6. 6
Often called ‘the disease of kings’ because it was carried
by many members of Europe’s royal family.
Queen Victoria of England was a carrier of Hemophilia
HEMOPHILIA
7. TYPES
Disease Factor deficiency Inheritance
Hemophilia A VIII X linked recessive
Hemophilia B IX X linked recessive
Hemophilia C XI Autosomal recessive
Parahemophilia V Autosomal recessive
7
8. 8
Distribution Clotting factor
activity
Severe hemophilia 50% <1%
Moderate hemophilia 10% 1-5%
Mild hemophilia 30-40% 5-40%
Severity of Hemophilia is defined by measured level of
clotting factor activity
10. Haemophilia A
• Haemophilia A (classical haemophilia)- most common hereditary coagulation
disorder.
• occurs in approximately 1:10,000 individuals.
• caused by hereditary deficiency or dysfunction of Factor VIII.
• In India, about 1300 haemophilics are born every year and currently there are
about 50,000 patients with severe disease.
11. Inheritence
• Positive family history is not obtained in about 30% of patients with haemophilia.
These cases probably arise from spontaneous mutation.
• The disease manifests only in males because they lack the complementary normal
X chromosome.
• Majority of female carriers of haemophilia A do not suffer from haemorrhagic
diathesis. This is because F VIII synthesised by complementary gene on the
normal X chromosome is adequate to achieve haemostasis.
• However, haemophilia may develop in carrier females when there is lyonisation
predominantly of normal X chromosomes during embryogenesis or in Turner’s
Syndrome (XO)
12.
13.
14. Laboratory Features
Coagulation Profile
• Tests for primary haemostasis (platelet count, bleeding time) and for extrinsic and
common coagulation pathway (prothrombin time) are normal.
• The only abnormality in coagulation profile is prolongation of activated partial
thromboplastin time (APTT), i.e. a measure of intrinsic and common pathways.
• Thromboplastin generation test (TGT) is a second-line test and is abnormal
• The combination of normal PT, prolonged APTT, and abnormal TGT are highly
suggestive of F VIII deficiency.
15.
16. Prenatal analysis
• Two methods of prenatal diagnosis are available—foetal blood sampling and
genotypic analysis.
• Foetal sex is determined by amniocentesis around 14 to 15 weeks of gestation.
• Foetal blood is obtained at 18 to 20 weeks by foetoscopy.
• For genotypic analysis, foetal DNA can be obtained either by amniocentesis (14-15
weeks) or by chorionic villus biopsy (9–12 weeks).
• Various methods of genetic analysis are outlined under “Detection of carriers”.
• Prenatal diagnosis by genetic analysis using chorionic villus sampling is possible in
the 1st trimester while foetal blood sampling can be applied only in the 2nd trimester.
17. Hemophilia B
• Haemophilia B (also known as Christmas disease) is a hereditary F IX deficiency
state with X-linked recessive mode of inheritance.
• The incidence is about 1:60,000 populations.
• Clinical features and inheritance pattern are similar to haemophilia A.
• It is essential to distinguish between haemophilia A and B in the laboratory
because of different therapeutic products required.
18. • Coagulation profile shows selective prolongation of activated partial thromboplastin
time (APTT).
• In mild cases APTT may be normal and in such cases if clinical features are
suggestive then specific F VIII and IX assay should be performed (F VIII assay
should always be performed first).
• About 1 to 2% of patients with severe hemophilia B develop inhibitor antibodies
against F IX.
19. Haemophilia B Leiden: In this form of haemophila B, F IX levels in blood increase
at the time of puberty followed by resolution of bleeding manifestations.
It is seen in 3% of haemophilia B patients and results from specific F IX promoter
mutations.
20. 21
• Bleeding can happen
anywhere in the body.
• Following an
injury / surgery or
rarely spontaneous.
CLINICAL MANIFESTATIONS
21. 22
CLINICAL MANIFESTATIONS
Musculoskeletal bleeding
• Deep bleeding into joints and muscles
• Begin when child reaches toddler age.
• In toddlers ankle the most common
site.
• Later knees and elbow become common sites.
22.
23. Hemophilia : Diagnosis
• Screening tests
• Normal PT , Raised APTT.
• Definitive diagnosis specific factor VIII or IX by assays
24. 25
Carrier state and Genetic testing
Three approaches:
1. Patient and family history
2. Coagulation-based assays: unreliable
3. DNA testing: GOLD standard
Prenatal diagnosis
25. Hemophilia: Management
Lifestyle modifications: Goal - Prevention of bleeding.
- Avoid drugs that affect platelet function -NSAIDs
- paracetamol - safe for analgesia.
- Regular exercise to promote strong muscles, protect joints, and
improve fitness.
- Avoid contact sports ; swimming and cycling encouraged.
- Recognize early signs of bleeding - a tingling sensation or “aura”.
- trained to seek treatment at this stage.
- Carry identification indicating the diagnosis, severity, and contact
information .
27. Factor VIII Factor IX
•Half-life – approx. 8–12 hours. • About 18-24 hours.
•Each FVIII unit/ per kg i.v. will raise
plasma FVIII level approximately 2%.
• Each FIX unit per kg i.v. will raise
plasma FIX level approx. 0.7 to 1.0%.
•Dose of factor VIII= desired % rise x body
wt (kg) x 0.5
• Dose of factor IX= desired % rise x body
wt (kg) x 1.4
Factor concentrates
28. Cryoprecipitate
- Prepared by slow thawing of FFP at 4°C for 10–24 hours.
- Contains – FVIII, vWF, fibrinogen, & FXIII (not FIX or XI).
- supernatant - cryo-poor plasma and contains other coagulation factors VII,
IX, X, and XI.
- FVIII /bag of cryoprecipitate is 60-100 units (avg-80 units) in a 30-40 ml vol.
-does not contain factor IX, so no use in Haemophilia B
Concerns :
- factor content of individual packs variable.
29. Desmopressin
• Only effective in mild hemophilia A - single i.v. infusion
of 0.3 mg/kg expected to boost FVIII level 3-6 fold
• Ineffective in severe hemophilia A
• No value in hemophilia B - does not affect FIX levels
• Nasal spray available - useful for home treatment of
minor bleeding problems.
30. Tranexamic acid / EACA
• Antifibrinolytic agent, competitively inhibits activation of
plasminogen to plasmin.
• Valuable in controlling bleeding from mucosal surfaces (e.g.,
oral bleeding, epistaxis, menorrhagia)
- dental surgery
- eruption of teeth
• Tranexa dose for children - 25 mg/kg up to three times daily
- 500 mg tablet can be crushed, dissolved in water for
topical use on bleeding mucosal lesions.
31. Prophylactic Therapy
• Administration of clotting factors at regular intervals to prevent
bleeding
- Patients with clotting factor level > 1% seldom have
spontaneous bleeding
• 25-40 IU/kg of clotting factor concentrates
- 3 times/week for hemophilia A
- twice a week for hemophilia B
• Expensive but preservation of joint function & improved QOL
• Administered by subcutaneous access port of central line
34. Normal Von Willebrand Factor
• The vWF gene is located on chromosome 12.
• The basic mature vWF molecule is a monomer composed of 2050 amino acids.
• vWF monomers associate with each other through disulphide bonds to form
multimers of varying sizes.
• The large multimers of vWF are more effective in haemostasis as they have greater
binding sites for mediating adhesion of platelets to subendothelium.
• Most of the vWF is synthesised by endothelial cells from where they are secreted
constitutively or are stored in Weibel-Palade bodies for later secretion.
35. • In megakaryocytes vWF is stored in a granules and is secreted when platelets
are activated.
• Soon after their secretion into the blood, vWF multimers are cleaved by the
metalloprotease ADAMTS13 (A Disintegrin And Metalloprotease with
Thrombospondin type 1 motif 13).
• ADAMTS13 cleaves a site within the A2 domain of vWF.
• In thrombotic thrombocytopenic purpura, degradation of large vWF multimers
does not occur due to deficiency of ADAMTS13.
• In plasma, vWF and F VIII circulate as a non-covalently bound complex.
36.
37.
38. Major Function of vWF
Haemostasis–
(i) vWF
mediates adhesion of platelets to subendothelium by binding to platelet glycoprotein
receptor Gp Ib (and also to Gp IIb/IIIa when platelets are activated) and
subendothelium;
and
(ii) vWF forms a noncovalent complex with F VIII in circulation and serves to
prevent the degradation and rapid removal of F VIII from circulation.
39. Von Willebrand disease
• is a markedly heterogeneous congenital bleeding disorder characterised by
deficiency or functional defect of vWF.
• most common congenital bleeding disorder with overall prevalence in the general
population being 1%.
48. • For mild mucous membrane bleeding, antifibrinolytic agents tranexamic acid can
be used.
• For significant bleeding, two treatment options in vWD are desmopressin and
plasma-derived F VIII concentrate rich in high molecular weight multimers or
cryoprecipitate.
• Desmopressin or 1-deamino-(8-D-arginine)- vasopressin (DDAVP), a synthetic
vasopressin analogue, is the treatment of choice in type 1 vWD. (iv/nasal spray)
• Desmopressin raises vWF and F VIII:C levels by stimulating their release from
storage sites. It is not much effective in vWD types 2A and 3.
49. • Desmopressin is contraindicated in type 2B as it aggravates thrombocytopaenia.
• Plasma-derived F VIII concentrate rich in vWF or cryoprecipitate is the treatment
of choice in those cases not responsive to desmopressin such as type 2 variant and
type 3 vWD.
• In platelet-type vWD, platelet concentrates may be tried as both desmopressin and
cryoprecipitate can induce thrombocytopaenia.
50.
51. References
• Essentials of Hematology- Kawathalkar 2nd edition
• World Federation of Hemophilia guidelines 2021
• https://www.slideshare.net/vardhanbobby/von-willebrand-disease-232841948
• https://www.slideshare.net/derosaMSKCC/vwd
Notes de l'éditeur
Clotting factor activity is defined as the activity present in 1 ml of fresh plasma from normal donors
Blood coagulation reaction can be described as ocurring in 3 overlapping phases: Initiation, Propagation and Termination.
Initiation: Perforation results in delivery of blood and with it circulating FVIIa and platelets to the extravascular space rich in membrane bound TF. This activates the extrinsic pathway. The TF:VIIA complex activates F IX and X to IXa and Xa. F Xa activates small amount of prothrombin to thrombin, which activates more platelets, and converts F V and VIII to Va and VIIIa.
Propagation: The activated F VIIIa combines with F IXa to form the intrinsic factor Xase (FVIIIa-FIXa complex). >90% of factor Xa is produced by this intrinsic factor Xase. FXa combines with FVa to form FVa – FXa prothrombinase complex, which converts most prothrombin to thrombin.
Mixing studies: With control plasma- confirms factor deficiency and not circulating inhibitors as cause of APTT prolongation.
With FVIII deficient plasma (from known patients) - suggests FIX deficiency.
With FIX deficient plasma (from known patients) - suggests FVIII deficiency
A woman is a definite carrier if (i)her father has hemophilia, (ii)she has one son with hemophilia and a 1st degree male relative with hemophilia, (iii)she has two sons with hemophilia.
- A possible carrier if (i)she has one or more maternal relatives with hemophilia, (ii)she has one son with hemophilia & no other affected relative.