Hemostasis is the process of blood clotting and subsequent dissolution of the clot following tissue repair. It involves 3 main events: 1) vascular constriction, 2) platelet aggregation forming a temporary plug, and 3) fibrin formation creating a stable clot. The clot must later dissolve for normal blood flow to resume. Von Willebrand disease is a bleeding disorder caused by deficient or abnormal von Willebrand factor, which helps platelets bind to collagen. It ranges from mild to severe and is diagnosed based on bleeding history and lab tests of von Willebrand factor and coagulation factors. Treatment depends on severity but may include desmopressin or coagulation factor replacement.

2. Hemostasis
The process of blood clotting and
then the subsequent dissolution
of the clot, following repair of the
injured tissue, is termed
hemostasis.

3. BV Injury
Contact/
Tissue
Factor
Neural
Blood Vessel
Constriction
Haemostasis
overview:
Platelet
Aggregation
Coagulation
Cascade
Primary hemostatic plug
Reduced
Blood flow
Platelet
Activation
Stable Hemostatic Plug
Fibrin
formation

4. Hemostasis - major events
1. Vascular constriction.
2. Platelets become activated by
thrombin and aggregate at
the site of injury, forming a
temporary, loose platelet
plug.
3. To insure stability of the
initially loose platelet plug, a
fibrin mesh (also called the
clot) forms and entraps the
plug.
4. The clot must be dissolved in
order for normal blood flow
to resume following tissue
repair.

5. HK = high molecular
wt. kininogen.
PK = prekallikrein.
PL = phospholipid.

7. Endogeneous anticoagulants
• AT lll
– (binds to thrombin and prevents fibrinogen-fibrin)
• Heparin co-factor II
– (homologous with AT lll)
• Prot C
– (inhibits activity of factors V and Vll)
• Prot S
– (enhances the effect of protein C).
• TFPI
– (tissue factor pathway inhibitor - inhibits the
tissue factor-Vlla complex)

8. Vitamin K Dependent Factors
• Factors II, VII, lX, X.
• Protein C and Protein S

9. Role of the liver
Loss of liver parenchyma decreases:
– all coagulation factors - except F Vlll and von
Willebrand co-factor .
– physiologic inhibtors of the coagulation (AT lll,
Prot C and Prot S)
– components of the fibrinolytic system ( mainly
plasminogen, and a2 anti plasmines).
• Liver dysfunction induces:
– platelet dysfunction
– dysfibrinogenemia
– accelerated fibrinolysis (impaired clearance of
tissue plasminogen activators t-PA)

10. Disorders of Hemostasis

11. Hematologic disorders causing bleeding
• Vascular disorders
– Scurvy, easy bruising,
• Platelet disorders
– Low Number or abnormal
function
• Coagulation disorders
– Factor deficiency.
• Mixed/Consumption
– DIC

12. Approach to Bleeding
Disorders
HISTORY
• Is the patient bleeding?
• Surrogate markers of bleeding
– declining hemoglobin
• Age of onset
• Surgical procedures
• Medications
– Aspirin, anticoagulants, etc.
• Birth & Family

13. Approach to Bleeding Disorders
Platelet
Disorder
•Petechiae,
• Echymoses,
• Menorrhagia
• GI bleeding
Coagulation
Disorders
• Echymoses
• Late wounds bleeding
• Extensive hemorrhage
( joint spaces,
after immu.)
D.I.C.
•
• Bleeding from
multiple sites in an
ill patient

14. Approach to Bleeding Disorders
If a patient has
tolerated tonsillectomy
and / or adenoidectomy
or extraction of multiple wisdom teeth
without major hemorrhage,
a significant
bleeding disorder
is unlikely.

15. Clinical aspects of bleeding
Petechiae - (typical of platelet disorders)
•
•
Do not blanch with pressure
(cf. angiomas)
Not palpable
(cf. vasculitis)

16. Platelet
Petechiae, Purpura
Coagulation
Hematoma, Joint bl.

17. Clinical aspects of bleeding
Platelet factor disorders
Coagulation disorders
Site of bleeding
Skin, Mucous
membranes (epistaxis,
gum, vaginal, GIT)
Deep in soft tissues
Petechiae
Yes
No
Ecchymoses
(“bruises”)
Small, superficial
Large, deep
Hemarthrosis /
muscle bleeding
Extremely rare
Common
Bleeding after
cuts & scratches
Yes
No
Bleeding after
surgery or trauma
Immediate, usually mild
Delayed (1-2 days),
often severe
Mucus membrane
bleeds
Spontaneous
With trauma

19. Investigations
Platelet count
150,000 to 450,000 platelets per ml of blood.
< 20,000 per mL - spontaneous bleeding
Bleeding time
Test for platelet function in
Normal : 2 - 5 minutes
Prothrombin
Time
measures the clotting activity of factors I, II, V,
VII, and X Normal : 12-15 seconds
Activated Partial
Thromboplastin
Time
Measures clotting activity of factors I, II, V, VIII,
IX, X, XI, and XII Normal : 25 - 39 sec
Factor assays
Measure the amount of specific clotting factors
FDPs
Fibrin degradation products

20. Activated partial thromboplastin time (aPTT
or APTT)
• is a performance indicator measuring the
efficacy of both the "intrinsic" (now referred
to as the contact activation pathway) and the
common coagulation pathways.
• It is also used to monitor the treatment effects
with heparin, a major anticoagulant.

21. aPTT
- Interpretation
• Normal = 25 to 39 sec
• Prolonged APTT may indicate:
• heparin,
• direct thrombin inhibitors,
• a deficiency or inhibitor for factors in the intrinsic and
common pathway
• factors II, V, VIII, IX, X, XI, XII,
• lupus anticoagulant,
• vitamin K deficiency, or
• severe liver disease

22. (Inaccurate)
Whole blood clotting time
• 5 ml of blood is placed in a glass container,
kept at body temperature and observed
• A clot should occur in 5 to 15 minutes
• Prolonged = Severe deficiency of any of the
coagulation proteins
• The clot should retract in 30 to 60 minutes
• Weak friable clot = hypofibrinogenaemia
• Early dissolution = enhanced fibrinolysis

23. Prothrombin time
• The time taken for plasma to clot after addition of
tissue factor (obtained from animals) and calcium
to citrated blood.
• This measures the quality of the extrinsic pathway
(as well as the common pathway) of coagulation.

24. Prothrombin time
• The reference range for prothrombin time is
usually around 12-15 seconds;
• Prolonged
• Deficiencies of factors II, V, VII, X or
fibrinogen;
• Liver disease;
• Vitamin K deficiency and
• Oral anticoagulants (warfarin)

25. International normalized ratio
• Each manufacturer gives an ISI (International Sensitivity
Index) for any tissue factor they make. The ISI value
indicates how the particular batch of tissue factor
compares to an internationally standardized sample.
The ISI is usually between 1.0 and 1.4
• The INR is the ratio of a patient's prothrombin time to a
normal (control) sample, raised to the power of the ISI
value for the control sample used.

26. Thrombin time
• Time to clot formation after the addition of
thrombin to citrated blood
• Prolonged by
•
•
•
•
•
Heparin,
Direct thrombin inhibitors,
Fibrin degradation products (FDPs),
Paraproteins, and
Fibrinogen deficiency (both qualitative and
quantitative)

27. Bleeding time - Ivy method
• A blood pressure cuff is placed on the upper arm and
inflated to 40 mm Hg. A lancet is used to make a stab
wound on the underside of the forearm.
• The time from when the stab wound is made until all
bleeding has stopped is measured and is called the
bleeding time.
• Every 30 seconds, filter paper or a paper towel is
used to draw off the blood.
• Normal values fall between 2 - 5 minutes depending
on the method used

29. FDPs
• Fragments resulting from the action of
plasmin on fibrin or fibrinogen
• Reflect high fibrinolysis states (such as
DIC) when they are elevated

30. Platelet Count
• In an adult, a normal count is about
150,000 to 450,000 platelets / µL of blood.
• Platelet levels fall below 20,000/µL,
spontaneous bleeding may occur and is
considered a life-threatening risk.
• Increased platelet counts (thrombocytosis)
• Myeloproliferative disorder

31. Others Tests
• Von Willebrand factor antigen (vWF:Ag):
immunoassay for circulating vWF.
• Von Willebrand factor activity (vWF:RCo):
measures the functional ability of a patient's
vWF to agglutinate platelets in the presence of
Ristocetin.
• Factor VIII C activity: is functional assay for
factor VIII. It is measured by mixing normal
plasma with factor VIII-deficient plasma
• Platelet function studies
• Bone marrow examination – plt

32. Laboratory Evaluation of the Coagulation
Pathways
Partial thromboplastin time
(PTT)
Prothrombin time
(PT)
Surface activating agent
(Ellagic acid, kaolin)
Phospholipid
Calcium
Thromboplastin
Tissue factor
Phospholipid
Calcium
Intrinsic pathway
Extrinsic pathway
Thrombin time
Common pathway
Thrombin
Fibrin clot

33. Extrinsic Pathway
Intrinsic Pathway
II X
VI
I
*
IX
*
I
X
Prolonged
PTT
*
V
III
X
Prolonged
PT
Abnormal
PTT, PT &
TT
V
II
- - - - - - - - - - I - - - - - XIII
Both
Urea
PTT & PT
Stability
Abnormal or DIC
Test

34. Correction Tests
Only PTT abnormal :
XI, IX & VIII
(XII never presents clinically)
Abnormal PTT
corrected by
Plasma
Adsorbed Serum
VIII
Yes
No
IX
No
Yes

35. Some Rules of Thumb

36. Both aPTT and PT Elevated

37. Only PT prolonged

38. Only aPTT prolonged

39. von Willebrand Disease
An inherited bleeding disorder described by Finnish Physician
Erik Adolf von Willebrand
Low levels of a protein called von Willebrand
factor that helps the blood to clot
Von Willebrand factor that doesn’t work properly

40. Platelet Activation and
von Willebrand Factor (vWF)
In order for hemostasis to occur, platelets must
adhere to exposed collagen, release the contents
of their granules, and aggregate.
The adhesion of platelets to the collagen
exposed on endothelial cell surfaces is mediated
by von Willebrand factor (vWF).

41. Platelet Activation and
von Willebrand Factor (vWF)
The function of vWF is to act as a bridge between
a specific glycoprotein on the surface of platelets
(GPIb/IX) and collagen fibrils.
vWF binds to and stabilizes coagulation factor
VIII.
Binding of factor VIII by vWF is required for
normal survival of factor VIII in the circulation.

42. von Willebrand Disease
Type 1
Low level of von Willebrand factor. The level of factor VIII may also
be lower than normal
Mildest and most common form of the disease.
About 3 out of 4 people diagnosed with vWD have type 1 disease.
Type 2
Defect in von Willebrand factor causes it to not work properly. Type
2 is divided into 2A, 2B, 2M, and 2N. Each is treated differently, so
knowing the exact type is important.
Type 3
No von Willebrand factor and very low factor VIII.
Type 3 is severe and very rare.

43. von Willebrand Disease
Incidence
roughly about 1 in 100 individuals.
Because most forms are rather mild, they are detected
more often in women, whose bleeding tendency
shows during menstruation.
It may be more severe or apparent in people with
blood type O.

44. von Willebrand Disease
Genetics
vWF gene is located on chromosome twelve
(12p13.2).
o Types 1 and 2 are inherited as autosomal dominant
traits and
o type 3 is inherited as autosomal recessive.
o Occasionally type 2 also inherits recessively.

45. von Willebrand Disease

46. Weibel-Palade bodies
 Organelles in the endothelial cells
 There are two major constituents
1. von Willebrand factor (vWF), a
multimeric protein involved in blood
coagulation
2. The second is P-selectin - binds to
passing immune cells (leukocytes).

47. von Willebrand Disease
Manifestations:
Bruising that's unusual in location or frequency
Abnormal menstrual bleeding
Bleeding in the mucous membranes
Excessive or prolonged bleeding after a tooth
extraction or tonsillectomy

48. Investigations
 Bleeding time
 Factor VIII level test (factor VIII coagulant)
 von Willebrand factor antigen test (factor VIII antigen) - which
measures the amount of von Willebrand factor. ( mild if a person
has 20% to 40% of the normal, severe if the amount is less than 10% of
normal. )
 Ristocetin co-factor activity test
 measures how well the von Willebrand factor is working
 von Willebrand factor multimers test - to classify the type of
vWD
 Platelet function tests
 which determine how well the platelets work and help identify the type of vWD
or the presence of another disorder
Tests may need to be done more than once because these levels may rise
and fall over time in an individual.

49. von Willebrand Disease
Treatment:
No regular treatment
 Prophylactic treatment is sometimes given for
patients are scheduled for surgery.
 They can be treated with human derived medium
purity factor VIII concentrates complexed to vWF
 Mild cases - treated with desmopressin
(1-desamino
8-D-arginine vasopressin, DDAVP)
 Rises patient's own plasma levels of vWF by inducing
release of vWF stored in the Weibel-Palade bodies in the
endothelial cells

50. Than Q