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Coagulation Disorders

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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
Factor VIII:VWF
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

2) **PROLONGED BLEEDING TIME
- OCCASIONALLY NORMAL

3) Normal to reduced Factor VIII:C

4) Reduced VWF antigen

5) Reduced Ristocetin cofactor activity
Von Willebrand's Disease
In comparing Von Willebrand's Disease vs. Hemophilia A, which one demonstrates the following:

1) Elevated PTT

2) *NORMAL BLEEDING TIME

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?
No
This a glycopeptide antibiotic that initiates binding of vWF to platelet glycoprotein Ib
Ristocetin
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
Hemophilia
T or F. Hemophilia has male predominance
True
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
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
True
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
Coumadin
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?
Yes
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?
Thrombopoietin
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?
Yes
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
True
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
- BLEEDING (64 PERCENT)
- RENAL DYSFUNCTION (25 PERCENT)
- Hepatic dysfunction (19 percent)
- Respiratory dysfunction (16 percent) )
- Thromboembolism (7 percent)
- Central nervous system involvement (2 percent)
How is Disseminated intravascular coagulation (DIC) diagnosed?
Clinically
Are there any labs that will diagnose Disseminated intravascular coagulation (DIC)?
NO

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
DIC
Based on PT & PTT results
PT- Vit K

PTT - XII, XI, IX, VIII, & X