Coagulation signaling pathway
Coagulation Disorders
Hereditary Acquired
↓ ↓ ↓ ↓
Extrinsic 1- Vitamin K
Common pathway
Intrinsic pathway disorders pathway deficiency
disorders
disorders 2- Liver cell
- Factor VIII deficiency - Factor VII - Factors II, X deficiency failure
(Hemophilia A) deficiency - Factors V (Para 3- DIC.
- Factor IX deficiency Hemophilia)
(Hemophilia B) - Fibrinogen deficiency:
- Factor XI deficiency a. Congenital
(Hemophilia C). afibrinogenaemia.
- Factor XII deficiency b. Congenital dys-
- Von Willbrand disease (Vascular fibrinogenaemia
hemophilia) - Factor XIII deficiency
First: Hemophilia A = Classic hemophilia
Definition
- Sex-linked recessive coagulation defect due to deficiency of F.VIllc
- 20% of cases are new mutations.
Incidence: Hemophilia A represents 85% of all hemophilias
Pattern of deficiency
- -Hemostatic level of factor VIII is >30-40U/L (30-40%); below this level bleeding occur
- -Plasma level of Factor VIII in carrier females is between 40-60%
Clinical picture
- The severity of bleeding: depends on plasma Level of factor VIII & severity of trauma.
Mild Moderate Sever
F VIIIc 6-30% 1-5% ˂1%
Bleeding With severe trauma With mild trauma Spontaneous bleeding
- At birth: unusual bleeding from the umbilicus or circumcision site
- Later:
- External bleeding: epistaxis, dental bleeding ,hematuria, gastrointestinal
- Internal bleeding: intracranial hemorrhage, muscle hematoma
- Skin: ecchymosis & hematoma (no petechiae)
- Hemarthrosis: mainly in big joints of lower limbs:
o Joint become swollen, red, hot, and tender with limited mobility.
o Later on → fibrosis & ankyloses
Investigations:
For diagnosis For Carrier detection
1- coagulation profile: - Direct gene mutation analysis
Bleeding time (BT) Normal - F.VIII/vWF ratio ( <1.0)
Clotting time prolonged
Prothrombin time
Normal Prenatal diagnosis
(PT)
Prolonged - CVS or amniocentesis & DNA
Activated Partial (it is corrected by barium analysis.
Thromboplastin sulphate adsorbed - Fetal blood sample: at 18-20
Time (aPTT) plasma (contain F8 & F weeks
11) not by serum
(contain F9 & F11))
2- Factors assay:
F.VIllc assay low
Treatment
1- Prophylactic treatment
o Regular F VIII replacement 20 unit/kg 3 times a week.
o Hepatitis B vaccine.
o Avoid trauma, I.M. injections & aspirin.
2- During bleeding attacks
Factor VIII replacement Adjuvant drugs Special cases
1- Recombinant factor 1- Desmopressin (DDA VP) → ↑ Intracranial Hemorrhage:
VIII→ dose= 25-50 plasma F VIII by 4 folds. High dose of F.VIII (50-75
unit/kg according to 2- Antifibrinolytics → inhibit unit/kg) for 2 weeks.
severity. fibrinolysis → stabilize the clot Hemarthrosis:
2- Others: e.g. (Tranexamic acid) - Local cold
a. Fresh frozen Indications: compresses.
plasma. - Mucosal bleeding (oral - F VIII replacement+
b. Cryo-preciptate bleeding, epistaxis). prednisone (short
c. Factor VIII - Menorrhagia course)
concentrate. 3- Prednisone (short course) in - Rest for 48 hr. then
hemarthrosis & hematuria physiotherapy to
(minimize fibrosis). avoid ankylosis
Complications
1- Complications Of bleeding:
o Severe blood loss → hypovolemic shock
o Severe intracranial hemorrhage.
o Hemophilic arthropathy→ joint stiffness (Joint MRI show ↑ iron deposition)
o Muscle atrophy
2- Complications Of treatment:
a. Complications of transfusion
b. Factor VIII inhibitors:
i. About 5-10 % of hemophilics develop antibodies against factor
Vlll. So, become refractory to treatment.
ii. Antibody titre is measured by Bethaseda units
Second: Hemophilia B and C
Hemophilia B =
Hemophilia C
Christmas disease
Defect ↓↓ F.IX ↓↓ F.XI
Half life 24 hrs 48hrs
Incidence 10-15 % 2-3%
Inheritanc X-Linked Recessive Autosomal Recessive
e
C/p as hemophilia A milder or no bleeding
↓↓ F.XI
↓↓ F.IX assay
Lab ↑↑ aPTT (corrected by
↑↑ aPTT (corrected by serum)
serum & plasma)
FIX (recombinant/lyophilized),
Fresh Frozen Plasma
Treatment Fresh Frozen Plasma
desmopressin & cryoprecipitate are ineffective
Third: Vascular hemophilia (Von Willbrand disease)
Incidence: - The commonest hereditary bleeding disorder (3-4 out of I 00.000)
Physiology of vWF:
- El Structure: large multimeric glycoprotein.
- Synthesis:
o Endothelial cells released into plasma & sub-endothelial matrix
o Megakaryocytes → stored in platelets
- Function:
o Platelet adhesion: through binding to platelet GPIb receptors
o Carrier for F VIII protecting it from proteolysis
Clinical picture (♂ > ♀)
• Muco-cutaneous bleeding. (epistaxis, bleeding gums, post-tonsillectomy &
post-tooth extraction bleeding, menorrhagia) & easy bruising
• Hemarthrosis is rare
• No bleeding with stressful procedures (childbirth, appendectomy)
Investigations
• CBC: • Coagulation profile:
Usually Normal Bleeding time (BT) Prolonged
(But low in Clotting time Prolonged
Platelets
Type 2B & Prothrombin time (PT) Normal
pseudo-vWd) Activated Partial
RIPA = Thromboplastin Time Prolonged
ristocetin (aPTT)
Platelet inauced
• Factors assay:
function platelet-
F.VIllc assay Maybe low
aggregation:
• Low (type 1)
impaired
VWF assay • abnormal (type 2)
• Absent (type 3).
Treatment
• Desmopressin (DDAVP): ↑ release of vWF from the endothelium →↑ vWF &
F.VIII
• Cryoprecipitate (vWF& FVIII).
• Anti-fibrinolytic agents (€-aminocaproic acid): in dental bleeding & epistaxis
Types of vWD:
