome
Clinical Manifestations
▪ 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
Antiphospholipid Antibodies
▪ 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
Lupus Anticoagulant
▪ 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
APLS Serologic Antibodies
▪ 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
When To Think About
Lupus Anticoagulant?
▪ Any thrombotic event
▪ With Prolonged aPTT + PT
▪ Prolonged aPTT + PT with no bleeding history
▪ Other causes of thrombocytopenia
Lupus Anticoagulant
Etiology
▪ Idiopathic
▪ Connective tissue disease
▪ Malignancy
▪ Drugs:
▪ phenothiazine
▪ quinidine
▪ hydralazine
▪ procainamide
▪ Infections
Diagnosis Criteria for APLS:
Sydney Criteria
▪ 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
APLS Treatment
▪ 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
APLS Treatment
▪ 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
APLS Mortality
▪ 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%
Catastrophic APLS (CAPS) - diagnostic criteria
Catastrophic APLS (CAPS)
organ involvement and lab findings
CAPS Treatment
▪ High dose steroids
▪ Plasma exchange
▪ Anticoagulation
Other Thrombophilias
▪ Lipoprotein (a)
▪ Impairs plasminogen activation and fibrinolysis
▪ Increase MI/CVA – atherosclerotic plaques
▪ FVIII elevation
▪ Independent risk factor for VTE (FVIII >150%, ~5x)
▪ Controversial
Congenital Vascular Anomalies
(Somewhat Hereditary)
▪ 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
