MEDICAL LECTURE

HEMOPHILIA
SUSANTO NUGROHO

Haematology-Oncology Division Department of Child Health Faculty of Medicine University of Brawijaya/Dr. Saiful Anwar Hospital Malang

DEFINITION
Hemophilia is an x-linked inherited bleeding disorder caused by coagulation factor deficiencies

Three types of hemophilia : hemophilia A (factor VIII deficiency) hemophilia B (factor IX deficiency) hemophilia C (factor XI deficiency)

EPIDEMIOLOGY
Frequency : about 1 in 10,000 births, and occurs in 1 : 5,000 males The number of affected person worldwide : about 400,000 Hemophilia A (85% patients) more than hemophilia B (10-15% patients) No apparent racial predilection, appearing in all ethnic groups

PATHOPHYSIOLOGY
The role of the coagulation system to produce a stable fibrin clot at sites of injury

The clotting mechanism (coagulation cascade) has 2 pathways : 1. Intrinsic pathway 2. Extrinsic pathway

PATHOPHYSIOLOGY..
INTRINSIC PATHWAY F.XII is activated by contact damaged endothelium, HMWK, PK F.XIIa F.XIIa (HMWK, Ca) : F.XI F.XIa F.XIa (F.VIIa, Ca) : F.IX F.IXa F.IXa (F.VIIa, TF, F.VIIIa, Ca & PL) : F.X F.Xa F.Xa (F.Va, Ca & PL) : prothrombin thrombin

PATHOPHYSIOLOGY..
EXTRINSIC PATHWAY TF is released from the damaged cells. The conversion of F.X to F.Xa involves TF or thromboplastin, F.VII & Ca ions.

In common pathway : F.Xa (generated through the intrinsic & extrinsic pathways) forms a prothrombinase complex with PL, Ca ions & thrombin-activated F.Va. The complex claves prothrombin into thrombin. Thrombin converts fibrinogen into fibrin.

Figure 1. Coagulation cascade

Fig 2. A stable fibrin clot was produced at sites of injury

Fig 3. Children with hemophilia bleed longer than other children

CLASSIFICATION
Hemophilia is classified based on factor coagulation (F.VIII or F.IX) levels or activity correlate with the severity of bleeding symptoms
Fig 4. Degrees of severity of hemophilia

CLASSIFICATION..
Table 1. Classification of hemophilia
Classification Severe

Coagulation factor levels or activity

< 1 U/dl (< 1%)

Cause of hemorrhage Frequent spontaneous bleeding episodes from early life; joint deformity & cripping if not adequately treated Post-traumatic bleeding (mildto-moderate); occasional spontaneous bleeding episodes Post-traumatic bleeding (major trauma or surgery)

Moderate

1-5 U/dl (1-5%)

Mild

5-40 U/dl (5-40%)

DIAGNOSIS
Clinical features History of : - easy bruising in early childhood - spontaneous bleeding (joints & soft tissues) - excessive bleeding following trauma or surgery Family history of bleeding is obtained Generally affects on the maternal side

DIAGNOSIS..

Fig 5. The chances a baby will have hemophilia

DIAGNOSIS..

Fig 6. Hemophilia is lifelong disease

DIAGNOSIS..
Common signs of hemophilia : Spontaneous bleeding (hematuria, GIT bleeding, ICH) Post-traumatic bleeding : surgery, postcircumcision, dental extraction, injection Reccurent painful hemarthroses & muscle hematomas joint deformity & disability Hemophilic pseudotumors in the long bones, pelvis, fingers & toes repeated subperiosteal hemorrhages with bone destruction & pathological fractures

Figure 7. Common signs of hemophilia

Figure 8. Common sites of joint & muscle bleeding

DIAGNOSIS..
Table 2. Main laboratory findings in hemophilia
Laboratory test Platelet count Bleeding time (BT) Clotting time (CT) Prothrombin time (PT) Partial thromboplastin time (PTT) Factor VIII level Factor IX level Von Willebrand factor level Platelet aggregation test * Hemophilia A Normal Normal Prolonged Normal Prolonged Low Normal Normal Normal Hemophilia B Normal Normal Prolonged Normal Prolonged Normal Low Normal Normal

* Ristocetin-induced platelet aggregation

DIAGNOSIS..
Carrier detection & antenatal diagnosis Until recently, were limited to measuring plasma levels of F.VIII, F.IX and vWF Antenatal dx : low levels of F.VIII or F.IX in fetal blood is aspirated at 16-20 weeks of gestation from the umbilical vein Carriers are now better detected with DNA probes A known specific mutation can be identified Chorionic biopsies at 8-10 weeks of gestation sufficient fetal DNA for analysis

TREATMENT
a. Coagulation factor replacement therapy Hemophilia A : FFP, cryoprecipitate or F.VIII concentrate Do : 0.5 x BW x F.VIII level (%) was achieved or 20-25 U/kgBW every 12 hrs (empiric) Hemophilia B : F.IX concentrate Do : same with hemophilia A

TREATMENT..
Table 3. Guidelines for F.VIII levels was needed in bleeding episodes or procedures Bleedings/procedures Mild hemarthroses F.VIII levels (%) 15-20%

Severe hemarthroses/minor surgery

Major surgery Intracranial hemorrhage

20-40%
60-80% 100%

TREATMENT..
b. Desmopressin (DDAVP) : alternative therapy to increase the plasma factor VIII level in milder hemophilia c. Local supportive treatment to treat hemarthroses & hematomas : R : resting as soon as possible after trauma I : cold compress (with ice) C : compress/pressure the proximal site of trauma E : elevate the site of trauma

PROPHYLACTIC
a. Regular prophylactic treatment (?) Recommendation : prophylaxis begun before the age of 3 yrs aimed at keeping F.VIII or F.IX levels above 1% b. Advised to have regular concervative dental care c. Often require extensive help with social & psychologic matters d. Certain activities such as body contact sports are to be avioded

PROPHYLACTIC..

Fig 9. Many activities can be done to stay healthy in children with hemophilia

COMPLICATIONS

Fig 10. The long-term effects of joint bleeding : deformity & disability

COMPLICATIONS..

Fig 11. The long-term effects of muscle bleeding : deformity & disability