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
Discuss each item as it relates to the Lupus Anticoagulant.
Lab results and Diagnosis protocol
Implications in the Lab
Diagnostic Protocol
Confirmatory Procedures
Implications for the Laboratory:
PTT prolonged cuz LA antibody reacts with the phospholipids in the reagent. PT occasionally prolonged
Diagnostic Protocol
Screening procedures—two or more using single concentration of phospholipids
Demonstrate at least one prolonged phospholipid-based clotting test (PTT)
Demonstrate at least one additional prolonged LA screening test (PT)
Confirmatory procedures—modify abnormal screening procedure by altering phospholipid content of the test procedure, which demonstrates that the LA depends on phospholipid
Dilute Russell’s Viper Venom Time (dRVVT)
Purpose/principle, Reagent, interpretation of results
Principle/Purpose: Also known as the Stypven Time; Reagent is added to patient plasma activating Factor and time to clot formation is measured.
Reagent: Russell’s viper venom, calcium chloride, and phospholipids
Interpretation of results: Ratio of patient’s clotting time to clotting time of normal control determined
Normal ratio is <1:2
Increased ratio suggests the presence of LA
Plasma Clot time (PCT) for Lupus Anticoagulant
Purpose/principle, Reagent
Principle/Purpose: Reagent with a contact factor activator is added and the time to clot formation is measured (much like the PTT)
Reagent: contact activator
Kaolin Clotting time (KCT) for Lupus Anticoagulant
Purpose/principle, Reagent, interpretation of results
Principle/Purpose: Kaolin is a substance that can activate contact factors; It is added to patient plasma and the time for the clot formation is measured
Reagent: kaolin (a neg charged particulate activator) instead of phospholipid
Interpretation of results: Test to control ratio of >1:2 indicates an inhibitor such as LA
Discuss normal and abnormal bleeding disorders that can arise in newborns. Include a description of clinical manifestations and pathophysiology.
Neonates are at risk for coagulation issues naturally
The most common hemostatic problem is Vit K deficiency and immune thrombocytopenia
Discuss how each of the following lab tests could (or could not) be used to help differentiate liver disease and DIC.
PT/PTT
Liver disease: PT, PTT, TT: increased because there is a lower amount of factors being produced
DIC: PT, PTT, TT: increased because of the consumption of factors
Discuss how each of the following lab tests could (or could not) be used to help differentiate liver disease and DIC.
Platelet count
Liver Disease: decreased because of enlarged liver → enlarged spleen→ more platelets sequestered
DIC: decreased because of over activated and used up
Discuss how each of the following lab tests could (or could not) be used to help differentiate liver disease and DIC.
D-dimer
Liver disease: normal: no clotting therefore no fibrinolysis
DIC: Increased: excessive breakdown of the clots that were forming
Discuss how each of the following lab tests could (or could not) be used to help differentiate liver disease and DIC.
Blood Smear
Liver Disease: Macrocytes, target cells, acanthocytes
DIC: Schistocytes (RBC interacting with clots) and decreased platelets
Discuss how each of the following lab tests could (or could not) be used to help differentiate liver disease and DIC.
Factor VIII assay
Liver Disease: Increased factor levels (acute phase reactant)
DIC: decreased because used up
Discuss how each of the following lab tests could (or could not) be used to help differentiate liver disease and DIC.
Factor IX assay
Liver Disease: decreased (production)
DIC: decreased (used up)
Discuss how each of the following lab tests could (or could not) be used to help differentiate liver disease and DIC.
Factor X assay
Liver Disease: decreased (production)
DIC: decreased (used up)
Disseminated Intravascular Coagulation
Clinical Manifestation and Pathophysiology
Clinical Manifestations
Bleeding: abrupt, hemorrhage, multiple sites
Pathophysiology
Inappropriate activation of thrombin that leads to a systemic activation of coagulation that consumes factors and inhibitors needed for hemostatic control
Disseminated Intravasclar Coagulation
Lab Results and Treatment
Expected Lab Results
PT, PTT, TT elevated
Low fibrinogen
Platelet count decreased
DD abnormal
schistocytes RBCs are forced through fibrin clots, slicing them
Treatment Options
Eliminate the underlying cause; give RBCs, platelets, cryo or FFP
DO NOT USE FIBRIN INHIBITORS
Liver Disease
Clinical Manifestations and Pathophysiology
Clinical Manifestations
Minimal bleeding except in severe disease states where ecchymoses and epistaxis are common
Pathophysiology
Liver is unable to keep up with its normal tasks of producing coagulation factors and removing activated factors
Most hemostatic proteins are synthesized in the liver and liver macs play a major role in the removal of activated hemostatic components
Liver Disease
Lab Results and Treatment
Expected Lab Results
Platelet count decreased result of liver being enlarged→ enlarged spleen
PT, PTT,TT increased lower amount of factors being produced
Fibrinogen assay decreased lower amount of factors being produced
DDimer Normal
FDPs increased liver is unable to remove them in circulation
Blood Morph acanth, target cells, macrocytes changes in RBC membrane lipids
Treatment Options
Replacement therapy as needed
Vitamin K Deficiency
Clinical Manifestations and Pathophysiology
Clinical Manifestations
Bleeding, HDN in newborns bleeding in the skin or from mucosal surfaces, circumcision
Pathophysiology
Not enough Vit K for Vit K dependent factors (II, VII, IX, X) to be properly synthesized, unable to participate in fibrin formation. Caused by dietary insufficiency, prolonged antibiotic therapy.
Vitamin K Deficiency
Lab Results and Treatment
Expected Lab Results
Platelet count normal
PT, PTT increased II, VII, IX, X are all vitamin K deficient
TT and Fibrinogen Assay Normal
DDimer normal
Protein C & S decreased
Blood smear normal RBCs
Treatment Options
Administer Vitamin K, replacement of normal flora in GI tract
Primary Fibrinogenolysis
Clinical Manifestations and Pathophysiology
Clinical Manifestations
DIC like bleeding symptoms
Pathophysiology
Plasminogen becomes inappropriately activated to plasmin without thrombin generation
Primary Fibrinogenolysis
Lab Results and Treatment
Expected Lab Results
PT, PTT, TT elevated plasmin degrades fibrinogen and other factors
Fibrinogen decreased
Platelet count normal
FDPs increased
DDimer normal
Treatment Options
Epsilon aminocaproic acid (EACA)—a plasmin inhibitor
Oral Anticoagulants (ex. coumadin) Mode of action, reason for use, lab monitoring, results
Mode of action: Prevents liver from using Vit K therefore prevent carboxylation of factors so they can’t bind to calcium and are rendered useless
Reason for use: Long term treatment of DVT and PE—pill
Lab monitoring:
PT—increased
INR—used to monitor oral anticoag dosing
Results:
Low/no oral anticoagulants: 1.0
Therapeutic Range: 2.0-4.0
Critical Value: 5.0
Oral Anticoagulants (ex. coumadin) potential complications, antidote, source
Potential complications
Bleeding: increased dose
Thrombosis: possible at start of the treatment, Vit K dependent factors (PS and PC) are inhibited before the rest therefore excess fibrin made and skin necrosis
Antidote: Heparin and coumadin till PS and PC and other proteins are replaced
Source:Vitamin K shot
Unfractionated Heparin
Mode of action, reason for use, lab monitoring,
Mode of action: Given intravenously because can’t be absorbed via intestines
Reason for use: To prevent further thrombosis; presurgical; to treat inpatients with DVT
Lab monitoring: PTT—increased proportionally with dose
Anti-Xa assay—new way of monitoring heparin
Unfractionated Heparin
potential complications, antidote, source
Potential complications: Bleeding—dose too high cuz to much fibrin inhibition
Thrombocytopenia—heparin induced
Osteoporosis and Resistance—long time use
Antidote: Decrease dose or discontinue it cuz short half life
Normal in few hours
Source: Intestines of pigs or cow lungs
Explain why some hospital patients are receiving oral anticoagulants and heparin therapy simultaneously.
Heparin is given because it has an immediate effect. It is given intravenously so they must transition to oral anticoagulants so the hospital patients are on both of them since the oral anticoagulants take 3-5 days to take affect.
What is the INR? How is it calculated? How are the results interpreted (include a discussion of normal, therapeutic, and therapeutic ranges)?
Calculation: Patient PT results in seconds/mean of PT reference range in seconds)
ISI: International Sensitivity Index—this number is assigned to thromboplastin reagent the closer it is to 1.0 the purer it is
Results
Normal (around 1.0)—patient not on oral anticoagulants
Therapeutic (2.0-4.0)
Critical (>5.0) Dose of oral anticoagulants too high
Low Molecular Weight Heparin
Mode of action, indications for use, lab monitoring, potential complications
Mode of Action: Catalyzes the interaction of Antithrombin with Factor Xa, leading to increased inhibition of thrombin and other serine protease
Indications for Use: An alteration to unfractionated heparin for patients with thrombosis to treat current condition
Lab Monitoring: PTT not recommended; anti-Xa assay preferred
Potential Complications: Rare; reduced occurrence of HIT (compared to UFH) and fewer adverse complication
Thrombolytic therapy
Mode of action, indications for use, lab monitoring, potential complications, examples
Mode of Action: Plasminogen activators used to lyse thrombi in vivo
Indications for Use: Myocardial infarction, acute stroke, PE, DVT, peripheral arterial occlusion
Lab Monitoring: TT is prolonged and can be used to monitor therapy; FDPs and DDimer would be elevated if therapy is working
Potential Complications: Lysis of normal fibrin clots can lead to bleeding
Examples: Streptokinase, anything with kinase
Antiplatelet therapy
Mode of action, indications for use, lab monitoring, potential complications, examples
Mode of Action:Inhibits platelet function
Indications for Use: Current or at-risk arterial thrombosis patients; in dental implant procedures
Lab Monitoring: Platelet count might be monitored to watch for thrombocytopenia caused by certain drugs; Platelet aggregation and PFT tests would be abnormal
Potential Complications: Platelet like bleeding (petechiae, oozing), Thrombocytopenia
Examples: COX-1 inhibitors (Asprin), ADP receptor inhibitors (ex: Plavix), phosphodiesterase inhibitors; GPIIb/IIIa inhibitors
What effect do thrombolytic agents have on lab results?
Increased: PT, PTT, TT, FDP, Plasmin
Decreased: Fibrinogen, Plasminogen, α2-antiplasmin
Discuss laboratory tests used in the evaluation of hypercoagulable states:
Antithrombin III
Chromogenic is a coupled enzymatic reaction with thrombin in the presence of heparin. Thrombin activity is inversely proportional to the amount of AT-III in plasma, p-nitroaniline is measured at 405nm. Normal 85-122%
Discuss laboratory tests used in the evaluation of hypercoagulable states:
Protein C
Deficiencies associated with Vitamin K deficiency, liver disease, DIC and oral anticoagulant therapy
Measures p-nitroaniline, amount directly proportional to amount of activated protein C.
Discuss laboratory tests used in the evaluation of hypercoagulable states:
Protein S
Measures the free protein S fraction. Clotting time prolonged in the presence of increased levels of protein S. Associated disease states include liver disease, diabetes mellitus, pregnancy, DIC, and oral anticoagulant therapy
Discuss laboratory tests used in the evaluation of hypercoagulable states:
Plasminogen
Coupled enzymatic reaction, utilizing streptokinase. Measures activity of p-nitroaniline. Useful in determining effectiveness of plasminogen therapy
Discuss laboratory tests used in the evaluation of hypercoagulable states:
Antiplasmin
Measures circulating α2-antiplasmin, useful in determining efficacy of fibrinolytic therapy. Normal levels 80-120%
Discuss laboratory tests used in the evaluation of hypercoagulable states:
D-dimer
Detects unique breakdown products of fibrin; useful as a screen/negative predictor of DVT
Electromechanical Methodology
Measures the time for clot formation by detecting changes in the reaction mixture
Fibrometer detects the completion of an electrical circuit that occurs when fibrin forms between two electrodes
Optical Density Methodology
Detects changes in optical density that occur when fibrin forms
Chromogenic Methodology
An enzyme (such as an activated coagulation factor) cleaves a chromogenic substrate that releases a chromophore tag; color intensity is measured spectrophotometrically and is directly proportional to the concentration of the chromophore tag.
Antithrombin Deficiency Type I, II, III
Type I
Quantitative Concentration: decreased
Heparin cofactor: decreased
Progressive AT: decreased
Type II (Active Site Defect)
Qualitative Concentration: normal
Heparin Cofactor: decreased
Progressive AT: decreased
Type II (Heparin-binding Site Defect)
Qualitative Concentration: Normal
Heparin Cofactor: decreased
Progressive AT: normal
