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. HEMOPHILIA
Abdul-Kader Souid9/26/2018 1
Hemophilia A (OMIM#306700) = Factor VIII Deficiency (85% of patients)
Hemophilia B (OMIM#306900) = Factor IX Deficiency (15% of patients)
http://www.omim.org/
Collagen
Endothelial cell
Platelet recruitment Platelet plug Fibrin clot
Primary hemostasis Secondary hemostasis
+ADP
+Epinephrine
Impaired Secondary Hemostasis
prothrombin thrombin
(IIa)
fibrinogen
fibrin
prothrombinase complex
(X, V, PL, Ca2+
)
tissue factorVII
IX
XI
VIII
IIa
TFPI

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3. 9/26/2018 3
Female
asymptomatic
Male
symptomatic

4. • Patients are males (affecting 1 per 5,000 males) -
Females are carriers (X-linked recessive).
• Symptoms usually begin by one year of age, at the time
of crawling and walking.
• The hallmark of hemophilia is bleeding into joints
(hemarthrosis) and muscles (hematoma).
• Intracranial bleeding is the leading cause of death.
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Factor VIII Deficiency
female male

5. 1. Positive maternal history exists in 2/3 of patients; 1/3 have de
novo mutations.
2. Clinical bleeding (joint, muscle, post-op)
3. ↑aPTT that corrects when mixing equal volume of normal
plasma with patient plasma (i.e., factor deficiency). PT/INR,
TT, platelet count, and vWF are normal.
4. Factor VIII activity is <30 units/dL (normal, 50-150 units/dL):
– Severe disease (Factor VIII activity <1 unit/dL) occurs in 50%
of patients (spontaneous bleeding, 90% develop joint disease)
– Moderate disease (Factor VIII activity 1-5 unit/dL); bleeding
occurs after trauma or surgery
– Mild disease (Factor VIII activity >5 unit/dL)
Factor VIII Deficiency: Diagnosis
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Must know

6. • Initial symptoms are warmness and tingling
sensation, which require immediate replacement.
• As blood fills the joint space, swelling, pain and
limitation of movements occur (late symptoms).
• Bleeding into a target joint (a joint that patient
bleeds into repetitively) produces progressive
synovitis and irreversible arthropathy. Knee MRI with a bleeding
inside the joint
Factor VIII Deficiency: Hemarthrosis
JOINT BLEEDING SHOULD BE TREATED AT THE EARLIEST
SYMPTOMS TO AVOID IRREVERSIBLE DAMAGES. THE JOINT
SHOULD BE KEPT AT REST, BY USING CRUTCHES FOR WEIGHT
BEARING JOINTS OR SLING/SPLINTING FOR JOINT SUPPORT. LIMB
ELEVATION, ICE PACKING AND WRAPPING ARE RECOMMENDED.
6
Must know

7. Joint Disease in Hemophilia
• Joint disease occurs in 90% of patients with severe
hemophilia.
– The frequency of joint bleeding is 15 ± 12 per year.
– At least 50% of patients have restricted activity.
• Prophylaxis treatment prevents joint bleeding and
damage and is cost-effective; this modality should be the
goal of therapy to preserve the joints.
– Prophylaxis starts before 3 years of age and before
any joint damage. Keep trough factor level ≥2%.
– 15 to 40 units/kg rFVIII (or rFIX) every 2 to 3 days.
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Must know

8. • Hemophilia A is treated by recombinant factor VIII infusion (produced
by cell lines transfected with human factor VIII gene; thus, avoiding the infectious
risk of plasma-derived transfusion-transmitted diseases).
• One unit/kg ↑plasma level by two units/dL; half-life = 8 h.
• For mild-to-moderate bleeding (joint, laceration, minor trauma) give
25 units/kg (↑plasma level to 50 units/dL).
• For moderate-to-severe bleeding (surgery, major trauma, intracranial,
retroperitoneal, pharyngeal or neck bleeding) give 50 units/kg
(↑plasma level to 100 units/dL) + monitor factor VIII level.
Factor VIII On-Demand Replacements
• Calculate the rFactor VIII dose for a 20-kg patient with a mild joint bleeding.
Dose = 25 units/kg x 20 kg = 500 units (↑plasma level to 50 units/dL).
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Must know
• Calculate the initial rFactor VIII dose for a 20-kg patient with a major trauma.
Dose = 50 units/kg x 20 kg = 1,000 units (↑plasma level to 100 units/dL).

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.

11. • This X-linked recessive disorder affects 1 in ~50,000 males.
– About 1/3 of patients have a de novo mutation.
• The clinical presentation is indistinguishable from hemophilia A.
Factor IX Deficiency
• Treatment is recombinant factor IX.
• One unit/kg ↑plasma level by one unit/dL; half-life is ~24 h.
– For mild-to-moderate bleeding (e.g., joint, muscle, laceration) give 50 units/kg
(↑plasma level to 50 units/dL).
– For moderate-to-severe bleeding (e.g., surgery, major trauma, intracranial,
retroperitoneal, pharyngeal, neck) give 100 units/kg (↑plasma level to 100
units/dL).
– Tranexamic Acid is also given for oral or dental bleed.
– Desmopressin is ineffective in hemophilia B.
• The rFactor IX dose for a 20-kg patient who has a joint bleeding is 50 units/kg x
20 kg = 1,000 units (↑plasma level to 50 units/dL).
11
Must know

12. Treatment of hemophilia
Deficiency Treatment Dosing
Factor VIII
Recombinant
factor VIII
Mild-to-moderate bleeding: 20-30 units/kg.1
Moderate-to-severe bleeding: 40-75 units/kg.1
Desmopressin
DDAVP Injection: 0.3 µg/kg iv or sc. (single daily
dose).2
Stimate Nasal Spray: One or two sprays (single daily
dose).2
Antifibrinolytic
drugs
Aminocaproic acid: 50 mg/kg every 6-8 h (max. 24 g
daily) x 7 days. OR
Tranexamic acid: One g/dose or 10 mg/kg/dose 3 times
daily x 7 days.
Factor IX
Recombinant
factor IX
Mild-to-moderate bleeding: 50-70 units/kg.3
Moderate-to-severe bleeding: 100-120 units/kg.3
Antifibrinolytic
drugs
As above
1, For repetitive infusions, factor VIII is commonly given every 8-12 h; 2, the same dose
can be repeated once a day for 3-5 days if necessary; 3, For repetitive infusions, factor IX
is commonly given every 12-24 h.

13. Required Reading
• Manco-Johnson MJ, Abshire TC, Shapiro AD, et al., Prophylaxis versus
episodic treatment to prevent joint disease in boys with severe hemophilia. N
Engl J Med. 2007;357:535-44.
• den Uijl I, Biesma D, Grobbee D, Fischer K. Turning severe into moderate
haemophilia by prophylaxis: are we reaching our goal? Blood Transfus.
2013;11:364-9.
• http://www1.wfh.org/publications/files/pdf-1472.pdf
• Handout in the Blackboard.
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14. • The disease is X-linked recessive (heterozygous females are asymptomatic).
• About ½ of male patients with severe disease have intron 22
inversion, which shuts down the gene expression.
Factor VIII Deficiency
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Optional

15. • Ileopsoas bleeding (may follow heavy lifting or strenuous exercise) causes
leg flexion, pain in the anterior surface of the thigh (femoral nerve
compression) and inability to extend the leg.
• Abdominal bleeding (into the liver, spleen, pancreas or retroperitoneum)
produces falling hemoglobin and abdominal pain.
• Buttock, thigh and forearm bleeding may produce neurovascular
compression (compartment syndrome).
• Neck or oral hematoma cause dyspnea, dysphagia and compromise airway.
Factor VIII Deficiency: Hematoma
• Psoas bleeding causes pain in the right lower
quadrant, resembling appendicitis or hip problem.
These situations require immediate replacement and close observation.
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Optional

16. • Arterial sticks and intramuscular injections are contraindicated.
• Proximal and deep (non-compressible) venous accesses (e.g.,
jugular, subclavian, brachial, and femoral veins), should be
avoided as bleeding can lead to a neurovascular compromise.
– The dorsum of hands and feet are the most suitable sites.
Factor VIII Deficiency: Prophylaxis & Precautions
• Prophylaxis is the standard of care for most patients with severe disease.
• Prophylactic replacements (15-40 units/kg) are given every 2-3 days to
keep trough levels of 1-2%.
The anti-fibrinolytic agent aminocaproic acid (Amicar) can also be
given as a prophylactic therapy for oral or dental bleeding. The
dose is 25-100 mg/kg every 6-8 h for 7 days.
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Optional

17. • It is the leading cause of death and can occur spontaneously.
• Head trauma or signs of intracranial hemorrhage (headache, irritability,
vomiting, seizure, visual problems, focal deficits, stiff neck, or change of
consciousness) should be immediately treated with a major-factor infusion prior
to diagnostic imaging.
• The onset of neurological signs following head trauma may be delayed a few
days due to a slowly oozing nature of hemophiliac bleeding.
Factor VIII Deficiency: Intracranial Bleeding
Bilateral subdural bleeding
bleeding
dura
Epidural (extradural) bleeding
bleeding
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Optional

18. 18

19. Inhibitors to Factors VIII and IX
• Inhibitors to factors VIII and IX are common in severely affected
patients. These antibodies neutralize the activity of infused factors.
– Presence of factor inhibitor is suspected if the bleeding does not stop
after adequate infusion.
– The inhibitor is expressed in Bethesda inhibitor units (BIU). One BIU
causes 50% reduction in factor activity.
– Patients with low-titer (low responding) inhibitors (<10 BIU) can be
treated with increased factor dosing (using 2-3 times the
recommended dose).
– Patients with high-titer (high responding) inhibitors (>10 BIU),
require bypassing products, such as recombinant factor VII
(NovoSeven®) or activated prothrombin complex concentrates
(FEIBA®). Both preparations may cause thrombosis and disseminated
intravascular coagulation.
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Optional

20. 9/26/2018 20
13-month-old Boy with Abnormal Bruising
Normal platelet count & function + normal vWF
antigen & activity = intact primary hemostasis
Normal PT/INR & TT + prolonged aPTT + low Factor
IX activity = Factor IX deficiency (hemophilia B)

21. A 2-year-old boy presents to the emergency department with the sudden
onset of a large swelling of the left knee. The parents report no history
of trauma. He is afebrile and his only complaint is pain in the left knee.
His platelet count is 196 x109/L (normal, 150 to 400), aPTT 135.6 sec
(normal, 35.2 to 40.4), PT 13.2 sec (normal, 12.2 to 14.6), INR 1.0
(normal, 0.8 to 1.2), and TT 11.4 sec (normal, 9.2 - 12.3).
Which one of the following is the MOST likely cause of his findings?
A. von Willebrand factor deficiency
B. Vitamin K deficiency
C. Factor VII deficiency
D. Factor VIII deficiency
E. Dysfibrinogenemia
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22. A 13-month-old boy presents to the emergency department with the sudden
onset of a large swelling of the left knee. The parents report no history of
significant trauma. He is afebrile and his only complaint is pain in the left
knee.
His platelet count is 196 x109/L (normal, 150 to 400), aPTT 135.6 sec (normal,
35.2 to 40.4), PT 13.2 sec (normal, 12.2 to 14.6), INR 1.0 (normal, 0.8 to 1.2),
and TT 11.4 sec (normal, 9.2 - 12.3).
Which one of the following is the MOST appropriate next diagnostic work-up?
A. von Willebrand factor antigen and activity
B. Factor V and X
C. Fibrinogen
D. Factors XII, XI, IX and VIII
E. Factor VII
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23. A 2-year-old boy presents to the emergency department with the sudden
onset of a large swelling of the left knee. The parents report no history
of trauma. He is afebrile and his only complaint is pain in the left knee.
His platelet count is 196 x109/L (normal, 150 to 400), aPTT 135.6 sec
(normal, 35.2 to 40.4), PT 13.2 sec (normal, 12.2 to 14.6), INR 1.0
(normal, 0.8 to 1.2), and TT 11.4 sec (normal, 9.2 - 12.3). Factor VIII
activity is 2 units/dL (normal, 50 to 100).
Which one of the following is the MOST appropriate treatment?
A. Fresh frozen plasma
B. Cryoprecipitate
C. Recombinant factor VIII
D. Factor VIII concentrate
E. Recombinant factor IX
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