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74 Coagulation Laboratory: Methods, Standards and Cost Effective Testing (Part 2) 74 Coagulation Laboratory: Methods, Standards and Cost Effective Testing (Part 2) Donna Castellone MS, MT(ASCP)SH 2011 Annual Meeting – Las Vegas, NV AMERICAN SOCIETY FOR CLINICAL PATHOLOGY 33 W. Monroe, Ste. 1600 Chicago, IL 60603 74 Coagulation Laboratory: Methods, Standards and Cost Effective Testing (Part 2) This session features a case study approach to examine issues that impact coagulation results: sources of errors, methods of standardization, and new and cost effective testing. Coagulation testing is complex and there can be a disconnect in what the clinician expects to come forth from the laboratory and what can actually be provided by the laboratory. • Identify solutions to areas of coagulation testing that can be enhanced by implementing good laboratory practices and standard operating procedures. • Analyze real case studies and how to troubleshoot testing to determine the root cause and what steps to take to prevent reoccurance. • Enhance general knowledge of coagulation, standards and methods. FACULTY: Donna Castellone MS, MT(ASCP)SH Entire Pathology Team Hematopathology Hematopathology 1.0 CME/CMLE Credit Accreditation Statement: The American Society for Clinical Pathology (ASCP) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education (CME) for physicians. This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME). Credit Designation: The ASCP designates this enduring material for a maximum of 1 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. ASCP continuing education activities are accepted by California, Florida, and many other states for relicensure of clinical laboratory personnel. ASCP designates these activities for the indicated number of Continuing Medical Laboratory Education (CMLE) credit hours. ASCP CMLE credit hours are acceptable to meet the continuing education requirements for the ASCP Board of Registry Certification Maintenance Program. All ASCP CMLE programs are conducted at intermediate to advanced levels of learning. Continuing medical education (CME) activities offered by ASCP are acceptable for the American Board of Pathology’s Maintenance of Certification Program. 10/8/2011 Part II: Coagulation Laboratory: Methods, Standards & Cost Effective Testing Donna D. Castellone Understanding Coagulation • Case Studies - clinical picture - analysis - diagnosis Case Study • A 15 yr old female presents with heavy periods • Her HGB is 9.0 g/dl • She has had intermittent periods of nose bleeding as a child • An evaluation for a bleeding work-up was ordered • PT= 12.1 sec • APTT= 42.1 sec • Mixing study: APTT 1:1 mix = 31.5 sec Correction • FVIII= 38% 1 10/8/2011 Additional Testing: • Decreased Factor VIII, need to distinguish between vWD and Hemophilia • vWD is autosomal dominant, 1/200 people, most common cause of bleeding • This is a test of platelets- ppyrimary hemostasis • Hemophilia is sex-linked recessive • Mostly in males- secondary hemostasis Hemophilia or vWD • Second level testing: • Ristocetin cofactor: 38% (nr 50-150%) • vWF: antigen: 35% (nr 50- 150%) • Diagnosis: von Willebrand Disease • Multimer analysis: all multimers decreased • Type 1 VWD Von Willebrand Disease • Described in 1926 by Eric von Willebrand described a bleeding disorder that occurred in 24/66 families • vW factor is a plasma protein that mediates the initial adhesion of platelets at the site of vascular injury • It also stabilizes FVIII in circulation • Caused by a deficiency or dysfunction of vWF 2 10/8/2011 von Willebrand Disease: • Affects 1-2% of general population, about 2.6 million people • Autosomal dominant: 50% chance of passing the gene to a child • Caused by a deficiency and/or qualitative abnormality of the VWF protein • Can be acquired with certain malignancies, drugs or autoimmune disorders Von Willebrand Factor • vWF is a multimeric high molecular weight protein present in plasma and platelets • In response to vascular injury it mediates platelet adhesion to the subendothelium and platelet aggregation • Serves as a carrier protein and a stabilizer for FVIII- which is why FVIII i s d ecrease d in VWD • Synthesized in endothelial cells and megakarocytes controlled by a gene on chromosome 7 • Stored in the Weibel-Palade bodies Types of von Willebrand Disease: • Type 1: decreased vWF activity & antigen 70-80% of cases; mild bleeding symptoms, may be asymptomatic. • Type 2: abnormal vWF protein, qualitative, 2:1 ratio of activity to antigen; deficiency of higher weight multimers; mild to severe bleeding • Type 3: severely reduced or absent circulating vWF, rare & life threatening bleeding 3 10/8/2011 Clinical Findings • Mucosal bleeding (epistaxis, gingival bleeding. menorrhagia) • Superficial ecchymosis: common • Hemarthrosis, delayed bleeding, deep dissecting hematoma: rare • Not one laboratory test can make the diagnosis • Some screening tests may be normal, need specific vW laboratory tests. How to test: • PT, APTT, Fibrinogen, PLT • FVIII measures the ability of vWF to bind and maintain the level of FVIII in circulation • vWF Antigen measures the concentration of vWF protein in plasma • vWF Ristocetin cofactor assay: functional assay of vWF measures its ability to interact with normal platelets • the antibiotic ristocetin causes vWF to bind to platelets, resulting in clumps and remove from circulation Additional testing: • Collagen binding assay: ELISA assay • Ristocetin Induced Platelet Aggregation (RIPA) • vWF multimers: looks at the different molecular forms of vWF from dimer to high molecular weight multimers (HMWM). This is important in determining subtypes of vWD 4 10/8/2011 Blood Typing: • Different blood types have different normal ranges of vWF • May be a consideration when classifying patients: Type O = 36-157% Type A = 49-234% Type B = 57-241% Type AB= 64-238% Technical Manual 9th ed AABB NHLB/NIH Guidelines TypeDescription R; vWF Ag FVIII R:CoF/A CoF %% % g NL 50-20050-200 NL >.5-.7 1 Partial quantitative vWF deficiency <30 <30 NL or >.5-.7 low 2A Decreased vWF dependent plt <30 <30- NL or <.5-.7 adhesion 200 low & selective deficiency of HMWM 2B Increased vWF affinity to GPib <30 <30- NL or <.5-.7 200 low 2M Decreased vWF dependent platelet <30 <30- NL or <.5-.7 adhesion 200 low 2N Markedly decreased vWF binding 30-20030-200 Very >.5-.7 affinity for FVIII low 3 Complete deficiency of vWF <3 <3 Very NA low Von Willebrand testing • Sample integrity is important, antigen is more stable than activity • Should freeze sample ASAP, but after thawing do not place on ice • Thaw in water bath • Mix, mix and mix • Blood type is important 5 10/8/2011 Case Study: • A pregnant women has a routine OB visit • This is her third pregnancy, no prior problems • Upon taking a history, her only complaint is shortness of breath • The physician orders a work-up Thrombosis & Pregnancy: • 6 times more thrombotic • Recurrent rate: 1/71 • Most prone 3rd trimester • Post-partum • Can have micro vascular thrombosis • 110 women with obstetrical complaints- 53 had thrombophilia-50% • PE most common cause Recommended Thrombosis ‘Panel’ • APC Resistance screen • Protein C activity • Protein S activity • Antithrombin activity • Prothrombin 20210 gene mutation • Factor VIII • Lupus Anticoagulant screening • Homocysteine 6 10/8/2011 c2 Laboratory Evaluation ¾ Must perform a panel of tests ¾ No global test available ¾ Must confirm plasma based assays before establishing diagnosis ¾ Many drugs and physiologic conditions may influence results ¾ Should consider evaluation of family What happens? • Increase in VII, VIII, IX, X and fibrinogen •vWF • Increased venous stasis • Increased activation of platelets • Increased PAI-1 • Physiological resistance to APC Why? • Hemostatic changes: – Physiological changes – Congenital: Thrombophilia – Mechanical: Change in Uterus – 1600 women/day die in pregnancy 7 Slide 19 c2 castdo10, 12/17/2010 10/8/2011 Additional risks: • DVT 35 fold increased risk: 5/100 • 50% of women that have thrombotic • Post partum ovarian DVT 1:500-1:2000 women • High risk in thrombophilia patients – 30-36% ATIII deficiency – 3-10% Protein C deficiency – 0-6% Protein S deficiency pre-partum – 0-15% post-partum – 46% APCR Acquired Risk Factors: • Cesarean delivery • Maternal age>35 = 3 X risk; >40 =6 X risk • Obesity >180 lbs • Surgical procedure during pregnancy or post partum How do you treat? • Warfarin can cross the placenta, risk to the fetus • Can use 13-30 weeks, or post partum • Heparin doesn’t cross placenta, monitor with APTT • Aspirin • LMWH safe, 1/day, must remove 24 hours before labor 8 10/8/2011 Advantages: • Excessive blood loss is >600mls • APCR + patients have a lower risk • 14% of APCR – patients will bleed • Only 1% of APCR + patients bleed Results: • Fibrinogen= 485mg/dl (180-400) • Factor VIII=210% (50-150%) • Factor V Leiden: negative • Lupus anticoagulant: negative • AT= 82% (80-120%) • Protein C = 84% (70-130% • Protein S= 50% (62-154%) • What do we see? Diagnosis: • Physician tells the patient she was Protein S deficient • Recommends a therapeutic abortion • After much thought the patient agreed, since she had 2 small children at home • What is wrong with this picture 9 10/8/2011 Protein S: • Protein S is a Vitamin K dependent factor • It is an inherited disorder, occurring in about 3% of the thrombotic population • However, protein S is
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