Inherited and Acquired Coagulation Disorders Flashcards
Grading of hemophilias
Severe: <1% factor
Moderate: 1%-4% factor
Mild: >4% factor
Hemophilia A is a deficiency in ____.
Hemophilia B is a deficiency in ____.
Hemophilia A is a deficiency in Factor VIII.
Hemophilia B is a deficiency in Factor IX.
Why is it that hemophilia A and B are truly identical in phenotype?
Because factor XIII and IX have to complex together in the coagulation cascade. Both hemophilias are essentially a deficiency in the XIII-IX complex, aka, the tenase complex.
Genetics of hemophilia A and B
Both hemophilia A and B are X-linked recessive Mendelian diseases
As it happens, most female cases of hemophilia A are thought to be due to unfavorable lyonization rather than homozygosity.
Clinical presentation of hemophilia A
-
Hemarthroses (deep bleeding into joints)
- Chronic disability due to swelling, deformity, severe pain, limitation of motion, and contractures that can be corrected only by joint replacement
- Gastrointestinal or genitourinary bleeding
- Less common
- Intracerebral hemorrhage
- Very rare but very serious
Because factor VIII is part of the ___ pathway of coagulation, the ___ in a patient with hemophilia A is prolonged, whereas the ___ time is normal.
Because factor VIII is part of the intrinsic pathway of coagulation, the partial thromboplastin time (PTT) in a patient with hemophilia A is prolonged, whereas the prothrombin time (PT) is normal.
Treating hemophilia A
-
Infusions of either recombinant factor VIII or highly purified plasma-derived factor VIII prepared from human donor plasma
- However, patients are less likely to develop immune resistance to plasma-derived factor VIII
- Both are equally effective and free of viral pathogens
- The recombinant product costs two to three times as much as the plasma concentrates
- Factor VIII has a half-life of 8-12 hours, so 2 infusions per day are required
- Isolated hemorrhages like joint hemorrhage may be treated by raising VIII to 30% reference with a single infusion
Limiting factor with most hemophilia treatment
Cost
Prophylactic treatment of children with factor VIII deficiency costs over $100,000 per year.
Desmopressin
Releases vWF from its stores within endothelial cells. This results in a significant increase in plasma levels of factor VIII, which binds and is stabilized by vWF
As a general rule, when given daily for up to 3 days, desmopressin treatment raises factor VIII levels three- to four-fold.
Treating hemophilia A patients who have developed anamnestic anti-factor VIII
- Porcine factor VIII infusion
- Recombinant factor VIIa (bypass factor VIII and the intrinsic pathway)
- Bispecific IgG against factor IX and factor X (mimicking factor VIIIa)
Treating hemophilia B
- Recombinant factor IX
- ultrapure plasma-derived factor IX
- Half-life of about 24 hours, so only once-a-day infusions
- However, twice as much must be given to achieve the same bioavailability due to its different volume of distribution
- Treatments for alloantibodies against factor IX are similar to those for hemophilia A with alloantibodies against factor VIII
- Unfortunately, as hemophilia B is less prevalent, there are fewer novel treatments for this disease (no bispecific antibodies or progress on gene therapy)
von Willebrand disease
- Most prevalent bleeding disorder ( 1 in 90 in the US )
- Very mild, overwhelmingly asymptomatic in general population
- Unlike hemophilias:
- Inherited autosomal dominant
- Bleeding primarily from mucous membranes
- Association with purpura
- Bleeding time is prolonged
___ have lower levels of plasma vWF and are commonly misdiagnosed as having von Willebrand disease.
Humans with group O blood have lower levels of plasma vWF and are commonly misdiagnosed as having von Willebrand disease.
Diagnosing von Willebrand’s disease
- Factor VIII activity is measured with the PTT assay
- vWF antigen is measured with an immunologic assay that detects both normal and mutant vWF proteins
- The ristocetin cofactor assay provides a functional assessment of vWF protein
- ‘Dead’ platelet test
- Western blot for vWF MW
- Also used to diagnose TTP and IATP
Rule of thumb for bleeding disorders
If it’s just internal bleeding, probably hemophilia A or B
If it’s just mucosal bleeding or purpura, probably vWD type I or II.
If it’s both, probably vWD type III
Type I, IIA, IIB, and III vWD
- Type I: Heterozygous, most prevalent (70%), 15-60% normal vWF
-
Type II: Normal levels vWF and factor VIII, but impaired function (low ristocetin cofactor activity)
- Type IIA: Heterozygous. Defective multimerization of vWF. Impaired ability to tether platelets to endothelium and one another.
- Type IIB: Heterozygous. vWF affinity for platelet glycoproteins is too high and impairs multimerization. Clearance of multimers from plasma and mild thrombocytopenia. Unusually sensitive to ristocetin agglutination.
- Type IIN: Homozygous, autosomal recessive. N-terminal mutations that abolish vWF binding to factor VIII. Normal ristocetin cofactor activity, but no circulating factor VIII. Similar in phenotype to hemophilia A.
- Type III: Homozygous, rare, 0% vWF, effectively 0% factor VIII function
vWD therapy
- Intravenous infusion of factor VIII concentrates, which are enriched in vWF
- Patients with less severe disease are often treated quite effectively with desmopressin, a vasopressin analog, which triggers the release into the plasma of vWF protein stored in endothelial cells.
- Desmopressin is contraindicated in type 2B von Willebrand disease because it induces severe thrombocytopenia.
All clotting factor deficiencies except ___ may be diagnosed by a panel of factor exclusion serum tests.
All clotting factor deficiencies except factor XIII may be diagnosed by a panel of factor exclusion serum tests.
Chaotropic agent
A molecule in water solution that can disrupt the hydrogen bonding network between water molecules.
This has an effect in the stability of the native state of other molecules in the solution, mainly macromolecules (proteins, nucleic acids) by weakening the hydrophobic effect.
Ex, urea
Testing for factor XIII deficiency
Deficiency of factor XIII can be demonstrated by testing the stability of the fibrin clot in a chaotropic solution such as 5 M urea
___ is a clotting disorder encountered primarily among Ashkenazi Jewish populations.
Factor XI deficiency is a clotting disorder encountered primarily among Ashkenazi Jewish populations.
Individuals with factor XI deficiency, even when severe, seldom bleed abnormally unless challenged by trauma or major surgery. Because factor XI has a relatively long half-life, patients can be effectively treated with infusions of fresh frozen plasma.
Where is vitamin K found?
Vitamin K is a fat-soluble vitamin found primarily in leafy green vegetables but also in meat and dairy products.
Some vitamin K is also synthesized by gut flora.
Vitamin K cycle
In which patients do you worry about nutritional vitamin K deficiency?
Patients who are not eating and who are receiving broad-spectrum antibiotics are at risk for vitamin K deficiency. This scenario is commonly encountered in hospitalized patients and often is not diagnosed until clinically significant bleeding develops.
Less often, vitamin K deficiency is caused by obstructive liver disease or by disorders of the intestinal mucosa that lead to chronic malabsorption.
