Clotting disorders
(Haemophilia and Factor XI deficiency)
Presented by - Saksham Ranot
Roll No. - 22088.
Coagulation disorders
The most common inherited factor deficiencies are:
Hemophilias
X-linked diseases caused by deficiency of factor(F) VIII
(haemophilia A) or F IX (haemophilia B).
Deficiencies of other factors - FII(prothrombin), FV, FVII, FX, FXI,
FXIII, fibrinogen, are commonly autosomal recessive.
Congenital F XII deficiency with prolongation in activated partial
thromboplastin time(aPTT).
Accquired deficiencies of plasma coagulation factors are
more frequent eg:
Hemorrhagic diathesis of liver.
Disseminated intravascular coagulation (DIC).
Vitamin K deficiency.
In these disorders tere is deficiency of more than one clotting
factor.
Bleeding episdoes are result of perturbation of both primary
and secondary
Coagulation cascade
Tests of hemostasis
The most commonly used tests of hemostasis are
1. PT(Prothrombin Time)
2. aPTT
Interpretation-
Prolonged PT suggests F VII deficiency.
Prolonged aPTT indicators intrinsic pathway deficiency like
haemophilia A(FVIII) or B(FIX) or FXI deficiency.
Prolongation of both PT and aPTT suggests a deficiency of FV,
FX, FII, or fibrinogen abnormalities.
Inhibitors
The development of alloantibodies against coagulation plasma protiens are
termed inhibitor.
It is a rare disease that often affects hemophilia and FXI deficient patients
on repetitive exposur to missing protiens to control bleeding.
These can occur as manifestation of -
Autoimmune disease
Neoplastic disease
Idiopathically
Rarely accquired inhibitors to thrombin or FV have been reported in
patients receiving topical bovine thrombin preprations as hemostatic
agents on surgeries.
Inhibitor detection in hemophilia patients is done yearly at most hemophilia
treatment centers.
Hemophilia
Pathogenesis -Hemophilia is an X-linked recessive hemorrhagic
disease due to muta tions in the F8 gene (hemophilia A or classic
hemophilia) or F9 gene (hemophilia B).
Affects 1 in 10,000 males.
Hemophilia A represents 80% of all cases.
The large size of the F8 gene makes it more susceptible to
mutation events than the smaller F9 gene.
Family history of the disease is absent in 30% of cases. In
these cases mother carries the de novo mutated allele.
Clinical presentation
Clinically can be classified into:
Severe (<1%).
Moderate (1-5%).
Mild (6-30%).
1.Severe and moderate forms are characterised by-
Bleeding into the joints (hemarthrosis) with swelling, erythema
and pain.
Haematoma in soft tissues and muscles can lead to
compartment syndrome.
Or spontaneously
2.Mild forms are characteristics by infrequent bleeding secondary to
trauma.
Treatment
1. Factor Replacement Therapy
Primary prophylaxis: Maintain clotting factor levels ≥1% to
prevent bleeding.
On-demand therapy: Given in response to bleeding episodes.
Dosing:
FVIII: 1 IU/kg ↑ FVIII by 2%.
Dose = (Target level - Baseline level) × Body weight (kg) ×
0.5
FIX: Lower recovery (50%), different formula:
Dose = (Target level - Baseline level) × Body weight (kg) ×
1.0
Example: 3500 IU of FVIII raises levels to 100% in a 70-kg
patient.
2. Historical Advances
Plasma use began during WWII.
1990s: Recombinant FVIII/FIX development reduced infection risk to
HIV & hepatitis.
3. Prophylactic Treatment
Children on regular prophylaxis reach puberty without joint damage.
It has become more common, improved life expectancy and quality
of life.
4. Special Considerations
Surgical settings: Factor levels maintained at higher levels (50–
100%) for 7–10 days.
Mild bleeds: Local measures + factor infusions to maintain 15–25%.
Severe bleeds: High-dose replacement + extended therapy.
5. DDAVP (Desmopressin)
for mild/moderate Hemophilia A.
Not effective in Hemophilia B.
Administered IV, SC, or intranasally.
Tachyphylaxis can occur after repeated dosing.
6. Antifibrinolytic Therapy
Tranexamic acid / EACA used in mucosal bleeds (oral, GI, GU).
Dosing: e.g., Tranexamic acid 25 mg/kg every 8h for up to 1 week.
Contraindicated in hematuria (risk of obstruction).
7. Newer Therapies
Gene therapy and long-acting factor concentrates.
Emicizumab: Used in Hemophilia A. SC injection weekly or
biweekly.
Complications
Inhibitor Formation
Most important complication of hemophilia treatment.
Inhibitors are antibodies that neutralize infused FVIII or FIX.
Prevalence:
Up to 30% in severe Hemophilia A.
About 3–5% in Hemophilia B.
High-risk groups for inhibitor formation:
Severe factor deficiency.
Family history of inhibitors.
African descent.
Large gene deletions/inversions in FVIII or FIX genes.
Clinical Consequences
Inhibitors lead to:
Reduced efficacy of factor replacement therapy.
Increased bleeding frequency and morbidity.
Need for bypassing agents or alternative therapies.
Bethesda Assay: measures inhibitor level in Bethesda Units (BU).
<5 BU: Low responder.
>5 BU: High responder (require bypass agents). High
responders do not respond to FVIII therapy.
Management of Inhibitors
Immune Tolerance Induction (ITI): Daily infusion of missing factor
over >1 year.
New/emerging therapies: Anti-CD20 monoclonal antibodies &
emicizumab
Factor XI deficiency
(Haemophilia C)
It is a rare autosomal bleeding disorder.
Normal FXI activity ranges from 70-150 U/dL
severe deficiency (<1U/dL) is seen in homozygous or double
heterozygou.
FXI level <10% have increased risk of bleeding
Clinical manifestations- Mucotutaneous hemorrhages in gums,
epistaxis, hematuria.
Treatment-
FFP at dose 15-20mL/kg in surgery
Plasma derived FXI concentrates are available
Antifibrinolytic drugs for minor bleeds as adjunctive treatment
PCC/ aPCC or recombinant FVIII for treatment of inhibitor.
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