Hemophilia C/Factor XI deficiency

Question 1

How common is Factor XI deficiency?

Answer 1

1 in 1 million people

Question 2

Approximately how many people experience bleeding?

Answer 2

20%

Question 3

List risk factors

Answer 3

Ashkenazi Jews (Phe283 Leu missense mutation)
French Basques (Cys38Arg)
Acquired from exogenous factor XI
Cancer
AI dx (SLE)
DIC
Liver disease

Question 4

Ddx for Factor XI deficiency

Answer 4

Bleeding dsrs: Hemophilia A/B (X-linked – mostly males), vWD, acquired factor inhibitors

Prolonged aPTT w/o bleed: APS, contact factor deficiencies

Question 5

How does Factor XI deficiency lead to bleeding?

Answer 5

Initial steps in hemostasis (initial platelet plus and initial thrombin generation in response to tissue factor exposure) occur normally and only subsequent amplification of the thrombin response and resistance of the clots to fibrinolysis are affected by lack of factor XI.

Factor XI is activated by injury (thrombin, IIa, factor XIIa and itself) –> thrombin generation by plasma protease factor VIIa and tissue factor complex

Complex promotes thrombin generation by activating factors X and IX

More commonly urinary tract, oral cavity or nasopharynx bleeding

Question 6

Is there a correlation between plasma factor activity and bleeding tendency?

Answer 6

No, it is weakest for FXI

Question 7

What are symptoms experienced by the patient?

Answer 7

Generally do not have spontaneous bleeding; but rather with trauma or surgery

easy bruising, mucous membrane bleeding (epistaxis, GI bleed, hematuria), heavy menstrual bleed, post-op, post dental extraction or ppm bleeds

Question 8

How do you evaluate for Factor XI deficiency?

Answer 8

aPTT, PT and platelet count

Mixing study – will correct with normal plasma

Factor XI activity level

Question 9

How is Factor XI deficiency diagnosed?

Answer 9

prolonged aPTT assay (partial thromboplastic time)

Normal 65-130%
Severe FXI activity <20%
Partial FXI deficiency 20-60%

Question 10

What is the prognostic factor for FXI deficiency?

Answer 10

Prior history of bleeding

Question 11

How do you manage FXI deficiency?

Answer 11

Multidiscciplinary - Anesthesia (usually safe level is 40), Hematology, MFM

Obtain Factor XI level in pregnancy, in the third trimester and admission to L&D; checking fetus not required

Active management of the 3rd stage of labor; c-section for ob indications; mode of deliver unaffected

Pharmacologic VTE prophylaxis likely not needed if level <20%

Avoid NSAIDs, aspirin or anti-platelet products (bleeding risk). Pain management with Tylenol or opioid products.

Avoid circumcision and IM injections until factor XI level is known

Question 12

How would you manage if factor level is above 40%?

Answer 12

routine ob care with neuraxial anesthesia

Question 13

How would you manage if factor level is between 20-40%?

Answer 13

prophylactic antifibrinolytic agent (10 mg/kg of IV tranexamic acid) with plasma product (FFP) or rFVIIa with neuraxial anesthesia or delivery

Question 14

How would you manage if factor level is below 20%?

Answer 14

start FFP 10-20 ml/kg the evening before scheduled induction/cesarean up to 1 or 2 doses
In combination with an antifibrinolytic agent for 3-5 days
<10% with exposure to factor XI –> inhibitor testing

Question 15

How would you manage acute bleeds?

Answer 15

factor XI replacement with or w/o antifibrinolytic agent with target of > 30-45%

Question 16

How do you treat FXI deficiency?

Answer 16

Antifibrinolytic

Tranexamic acid 1 gram QID (oral 15-25 mg/kg q6-8 hrs or IV 10 mg/kg q6-8 hrs) US oral is 650 mg tabs
-on L&D 1 gram IV
Epsilon aminocaproic acid (EACA)

Plasma product

FXI replacement (not found in cryoprecipitate or prothrombin complex concentrates)

XI concentrate (15 U/kg) - lapse 24 hrs if used with other agents, anticipate >30% q48-72 hrs 
   C – thrombotic complications, formation of neutralizing anti-FXI alloantibodies (inhibitor development), esp in those with severe deficiencies (<2%), some FXI also found in prep of Rhogam 
Therefore, can bypass with alternatives with recombinant factor VIIa 
Therefore, test for inhibitors when planning for elective surgery in those who have been exposed to exogenous factor XI 

For those, they may not respond to future factor XI admin and require alts as below

FFP (1 unit/mL) 10-20 ml/kg raises factor XI level to 10-20% above baseline
C – volume overload, TRALI, TACO

Low-dose recombinant factor VII (15-30 mcg/kg q2-6 hours or cont infusion (1.8-3.6 mcg/kg/hr))
May use with tranexamic acid in severe deficiency

?Desmopressin 0.3 mcg/kg

Question 17

What is the risk for PPH with FXI deficiency?

Answer 17

16-31%

Question 18

What are obstetric complications associated with FXI deficiency?

Answer 18

SAB and PPH