Keywords
factor XII - surgery - bleeding - thromboembolism
Introduction
Inherited bleeding and clotting disorders can complicate the intraoperative anesthetic
management especially in neurosurgical procedures where significant amount of blood
loss is expected. Perioperative management of patients with these disorders remains
a challenge to the neuroanesthesiologist. Of all these disorders, factor XII deficiency
is extremely rare and is usually diagnosed incidentally when a prolonged activated
partial thromboplastin time (aPTT) is observed during preoperative evaluation. We
report the perioperative management of a patient with factor XII deficiency who underwent
cervical vertebral fusion (C1-C2) for atlantoaxial dislocation (AAD).
Case Report
A 38-year-old male, weighing 38 kg and height of 160 cm, presented with increasing
neck pain with tingling and numbness of both upper limbs. The patient was moderately
built and had pallor. The muscle power was ⅗ at the right wrist and ⅘ at the left
wrist joint. Airway examination showed restricted mouth opening (<1 finger breadth)
and a Modified Mallampatti Class IV. Echocardiography was normal and the pulmonary
function tests showed moderate restrictive lung disease. After magnetic resonance
imaging, a diagnosis of ankylosing spondylitis with AAD was made. He was planned for
posterior fusion of C1–C2 with lateral mass screws.
During evaluation, hemoglobin (Hb) of 7.3 g/dL and a prolonged aPTT value (73 seconds)
with a normal platelet count (4.12 lakhs/cu mm) and prothrombin time (12.8 seconds)
was observed. The test was repeated twice and consecutive values were high. Patient
denied any history of prolonged bleeding after injury. Hematologist diagnosed him
with anemia and reduced levels of factor XII (18 IU/mL, normal value—50 IU/mL). Factor
VIII, factor IX, protein C and S assays were normal. Mixing studies were performed
to rule out the presence of factor XII inhibitors. Mixing patient’s plasma and test
plasma in the ratio of 1:1 led to shortening of aPTT indicating the absence of factor
XII inhibitors. Therefore, aPTT prolongation was due to deficiency of factor XII.
The patient was started on hematinics and a follow-up was planned after 2 weeks.
On re-evaluation, the reduction in factor XII levels (28.9 IU/mL) and mild prolongation
of aPTT (44 seconds) persisted and Hb improved to 8.2 g/dL. Literature search revealed
that there were no guidelines with respect to the range at which correction of aPTT
is recommended in factor XII deficiency.[1] Also, there is no consensus for minimum desired factor XII level for hemostasis
in vivo.[1] Hence, surgery was scheduled.
Adequate blood and blood products were reserved. Patient was counseled about the nature
of the condition, expected complications, and informed consent was taken. We did not
transfuse fresh frozen plasma (FFP) preoperatively and plan was to transfuse, based
on intraoperative blood loss, to avoid unnecessary complications of blood product
administration. Awake orotracheal fiberoptic intubation was performed. Anesthesia
was thereafter induced; adequate venous access and invasive arterial line were secured.
An intermittent pneumatic compression device (IPCD) was placed to prevent venous thrombosis.
A close watch was maintained for abnormal bleeding. However, no abnormal bleeding
occurred and surgery lasted 9 hours. A total blood loss of 500 mL occurred that was
replaced with two units of packed red blood cells and Hb was 8.6 g/dL at the end of
surgery. After reversal of neuromuscular blockade, motor power was ⅘ in both upper
limbs and 5/5 bilaterally in the lower limbs. Patient was not extubated in view of
difficult airway, nature of surgery, and prolonged procedure time and was shifted
to intensive care unit. Patient was extubated the next day, mobilised and started
on enoxaparin 60 mg subcutaneously once a day with daily screening for occurrence
of deep venous thrombosis (DVT). The postoperative course was uneventful and patient
was discharged on 5th postoperative day.
Discussion
Factor XII also known as Hageman factor is synthesized in the liver. It is a single
chain glycoprotein with molecular weight of 80,000 daltons, half-life of 60 hours,
and normal plasma concentration of 50 IU/mL (30 µg/mL).[1] Factor XII deficiency can be both inherited (autosomal recessive) and acquired.
Acquired causes include nephrotic syndrome, sepsis, and disseminated intravascular
coagulation. The overall prevalence of the disorder is ~1.5 to 3.0%, with severe factor
XII deficiency (activity <1%) in a minority.[2]
Factor XII deficiency is one of the causes for prolongation of aPTT. Other causes
of prolonged aPTT include deficiency of coagulation factors VIII, IX, X, XI, V, or
II; deficiency of factors for contact phase activation; Von Willebrand disease, liver
disease, vitamin K deficiency; therapeutic anticoagulation; and autoimmune diseases
(due to anti-phospholipid antibodies). Whenever isolated prolongation of aPTT is encountered,
management involves identification of the cause (with specific assays) and correcting
it, administration of recombinant clotting factors, factor concentrates, FFP, or cryoprecipitate
as per the clinical manifestations.[3]
Factor XII, prekallikrein, and high-molecular-weight kininogen are important for activation
of contact phase of coagulation. Factor XII is activated by plasma kallikrein during
endothelial injury. Activated factor XII is the first component of intrinsic pathway
of coagulation. Also, fragments of factor XII activate plasminogen during the initiation
of normal fibrinolysis. Therefore, factor XII deficiency affects coagulation as well
as fibrinolysis.
In our patient, the activity of factor XII was 31% of mean normal range with mild
prolongation of aPTT. In patients with severe factor XII deficiency, aPTT values may
exceed 120 seconds. Unlike previous literature reports, we did not transfuse FFP for
normalization of aPTT.[4] This is justified by the fact that although factor XII plays an important role in
activation of coagulation cascade in vitro, its role is very negligible in in vivo
coagulation activation and extrinsic pathway is sufficient for activation of coagulation
pathway in humans.[1] Thus, even severe form of isolated factor XII deficiency does not cause hemostatic
problems perioperatively, and prophylactic transfusion with FFP/cryoprecipitate is
not warranted. This also explains why there was no abnormal bleeding intraoperatively
in our patient. However, the factor XII levels were not very low and there was only
a mild prolongation of aPTT in our case.
Factor XII deficiency inhibits fibrinolysis and therefore can lead to thromboembolic
complications.[5] Patients with isolated factor XII deficiency have a high rate of venous thromboembolism
and arterial thrombosis, leading to life threatening complications such as pulmonary
embolism and myocardial infarction.[6] In addition, surgical trauma and immobilization increase the risk of thromboembolic
complications. This necessitates the use of thromboprophylaxis perioperatively (mechanical
and pharmacological) and early aggressive mobilization postoperatively.[7] We used IPCD intraoperatively and in the postoperative period, low molecular weight
heparin, early mobilization, and daily screening for DVT was done in addition to continued
use of IPCD.
In conclusion, patients with factor XII deficiency are at high risk of thromboembolism
for which vigilant monitoring and measures for thromboprophylaxis should be undertaken
perioperatively. The risk of bleeding, although present, is not so alarming. The prophylactic
correction of prolonged aPTT should be given a second thought.
