Lecture 17 Hemorrhagic Disorders & Laboratory Assessment

Question 1

What is the most common bleeding disorder?

Answer 1

Von Willebrand Disease, seen in 1% of the population.

Followed by Factor deficiencies (affects 1:10,000) with Hemophilia A (Factor VIII def) in 85% of cases.

Question 2

What factor deficiencies are linked to the X chromosome? What is the implication of this?

Answer 2

Factor VIII and IX deficiencies are inherited as X-linked recessive traits.

VIII –> Hemophilia A
IX –> Hemophilia B

If females inherit this disorder (XX) they are usually unaffected as they typically have one unaffected chromosome X along with one affected resulting in sufficient factor to prevent bleeding. If the female is homozygous that means she will get the disease and experience bleeding.

Question 3

What are the factors inherited as (except the X-linked)?

Answer 3

Autosomal dominant or autosomal recessive.

See slide 4 for details.

Question 4

Where is von Willebrand Factor produced?

Answer 4

Synthesized by vessel endothelial cells and megakaryocytes.

Question 5

Where do you find vWF in the body?

Answer 5

Two sources of vWF: plasma pool and alpha granule platelet pool.

Circulates in plasma with Factor VIII as a complex.

Question 6

What is nonmenclature for Factor VIII and vWF is used?

Answer 6

1. VIII/vWF: Circulating molecule in plasma
2. vWF: Refers to bridge function and carrier of VIII
3. vWF:Ag: von WIlledbrand Factor antigen measured by immunoassay.
4. VIII:C: Intrinsic system co-factor, tested by clotting assay
5. VIIIC:Ag: Antigenic property of procoagulant VIII:C tested by immunoassay.
6. vWF:RCoF: Ristocetin cofactor activity which induces binding of vWF to platelets, RXN may be measured by aggregometry.

Question 7

What coagulation defects are found in Von Willebrand Disease?

Answer 7

1. Increased Bleeding Time, abnormal platelet adhesion and aggregation tests.
2. Low FVIIIC (<50%) is common but may be normal.
3. vWF and FVIII commonly display parallel decrease between 15-59%. (In severe disease FVIII<30%)
4. Can have both qualitative and quantitative defects.

Question 8

What are the normal levels for vWF and FVIII?

Answer 8

50 to 150%

Question 9

What is one of the most diagnostic tests for von Willedbrand’s Disease?

Answer 9

One of the most diagnostic tests is Ristocetin Cofactor Activity Test because is almost always low. Type IIb normal or decreased.

It contains normal formalized platelets and antibiotic Ristocetin. In the presence of patient’s plasma supply vWF agglutination occurs.

Dilutions are made of patient’s plasma and tested to determine if normal levels exist and severity of disease.

If there is a vWF deficiency there will be no agglutination.

Question 10

What was Ristocetin used for?

Answer 10

Ristocetin was used as antibiotic till it was determined that it caused agglutination and thrombocytopenia. Then pulled from market.

Question 11

What is von Willebrand antigen made of?

Answer 11

Combination of low, medium and high molecular weight multimers.

Question 12

Which von Willebrand antigen promotes normal platelet adhesion?

Answer 12

Only the high molecular weight multimers promote normal platelet adhesion.

In vWF disease there is lower numbers of these causing bleeding.

Question 13

What is the most severe type of von Willebrand Disease?

Answer 13

Most severe type is Type III.

Von Willebrand disease can be subtyped in 5 major classes each with its own characteristic’s.

Up to 40 known variants.

Measurement of vWF multimers can be helpful in identifying specific type.

Question 14

What is the synonym for Factor VIII deficiency?

Answer 14

Hemophilia A

You may want to review slide 14, but no flash cards on it as it repeats stuff already learned.

Question 15

What are the clinical manifestations of Hemophilia A

Answer 15

1. Anatomical bleeds with deep muscle and joint hemorrhages. Bleeds in muscles can cause nerve compression injury with temporary then lasting disability.
2. Wound oozing after trauma and surgery.
3. Bleeding into nervous system, peritoneum, GI tract and kidneys. Cranial bleeds may lead to loss of memory, paralysis, seizures, coma or death.
4. Acute joint bleed causing pain and immobilization.
5. Chronic joint bleeds may cause inflammation and permanent loss of mobility.
6. Limited productivity, low self-esteem, poverty, drug dependency, depression are common problems.

Question 16

What kind of issues are platelet defects known for?

Answer 16

Skin and superficial tissue bleeding and bruising.

Question 17

What historical problems did the treatment for hemophiliacs cause?

Answer 17

1. 70% of hemophiliacs treated before 1984 HIV testing are HIV positive or have died from HIV.
2. Repeated exposure to blood products before stringent testing and new therapies often caused hepatitis.

Question 18

What are the laboratory findings for Hemophilia A?

Answer 18

1. Quantitative defects more common, qualitative defect rare.
2. PT/INR, Thrombin Time are normal.
3. APTT is prolonged provided APTT reagent is sensitive to factor deficiency of less than 30% plasma value.

Question 19

What do the various activity levels relate to in terms of risk of hemophilia symptoms?

Answer 19

1. Activity levels of 5% to 30% mild hemophilia risk of hemorrhage in trauma, surgery or dental extraction.
2. Activity levels 1% to 5% moderate hemophilia diagnosed in early childhood after apparent symptoms.
3. Activity levels <1% severe hemophilia with spontaneous and pronounced bleeding in neonates.

Question 20

Why is the APTT prolonged but the PT/INR and Thrombin Time are normal for patient with Hemophilia A?

Answer 20

Hemophilia A is a Factor VIII deficiency and VIII is found only in the Intrinsic pathway so only APTT is affected.

Question 21

What are some treatments for Hemophilia A?

Answer 21

1. Desmopressin acetate (DDAVP) stimulates release of vWF from endothelial cells with subsequent increase in VIII due to complexing. May be used in mild cases.
2. In more severe cases FVIII concentrates from recombinant DNA technology or derived from human plasma are used to meet coagulation needs.

Question 22

What are the synonyms for Factor IX deficiency?

Answer 22

Hemophilia B and Christmas Disease

Second most common hemophilia at 14%.

Question 23

What do coagulation tests show for Hemophilia B?

Answer 23

PT and Thrombin time normal. APTT prolonged providing it is sufficiently sensitive to the decreased level.

Same as for Hemophilia A.

Question 24

What testing may be used to establish carrier status for Hemophilia B?

Answer 24

DNA analysis.

Sex-linked involving numerous mutations causing mild to severe bleeding similar to Hemophilia A.

Question 25

What is the treatment for Hemophilia B?

Answer 25

Recombinant or plasma derived Factor IX concentrates.

Question 26

What is the synonym of Factor XI deficiency?

Answer 26

Hemophilia C

Question 27

How is Factor XI deficiency inherited? Degree of symptoms?

Answer 27

Autosomal dominant.

Hemophilia with mild to moderate bleeding symptoms.

More than half of the cases are Ashkenazi Jews, but any ethnic group may be affected.

Question 28

What are the coagulation lab results for Hemophilia C?

Answer 28

PT and Thrombin Time are normal. APTT is prolonged assuming proper sensitivity of reagent.

Question 29

Why are Hemophilia A, B and C all have the same coagulation lab results?

Answer 29

Factor VIII, IX and XI found only in intrinsic pathway.

Question 30

When is Fresh frozen plasma used to treat Hemophilia C?

Answer 30

FFP is only used if bleeding occurs due to mild or moderate bleeding during hemostatic challenges such as cuts, surgery, and dental extractions.

Question 31

How are other congenital single-factor deficiencies inherited?

Answer 31

Autosomal recessive mutations.

Question 32

What kind of defects (general) may exist in other congenital single-factor deficiencies?

Answer 32

Quantitative and qualitative (less prevalent) abnormalities present.

Question 33

How are the coagulation tests used in other congenital single-factor deficiencies?

Answer 33

PT, APTT and Thrombin Time may be used to separate specific factor(s).

Reflex testing with specific factor assays may be required to isolate and confirm defect.

Question 34

Most factors result if bleeding risk if levels below 30%, what are the two exceptions to this?

Answer 34

Factor XI <50% results in bleeding risk.
Factor XIII <1% Bleeding Risk.

Question 35

What factor does INR/APTT and Thrombin time does not measure?

Answer 35

Factor XIII.

Question 36

What are the three steps to convert fibrinogen to stable fibrin? What step is factor XIII required for?

Answer 36

1. Enzymatic (Proteolytic) - Thrombin cleaves fibrinogen releasing fibrinopeptides thus producing a soluble fibrin monomers.
2. Polymerization - Fibrin monomers aggregate side to side then end to end to produce a unstable fibrin clot.
3. Stabilization - occurs when factor XIIIa in the presence of calcium crosslinks fibrin monomers forming stable covalent bonds and clot.

Factor XIII is required for Stabilization.

Look at diagram on slide 26 that illustrates the stages.

Question 37

What is the clinical manifestations of Factor XIII deficiency?

Answer 37

Patients with this deficiency only rarely have hemorrhagic problems except following surgery. Delayed wound healing is a typical finding in these patients.

Question 38

How is Factor XIII tested for?

Answer 38

The 5 M urea or 1% monochloroacetic acid test screens for factor XIII deficiency.

If deficient the fibrin polymers are soluble in these solutions.

Question 39

What is being developed that may replace 5 M urea of 1% monochloroacetic acid test for factor XIII?

Answer 39

Some manufacturers are creating factor XIII activity assays which are rapidly replacing Urea Solubility Test.