Page 2304 - Hematology_ Basic Principles and Practice ( PDFDrive )

2046 Part XII Hemostasis and Thrombosis

Treating Factor XI–Deficient Patients
When preparing patients with severe factor XI deficiency (plasma factor occurs appears to be appropriate for procedures such as circumcision,
XI level <15%–20% of normal) for an invasive procedure it is important to appendectomy and some orthopedic surgery, and with normal vaginal
keep in mind that (1) a negative bleeding history does not indicate a low deliveries. In a recent phase 2 trial in which antisense oligonucleotide
risk with subsequent procedures, (2) certain procedures are associated therapy was used to reduce plasma factor XI as prophylaxis to prevent
with lower bleeding risks than others, and (3) patients with very low factor venous thrombosis in total knee arthroplasty, patients underwent surgery
XI levels (<1%) frequently develop neutralizing inhibitors after replace- with factor XI levels as low as a few percent of normal, without excessive
ment therapy. These observations have led to refinements in treatment bleeding. This demonstrates that factor XI probably plays a minor role,
recommendations that limit exposure to factor XI by targeting replacement at most, in hemostasis during certain types of procedures. In pregnancy,
to certain clinical situations. In the Jewish population, patients with severe there is little data to evaluate the safety of epidural anesthesia in the
deficiency have more bleeding problems than those with mild deficiency, absence of factor coverage, and replacement therapy is generally advised.
but this does not appear to hold for the general population. The poor Low doses of recombinant factor VIIa (15–30 µg/kg) every 2 to 4 hours
correlation between plasma factor XI level and bleeding propensity means in conjunction with antifibrinolytic therapy has been used successfully
that some patients with mild deficiency (levels of 20%–40% of normal) in lieu of replacement therapy in patients without factor XI inhibitors
may require factor replacement for certain types of procedures, such as undergoing surgery. This strategy may be preferable to factor replace-
surgery on the prostate or on the oral and nasal cavity. ment in some patients with very low plasma factor XI levels (<1% of
Antiplatelet drugs should be stopped one week before surgery. The normal) because of their propensity to develop neutralizing antifactor XI
prothrombin time and platelet count should be normal, and the possibility antibodies. In patients with known factor XI inhibitors, a strategy based
of co-existing hemostatic abnormalities thoroughly investigated. Patients on a single dose of recombinant factor VIIa (15–30 µg/kg) followed
with factor XI levels greater than 40% to 50% of normal generally do not by antifibrinolytic therapy maintained hemostasis in several patients
experience abnormal bleeding, and a history of excessive bleeding in undergoing major surgery, including a patient who required repair of an
such an individual suggests other hemostatic abnormalities are present. If aortic dissection. The higher doses of factor VIIa typically used to treat
the patient has been exposed to factor XI in the recent past, the possibility patients with factor VIII inhibitors are not required in factor XI deficient
that a neutralizing inhibitor is present should be considered. patients with or without inhibitors, and should not be used as they may
Factor replacement is required for most major surgery in factor XI increase the risk of thrombotic complications.
deficient patients, and should be initiated prior to the procedure. Surgery Alternatives to factor replacement are recommended in several situa-
on the oropharynx, nasopharynx or urinary tract should be treated with tions. Tooth extraction or skin biopsies can be managed with antifibrino-
fresh frozen plasma (FFP) or factor XI concentrate to keep the plasma lytic drugs alone (ε-amino caproic acid 5 to 6 g q6 hours or tranexamic
trough factor XI level above 40% of normal for at least seven days. acid 1 to 1.3 g q6 hours), starting 12 hours before the procedure and
Administering FFP at 15 mL/kg every 1 to 2 days is the most common continuing for seven days. Dental procedures such as scaling or root
way to achieve this. A similar strategy is appropriate for neurosurgery, canal can be performed safely using ε-amino caproic acid or tranexamic
head and neck surgery, cardiothoracic procedures, and major abdominal acid mouthwash prepared from the intravenous formulation three to four
or pelvic surgery. For nasal surgery and oral procedures such as tonsil- times daily with or without systemic antifibrinolytic therapy. Fibrin glues
lectomy, supplementing FFP therapy with antifibrinolytic therapy should can be used in place of fibrinolytic therapy for skin biopsy or resection
be considered. Antifibrinolytics must be used with caution in patients of skin lesions.
receiving factor XI concentrate because of the potential for thrombotic Patients with factor XI deficiency can experience thromboembolic
events. For prostatectomy and other surgery on the lower urinary tract, episodes. Aspirin or clopidogrel can be used in factor XI-deficient patients
flushing the bladder with saline containing an antifibrinolytic agent may with myocardial infarction or other manifestations of atherosclerosis,
be beneficial. In some types of minor surgery patients may receive while atrial fibrillation or venous thromboembolism should be treated
replacement to maintain levels of 30% for 5 days. However, a “wait with warfarin, with the goal of not allowing the international normalized
and see” strategy in which replacement is withheld unless bleeding ratio (INR) to exceed 2.5.

and later designated factor XII. The incidence of severe factor XII low factor XII levels to pregnancy loss or failure of in vitro fertiliza-
deficiency is not known as many deficient persons likely go undiag- tion. Interestingly, factor XII deficient mice do not display an
nosed. Factor XII deficiency was reported in 1.5% to 3.0% of healthy abnormality in reproduction. It is possible that antibodies that
blood donors. This high number may be partly explained by antifac- interfere with factor XII function, rather than true deficiency, are
tor XII or antiphospholipid antibodies that interfere with factor XII responsible for pregnancy-related complications in humans.
activity assays. α-Factor XIIa, the activated form of factor XII, is an Factor XII undergoes autoactivation when exposed to the contact
80,000-Da protease that activates factor XI and prekallikrein in the surface used to initiate clotting in the aPTT assay. Factor XIIa acti-
contact phase of the PTT assay (Fig. 137.5). A C/T polymorphism vates prekallikrein to α-kallikrein, which reciprocally activates addi-
in the 5′-untranslated region of the factor XII gene (referred to as tional factor XII (Fig. 137.3). Factor XIIa also activates factor XI to
46C/T [or −4C/T]) strongly influences plasma factor XII levels. The XIa. In severe factor XII deficiency the aPTT is very long. Definitive
frequency of 46T is high (73%) in Japanese and Han Chinese indi- diagnosis is established using a modified aPTT with factor XII–
viduals who have lower factor XII levels than members of other ethnic deficient plasma. Antiphospholipid antibodies may disproportion-
groups, compared to 20% in whites. Factor XII activity and antigen ately affect factor XII measurements in aPTT-based assays. Factor XII
are usually reduced in parallel, and circulating dysfunctional variants antibodies are present in up to half of plasmas with antiphospholipid
are rare. antibodies, and may account for many cases of presumed mild factor
About thirty factor XII gene mutations have been identified. XII deficiency.
Factor XII deficiency is not associated with spontaneous or excessive
posttraumatic bleeding, and most cases are identified by the incidental
finding of a prolonged aPTT. There is conflicting literature regarding Prekallikrein Deficiency (OMIM 229000)
an association between factor XII deficiency and thrombosis. Two
studies reported an inverse relationship between plasma factor XII In 1965 Hathaway and coworkers described members of a family
levels within the broad normal range and the risk of cardiovascular with long plasma clotting times that corrected on prolonged incuba-
events; however, most work indicates that severe deficiency does not tion with glass. They did not have histories of abnormal hemostasis.
prevent thrombosis or increase its risk. A meta-analysis of studies The missing plasma component, initially called Fletcher factor after
examining the 46C/T factor XII gene polymorphism suggests that the index cases, was subsequently shown to be prekallikrein. Severe
the correlation between the polymorphism and venous thrombosis or prekallikrein deficiency appears to be rare. Mild cases may be missed
myocardial infarction, if present, is weak. There are reports linking because a low level of prekallikrein activity is often sufficient to bring