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Von Willebrand's Disease is an Autosomal dominant disorder characterized by variable deficiency of von Willebrand Factor. Why is it classified as a "Dual defect" disorder?

1) Inadequate platelet aggregation due to inadequate subendothelial vWF

2) Defective/deficient circulating factor VIII

*VWF and factor VIII exist as a complex in plasma but are under separate genetic control

This is described as the following:

- Deficient in VWD
- "Big" molecular size
- Coded for by *CHROMOSOME 12


This is described as the following:

- Deficient in hemophilia A
- "Small" molecular size
- Coded for by "X CHROMOSOME"

Factor VIII:C (coagulant)

In comparing Von Willebrand's Disease vs. Hemophilia A, which one demonstrates the following:

1) Elevated PTT


3) Normal to reduced Factor VIII:C

4) Reduced VWF antigen

5) Reduced Ristocetin cofactor activity

Von Willebrand's Disease


1) Elevated PTT


3) Reduced Factor VIII:C

4) Normal VWF antigen

5) Normal Ristocetin cofactor activity

Hemophilia A

In Type I von Willebrand's Disease, what is the elevated PTT due to?

Factor VIII deficiency

In Type I von Willebrand's Disease, prolonged bleeding time reflects platelet function. What causes variation?

- There is more severe bleeding time prolongation when patient is also taking aspirin

- Because of variable deficiencies from patient to patient, bleeding time occasionally will be normal

**In Type I von Willebrand's Disease, what is the Immunologic measurement of Factor VIII:VWF?

Reduced VWF antigen

Does the degree of reduction of VWF antigen predict the bleeding risk?


This a glycopeptide antibiotic that initiates binding of vWF to platelet glycoprotein Ib


In Type I von Willebrand's Disease, there is Reduced Ristocetin cofactor activity. How is this tested?

-Ristocetin is added to plasma where it triggers platelet binding to available vWF and subsequent agglutination

-If vWF reduced, agglutination will be reduced

What are the clinical characteristics of Von Willebrand's Disease?

Variable bleeding severity and generally less severe than that seen in hemophilia

What does the treatment of Von Willebrand's Disease depend on?

1) Severity of vWD

2) Severity of bleeding risk

What is the treatment of mild to moderate Von Willebrand's Disease?

1) Possibly no treatment other than aspirin avoidance

2) DDAVP- desmopressin acetate (synthetic ADH) Stimulates release of endothelial Von Willebrand's factor with a modest risk

3) May be given intravenously, intranasally or subcutaneously

What is the treatment of severe Von Willebrand's Disease?

1) Humate-P
- Plasma derived product
- Contains approximately three times more VWF than factor VIII

2) Cryoprecipitate (fibrinogen, factor VIII, factor XIII, VWF)
- Used less commonly due to difficulty in eliminating viral infection risk and increased transfusion volume requirement

This is X-linked recessive hereditary coagulation factor deficiencies


T or F. Hemophilia has male predominance


This is described as the following:

1) Factor VIII deficiency

2 )Second most common type of inherited bleeding disorder (85% of cases)

3) Incidence about 1 in 5,000 live births

Hemophilia A ("classic")

This is described as the following:

1) 12% of cases

2) Factor IX deficiency

3) Incidence about 1 in 30,000 live births

Hemophilia B ("Christmas disease")

Which Hemophilia has elevated PTT?

- Hemophilia A
- Hemophilia B
- Both


Which Hemophilia is associated with reduced Factor VII?

Hemophilia A

Which Hemophilia is associated with reduced Factor IX?

Hemophilia B

How is Hemophilia A distinguished from Von Willebrand's disease?

1) More significantly reduced Factor VIII levels

2) Normal VWF antigen levels

3) Normal bleeding time

What are the clinical characteristics of both Hemophilia A & B?

1) Prominent family history

2) Greater bleeding severity than vWD or platelet disorders

3) Spontaneous bleeds (hemarthroses, intramuscular hematomas, postoperative bleeding complications.)

4) Retroperitoneal hemorrhage

What is the treatment of Hemophilia?

1) Factor VIII replacement
- Recombinant (synthetic) or plasma-derived
- Still a moderate transfusion infection risk due to frequency of blood product requirements
- Degree of replacement based on clinical need

2) Genetic Counseling

Unfractionated Heparin will lead to elevated PTT. What will excessive, continuous heparin infusion will also eventually lead to?

An elevated PT

Low molecular weight heparin does not typically elevate the PTT but will reduce ________

Factor Xa levels

How is the Effectiveness of anticoagulation with low molecular weight heparins is usually measured by?

Factor Xa levels

T or F. Fibrinogen, prothrombin, Factor V, Factor VII, Factor X, Factor XI, Factor XIII can all cause elevated PTT


What coagulation inhibitors increase PTT?

Antibodies against a particular coagulation factor or Von Willebrand's factor
- Potentially related to antigenic stimulation from plasma factor replacement therapy and a particularly complicated problem in hemophilia and severe Von Willebrand's disease

- Increased frequency in autoimmune and lymphoproliferative disorders

What is the treatment for acute bleeding episodes?

It is very complicated, but it Usually involves immunosuppression (Cyclophosphamide, prednisone) & Immune tolerance therapy

This disorder causes an elevation of PTT and is described as the following:

- The "Classic Example

- Antibody to phospholipids which results in benign prolongation of the PTT since phospholipids play a small but necessary role in the coagulation cascade

- Counterintuitive predisposition towards thrombosis instead of bleeding in context of the antiphospholipid antibody syndrome

Lupus anticoagulant

This drug Antagonizes vitamin K and therefore reduces production of factors II, VII, IX, X

- which in turn elevates the PT


How are the effects of Coumadin often potentiated by other medications?

1) Antibiotics often alter gut flora which results in decreased in vivo vitamin K production

2) Frequent cause of iatrogenic coagulopathies

Vitamin K deficiency elevates the PT, how does this happen?

1) Vitamin K usually found in green, leafy vegetables like spinach

2) Most common setting for vitamin K deficiency in US is the hospitalized patient, especially complicated postoperative patients

What is the treatment for vitamin K deficiency?

1) Vitamin K replacement (oral, SQ or IV)

2) Fresh Frozen Plasma in severe cases

3) This is also the treatment for excess Coumadin

Does Coagulopathy of liver disease cause an elevated PT?


This is Reduced hepatic function first leads to reduced production of coagulation factors, especially factor VII due to its very short half-life

Coagulopathy of liver disease

As liver disease progresses, what else is also decreases aside from coagulation factors?


T or F thrombopoietin will further complicate coagulopathy?

True. Especially if underlying liver disease leads to portal hypertension and splenomegaly, which will lead to platelet sequestration as well

Are both PT & PTT elevated in Coagulopathy of liver disease?


What is considered a better marker for hepatic synthetic function in liver disease:

a. Liver disease
b. Albumin
c. Total Protein
d. Liver enzymes
e. Prothrombin Time (PT)

Prothrombin Time (PT)

T or F. Coagulation inhibitors are more typically associated with PTT prolongation, occasional inhibitors can develop towards the factors of the extrinsic system and lead to PT prolongation as well


What are some examples of inhibitors that elevate PT?

Factor V inhibitors and certain types of lupus anticoagulant

What can cause elevated PT & PTT?

1) Coagulopathy of liver disease

2) Excessive unfractionated heparinization

3) Disseminated intravascular coagulation
- Widespread activation of coagulation resulting in intravascular fibrin formation and thrombotic occlusion of small vessels
- Widespread coagulation creates a state of "consumptive" coagulopathy which thereby leads to bleeding

What are the clinical features of Disseminated intravascular coagulation (DIC)?

1) Microangiopathic hemolytic anemia (MAHA)

2) Symptoms
- Hepatic dysfunction (19 percent)
- Respiratory dysfunction (16 percent) )
- Thromboembolism (7 percent)
- Central nervous system involvement (2 percent)

How is Disseminated intravascular coagulation (DIC) diagnosed?


Are there any labs that will diagnose Disseminated intravascular coagulation (DIC)?


Labs (none definitive but several are helpful)
- Increased PT & PTT
- Fibrinogen < 100
- Elevated D-dimer
- Increased fibrin split products
- Thrombocytopenia

Although DIC and TTP/HUS may be clinically indistinguishable in their late stages, what is the difference?

1) Coagulation deficiency should predominate in DIC

2) Thrombocytopenia should predominate in TTP/HUS

What is the treatment for Disseminated intravascular coagulation (DIC)?

1) Treat the underlying cause

2) Fresh frozen plasma to replace coagulation factors

3) Cryoprecipitate for patients with severe hypofibrinogenemia

4) Platelet transfusions

5) Heparin (What the f@*$?) may be considered when thrombotic complications are prominent but is usually avoided due to excess bleeding risk

Is Clinically significant bleeding more likely to be coagulation problem or platelet problem?

Coagulation problem

Elevated PTT is associated with

1) VWD

2) Hemophilias

3) Heparin

Elevated PT is associated with

1) Coumadin

2) Vit K deficiency

3) Coagulopathy of liver disease

What causes both PT & PTT to be elevated?

1) Liver disease

2) Heparin

3) DIC

This has multiple causes leading to consumption of existing platelets


Based on PT & PTT results

PT- Vit K


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