Prothrombotic Disorders

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    Introduction

    • Thrombosis occurs when delicate balance between prothrombotic and anticoagulant forces disturbed.
    • Classic Triad: (Virchow's triad)
    1. Stasis (Accumulated coagulation proteins)
    2. Hypercoagulability (Synergizes with stasis/vascular damage to tip balance)
    3. Vascular Damage (Exposes tissue factor TF and collagen, reduces conc of antithrombotics)

    Overview

    • Inherited Thrombophilia
    • Type Risk of VTE

      Recurrent

      VTE?

      How Common Diagnosis / Notes
      Factor V Leiden (FVL)

      LOW

      (homo- 1.8%/year)

      (hetero- 0.5%/year)

      NO!

      MOST COMMON

      - Activated Protein C resistance assay

      - Confirmed by: PCR-based DNA testing

      Prothrombin Mutation

      (PGM) [G20210A mutation]

      LOW

      (hetero --> 2.5x)

      (Recurrence unlikely)

      NO! COMMON  

      Antithrombin Deficiency

      (ATD)

      HIGHER

      (Initial: 1.8%/y

      Recurrence: Rate 55%)

      YES RARE - Antithrombin Activity Assay
      Protein C & S Deficiency

      MODERATE

      (Initial: 1.5%

      Recurrence: 6.2%/y)

      YES RARE  
      Dysfibrinogenemia    

      RARE

      (Primary) 

      - Disproportionate reduction in fibrinogen

        activity compared with antigen levels.

      - OR: Reptilase Time (from snake)

      - Can bleed or clot.

     

    • Acquired Thrombophilias
      • More common, and often greater thrombotic risk than inherited thrombophilias.
    • Syndrome Risk of VTE Diagnosis/Notes
      Antiphospholipid Syndrome

      VERY HIGH (Highest!)

      (Venous and Arterial)

      - Clinical + Lab evidence

      (Lab Evidence: Anticardiolipin,

      Anti-β2-Glycoprotein, Lupus Anticoagulant)

      - Use Anti-Xa to monitor UFH (or LMWH), PTT unreliable

       in lupus anticoagulant.  Long-term anticoag w/ warfarin.

      Catastrophic Antiphospholipid

      Syndrome

      VERY RARE

      LIFE Threatening (48% mort.)

      Disseminated microvascular

      thrombosis, multi-organ failure.

      - Anticoagulation

      - High dose corticosteroids, IVIG, plasma exchange.

      Cancer

      High: Pancreatic, Brain

      Med: Lung, Lymphoma

      Low: Prostate, Breast

       
      Surgery

      - Inpatient surgery (70 fold incr)

      - Outpatient surgery (10-fold)

      - Hip, Knee arthroplasty, and cancer surgery = highest risk

      Other:

      - Acquired Protein C/S deficiency 

      - Antithrombin deficiency

      - Dysfibronogenemia

      Variable

      - In acute thrombosis, liver disease, anticoagulant therapy

      - Antithrombin deficiency (Nephrotic Syndrome)

      - Protein S deficiency (estrogen therapy, incr C4b)

      - Vitamin K Deficiency (Protein C & S)

      - Dysfibrinogenemia: Cirrhosis,  liver cancer, renal cell ca.

     

    Indications for Thrombophilia Testing

    • Big debate around whether it's valuable.
    • More common disorders are not associated with recurrent thrombosis (in heterozygotes), such as Factor V Leiden and Prothrombin mutation.
      • and most higher-risk syndromes (like AT3 deficiency) are RARE.
    • Thrombophilia testing often does not change management
    • Provoked vs. Unprovoked is a better indicator of recurrence.
    • Testing "higher risk" groups may increase yield:
      • Younger patients ≤ 40yo
      • Patients with positive family hx (1st deg. relative with VTE)
      • Patients with idiopathic VTE
      • VTE in unusual sites
      • Recurrent VTE
      • Warfarin skin necrosis
      • Pediatric patients with purpura fulminans
      • Patients planning future pregnancies.
    • When to screen?
      • Affected by Acute Thrombosis Unaffected by Acute Thrombosis

        - Antithrombin

        - Protein C

        - Protein S

        - Dysfibronogenemia

         

        (Must wait until after off of

        anticoagulants x2-4weeks)

        - Factor V Leiden

        - Prothrombin G20210A

    • Bottom Line:
      • DO NOT test for inherited thrombophilia disorders in the setting of an acute thrombus!
        • One you can test for (genetic) have no increased recurrence rate, and others are inaccurate.
      • If you must test, test only >2weeks after anticoagulation is finished
      • Generally does not change the management.
      • Best predictor of recurrent thromboembolism is "unprovoked" vs. "provoked".
        • Many unprovoked VTE patients are on lifetime of anticoagulation, but a discussion of risks/benefits needs to be done with the patient.

     

    • Some clinicians do D-Dimer 2 weeks before stopping anticoagulation as an indicator for recurrence risk (if high, continue anticoagulation), and also repeat 2 weeks after stopping to re-check risk.

    Inherited

     

    • Least potency, more common
      • Factor V Leiden
        • (MOST COMMON 5% of Caucasians, 2% of Latinos, 1% of African-Americans, 0.5% Asian)
      • Prothrombin G20210A mutation
    • Most potent and most rare: (1 in 4000 -6000)
      • Antithrombin Deficiency
      • Protein C & Protein S Deficiencies

     

    Factor V Leiden

    • MOST COMMON inherited thrombophilic disorder
      • 5% of Caucasians, 2% of Latinos, 1% of African-Americans, 0.5% Asian
    • Pathophysiology:
      • Thrombin binds endothelial receptor thrombomodulin --> Protein C is activated to "Activated Protein C"
      • When Protein S is a cofactor, activated protein C inhibits Factor V and Factor VIII.
      • Factor V Leiden is a mutation making it resistant to activated protein C --> cause persistently active Factor V.
      • Factor V heterozygocity and homozygocity both increase risk of VTE (between 2-5 fold)
        • DO NOT increase risk of arterial thrombosis.
        • Heterozygocity (2-5x VTE incidence, absolute annual risk 0.5%)
        • Homozygous (up to 50x VTE incidence, absolute annual risk 1.8%)
    • Pts with OCP, immobility, pregnancy synergize with Factor V Leiden to increase VTE risk.
    • Diagnosis:
      • Activated Protein C Resistance Assay --> Abnormal
      • DNA Testing (PCR-based) to check for mutation.
    • NOTE: Does not appear to be a risk factor for recurrent thrombosis

     

    Prothrombin Mutation (PGM)

    • Prothrombin G20210A mutation (PGM) --> 1-2% of non-Hispanic Whites, Mexican Americans.
    • Most common inherited cause of thrombosis (although risk is low, and it's not common)
    • Mutation stabilizes non-translated region of prothrombin mRNA --> increases prothrombin protein levels.
      • Heterozygous --> 30% more prothrombin  --> 2.5x risk of VTE
      • Homozygous --> 70% more
      • Double-heterozygous Factor V Leiden + Prothrombin = 7x increased risk of VTE (5x recurrence risk)
    • Diagnosis:
      • PGM DNA testing
    • NOTE: This does not appear to be a risk factor for recurrent thrombisis.

     

    Antithrombin Deficiency (ATD)

    • RARE, but reasonably high risk of thrombosis
    • Pathophysiology:
      • Antithrombin (used to be AT3, but no 1 or 2, so removed number) endogenous antithrombotic protein that inhibits serine proteases (thrombin and factor Xa).  
      • Heparin/LMWH/fondaparinux usually accelerates Antithrombin activity several thousand-fold. 
    • 1.8%/year additional risk of thrombosis (recurrence rate of 55%)
    • Venous + Arterial (under FVL and PGM)
    • Rarely causes heparin resistance
    • Various types:
      • Type I - impair protein synthesis (high risk of VTE)
      • Type II - Mutations affecting thrombin (type IIa) and heparin (IIb) binding sites.
    • Diagnosis:
      • Antithrombin activity assay (detects all 3 types).

     

    Protein C & S

    • Protein C (anticoagulant)
      • When thrombin binds to endothelial receptor (thrombomodulin) activates protein C.  Protein C (cofactor protein S) binds to inactivate Factors V and VIII.
      • Deficiency = hypercoagulability
      • 1.5%/year risk of initial thrombosis + recurrent VTE (6.2%/year) --> present 10-15yo.
    • Protein S
      • Cofactor for Protein C to degrade Factor V and VIII
      • Vitamin K-dependent factor
      • Facilitates inactivation of FXa by tissue factor inhibitor
      • Circulates in free form (40%) and bound to C4b binding protein.
        • Can be Type I (quantitiative abnormality) and Type II (qualitative)
        • Type III - increase in C4b bound fraction
      • Half of VTE events are unprovoked. (50% symptomatic before 55yo).

     

    Dysfibrinogenemia

    • Fibrinogen converted to fibrin, fibrin cross-linked.
    • Mutation in Aα, Bβ, or γ fibrinogen genes
    • Can bleed or clot!

     

    Acquired

    • Much more common, and often greater thrombotic risk than inherited thrombophilia

    Increased Risk States

    • Increased risk of thrombosis:
      • Age
      • Surgery
        • Found that thromboembolic risk is high 1 year post surgery.
        • Major inpatient surgery = 70-fold increased risk of VTE (Ambulatory surgery = 10-fold)
      • Cancer (increases risk by 4-20-fold)
        • Called Trousseau Syndrome 
          (described in pancreatic cancer, and described in himself as he was dying of gastric cancer)
          (Cancer expresses tissue factor, platelet disorders, chemo, etc..)
        • High Risk: Pancreatic, Brain
        • Intermediate Risk: Lung Cancer, Lymphoma
        • Low Risk: Breast & Prostate Ca.
        • Hence: if active VTE, must anticoagulate with LMWH.

     

    Antiphospholipid Syndrome

    • Acquired autoimmune disorder associated with venous or arterial thromboembolism. 
    • Pathophysiology:
      • Antibodies to phospholipids such as cardiolipin or phospholipin-binding proteins such as Beta-2-glycoprotein 1.
      • Why they clot is not understood.
    • Presentation:
      • Pregnancy loss
      • Thrombocytopenia
      • Renal insufficiency, Vasculitis, Cardiac Valvular abnormalities
    • Manifestations:
      • VTE (59%)
      • Arterial Thrombosis (28%)
      • Aterial Thromboembolism (13%)
    • Primary or Associated with other autoimmune diseases (i.e. Lupus)
    • Diagnosis:
      • IgG, IgM,[sometimes IgA] --> Anti-cardiolipin, Anti-β2-glycoprotein 1 (ELISA's)
        • Can cause increased clotting times (PTT, Dilute Russel's Viper Venom time)
      • Lupus Anticoagulant --> When anti-phospholipid antibodies cause a prolongation of the PTT
      • MUST have clinical symptoms (1-5% will have positive tests)
      • Clinical Criteria (one of) Laboratory Criteria (one of)

        1. Vascular Events (Arterial, Venous,

            or microvascular thrombosis).

            - Histopathology cannot demonstrate

             vessel wall inflammation

        2. Pregnancy Morbidity

            (≥1 unexplained fetal deaths ≥10w)

            (≥1 premature births <34w due to 

             eclampsia, pre-eclampsia, placental)

        1.  Lupus Anticoagulant

             -  must be positive using

             a phospholipid-dependent clotting assay

             (aPTT, Russell viper venom assay, kaolin 

              clotting time, dilute PT) with phospholipid

              dependence ≥2 times at least 12w apart

        2.  Anticardiolipin Antibody

             - By ELISA (IgG or IgM)

               ≥2 occasions >12w apart.

        3.  β2-Glycoprotein I antibody

             - By ELISA (IgG or IgM by ELISA)

               on ≥2 occasions >12w apart

         

         

     

    • Management:
      • If positive APS and prolongued PTT, must has anti-Xa assays for UHF monitoring (or use LMWH).
      • Long-term anticoagulation with warfarin (INR 2-3) [Recurrence Risk is HIGH]
        (IN the past targeted higher INRs, but now studies show no need)
        • If recurrent thromboembolism despite warfarin --> target INR 3-4. (or consider LMWH or fondaparinux)
        • If INR elevated, may need to use chromogenic Factor X to monitor warfarin.
      • Reducing miscarriage risk: UNFH or LMWH +ASA.
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