Intracranial Hemorrhage in Patients With Hemophilia A

Introduction: Intracranial hemorrhage in inherited bleeding disorders is a medical emergency. The location of bleeding in most children is subdural and the most common cause is hemophilia. Although intracranial bleeding that occurs in people with hemophilia ranges from less than 5% of events, it is a life-threatening medical emergency so appropriate treatment is needed. Case Report: A boy patient 11 years old, 20kg weights have a seizure at home and followed by a decrease in consciousness. It was founded abnormalities in the form of anemia, prolonged FH (PPT 4x and APTT 4x), and hypocalcemia. The patient then was given main therapy; FVIII 100 IU/dL according to the FVIII target level calculated. The therapy continued with 500IU/12 hours according to the daily target of FVIII 50IU/dL. Discussion: The patient’s condition was getting better day by day. The patient’s consciousness started to improve after 14 days of postoperative. One month after that, the patient received koate treatment as the episodic handler. Diagnosing the exact cause in patients who have intracranial hemorrhage provides appropriate management so that the patients could be helped. Conclusion: Good collaboration between anesthesiologists, neurosurgeons, and pediatrics will increase the probability of successful management of critical bleeding without major sequelae.


INTRODUCTION
Intracranial bleeding in inherited bleeding disorders is a medical emergency. (1) The location of bleeding in most children is subdural and the most common cause is hemophilia.
(2) Although Intracranial Bleeding that occurs in people with hemophilia tends to be less than 5% of events, it is a medical emergency that requires the necessary soul needed. (1) (2) Hemophilia is a disorder of X-linked congenital bleeding caused by a lack of coagulation factor VIII (hemophilia A) or factor IX (hemophilia B). This lack of coagulation factor is due to mutations from the clotting factor gene.(1) the incidence is around 1 in 10,000 births. Based on the World Federation of Haemophilia's (WFH) annual global survey shows that the hemophilia sufferers around the world were 400,000 in 2012. Hemophilia A dominates hemophilia B, about 80-85% of the total patients were suffered Hemophilia A. Hemophilia commonly happens in boys than girls. However, the F8 and F9 genes are susceptible to mutation which explains why a third of cases have no prior family history. (1)(3) The right diagnosis provides the right management. Hemophilia presumed in patients who have an easy bruising history in their early childhood, spontaneous hemorrhage, especially internal hemorrhage such as hemorrhage in joints (70-80%), muscle (10-20%) and soft tissue (5-10%) where symptoms of bleeding occur when the child starts learning to walk or run. (1) In patients with mild hemophilia, excessive bleeding usually occurs after trauma or surgery. Family history of hemorrhage in about twothirds of total patients. A definitive diagnosis depends on the factor test to show FVIII or FIX deficiency. (1)(3)

CASE REPORT
A patient of a boy, 11 years old, weighing 20 kg, had a seizure at home and was followed by a decrease in consciousness at home and taken to the nearest hospital and treated. During treatment at the hospital, abnormalities such as anemia, longitudinal FH (4x PPT and 4x APTT) were found, and hypocalcemia was then given a PRC transfusion, vitamin K injection, calcium gluconate injection. The results of other examinations found that SDH appeared without the occurrence of trauma with 1.3 cm thick and MLS 1 cm which had been indicated as being operated (Thickness of cm1 cm and MLS ≥ 0.5 cm) but not due to blood coagulation abnormalities. The patient's condition deteriorated the following day because GCS decreased and FH remained being longer but for PPT it dropped to 2x normal while APTT but 4x normal so being referred to Dr. Soetomo General Hospital was further examined found an abnormality in the form of FVIII which was so low that hemophilia A was diagnosed in this patient while waiting for the results of the FVIII examination to be given FFP because there was an extension of the FH both PPT and APTT while preparing for the surgery. In this patient after entering 1 unit of FFP (100 ml) there is an improvement in the physiology of hemostasis namely normal PPT and 2.5x normal APTT and when the results of measurement FVIII come out to indicate a hemophilia A disorder whose main therapy is given FVIII 1000 IU according to the FVIII target level calculation 100 IU / dL should be maintained at 500 IU / 12 hours according to the daily target of FVIII 50 IU / dL.
During surgery, the hemorrhage that occurs in patients can be controlled by the surgeon and after surgery, the patient is maintained FVIII for 14 days as recommended by WFH. And FVIII treatment of patients is given episodically, for example, if the bleeding occurs significantly because the availability of FVIII is difficult to obtain. But the condition of the patient from day to day is getting better and even consciousness begins to improve after 14 days post-surgery and 1 month later the patient gets back coagulation as an episodic handler. Figure 3. Differential Diagnosis of Bleeding Disorders (4) Initially, the patient experienced subdural hemorrhage due to blood clotting disorders in the form of vitamin K deficiency. (3) Because of PPT and aPTT were extended to 4 times normal without thrombocytopenia and after being given vitamin K treatment, PPT was repaired but the aPTT was extended so that deficiency factors were suspected. (3)(5)(6) Indicates the presence of severe factor VIII deficiency (1%) and upright diagnosis of Hemophilia A in this patient.  (5) Finally, the patient can be given FVIII treatment and undergo clot evacuation craniotomy with controlled hemorrhage.

DISCUSSION
FVIII Concentrate is the first-line treatment for hemophilia A. All plasma derivative products currently on the market are listed in the WFH Registry of Clotting Factor Concentrates. Consult with product inserts for specific details. (1)(2) One bottle of factor concentrate is available in each dose ranging from 250 to 3000 units. In the absence of an inhibitor, each FVIII unit per kilogram of intravenous weight will increase plasma FVIII levels by about 2 IU / dl. Around 8 until 12 hours is the half-live of FVIII. Fifteen minutes after infusion to verify the dose, the patient factor level must be measured. The desired factor level in plasma (IU/dl) calculated by multiplying the patient's weight in kilograms by 0.5. (1)(2)  For example: 20 kg × 100 (IU / dl desired level rises) × 0.5 = 1,000 units of FVIII. See Tables 1 and 2 for the recommended factor level and the duration of replacement needed based on the type of hemorrhage. FVIII must be infused by slow IV injection with a speed not exceeding 3 ml for adults and 100 units per minute in children. Subsequent doses are ideally based on half of FVIII and recovery in individual patients for certain products. It is best to use all FVIII bottles after they are dissolved, although many products have been shown to have increased stability after being dissolved.
(1)(2) Continuous infusion avoids peaks and troughs and is considered by some to be profitable and more comfortable. However, patients must often be monitored for pump device failure.

Other therapies
So far many therapies can be used to treat hemophilia but depend on the severity of the disease. The following are therapies that can be used to treat hemophilia with their respective limitations.

Fresh Frozen Plasma (FFP)
FFP contains all coagulation factors. FFP contains FIX which is used to treat hemophilia B in countries that cannot afford FIX concentrates derived from plasma. (1)(2) The dose is 1 ml FFP = 1 unit factor. But in Hemophilia A it is difficult to reach FVIII levels higher than 30 IU / dl with FFP alone. FIX levels above 25 IU / dl are difficult to achieve. The initial acceptable dose is 15-20 ml/kg.

Cryoprecipitate
Cryoprecipitate is obtained by liquefying FFP slowly at 4 ° C for 10-24 hours and found deposits that are insoluble and separated by centrifugation. Cryoprecipitate contains FVIII (about 3-5 IU / ml), VWF, fibrinogen, and FXIII but not FIX or FXI. The resulting supernatant is called cryo-poor plasma and contains factors VII, IX, X, and XI. The dosage is 1 cryoprecipitate bag made from one FFP unit (200-250ml) which can contain 70-80 FVIII units in volumes of 30-40 ml. (1)(2)

Desmopressin
Desmopressin (1-deamino-8-D-arginine vasopressin) is a vasopressin synthetic analog that increases plasma levels of FVIII and VWF. Desmopressin does not affect FIX. The intranasal desmopressin response is more varied and less predictable. Increase FVIII 3-6 times the baseline level for patients with mild hemophilia, and maybe moderate. (1)(2) Desmopressin is not for pregnancy but can be used during labor and in the post-partum period in a normal pregnancy. This drug is contained of a high level of VWF, so it has to avoid for pre-eclampsia and eclampsia patients. (1)(2) The advantage of desmopressin compared to plasma products is the cost and risk of transmission of viral infections. Controlling hemorrhage is associated with hemostasis disorders. The decision to use DDAVP is the initial concentration of FVIII, the improvement achieved, and the duration of treatment needed because it can only be used for patients with mild and possibly moderate hemophilia. (1)(2)

Tranexamic acid
Tranexamic acid is an anti-fibrinolytic agent which competitively inhibits plasminogen activation into plasmin. Promotes clot stability and can be used as an adjunct therapy to hemophilia and several other hemorrhage disorders. Regular administration of the single-use of tranexamic acid does not prevent the hemarthroses in hemophilia. It is important to control the hemorrhage from the skin and mucous surfaces (for example; oral bleeding, epistaxis, menorrhagia). (1)(2) Dosage of administration : 1. oral tablets 3-4 times/day.

i.v. 2-3 times / day
Gastrointestinal disorders (nausea, vomiting, or diarrhea) infrequently happen as a side effect, but heal if the dose is reduced. The infusion should be slow because the rapid injection can cause dizziness and hypotension.
(1) (2) Tranexamic acid is usually specified for 7 days after tooth extraction to discourage postoperative hemorrhage. The dose of Tranexamic acid must be reduced if there was a kidney disorder. The reduction of the dose will highly avoid the accumulation of toxins.
(1) (2) In the treatment of hematuria, it prevents the dissolution of clots in the ureter which can cause serious obstructive uropathy. And on thoracic surgery causes the development of an insoluble hematoma. (1)(2)

CONCLUSION
Diagnosing the exact cause in patients who have intracranial hemorrhage provides appropriate management so that the patients could be helped. (1)(7) Good collaboration between anesthesiologist, neurosurgeons, and pediatrics will increase the probability of successful management of critical bleeding without major sequelae. (8)