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Laura Worfolk, Ph.D. Scientific Director, Hematology Quest Diagnostics Nichols Institute, Chantilly, VA
Hemostasis
Intricate system maintaining blood in fluid state
Reacts to vascular injury to stop blood loss and seal vessel wall
Bleeding
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Thrombosis
Interested Specialties
Anesthesiology
Anticoagulant Management HIT
Vascular Surgery
Graft Occlusion PAD
Cardiology
Premature CAD
Primary Care
Practice patterns vary
Hematology
Hemophilia Thrombophilia
OB/GYN
Fetal loss, Infertility, Menorrhagia
Nephrology
AV Graft Occlusion
Neurology
Stroke
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Hemostasis Statistics
#1 cause of death is CVD (includes heart attack & stroke)* ~1-2% of population w/ von Willebrands disease ~18,000 Americans w/ hemophilia ~600,000/year w/ venous thromboembolism
~ with long-term health consequences; ~60,000 fatalities ~5-8% of population w/ thrombophilia
*WHO. CDC www.dvt.org..
Primary Hemostasis
Platelet role:
Adhesion (via vWF), post injury to vessel wall
Activation: shape changed, contents released Aggregation, ie, plug formation Formation of surface for coagulation reactions fibrin glue
Coagulation Cascade
XII XI XIIa
HMWK/Prekallikrein
Injury
IX X
TF TF/VIIa
V
Xa
Va
XIII
Prothrombin Fibrinogen
Cascade Simplified
Activation/Injury
Intrinsic Pathway
(XIIa, XIa, IXa, VIIIa)
Extrinsic Pathway
(TF, VIIa)
Common Pathway
(Xa, Va, IIa, Fibrinogen)
Thrombin Regulation
Activity and formation tightly controlled
Antithrombin III
Inactivation of IIa and other enzymes involved in its formation
Fibrinolytic Pathway
Clot lysis vital in prevention of vessel occlusion
uPA, tPA PAI-1
Plasminogen
Alpha-2 AP
Hemostasis Balance
Thrombin Generation (ie, Factors II XII, cells) Plasmin Generation (ie, tPA, uPA, cells)
Coagulation
Healing
Fibrinolysis
Thrombin Regulation
Plasmin Regulation
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Alteration of Balance
Laboratory testing indicated if
Factor deficiencies Acquired inhibitors Anticoagulant therapy Consumption (DIC) Dysfibrinogenemia Platelet defects von Willebrands disease
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Alteration of Balance
Laboratory testing indicated if
Inhibitor deficiencies
Acquired inhibitors (eg, lupus anticoagulant) DIC Heparin induced thrombocytopenia
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Case Study #1
21 y/o female with vague family history of bleeding disorder; evaluated prior to taking scuba diving lessons Has nose bleeds following aspirin ingestion Differential diagnosis?
Role of laboratory testing???
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Comment Detects intrinsic/common pathway factor deficiency Rule out thrombocytopenia Rule out FVIII deficiency
231 K/L
(130 400)
85%
(50 150)
40%
(50 150)
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Comment If abnormal activity:antigen ratio, suspect qualitative (ie, Type II) defect
22%
(50 150)
Platelet aggregation
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Case Study #2
38 y/o Caucasian man admitted for evaluation of portal hypertension; history of recurrent thrombosis (>10 years)
PT, aPTT, fibrinogen: normal
Positive family history; father and sister with venous thrombotic episodes, but no laboratory investigation Differential diagnosis??
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% in Healthy
5 0.020.17 0.3
% in VTE
21 1 3
RR (%) of Thrombosis
37 15 40 5 12
Protein S deficiency
Prothrombin (FII) 20210GA mutation Hyperhomocysteinemia
0.7
2 510
2
6 10 25
4 - 10
23 3-4
VTE, venous thromboembolism; RR, relative risk; APC, activated protein C; AT, antithrombin.
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Not detected
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Prophylaxis during high-risk procedures Need to evaluate family members Estimate future risk (ie, risk associated with HRT)
Case Study #3
40 y/o woman with iron deficiency anemia due to menorrhagia; hysterectomy delayed due to prolonged screening test
aPTT: PT: Fibrinogen: 47.8 sec (elevated) 13.0 sec (normal) 300 mg/dL (normal)
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Lupus Anticoagulants
Antiphospholipid antibodies (APA) are directed against proteins bound to phospholipid membrane surfaces Lupus anticoagulants (LA) are a type of APA
Associated with thrombosis & recurrent fetal demise Characterized by prolongation of phospholipid dependent clotting assays (ie, aPTT)
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Lupus Anticoagulant Testing Test dRVVT screen & confirm Result Positive Comment Consistent with presence of lupus anticoagulant
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Pre-analytical Considerations
Proper specimen handling, processing, and storage is critical for accurate and precise results General specimen requirements available
www.questdiagnostics.com (click on Test Menu)
Quest Diagnostics Nichols Institute Directory of Services (contact your local representative)
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Resources
Laboratories performing routine, specialty, and esoteric hemostasis testing Consultative services available @ Quest Diagnostics Nichols Institute
Mervyn Sahud, MD San Juan Capistrano, CA 949-728-4794 Jeffrey Dlott, MD Chantilly, VA 703-802-6900, x7259
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References
ACOG committee opinion. von Willebrands disease in gynecologic practice. Int J Gynaecol Obstet. 2002;76:336. Brandt JT, et al. Laboratory identification of lupus anticoagulants: Results of the Second International Workshop for Identification of Lupus Anticoagulants. On behalf of the Subcommittee on Lupus Anticoagulants/ Antiphospholipid Antibodies of the ISTH. Thromb Haemost. 1995;74:1597. Miyakis et al. International consensus statement on an update of the classification criteria for definite APS. J Thrombo Haemost. 2006;4:295.
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References
Press et al. Clinical utility of FV Leiden testing for the diagnosis and management of thromboembolic disorders. Arch Pathol Lab Med. 2002;126:1304. Sadler et al. Update on the pathophysiology & classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. J Thrombo Haemost. 2006;10:2103.
Thrombophilia: Laboratory support of risk assessment and diagnosis. Available at: http://www.questdiagnostics.com/hcp/intguide/jsp/sh owintguidepage.jsp?fn=CF_Thrombophilia/CF_Thro mbophilia.htm. Accessed March 21, 2007.
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Thank you.