Acquired Disorders Flashcards
Factor V Leiden
Clinical Findings, Pathophysiology, Lab and therapy
Clinical finding: Caucasians; prone to thrombophilia as a result of venous thrombi
Pathophysiology: A mutation in the Factor V gene results in a conformation change in Factor V that makes its activated form resistant to Activated Protein C inhibition; Patients are unable to inhibit Factor Va
Lab: PT, PTT, plt count—normal
Diagnostic FVL PCR test
Therapy: antithrombotic treatment
Prothrombin 20210
Clinical Findings, Pathophysiology, Lab and therapy
Clinical Findings: Caucasians; At risk for Venous thrombosis; FVL mutation
Pathophysiology: A mutation in the prothrombin gene which leads to elevated prothrombin levels; Increased Factor II leads to thrombin formation which leads to excess thrombus formation
Lab: Prothrombin levels are high end of normal PCR is diagnostic
Therapy: antithrombotic agents
Protein C Deficiency
Clinical Findings, Pathophysiology, Lab and therapy
Clinical Findings: Recurrent DVT at a young age and PE
Homozygous—purpura fulminans, VT and DIC at birth
Heterozygous—skin necrosis within warfarin treatment
Pathophysiology: The diminishes capacity to destroy Factor Va and VIIIa results in an increased production of thrombin
Lab: PC Assay decreased
Therapy: warfarin; Liver transplant will “cure”
Protein S Deficiency
Clinical Findings, Pathophysiology, Lab and therapy
Clinical Findings: cases of arterial thrombi; warfarin induced skin necrosis possible
Pathophysiology: conditions where C4b-binding protein are increased; results in decreased functionality of Protein S to be able to act as a cofactor for Protein C, thus limiting the bodies capacity to inhibit factor Va and VIIIa, resulting in increased production of thrombin
Lab: PS Assays (total and free)
Therapy: warfarin, liver transplant
Antithrombin Deficiency Clinical Findings (Homozygote, Heterozygote), Pathophysiology (Type I and II), Lab and therapy
Clinical Findings: Recurrent venous thrombosis.
Homozygote: Type I: not compatible with life
Type II: severe thrombotic tendencies at birth
Heterozygote: asymptomatic when young; progress to more of DVT, PE with age
Pathophysiology: Type I—reduced synthesis; Type II—functional defect results in decreased normal inhibition of serine proteases of the coagulation cascade, leading to excess fibrin formation
Lab: AT assays
Therapy: Treatment with heparin and AT concentrates; Coumadin for long-term
Arterial thrombi
Formed in the arteries where blood flow is rapid; termed “white thrombi” because they are composed mostly of fibrin and platelets. Typically form at sites where endothelium is disturbed. Portions of the thrombus can break off (embolus) and lead to myocardial or cerebral infarction.
Venous thrombi
Formed in areas where blood flow is slow and disturbed. Composed mostly of RBCs and fibrin.
Antithrombin Deficiency Type I, II, III
Pathophysiology
Homozygotes
Heterozygotes
Pathophysiology: leads to inability to properly inhibit coagulation specifically serine proteases
Homozygotes: Type I: cannot survive, Type II: severe prenatal episodes
Heterozygotes: Symptomatic after puberty (DVT, PE, recurrence) Less severe in heparin binding site variant
Protein C Deficiency types
Homozygotes
Heterozygotes
Type I, II
Homozygotes: Thrombotic issues at birth (purpura fulminans)
Heterozygotes: Often asymptomatic until another risk factor presents: DVT, PE
Type I
Quantitative antigen quantity has decreased functional activity
Type II
Qualitative antigen quantity has normal functional activity
Protein S Deficiency types I, II, III
Pathophysiology
Types I, II, III
Pathophysiology: leads to inability to properly inhibit coagulation (specifically FVa and FVIIIa)
Type I
Quantitative Total protein: decreased
Free protein S: decreased
Protein S activity decreased
Type II
Qualitative Total protein normal
Free protein S: normal
Protein S Activity decreased
Type III Increased C4bp and normal amounts of PS Total protein S: normal Free protein S: decreased Protein S Activity: decreased
Deep Vein Thrombosis:
pathophysiology, lab testing, treatment.
Patho: Development of venous thrombosis in the deep veins of lower limbs. Symptoms include localized pain, warmth, redness, and swelling
Lab Testing: Thrombin generation and fibrinolysis are often elevated in cases of DVT, D-dimer
Treatment includes anticoagulant therapy, such as heparin
Pulmonary Embolism:
pathophysiology, lab testing, treatment
Patho: 50% of DVT cases lead to PE (termed venous thromboembolism—VTE), where a piece of the DVT breaks off and travels in circulation to the lungs, where it becomes lodged. Commonly fatal
Lab testing: venography or ultrasound confirmation
Treatment: anticoagulant therapy, such as heparin
Heparin Cofactor II Deficiency
Low thrombotic risk; decreased inhibition of thrombin, typically only a problem if another deficiency is present
Hyperhomocysteinemia
Mutation for enzyme required for HC breakdown (CBS or MTHFR) results in increased HC; increased HC is associated with premature atherosclerosis and thrombosis
Dysfibrinogenemia
Mutation that changes the structure of fibrinogen; decreases fibrinolytic activity because of 1) abnormal resistance to plasmin lysis or 2) reduced plasminogen activation
Elevated Factor VIII
Increased Factor VIII levels increased thrombotic risk because of increased thrombin formation and/or diminished APC effect
Factor XII Deficiency
Can be associated with thrombotic tendencies; thought to be the result because of Factor XII’s role in activation of fibrinolysis
Plasminogen Deficiency
The plasminogen deficiency can be either qualitative or quantitative. Less plasmin can be generated leading to decreased fibrinolytic capabilities
TTP (Thrombotic Thrombocytopenic Purpura)
vWF multimers cannot be properly cleaved; Ultralarge multimers directly agglutinate platelets causing thrombi
Deficiency in vWF cleaving proteases ADAMTS-13
HIT (Heparin induced Thrombocytopenia)
antibody/heparin/PF4 binds to platelets and leads to platelet activation and clearance
HIT: thrombocytopenia without thrombosis
HITT: thrombocytopenia with thrombosis
HUS (Hemolytic Uremic Syndrome)
Thought to be a result of endothelial damage from bacterial toxin (typically form E. coli O157:H7)
Malignancy
Thought to be the result of increased stasis, activation of blood coagulation and vascular injury
Pregnancy/Oral Contraceptives
Quantitative changes to hemostatic proteins lead to increased thrombotic risk, stasis, and also changes in hormone levels.
Discuss each item as it relates to the Lupus Anticoagulant definition
An antibody that reacts/binds with phospholipids; prolongs hemostasis screening tests that utilize a phospholipid-based reagent (PT and PTT)
Discuss each item as it relates to the Lupus Anticoagulant.
Naming confusion
Originally found in patients with lupus but more common with patients without lupus, associated with autoimmune diseases, drugs, infections.
Originally called anticoagulant because it prolonged screening tests like the PTT suggesting that it may have anticoagulant properties but later discovered that patient actually have thrombotic tendencies
Discuss each item as it relates to the Lupus Anticoagulant.
Clinical manifestation, application and pathophysiology
Clinical Manifestations & Applications
Thrombotic in nature, increased risk for DVT, PE, arterial thrombosis, stroke
Pathophysiology
inhibition of endothelial cell anticoagulant processes and causing cells in contact with blood to acquire procoagulant phenotype; can interfere with protein C activation, inhibit heparin sulfate and prostacyclin release, and stimulate platelet aggregation
