Alexander N. Shoushtari and Gerald A. Soff
• Definition: Hereditary or acquired d/o → ↑ thrombosis risk; aka “thrombophilia.”
• Acquired: Surgery, malignancy (see next page), immobility, obesity, hormonal (eg, pregnancy, OCPs, HRT, tamoxifen), autoimmune disease (eg, SLE, PNH), nephrotic syndrome, drugs (eg, lenalidomide)
Factor V Leiden
• Epidemiology: 5–8% of Caucasians, N Europeans > S Europeans. <2% of Asians, Africans, Hispanics
• Genetics: Factor V – 506th amino acid Arginine → Glutamine; Autosomal dominant.
• Pathophysiology: Mutated site of inactivation by APC → APC resistance →↑ coag, ↓ anticoag
• Thrombosis Risk: VTE – eg, DVT/PE heterozygote = 7–10× control (Lancet 1993;342:1503), homozygote >80× control (Blood 1995;85:1504). Unresolved if ↑ risk of recurrent VTE (NEJM 1999;341:801) or arterial thrombosis.
• Dx: Plasma assay for APC resistance = suggestive; PCR for FVL Mt = definitive
• Epidemiology: 2–7% Caucasians. Uncommon in Asians, Africans, Hispanics.
• Genetics: Prothrombin gene: Guanine → Adenine point Mt in 3′ untranslated region. Autosomal dominant inheritance
• Pathophysiology: Mt → ↑ mRNA half-life → 30% ↑ prothrombin levels
• Thrombosis Risk: VTE∼3× control (Blood 1996;88:3698); no Δ risk of arterial thrombosis.
• Dx: PCR for specific Mt.
Protein C Deficiency
• Epidemiology: 1:200–1:500, no ethnic or geographic disparity
• Genetics: Autosomal dominant; rarely homozygous. Multiple Mt → quantitative or qualitative defects.
• Pathophysiology: Protein C Mt or acquired deficiency (liver failure, septic shock, ARDS) → ↓ APC cleavage of FVa, FVIIIa → ↓ Fibrinolysis → ↑ Thrombosis
• Thrombosis Risk: VTE risk ∼10× control, No Δ risk of arterial thrombosis. ↑ risk of warfarin skin necrosis. Homozygotes → Neonatal purpura fulminans or stillbirth.
• Dx: Plasma Protein C levels (functional and/or Ag), typically <55%; thrombosis, warfarin ↓ level.
Protein S Deficiency
• Epidemiology: Rare; 1:1000–1:3000, no ethnic or geographic disparity
• Genetics: Autosomal dominant, rarely homozygous.
• Pathophysiology: Protein S Mt → ↓ APC cleavage of FVa, FVIIIa → ↓ Fibrinolysis → ↑ Thrombosis
• Thrombosis Risk: VTE risk ∼30× control, median 3rd decade. No Δ risk of arterial thrombosis. Warfarin skin necrosis & neonatal purpura fulminans or stillbirth similar to protein C deficiency.
• Dx: Plasma Protein S Ag & functional levels; note that warfarin → ↓ level.
Antithrombin (AT, formerly AT III) Deficiency
• Epidemiology: Rare; 1:2000–1:5000, no ethnic or geographic disparity.
• Genetics: Autosomal dominant; various Mt w/variable penetrance.
• Pathophysiology: AT Mt or acquired deficiency (liver failure, DIC, VOD in bone marrow transplant (BMT)) → ↓ inhibition of coagulation enzymes (thrombin, Xa, etc.); heparin resistance.
Type 1: Decr AT level + activity; Type 2: NL AT level, Decr activity.
• Thrombosis Risk: VTE risk ∼15–20×, heparin resistance (can give AT concentrate)
• Dx: ↓ plasma AT functional & Ag levels.
Methylene Tetrahydrofolate Reductase (MTHFR) Polymorphisms
• Epidemiology: Up to 10% of population have polymorphism in MTHFR gene.
• Genetics: 2 most common polymorphisms are C677T & A1298C
• Pathophysiology: Polymorphism → ↓ activity of MTHFR. If homozygous & folate deficient, may → ↑ serum homocysteine → endothelial injury.
• Thrombosis Risk: Controversial; may have ↑ risk if ↑ homocysteine.
Antiphospholipid Antibody Syndrome (APS)
• Definition: Clinicopathologic syndrome of (+) APLA & clinical manifestation of venous or arterial thrombosis or other clinical sequelae (see table). 2° APS = coexisting autoimmune condition, most often SLE; 1° APS if no predisposing condition
• Epidemiology: 1–5% have (+) Ab but far fewer have syndrome. More common in elderly.
• Pathophysiology: Autoimmune d/o – Ab’s against proteins & phospholipids → ↑ risk of venous & arterial thrombi; paradoxical prolonged PTT in vitro. Exact mechanism of prothrombotic state unclear.
• Clinical Manifestations: VTE (DVT/PE, arterial thrombi, CVA), placental insufficiency, recurrent fetal loss; livedo reticularis; cardiac valvular abnl; Catastrophic APS = thrombotic microangiopathy w/3+ organ dysfunction <1 wk + (+) Ab; ∼20% mortality.
• Dx: Suspect if thrombosis in age <40, unusual site (PV, cerebral vein), unprovoked, or has SLE; pregnancy loss & w/↑PTT (w/immediate acting inhibitor). Lab confirmation: Ag: β2-GP1, ACL Ab by ELISA. Functional: LA (DRVVT, Silica Clotting Time). FP: Syphilis, Lyme, EBV, HIV, varicella, drugs
Heparin-induced Thrombocytopenia and Thrombosis (HITT)
• Definition: Clinicopathologic syndrome of thrombosis, thrombocytopenia or skin necrosis & (+) HITT Ab by ELISA. Confirm w/serotonin release assay.
• Epidemiology: Highest w/surgical pts, UFH > LMWH.
• Pathophysiology: Ab against (Plt Factor 4:heparin) complex → activates plt → thrombosis
• Clinical Manifestations: Venous or Arterial thrombi (limb ischemia, MI, adrenal necrosis) OR Thrombocytopenia (>30–50% drop plt in 5–15 d). If heparin exposure w/in prior 100 d, may have more rapid decline OR skin necrosis s/p heparin
• Dx: Clinical suspicion → check HIT Ab by ELISA or (+) serotonin release assay
• Tx: Stop heparin agent → Start anticoag w/direct thrombin inhibitor (lepirudin, bivalirudin, argatroban) or FXa inhibitor (fondaparinux) until plt normalize → start warfarin, overlap until INR >2 for 24 h.
• Epidemiology: ∼1% per person-y (PLoS Med 2012;9:e1001275); highest in pancreas, brain, lung; also higher risk if chemo, XRT, surgery, met disease
• Pathophysiology: Multifactorial: ↑ inflammatory cytokines, ↓ mobility, ↑ viscosity (eg, Waldenstrom’s, acute leukemias)
• Tx: LMWH superior to warfarin for recurrent VTE prev (CLOT, NEJM 2003;349:146)
Treatment of Venous Thromboembolism (VTE)
• Generally by standard approach, in presence or absence of hypercoagulable state
• Initial UFH, LMWH, or fondaparinux → oral maintenance = warfarin OR rivaroxaban (NEJM 2010;363:2499). No warfarin in pregnancy or protein C/S deficiency; prefer LMWH in malignancy; avoid/adjust LMWH, fondaparinux, rivaroxaban in renal impairment.
• Duration: No definitive guidance; weigh risks/benefits of recurrent VTE vs. bleeding. Generally, 1st sx VTE = 6–12 mo; post-op VTE: 3 mo (Chest 2012;141:e419s)