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Case Reports Indian Pediatrics 2000;37: 656-659 |
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Factor X Deficiency: An Unusual Cause for Spontaneous Intracranial Bleeding |
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David Ode R.P. Warrier
Factor X deficiency is an extremely rare autosomal recessively inherited coagulation disorder. Clinical manifestations are variable but early onset of recurrent intracranial hemorrhage with associated morbidity and mortality has been reported(1). Diagnosis is confirmed by prolongation of prothrombin time (PT), partial thromboplastin time (PTT), Russell viper venom time (RVVT) as well as decreased levels of Factor X antigen and activity. We report such case with intracranial hemorrhage.
The child was the product of a fullterm, normal pregnancy in a 25-year-old gravida 2, para 1, Caucasian mother with an un-complicated antenatal period. Family history was negative for any form of hereditary or acquired bleeding disorder. He was delivered by a Caesarian section done for cephalic- pelvic disproportion and had an Apgar of 8 and 9 at l and 5 minutes, respectively. Physical examination by the pediatrician was normal. Intramuscular injection of Vit. K 1 mg (Phytonadione (R)) was followed within a couple of hours by development of a large hematoma at the site of injection. He had two episodes of vomiting mixed with frank blood. Hematemesis was confirmed to be of fetal origin. Prothrombin time (PT) and partial thromboplastin time (PTT) done at that time were markedly elevated at above 120 sec. Factor VIII, Factor IX, fibrinogen and platelet count were normal. He received three doses of FFP 10 cc/kg and his PT\PTT became normal. Over a couple of days, his PT\PTT again started to go up and he was referred for a coagulation workup. Physical examination was completely unremarkable except for a hematoma in the right antecubital area, related to previous blood drawings. Laboratory results were as follows: Hemoglobin 12.1 g/dl; Hct 34.5%, WBC 9500/mL; Platelet count 2,44,000/ml; WBC differential-Polys 43%, Lymph 45%, Mono 10%; Comprehensive metabolic panel-within normal limits; Fibrinogen-328 ng/ml (n-200-400); PT 157.0 sec (N 12-15.5 sec.); PTT 154.0 sec (N-23-41.0 sec;) Thrombin time: 14 sec (N 8-14 sec); Factor V 139% (N 50-150%); Factor VII 125% (50-150%); Factor X: <1% (N 31-87%); Factor II Activity 59% (33-93%); and Factor XIII Activity 102% (60-150%). Factor X activity was measured by standard clotting factor assay using Organon technical (R) as the reagent. Factor X antigen estimation could not be done due to certain restraints. He was asymptomatic and developing normally until he developed vomiting with focal seizures at four weeks of age. Physical examination at the peripheral hospital showed lethargy, pallor and a bulging anterior fontanel. CT scan of the head showed a right sided retro-occipital subdural hematoma with mass effect. He was treated with FFP 10 cc/kg to correct his PT/PTT and prevent any further hemorrhage. He also received two packed red blood cell transfusions. He was given conservative treat-ment without any neurosurgical intervention. Repeat CT scan at 48 hours showed evidence of ischemic infarct over the right cerebral area at the region of lower cerebral hemisphere most likely as a complication of the retro occipital subdural hematoma. He was discharged after one week without any clinical evidence of neuropsychological sequalae. He was also advised to take Phenobarbital for seizure precautions. At two and half months of age, he required hospitalization again for increased irritability with unremarkable clinical examina-tion except for a full anterior fontanel. CT scan of the head demonstrated a large subdural hematoma lying immediately adjacent to the right cerebral hemisphere and a very small intraparenchymal bleed in the right parietal lobe. He was admitted to the PICU and treated with FFP 10 cc/kg every 6 hours. After evaluation by a neurosurgeon, he was con-servatively managed. A repeat CT scan done after three days showed disappearance of the "small new bleed". Occurrence of two episodes of spontaneous, life threatening intracranial hemorrhage (ICH) within a few months of life and the very high risk of recurrence with risk of death or significant neurological sequalae led to the introduction of prophylactic therapy. Twice weekly infusion of prothrombin complex concentrate (Konyne, Bayer Labs). has been successful in preventing intracranial bleeds in Factor X deficiency(1). Heparin was added to the vial prior to the infusion to decrease the risk of thromboembolic complication. An indwelling central line (Hickman(R)) was placed after infusion of FFP without any complication. He has been maintained on a dose of 40 m/kg of prothrombin complex concentrate twice weekly. Factor X level 1 hour post infusion was 150% and 96 hours after infusion and just prior to next dose was 5%. A workup of the family including both parents revealed normal factor X levels. No further episodes of ICH or any other hemorrhage has occurred. He is nine months old with normal height and weight and a head circumference of 42 cm (<5 percentile). He has mild developmental delay in the areas of adaptive, gross motor and fine motor skills. He is responding appropriately to sensory stimulation and oral motor skills are within normal limits. His neurological examination is normal except for mildly decreased movement of his left hand. His most recent CT scan showed resolution of the earlier extra-axial bleed with infarctive and porencephalic changes in the right lower cerebral hemis- phere. Parents and primary physicians and healthcare providers have been educated regarding the nature and course of the disease as well as the risk of further spontaneous hemorrhage, complications of prothrombin complex concentrate infusion including the risk of infections and the need for immunizations against hepatitis B, central line care, and trauma precautions.
Factor X (Stuart Prower factor) is a Vitamin K dependant glycoprotein which is changed to its active form as a serine protease both by Factor VII and Ca++, with tissue thrombo-plastin in the extrinsic pathway. Factor IX with Factor VIII; Ca++ and Platelet factor 3 in the intrinsic pathway activate it. Factor Xa is also involved in macromolecular complex formation with its cofactor factor Va, a phospholipid surface and calcium to convert prothrombin into thrombin(2). The gene encoding factor X shares a number of structural and organizational features in common with the other Vitamin-K dependant coagulation proteins, suggesting that they have evolved from a common ancestral gene(3). Coagulation and immunological methods have shown different forms of Factor X defect. This rare autosomal recessively inherited disorder is characterized by mucous membrane bleeding, unusual bleeding with major or minor trauma, and menorrhagia. Intracerebral hemorrhage is rare and seen only occasionally(4). Clinical and laboratory abnormalities may appear similar to factor II and factor VII deficiency and other Vitamin K dependent factor defects. RVVT can help differentiate factor VII and X deficiency as this agent activates factor X directly. Factor X deficiency may be caused by complete deficiency of the protein, presence of a nonfunctional protein, or presence of decreased amounts of functional protein(5). Acquired deficiencies of factor X may occur with anticoagulant therapy, liver disease, Vitamin K deficiency, secondary to drugs such as phenytoin, and paraprotenemias like amyloidosis. Acquired deficiency of Factor X due to the presence of an endogenous inhibitor has been reported(6). Sun et al.(7) described a functional factor X deficiency which causes pronounced decrease in the in-vitro activation of the extrinsic pathway while only minimally affecting the in-vitro activation of the intrinsic pathway(7). FFP has been the mainstay of therapy for factor X deficiency. Half-life of factor X is 40 hours. The need for frequent use of large volumes of FFP is a problem in small children. Prothrombin complex has also been used more recently for elevating factor X levels. The degree of elevation for factor X is extremely variable with the added risk of thromboembolic complications and the development of inhibitors(9). The advantages of prothrombin complex over FFP include reduction in volume infused and decreased risk of viral contamination as the products are all heated or pasteurized. The product is also available in the lyophilized form, which is convenient for storage, and home administration. Autoplex T (Baxter health care) and FEIBA VH (Immuno US) are activated clotting factors which have also been reported to be effective in acquired factor X deficiency in which the usual prothrombin complex (Konyne) was in-effective, though they have an added risk of predisposing to DIC in the newborn. Prophylactic use of Factor X to prevent recurrent ICH was initially reported by Sandler et al.(1). Due to the rarity of the case and minimal experience with prophylactic use of Factor X, there are currently no data on duration, frequency, and dosage of therapy, long term complications or prognosis. Clinical experience in using the prothrombin complexes or their activated versions (autoplex) for emergency bleeds and as preparative for elective surgery is very limited in factor X deficiency.
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