UAEU - CMHS - Hematology-Oncology Course - MMH 302 - HONC 320. Education material for medical students - It cover basic principles of hematology and oncology, including CAR-T and gene editing. It can be used for study and review. It illustrates main principles of hematology and oncology.

1. von Willebrand Disease (VWD)
(impaired primary hemostasis)
Abdul-Kader Souid9/26/2018 1
Collagen
Endothelial cell
Platelet recruitment Platelet plug Fibrin clot
Primary hemostasis Secondary hemostasis
+ADP
+Epinephrine
http://www.omim.org/
VWF gene (OMIM#613160), VWD1 (OMIM#193400),
VWD2 (OMIM#613554) & VWD3 (OMIM#277480)

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4. von Willebrand Factor (VWF)
• This multimeric glycoprotein is found in plasma, platelet
α-granules, and subendothelial tissue.
• It binds to GP1b receptors on platelet surface to form
bridges between platelets and collagen in areas of
vascular damage.
• The RGD (Arg-Gly-Asp) motif of VWF bridges
between thrombin-activated platelets via the fibrinogen
receptors GPIIb/IIIa, forming platelet plugs.
• VWF also binds and stabilizes factor VIII.
– Severe deficiency (or absence) of VWF causes secondary
deficiency of factor VIII.
• Deficiency of VWF results in defective platelet adhesion
(impaired primary hemostasis).
Deficiency of GPIb → Bernard–Soulier syndrome
Deficiency of GPIIb/IIIa → Glanzmann thrombasthenia
3) Factor VIII delivery
1) Platelet adhesion to collagen
2) Platelet-platelet spreading and aggregation
Collagen
vWF
GPIb-a
Platelet
GPIIb/IIIa
vWF
Fibrinogen
Platelet
Factor VIII
Must know
Ristocetin causes in
vitro platelet
aggregation in the
presence of VWF.

5. Platelet activation by ADP (blocked
by clopidogrel) causes
conformational changes in platelet
GPIIb/IIIa (integrin αIIbβ3)
receptors that induce binding to
fibrinogen.
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3) Factor VIII delivery
1) Platelet adhesion to collagen
2) Platelet-platelet spreading and aggregation
Collagen
vWF
GPI
b-
a
Platelet
GPIIb/IIIa
vWF
Fibrinogen
Platelet
Factor VIII
Deficiency of GPIIb/IIIa → Glanzmann Thrombasthenia
Understanding of the role of GpIIb/IIIa (integrin αIIbβ3) in
Glanzmann thrombasthenia led to the development of GpIIb/IIIa
inhibitors, a class of powerful antiplatelet agents (e.g., abciximab,
eptifibatide, tirofiban).
Must know

6. Hemostatic Work-up:
• Platelet count
• ABO blood group
– Individuals with blood type O have 25% less VWF)
• Platelet function screen
• VWF antigen (VWF:Ag)
• VWF activity
– R:CoF; ristocetin co-factor activity
• aPTT, PT/INR, TT
• Factor VIII activity
– Typically normal
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Clinical Presentations:
• Recurrent epistaxis
• Menorrhagia
• Bleeding post tonsillectomy or dental extraction
Must know

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VWD ClassificationOptional

8. VWD: Treatment
• The treatment of choice is “desmopressin + tranexamic acid”.
• The recently approved (December 08, 2015) recombinant VWF
(rVWF, vonicog alfa, Vonvendi) is reserved for patients with R:CoF
levels <10 U/dL or with severe bleeding.
– The rVWF dose for minor bleeding is 40-50 IU/kg, repeated every 8-24 h
as needed clinically.
– The rVWF for major bleeding is 50-80 IU/kg, followed by 40-
60 IU/Kg every 8-24 h for 2-3 days as needed clinically.
– When using rVWF, it is recommended that rFVIII be given within 10
min of the first dose of rVWF.
– The antifibrinolytic agent tranexamic acid is also recommended.
Must know
Up-to-Date - Nov 27, 2017

9. (1) Aminocaproic acid (Amicar; DrugBank name
DB04134), not available in the UAE.
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Fibrinolytic inhibitors for Mucosal Bleeding
(2) Tranexamic Acid (DB00302); available in the UAE.
Must know
(halt fibrinolysis by inhibiting plasminogen & plasmin)
http://www.drugbank.ca/
The antifibrinolytic
drugs are indicated
for mucosal bleeding
due to factor VIII,
factor IX, or vWF
deficiency.
The World Federation of Hemophilia guidelines recommend oral tranexamic acid (1 g/dose or 10
mg/kg per dose 3 times daily) or aminocaproic acid (50 mg/kg 4 times daily with a maximum
dose of 24 g daily) the day before dental surgery and then for a total of 7 days. “Fibrin glue”
(fibrinogen + thrombin) is also used for local hemostasis during dental procedures.

10. • Desmopressin acetate (1-deamino-8-d-arginine vasopressin, or
DDAVP) is the treatment of choice for mild-to-moderate factor
VIII deficiency with minor bleeding.
• It ↑factor VIII (and von Willebrand factor) level by 3-5 fold
within 30 to 60 min of administration.
• IV desmopressin (DDAVP Injection) is given at 0.3 g/kg in 50
mL of 0.9% NaCl over 30 min.
• Intranasal desmopressin [Stimate Nasal Spray, one (150 g) or
two (300 g) puffs] is equally effective.
Desmopressin: Only for Factor VIII or VWF Deficiency
Vasopressin
Phe Gln
NH2-Cys-S-S-Cys-Pro-L-Arg-Gly-NH2
Tyr Asn AsnTyr
Cys-S-S-Cys-Pro-D-Arg-Gly-NH2
GlnPhe
DDAVP
[1-(deamino)-8-D-arginine vasopressin
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Must know
Desmopressin is
only indicated for
mucosal bleeding
due to factor VIII or
VWF deficiency.
A synthetic analog of vasopressin

11. Required Reading
• American Society of Hematology. Evaluation and management of von Willebrand
disease. American Society of Hematology website.
http://ashpocketguides.hematology.org/#/app/guides/2/pages/
• Mannucci PM, Kempton C, Millar C, et al. Pharmacokinetics and safety of a novel
recombinant human von Willebrand factor manufactured with a plasma-free
method: a prospective clinical trial. Blood 2013;122:648.
• James PD, Lillicrap D. von Willebrand disease: clinical and laboratory lessons
learned from the large von Willebrand disease studies. Am J Hematol. 2012;87,
Suppl 1:S4-S11.
• Tosetto A, Castaman G. How I treat type 2 variant forms of von Willebrand
disease. Blood 2015;125:907-914.
• Nichols WL, et al. Von Willebrand disease (VWD): evidence-based diagnosis and
management guidelines, the National Heart, Lung, and Blood Institute (NHLBI)
Expert Panel report (USA). Haemophilia 2008;14:171-232.
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12. A 16-year-old female presents to the clinic with severe menorrhagia. Her
hemoglobin is 104 g/L, platelet count 196 x109/L, aPTT 35.6 sec (normal,
35.2 - 40.4), PT 13.2 sec (normal, 12.2 - 14.6), INR 1.0 (normal, 0.8-1.2), and
TT 11.4 sec (normal, 9.2 - 12.3). Collagen-epinephrine channel closure time
is 201 sec (normal, ≤168) and collagen-ADP 138 sec (normal, ≤116).
Which one of the following diagnoses is correct?
A. von Willebrand disease
B. Hemophilia A
C. Hemophilia B
D. Glanzmann thrombasthenia
E. Bernard–Soulier syndrome

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A 23-year-old patient presents to the clinic for menorrhagia. Her
evaluation reveals a normal platelet count, thrombin time (TT),
prothrombin time (PT), activated partial thromboplastin time
(aPTT), von Willebrand factor antigen and activity, and platelet
function screen. Her older sister has a history of heavy menstrual
bleeding and delayed postpartum bleeding. Further testing shows
increased fibrinolysis.
Which one of the following laboratory findings is most likely to be
found in this patient?
A. Decreased plasminogen
B. Decreased plasminogen activator inhibitor-1 (PAI-1)
C. Increased α2-antiplasmin
D. Increased thrombin-activatable fibrinolysis inhibitor (TAFI)
E. Decreased tissue factor pathway inhibitor (TFPI)

14. VWD Classification
• Type I (85% of cases, OMIM#193400):
– Partial quantitative deficiency (levels 30-50%)
– Normal vWf structure and functions
– Autosomal dominant
• Type II (15% of cases; autosomal dominant/recessive qualitative defect of VWF;
OMIM#613554):
– A (12%), absent high- and intermediate-weight (HMW) multimers and low VWF
R:Co (loss-of-function).
– B (3%), absent HMW multimers, ↑affinity of VWF for GP Ib (gain-of-function),
thrombocytopenia; ↑aggregation to low-dose ristocetin.
– M (rare), normal HMW multimers and low VWF R:Co.
– N (Normandy, rare), normal vWf:Ag and VWF R:Co and decreased factor VIII
level due to abnormal vWf structure.
• Type III (nonsense mutations and gene deletion) - rare
Optional

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Optional

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Laboratory tests for von Willebrand disease
CBC, PT/INR,
aPTT, TT, factor
VIII
These tests are typically normal. PTT may be elevated in severe
VWD due to ↓factor VIII.
Blood type Individuals with blood type O have 25% less VWF.
Platelet Function
Screen (PFA-100)
Measures primary hemostasis. The instrument determines the time
taken for blood forced through a fine capillary tube to block a
membrane coated with collagen-epinephrine or collagen-ADP.
Normal closure time for the collagen-epinephrine channel is <164
sec and for the collagen-ADP channel <116 s. In VWD or platelet
dysfunction, the closure time for the collagen-epinephrine channel
is >164 s and for the collagen-ADP channel >116 s. In Aspirin or
NSAID, closure time for the collagen-epinephrine channel is >164
s and for the collagen-ADP channel <116 s.
Ristocetin co-
factor (vWf R:Co)
and vWf antigen
The most sensitive tests for VWD. Ristocetin (a positively charged
antibiotic) activates VWF, causing its binding to platelets. The
assays should be performed within 2 h of the venipuncture;
otherwise, the plasma must be removed immediately and stored at -
70oC.
Optional