Hypercoagulable disorders Notes

NOTES NOTES HYPERCOAGULABLE DISORDERS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Unregulated activation of coagulation cascade → vascular thrombosis CAUSES ▪ Inherited/acquired ▪ Secondary to liver disease, autoimmune systemic disorders, renal failure, acute thrombosis, exposure to toxins, anticoagulation therapy COMPLICATIONS ▪ Venous, arterial thrombosis, obstetric SIGNS & SYMPTOMS ▪ Deep vein thrombosis (DVT) → pulmonary embolism (PE) DIAGNOSIS ▪ Family history of thrombophilia, thrombosis under age of 50 years, thrombosis in unusual location (e.g. portal veins), recurrent thromboembolic episodes LAB RESULTS ▪ Assays for specific proteins/factors, antibodies ▪ Genetic testing TREATMENT MEDICATIONS ▪ Anticoagulants/thrombolysis ▫ If symptomatic ▪ Prophylactic anticoagulation when high risk for thrombosis ▫ E.g. perioperatively/in postpartum period ▫ If asymptomatic OSMOSIS.ORG 383

ANTIPHOSPHOLIPID SYNDROME (APS) osms.it/antiphospholipid-syndrome PATHOLOGY & CAUSES ▪ Acquired autoimmune multisystem disorder; associated underlying disorders, systemic lupus erythematosus (SLE) ▪ AKA lupus anticoagulant syndrome ▫ May be idiopathic; may appear after exposure drugs/infectious agents ▪ Antiphospholipid antibodies (aPL) bind to targets → induce hypercoagulable state ▪ Pathways ▫ Thromboembolic episodes/pregnancy morbidity ▫ Increase in atherosclerosis, fetal loss, neurological damage; aPL-associated increase in vascular tone ▪ Catastrophic APS (rare) ▫ Widespread thrombosis → multiorgan failure COMPLICATIONS Pregnancy complications ▪ Spontaneous abortions; fetal death ▪ Premature birth due to preeclampsia/placental insufficiency Cutaneous complications ▪ Livedo reticularis (most common) ▫ Obstruction of microvasculature → netlike purplish discolouration of skin ▪ Cutaneous ulcers Ocular complications ▪ Retinal venous/arterial circulation occlusion; anterior ischemic optic neuropathy 384 OSMOSIS.ORG SIGNS & SYMPTOMS ▪ Recurrent venous thromboses ▫ DVT → PE → pulmonary hypertension ▫ Superficial thrombophlebitis ▫ Hepatic/portal vein thrombosis → BuddChiari syndrome, hepatic infarction, portal hypertension, cirrhosis ▫ Adrenal vein thrombosis → hemorrhagic infarction ▪ Recurrent arterial thromboses (less common) ▫ Stroke/transient ischemic attack ▫ Myocardial infarction ▫ Bowel infarction ▫ Multiple capillary, arterial thromboses → renal microangiopathy → renovascular hypertension DIAGNOSIS LAB RESULTS ▪ ≥ one antiphospholipid antibodies ▫ Lupus anticoagulant, AKA lupus antibody ▫ Anticardiolipin antibody ▫ Anti-beta2 glycoprotein I ▪ ≥ one clinical feature ▫ Vascular thrombosis/pregnancy morbidity ▪ Moderate thrombocytopenia ▪ Prolonged PT, aPTT ▫ Not corrected by plasma transfusions ▪ False positive in venereal disease lab test, rapid plasma reagin test for syphilis ▫ Cardiolipin phospholipid as major reagent

Chapter 46 Hypercoagulable Disorders TREATMENT MEDICATIONS ▪ Aspirin/anticoagulants (e.g. warfarin) ▫ To stabilize coagulation pathways ▫ Lifelong systemic therapy with antiplatelet medications ANTITHROMBIN III DEFICIENCY osms.it/antithrombin-III-deficiency PATHOLOGY & CAUSES ▪ Endogenous serine protease inhibitor in coagulation cascade; inactivates thrombin (factor IIa), factor Xa. CAUSES ▪ Inherited ▫ Autosomal dominant gene mutation; variable penetrance ▪ Acquired ▫ Defective synthesis; liver disease, therapy with vitamin K antagonists (e.g. warfarin) ▫ Loss in urine; renal failure/nephrotic syndrome ▫ Depletion in acute thrombosis/ disseminated intravascular disease (DIC) COMPLICATIONS ▪ Venous thromboembolism ▪ Heparin resistance SIGNS & SYMPTOMS ▪ Deep vein thrombosis → pulmonary embolism DIAGNOSIS LAB RESULTS Genetic testing Functional assay ▪ Reduced plasma antithrombin III activity ▪ PT/aPTT/thrombin time ▫ No change + aPTT → diminished increase following heparin TREATMENT MEDICATIONS ▪ Treat deep vein thrombosis / pulmonary embolism ▫ Anticoagulants with vitamin K antagonists/direct oral anticoagulants (DOACS) ▪ If ≥ two thromboembolic events occur → lifelong anticoagulant therapy (e.g. vitamin K antagonists/ DOACs) ▪ Prophylactic antithrombin replacement ▫ High-risk thrombophilic situations (e.g. surgery/pregnancy) OSMOSIS.ORG 385

FACTOR V LEIDEN (FVL) osms.it/factor-v-leiden PATHOLOGY & CAUSES ▪ Inherited thrombophilia ▪ Mutant form of coagulation factor V, lacks Arg506 cleavage site CAUSES ▪ FVL → resistance to degradation by activated protein C (aPC) → unregulated activation of coagulation cascade → hypercoagulable state → venous thromboembolism (VTE) RISK FACTORS ▪ FVL homozygosity ▪ Coinheritance with other thrombophilia disorders ▪ Pregnancy (physiologic hypercoagulability) ▪ Oral hormonal contraceptives SIGNS & SYMPTOMS ▪ VTE ▪ DVT/thrombosis in superficial veins of lower extremities/cerebral, portal, hepatic veins ▪ Possible fetal loss 386 OSMOSIS.ORG DIAGNOSIS LAB RESULTS ▪ Genetic testing ▫ FVL mutation (direct analysis of genomic DNA) ▫ Functional aPC resistance assay (individual’s plasma mixed with factor V-deficient plasma) OTHER DIAGNOSTICS ▪ Family history of thrombophilia ▪ VTE at young age/in unusual location TREATMENT MEDICATIONS ▪ Anticoagulants/thrombolysis ▫ Treat for DVT/PE ▫ If ≥ two thromboembolic events → lifelong anticoagulant therapy ▪ Prophylactic anticoagulation ▫ High risk thrombophilic situations (e.g. surgery, pregnancy)

Chapter 46 Hypercoagulable Disorders PROTEIN C DEFICIENCY osms.it/protein-c-deficiency PATHOLOGY & CAUSES ▪ Protein C deficiency → familial thrombophilia ▪ Protein C ▫ Vitamin K-dependent inhibitor of factors V, VIII ▫ Protein C deficiency → unregulated activation of coagulation cascade → increased thrombotic risk TYPES ▪ Type I ▫ Reduced protein C levels ▪ Type II ▫ Normal protein C levels, reduced function CAUSES ▪ Autosomal dominant inherited disorder ▪ Acute thrombosis, disseminated intravascular coagulation, liver disease, vitamin K antagonist anticoagulants COMPLICATIONS ▪ Due to treatment ▫ Warfarin-induced thrombotic skin necrosis SIGNS & SYMPTOMS DIAGNOSIS LAB RESULTS Functional assay ▪ Reduced protein C OTHER DIAGNOSTICS ▪ Monitor if recurrent VTE, family history of VTE, thrombosis in unusual location/at young age TREATMENT MEDICATIONS ▪ Anticoagulants/thrombolysis ▫ Treat deep vein thrombosis/VTE ▪ Prophylactic protein C concentrate ▫ Asymptomatic individuals (e.g. perioperatively/in postpartum period) Warfarin-induced skin necrosis ▪ Stop warfarin; start vitamin K, heparin, protein C concentrate/fresh frozen plasma administration MNEMONIC Proteins C & S C and S inhibit coagulation: they are Clot Stoppers ▪ Venous thromboembolism (VTE) ▪ In homozygotes, neonatal purpura fulminans OSMOSIS.ORG 387

PROTEIN S DEFICIENCY osms.it/protein-s-deficiency PATHOLOGY & CAUSES ▪ Deficiency of protein S → familial thrombophilia ▪ Protein S ▫ Cofactor of protein C ▫ Protein S deficiency → decreased protein C activity → enhanced activity of coagulation cascade → increased thrombotic risk TYPES ▪ Type I (classic) ▫ Reduced total protein S, free protein S, protein S function ▪ Type II (rare) ▫ Normal total, free protein S, reduced function ▪ Type III ▫ Reduced free protein S, protein S function; normal total protein S CAUSES ▪ Autosomal dominant inherited condition ▫ Most individuals heterozygous for PROS1 gene mutation ▪ Pregnancy, oral hormonal contraceptive, disseminated intravascular coagulation (DIC), acute thrombosis, HIV infection, nephrotic syndrome, liver disease 388 OSMOSIS.ORG SIGNS & SYMPTOMS ▪ VTE ▪ In homozygotes, neonatal purpura fulminans DIAGNOSIS ▪ Monitor if recurrent venous thromboembolism (VTE), family history of VTE, thrombosis at young age/in unusual location LAB RESULTS ▪ Protein S assay TREATMENT MEDICATIONS ▪ Anticoagulants/thrombolysis ▫ Treat deep vein thrombosis ▪ If asymptomatic, avoid drugs that predispose to thrombosis (e.g. oral contraceptives) ▪ Prophylactic anticoagulation (e.g. preoperatively/in postpartum period)