Disorders of Secondary Hemostasis Flashcards
List 6 general features of Congenital coag. factor deficiencies.
- Incidence: 1 per 10,000 in the general population.
- Autosomal recessive or X-linked recessive inheritance.
- Variable severity of bleeding, mostly mild or moderate.
- Often unanticipated bleeding following trauma or surgery.
- Chronic complications in joints and soft tissues.
- Disease is lifelong; no cure.
List 7 characteristics of classic hemophilia.
- Hemophilia A.
- Deficiency of Factor VIII activity.
- X-linked recessive inheritance.
- Most common serious inherited coagulation
disorder.
- Incidence: 1 in 10,000 to 1 in 5,000 males.
- Affects the intrinsic pathway.
- aPTT is prolonged, others assays are normal.
Describe the genetics of hemophilia A
- X-linked recessive inheritance.
- One-third of all cases are due to new mutations.
- Only males are affected.
- Females are carriers.
- Their mothers are obligate carriers if father is unaffected.
- Rarely, females are affected, due to: – Father is affected and mother is a carrier – Turner syndrome, 45,X – Skewed X-inactivation (extreme Lyonization)
What is factor VIII like in circulation? Where is it synth? What is it structurally and functionally similar to? What is its role? How is it activated? What are the genetic defects like? What implications does this have?
- Large, heterotrimeric protein, 265 kD.
- Bound to vWF in the circulation.
- Synthesized by the liver and endothelial cells.
- Structural and functional homology to Factor V.
- Cofactor for activation of Factor X by Factor IXa.
- Essential for physiological clotting.
- Activated by thrombin, and less, by Factor Xa.
- Factor VIII gene is located on Xq.
- Genetic defects encompass various types of
mutations; heterogeneous at genetic level.
• Complicates genetic testing for hemophilia A.
Describe the clinical features of hemophilia A. When can it become life threatening?
• Symptomatic at Factor VIII levels below 10%.
• Severity of bleeding tends to be inversely. proportional
to Factor VIII level.
- Bleeding into soft tissues and joints.
- Bleeding starts hours to days after trauma.
- Bleeding could also occur spontaneously, and into any
tissue or organ.
- The hematoma may compress vital structures.
- Bleeding into joints (hemarthrosis) causes progressive
destruction of the joints—>osteoarthritis, fusion of bones
• Calcified hematomas may present as pseudotumors.
IM Injections can cause huge hemorrhages but are self-limiting.
Nerve damage can be caused.
• Most life-threatening bleeding: oropharyngeal and CNS.
List the 3 severities of hemophilia A including the factor VIII level and clinical manifestations.
Severe <0.01 U/ml)
- Spontaneous hemorrhage from early infancy, e.g., circumcision
- Frequent spontaneous hemarthrosis and other hemorrhages requiring clotting factor replacement
Moderate 1 – 5% of normal (0.01 – 0.05 U/ml)
- Hemorrhage secondary to trauma (crawling, walking) or surgery
- Occasional spontaneous hemarthrosis
Mild 6 – 30% of normal 0.06 – 0.30 U/ml)
- Hemorrhage secondary to trauma or surgery including dental surgery
- Rare spontaneous hemarthrosis
- Usually diagnosed later in life
Explain how hemophilia A is diagnosed in the lab. What tests are performed? What results are found? What additional tests can be done?
- Start with global screening tests.
- Prolonged aPTT (intrinsic pathway disorder).
- Normal bleeding time, platelet count and PT.
- Mixing study: Patient plasma + Normal plasma corrects
aPTT (= no inhibitor).
• Mixing study: Patient plasma + Factor VIII deficient
plasma fails to correct aPTT (= factor deficiency).
• Further tests: – Factor VIII activity – Factor VIII antigen concentration – These tests are used to further classify hemophilia A
Explain the difference between type I and type II Classic Hemophilia. Which is more common? How can carriers be detected? Explain. When is this indicated?
- Type I: Quantitative decrease in Factor VIII concentration.
- 90% of hemophiliacs are Type I.
• Type II: Qualitative decrease in Factor VIII activity with
normal protein concentration.
• Carriers may be detected using lab tests by determining
the vWF:Factor VIII antigen ratio: – Normal ratio: 1 – Carriers: ≈ 2 – Hemophiliacs: 3 to > 100
• All women in hemophilia pedigrees should have this test done to determine their carrier status.
Explain what RFLP is and what its role is with hemophilia.
Recently, it has become possible to trace the defective allele in some families by examining the inheritance of restriction fragment length polymorphisms (RFLP) linked to the mutation in the Factor VIII gene or by PCR amplification of a region of the Factor VIII gene linked to a specific inversion seen in about 20% of patients with severe Hemophilia A (see Figure 5).
However, because of the many different mutations causing Factor VIII deficiency, RFLP studies
require specimens from multiple affected and unaffected members to establish linkage of the
clinical phenotype to a specific RFLP. In families with “spontaneous” mutations, this can be very
difficult and may not provide a definitive answer. Genetic counseling should be offered to all
carrier females. Amniocentesis or chorionic villus sampling provides for early detection by
DNA-based methods so that elective termination or other options could be considered.
What are 3 treatments for classic hemophilia? Explain and describe the main one.
- Replace Factor VIII with Factor VIII Concentrate: – Symptomatic patients – Preparation for surgery – Preparation for tooth extraction(s)
- Goal is to maintain Factor VIII levels at: – 20 – 30% for soft tissue bleeding and hemarthrosis – 50 – 75% before and up to 14 days after surgery – 50 – 75% before and up to 3 weeks after joint surgery
- Epsilon aminocaproic acid (EACA) mouth wash after tooth extraction
- Desmopressin (DDAVP) for mild hemophilia.
Compare and contrast hemophilia A and B.
- Similar to hemophilia A in many respects.
- X-linked inheritance.
- Incidence: 1 in 40,000.
- Identical to hemophilia A in clinical presentation.
- Similar classification into mild, moderate and severe.
- Similarly has Type I and Type II patients.
- Similar lab results; prolonged aPTT, others normal.
- Distinguished using specific factor mixing studies.
- Treated with Factor IX concentrates.
- Like hemophilia A, therapy may lead to inhibitors
(antibodies) to Factor IX.
Describe hemophilia C.
Factor XI deficiency: Hemophilia C: – Autosomal recessive – Rare; seen in restricted populations e.g. Ashkenazi Jews – Manifesting heterozygotes; mild bleeding – Homozygotes bleed following trauma or surgery–
Treatment with plasma concentrate.
Describe • Deficiency of Factor XII, HMWK and Prekallikrein:
– Autosomal recessive – Markedly prolonged aPTT, other global tests normal – No bleeding disorder
More likely to have thromboses
Describe deficiency of factor XIII.
- Autosomal recessive inheritance.
- Severe bleeding disorder with poor wound healing
and spontaneous abortions.
- All global tests are normal.
- Diagnosed with clot solubility test in 5M Urea.
- Treat bleeding episodes with fresh frozen plasma.
See table of other deficiencies
See table
