HEMOPHILIA

Common hereditary bleeding disorder

caused by deficiencies of clotting factor VIII
or IX

• Hemophilia A - factor VIII deficiency

– Affects about 80% of patients with hemophilia
• Hemophilia B - factor IX deficiency
• Both are X-linked genetic disorders
• Both have identical clinical manifestations
and screening test abnormalities
• Specific factor assays are required to
distinguish the two
Etiology
• Inherited disorder when factor VIII or
Factor IX gene undergoes
– Mutations
– Deletions

• Because these genes are located on the X

chromosome, hemophilia affects males
almost exclusively
• Daughters of men with hemophilia are
obligate carriers, but sons are normal

• Each son of a carrier mother has a 50%

chance of having hemophilia, and each
daughter has a 50% chance of being a carrier
.
 PATHOPHYSIOLOGY
• Normal hemostasis requires > 30% of normal
factor VIII and IX levels
• Most patients with hemophilia have
levels < 5%;
– Depends on the specific mutation in the factor VIII or IX
gene
• Carriers usually have levels of about 50%
IX

Prothrombin
SYMPTOMS AND SIGNS
• Patients with hemophilia bleed into
tissues
–Hemarthroses
• When chronic or recurrent lead to
–Synovitis
–Arthropathy
–Muscle hematomas
• May cause compartment syndrome
 –Retroperitoneal hemorrhage
–Intracranial bleeding after trivial trauma
–Hematuria
–Bleeding into the base of the tongue
• Can cause life-threatening airway compression

• Pain often occurs with bleeding

• Severe hemophilia
– Severe bleeding throughout life
• Scalp hematoma after delivery or excessive bleeding
after circumcision

• Moderate hemophilia
– Bleeding after minimal trauma

• Mild hemophilia
– Excessive bleeding may occur after surgery or dental
extraction
D
I
A
G
N
O
S
I
S
• Von Willebrand's disease
• Vitamin K deficiency/antagonism with
anticoagulants
• Disorders of fibrinogen or fibrinolytic
production
• Platelet disorders
• Blood vessel disorders
INVESTIGATIONS
• FBC - low haematocrit and reduced Hb if
recent bleeding

• Normal
– Prothrombin time
– Bleeding time
– Fibrinogen levels
– Von Willebrand factor
• Activated partial thromboplastin time
(APTT) - usually prolonged
– can be normal in mild disease

• Mixing patient's plasma 1:1 with donor

plasma should normalise APTT
Factor VIII and IX assays
• Help in determining the
–Type of hemophilia
–Severity of hemophilia
–Carrier state
 Severe hemophilia
• Factor VIII or IX level < 1% of normal
–Severe bleeding throughout life
• Scalp hematoma after delivery or excessive
bleeding after circumcision
 Moderate hemophilia
• Factor levels 1 to 5% of normal
–Bleeding after minimal trauma
 Mild hemophilia
• Factor levels 5 to 25% of normal
–Excessive bleeding may occur after
surgery or dental extraction
• Factor VIII levels may also be reduced in
von Willebrand disease (VWD)
• Von Willebrand factor (VWF) activity measured
in patients with newly diagnosed hemophilia
A specially if H/O disease in both sexes
• After repeated exposure to factor VIII
replacement, about ¼ of patients with
hemophilia A develop factor VIII isoantibodies
(alloantibodies)
– It inhibit the coagulant activity of any additional factor
VIII infused
• Patients should be screened for isoantibodies
in hemophilia A
In acute situations imaging may be required –
• CT scan of the head and body to detect
haemorrhage
• Joint X-rays
• MRI and Doppler ultrasound - better
modalities for the detection of arthropathy
General principal
• Correct the bleeding tendency
• Treat pain
• Prevent deformity
 Haemophilia A
• IV infusion of a factor VIII concentrate
given
– Bleeds can be arrested by increasing the plasma
level of the deficient factor to 30 to 60% of
normal
• Cryoprecipitate - another source of Factor VIII
 CRYOPRECIPITATE
• Prepared from fresh frozen plasma
• Contains
– About 50% Factor VIII
– Von Willebrand factor
– Fibrinogen
– BUT NO FACTOR IX
• Mild haemophiliacs
–IV vasopressin (DDAVP)
• Increases levels of circulating Factor VIII
–And/or tranexamic acid (antifibrinolytic
agent)
 Haemophilia B
• Treated by infusion of factor IX
concentrate
• DDAVP & CRYOPRECIPITATE is not effective
 To relieve pain
• Prompt factor replacement and temporary
immobilization of painful joints
• If not
– Joint aspiration under Factor cover
• Analgesics
– Paracetamol or Ibuprofen which do not interfere with
platelet function
• NOT ASPIRIN
To prevent deformity
• During the early bleeding phase - limb should
be splinted in a position of function
• Active exercises should be commenced as
soon as pain has subsided under supervision
by an experienced physiotherapist
 COMPLICATIONS
• Infections:
– Hepatitis B
– Hepatitis C
– HIV
• Allergy - to other plasma components in
cryoprecipitate
• Development of anti-Factor VIII antibodies
Von Willebrand's Disease
• Von Willebrand's factor - Glycoprotein made
in the endothelium
• It has two functions
– Assists in platelet plug formation by attracting
circulating platelets to the site of damage
– Binds to coagulation factor VIII preventing its
clearance from the plasma
• Deficiency of vWF can also lead to deficiency of factor
VIII
• Most common hereditary coagulopathy in
humans
• Severity is variable
• Present with
– Bleeding tendency from mucosa - eg, epistaxis,
menorrhagia
– Heamarthrosis in sever cases
• Can be treated with
– Tranexamic acid
– Desmopressin (increases the factor VIII)
– Platelet transfusion
 Von Willebrand
Haemophilia A Haemophilia B
disease
Mode of Autosomal
X-linked X-linked
inheritance Dominant
Skin cuts, mucou
Main sites of muscle, joints, Muscle, joints,
membranes,
Bleeding following trauma following trauma
following trauma

Platelets Normal count Normal count Normal count

Bleeding time Normal Normal Prolonged

prothrombin time Normal Normal Normal

(APTT) Prolonged Prolonged Prolonged

VWF Normal Normal Reduced levels

factor VIII Low Normal Low

Factor IX Normal Low Low
 Coagulation factor Platelet disorders and von
defects Willebrand's disease
Bruising on Large bruises Small bruises
trunk and limbs
Bleeding from Relatively slight Profuse
cuts
Nose bleeds Uncommon Common

Gastrointestinal Uncommon Common

bleeding
Haematuria Common Rare

Haemarthrosis In severe haemophilia Very rare

Bleeding after Up to a day's delay immediate

surgery or before bleeding occurs
dental extraction
Thrombocytopenia and Platelet Function
Disorders
• Thrombocytopenia - a reduction in the
platelet count below the normal lower
limit
• Usually defined as 150 x 109/L
• Can have a variety of causes
1. Reduction in platelet production
2. Reduction in platelet survival
3. Dilution of platelet numbers resulting
from the transfusion of platelet-poor
blood
 Disorders affecting platelet production
• Viral infections
– Dengue, herpes simplex, cytomegalovirus, varicella-
zoster, Epstein-Barr, rubella, enterovirus, mumps,
hepatitis, HIV.
• Aplastic anaemia
• Marrow infiltration by a malignancy –
– Leukaemia, lymphoma, myeloma, metastatic malignant
disease.
• Drugs - eg, chemotherapy.
• Alcohol
• Paroxysmal nocturnal haemoglobinuria.
• Megaloblastic anaemia
• Myelofibrosis
• Miliary tuberculosis
 Decreased platelet survival
• Immune
–Idiopathic thrombocytopenia purpura
(ITP)
–Systemic lupus erythematosus
–Rheumatoid arthritis
–Sarcoidosis
–Antiphospholipid syndrome
• Post-transfusion thrombocytopenic purpura
(PTTP):
– Antigens on transfused platelets can lead to
destruction of not just the transfused platelets
but the patient's own platelets too.
• It starts about 10 days after transfusion but can last
several weeks or even several months.
• Neonatal alloimmune thrombocytopenia
(NAIT):
– Occurs when the mother produces antibodies
against fetal platelets with paternal antigens
• Drug-induced
– Heparin, carbamazepine, ibuprofen, quinidine,
quinine, rifampin, sulfamethoxazole,
trimethoprim and vancomycin

• MAHA
– Thrombotic thrombocytopenic purpura
– Haemolytic uraemic syndrome
– Disseminated intravascular coagulation
• Pregnancy - HELLP syndrome
characterised by:
–Haemolysis.
–EL (elevated liver) enzymes.
–LP (low platelet) count
• Cardiopulmonary bypass
• Splenomegaly and hypersplenism
–associated with a variety of conditions - eg,
cirrhosis, malaria, lymphoma.
 Platelet function disorders
• Inherited platelet function disorders
• Disorders of platelet adhesion: von
Willebrand's disease (vWD)
• Disorders of the platelet granules
 Acquired platelet function disorders
• Medications and chemicals
– Aspirin, other non-steroidal anti-inflammatory
drugs (NSAIDs), clopidogrel, dipyridamole, beta-
lactam antibiotics, dextran, alcohol & herbal
medicines
• Chronic kidney disease
• Heart valve disease, cardiopulmonary bypass
extracorporeal membrane oxygenation
• Myeloproliferative disorders
– Essential thrombocythaemia, polycythaemia vera
• Myelodysplastic syndromes
• Paraproteins
– Multiple myeloma a
– Waldenström's macroglobulinaemia
Purpura
• Purplish discolouration of the skin
produced by small bleeding vessels near
the surface
–May also occur in the mucous membranes
• Purpura is not a disease per se but is
indicative of an underlying cause of
bleeding.
• When purpura spots are very small (<1
cm in diameter), they are called
petechiae or petechial haemorrhages
• Larger, deeper purpura are known as
ecchymoses or bruising
• In general rule, purpura indicates a problem of the
platelet system
• Deficiency of clotting factors will cause
haematomas or haemarthrosis (as in haemophilia)
• Still clotting factor deficiency must be considered.
Purpura may occur with
• Normal platelet counts (non-
thrombocytopenic purpuras)
• Decreased platelet counts (thrombocytopenic
purpuras)
 Non-thrombocytopenic purpuras
• Congenital causes such as:
– Hereditary haemorrhagic telangiectasia (Osler-Weber-
Rendu syndrome).
– Connective tissue diseases such as Ehlers-Danlos
syndrome and pseudoxanthoma elasticum.
– Congenital cytomegalovirus (CMV) and congenital
rubella.
• Acquired causes such as severe infections
– septicaemia, meningococcal infections, measles
• Allergic causes
– Henoch-Schönlein purpura
– Connective tissue disorders like systemic lupus
erythematosus (SLE) rheumatoid arthritis
• Drug-induced causes
– Steroids and sulfonamides
• Other causes
–Senile purpura
–Trauma
–Scurvy
–Dependent purpura with venous
hypertension
 Thrombocytopenic purpura

• Impaired platelet production

• Excessive destruction
– Immune thrombocytopenic purpura