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H34 Hematology
Hypercoagulable Disorders Toronto Notes 2019
Common Causes of Hypercoagulability
CALM APES
Protein C deficiency Antiphospholipid Ab
Factor V Leiden Malignancy
Antithrombin deficiency Prothrombin G20210A Increased Factor VIII (Eight) Protein S deficiency
Causes of Both Venous and Arterial Thrombosis include:
• Antiphospholipid antibodies
• Myeloproliferative neoplasms
• Heparin-induced thrombocytopenia
• Distal venous clot with patent
foramen ovale
• Paroxysmal nocturnal hemoglobinuria
Protein C, protein S, and ATIII are decreased during acute thrombosis – therefore to test for deficiency, must be tested outside of this time period
• workup
■ initial
◆ CBC, blood smear, coagulation studies, liver/renal function, urinalysis, and hemolysis markers (if anemic)
◆ malignancy history, age appropriate cancer screening
◆ serology: APLA
■ post-treatment (or ≥6 wk, as protein levels depleted/consumed by clot)
◆ antithrombin (not on heparin)
◆ proteins C, S (not on warfarin)
• note:mostofthesetestsdonotchangemanagement,andanegativetestdoesnotruleouta
hypercoagulable state
■ thus, more focus on the reversible/treatable causes (APLA, cancer, etc.)
SELECTED CAUSES OF HYPERCOAGULABILITY
Activated Protein C Resistance (Factor V Leiden)
• most common cause of hereditary thrombophilia
• 3-7%ofEuropeanCaucasianpopulationareheterozygotes
• pointmutationintheFactorVgene(R506Q)resultsinresistancetoinactivationofFactorVaby
activated protein C
Prothrombin Gene Mutation (PT) G20210A
• 1-3%ofEuropeanCaucasianpopulationareheterozygotes
• GtoAtranspositionatnucleotideposition20210oftheprothrombingenepromoterregionresultsin
increased levels of prothrombin, thus increased thrombin generation
Protein C and Protein S Deficiency
• proteinCinactivatesFactorVaandVIIIausingproteinSasacofactor • proteinCdeficiency
■ homozygous or compound heterozygous: neonatal purpura fulminans ■ heterozygous
◆ type I: decreased protein C levels
◆ type II: decreased protein C activity
■ acquired: liver disease, sepsis, DIC, warfarin, and certain chemotherapeutic agents ■ 1/3 of patients with warfarin necrosis have underlying protein C deficiency
• proteinSdeficiency
■ type I: decreased free and total protein S levels
■ type II: decreased protein S activity
■ type III: decreased free protein S levels
■ acquired:liverdisease,DIC,pregnancy,nephroticsyndrome,inflammatoryconditions,andwarfarin
Antithrombin Deficiency
• antithrombinslowlyinactivatesthrombinintheabsenceofheparin,rapidlyinactivatesthrombininthe presence of heparin
• autosomaldominantinheritance,urinarylossesinnephroticsyndrome,orreducedsynthesisinliver disease
• diagnosismustbemadeoutsidewindowofacutethrombosisandanticoagulationtreatment(acute thrombosis, heparin, systemic disease all decrease antithrombin levels)
• deficiencymayresultinresistancetounfractionatedheparin(LMWHmaybeconsidered,with monitoring of anti-Xa levels)
■ heparin resistance: suspect if >35,000 units of UFH required during 24 h use
Elevated Factor VIII Levels
• anindependentmarkerofincreasedincidentandrecurrentthromboticrisk,butlevelscanalsobe increased in numerous states as an acute phase reactant, therefore its clinical use is controversial
Congenital Dysfibrinogenemia
• maypredisposetothromboembolicdisease,bleedingorboth
Disorders of Fibrinolysis
• includescongenitalplasminogendeficiency,tissueplasminogenactivatordeficiency,although association with VTE risk is not clear
Antiphospholipid Antibody Syndrome (APS)
• definition:≥1clinicaland≥1laboratorycriteria
■ clinical: thrombosis, recurrent (>3) early pregnancy losses <10 wk, one late fetal loss ≥10 wk
(morphologically normal), or premature birth before 34 wk due to (pre)eclampsia or placental
insufficiency
■ laboratory (must be confirmed on two occasions, tested ≥12 wk apart): anticardiolipin antibodies,
anti-β2 glycoprotein-I antibody, and lupus anticoagulant
• mechanism:notwellunderstood,antibodiesinteractwithplateletmembranephospholipidcausing
increased activation; can also interfere with thrombin regulation, fibrinolysis, and inhibit the protein C
pathway
• seeRheumatology,RH12
Malignancy is a common cause of acquired hypercoagulability
Workup should include:
• Complete history and physical
• Routine blood work
• Urinalysis
• CXR
• Age appropriate screening:
mammogram, Pap, PSA, colonoscopy
• Close follow-up
• No benefit with CT imaging
Although lupus anticoagulant prolongs PTT, this is a misnomer, as its main clinical feature is thrombosis