Dr Ira Shah
M.D, DNB, DCH(Gold Medalist), FCPS

A 13 years old right-handed male child presented with sudden onset aphasia and 2 episodes of generalized tonic clonic convulsions. There was no history of trauma. On examination he had Broca’s aphasia with right-sided lower limb hypertonia. There was no cranial nerve involvement. He had left sided wasting with hemiparesis suggestive of left sided old hemiplegia. At age of 4 years he had presented with fall from bed and unconciousness. CT scan (brain) at that time showed a bleed in right basal ganglia and right temporal region with mass effect with surrounding edema with bleed in right lateral ventricles. He subsequently developed hydrocephalus and had to be shunted (VP shunt) leaving behind a residual left sided hemiparesis. In view of the bleed with trivial trauma, he was worked up for a bleeding disorder. His PT, PTT and platelet counts were normal. Factor XIII screening test showed that the clot lysed in less than 1 hour in 5 M urea suggestive of severe Factor XIII deficiency, though he had no previous history of excessive bleeding or bleeding from umbilical cord. He was advised FFP transfusion every 4 weekly which he had omitted since past 1 year.

This episode was suggestive of a left frontal lobe bleed from the anterior cerebral artery. A CT scan (brain) was done suggestive of 3.4 x 2.8 cm hematoma in left frontal lobe with surrounding edema and mass effect on left lateral ventricle and midline shift. Old gliotic areas were seen in right temporal lobe and shunt tube on right side was noted (Figure 1).

He was treated with FFP (10 ml/kg) loading dose and 2/3rd fluid restriction and anticonvulsants (carbamazepine & phenobarbitone) and subsequently started with speech therapy and physiotherapy. He was again stressed and advised on regular FFP/cryoprecipitate transfusion every 4 weekly as prophylaxis for CNS bleeds.


Activated factor XIII (fibrin stabilizing factor) stabilizes the clot formation by causing cross-linking of fibrin molecules and fibrin polymers. It also inhibits plasminogen binding to cross-linked fibrin.

Deficiency of factor XIII results in bleeding diasthesis. The principal sites of bleeding are:

Intracranial


Umbilical cord


Superficial bruising and hematoma formation


Oral cavity

1. Acquired – Seen in conditions such as Crohn’s disease, leukemla, ulcerative colitis associated with DIC. Factor XIII may be decreased to about 50% in these diseases. The clinical significance of these decreased levels in unclear.



2. Hereditary Factor XIII deficiency- It is extremely rare with about 200 cases reported. Since Factor XIII is a heterotetramer with 2A chains and 2B protein chains, polymorphism in A and B proteins may lead to clinical manifestation. Factor XIII is not only in plasma but also in platelets, megakaryocytes and monocytes – macrophages. The intracellular form has no B protein and its specific functions are unknown. The gene for the A chain is located on chromosome 6 (2) and gene for B chain is on chromosome 1.(3)

Clinical features – The phenotype varies from moderate to severe life threatening bleeds. The first symptom is rebleeding from umbilical stump about 24-36 hours later after birth. Patients may have superficial bruising and subcutaneous hematomas. Spontaneous intracranial bleeds may occur in more than 30% of patients and may be the cause of death. Female patients who become pregnant always spontaneously abort unless treated.

Screening tests for bleeding are all normal because a clot will form normally. Clot solubility in dispersing solvents such as monochloroacetic acid or urea is a useful test. If clot is soluble quickly, it suggests severe deficiency (<1%) of either factor XIII or alpha 2-antiplasmin. Confirmation is by measurement of protein concentration quantitatively and enzyme activity.

1. Homozygous deficiency:– There is presence of undetectable levels of A protein and enzyme activity and around 50% of normal B protein. Some patients (in Japan & Italy) may have low levels of A with deficiency of B protein.
   
   
2. Heterozygous deficiency: – These patients have around 50% levels of A and 80% of B protein.

Any injury to the head should be treated aggressively and children should be treated prophylactically because of a high chance of intracranial bleed. Factor XIII concentrates, fresh-frozen plasma (FFP) and cryoprecipitate are all effective. 1 unit of factor XIII concentrate equals 1 ml of plasma factor XIII activity. Treatment is given to achieve an initial level of 50% for prophylaxis. Patients should be infused on a 4-6 week schedule as protein A has a long half-life of 8 to 14 days and very low concentration (5-10%) can achieve hemostasis. Infusion of 5 ml/kg of normal FFP is efficacious.

Inhibitors to Factor XIII – The development of inhibitors is rare. Patients with inhibitors present with massive bleeding. It has been reported in patients with prolonged treatment with isoniazid, penicillin or diphenylhydantoin. Plasma exchange, extracorporeal circulation through protein A, factor XIII concentrates and platelet concentrates have been tried without success.