Page 2296 - Hematology_ Basic Principles and Practice ( PDFDrive )

2038 Part XII Hemostasis and Thrombosis

β γ
α
FPA
ss RGDS
γ
RGDF ss α PI
FPB
s s
s s
D-domain E-domain
ss

α
γ β
Fig. 137.3 MODEL OF HUMAN FIBRINOGEN. A fibrinogen molecule consists of two trimers, each
containing an Aα-chain (blue), Bβ-chain (pink), and γ-chain (yellow). The amino-termini of the six chains
that compose the whole molecule are linked by disulfide bonds in the central E domain, and the C-termini
of the polypeptides form two nodular D domains at opposite ends of the molecule. Fibrinopeptides A (FPA;
green) and B (FPB; purple) reside in the E domain and are removed by the proteolytic activity of thrombin
during conversion of fibrinogen to fibrin monomer. (Adapted from Mosesson MW: The roles of fibrinogen and fibrin
in hemostasis and thrombosis. Semin Hematol. 29:177, 1992, with permission.)

0.04 L/kg body mass (40 mL/kg). Administering cryoprecipitate at hemorrhage. 2,5,7 Therapy should be initiated early as fetal loss in the
1 unit/5 kg of body mass will increase plasma fibrinogen in an afi- first trimester is common. One study suggested that initiating therapy
brinogenemic patient to approximately 1 g/L. The fibrinogen con- before conception is beneficial. Although some authors recommend
centrate RiaSTAP (Haemocomplettan) was approved by the Food keeping fibrinogen levels above 0.5 g/L during pregnancy and peri-
and Drug Administration (FDA) in 2009 for treating bleeding and partum, others suggest a higher level (1.0 g/L) based on reports of
for prophylaxis in severe fibrinogen deficiency. This preparation has fetal loss in patients with levels near 0.5 g/L. Long-term prophylaxis
gone through viral inactivation steps. In a study of 15 patients given may be useful in preventing initial bleeding in young patients or to
RiaSTAP (70 mg/kg), the median plasma fibrinogen concentration prevent recurrence, particularly after CNS hemorrhage. Administra-
1 hour postinfusion was 1.3 g/L with a half-life of 77.1 hours. In one tion of 20–30 mg/kg of concentrate every 7 to 14 days to maintain
study, the concentrate was effective in congenital fibrinogen deficiency plasma levels of approximately 0.5 g/L is recommended. 5,6
in 26 of 26 bleeding episodes, 10 of 11 surgical procedures, and all Increased use of fibrinogen concentrate has raised concerns regard-
90 prophylactic administrations. Subsequent studies involving ing adverse events. An analysis of 27 years of pharmacovigilance data
trauma, cardiothoracic surgery, and obstetrical hemorrhage confirmed identified 21 cases of suspected viral transmission (1 per 124,300),
5,6
its ability to improve coagulation and reduce blood loss. Low- 28 cases of thromboembolism (1 per 93,300), and 20 cases of hyper-
molecular-weight heparin may be administered with fibrinogen sensitivity (1 per 130,600 doses) suggesting a promising safety
8
concentrate if there is concern that therapy may precipitate a throm- profile. Acquired antibody inhibitors have been reported in only two
botic event. The required dose of concentrate can be determined patients with afibrinogenemia after replacement therapy.
using the following formula: Antifibrinolytic therapy with ε-amino caproic acid may be an
effective replacement for blood products for some mucosal bleeds and
for dental extractions. However, this therapy may increase the risk
[
[
( Target level mg/dL]− Measured level mg/dL]) for thrombosis and must be used cautiously in patients with a history
Dose mg/kg) = of thrombosis, or during pregnancy, surgery, or immobilization.
(
(
. 1 7 (kg body weight/dL ) Fibrin glue may be useful for tooth extraction, and estrogen/proges-
terone therapy may be helpful for controlling menorrhagia. 5
For treating bleeding, the United Kingdom Haemophilia Centre
Doctors Organization guidelines recommend that plasma fibrinogen
be maintained at 1.0 g/L until hemostasis is achieved and greater than DYSFIBRINOGENEMIA (OMIM 134820 Aα-CHAIN,
2
0.5 g/L until wound healing is complete. A similar strategy makes 134830 Bβ-CHAIN, AND 134850 γ-CHAIN)
sense for managing surgery. A review of replacement therapy and
outcomes for 50 patients with congenital fibrinogen deficiency gener- In dysfibrinogenemia structural variants of fibrinogen circulate in
ally agrees with these recommendations. A fibrinogen concentration plasma. 9,10 Cases in which the dysfunctional protein is present at low
of 0.5 to 1.0 g/L was sufficient for prevention or treatment of bleed- levels may be referred to as hypodysfibrinogenemia. The first family
ing in nonsurgical or obstetrical settings, while 1.0 to 2.0 g/L was with dysfibrinogenemia (15 amino acid insertion after Gln350 in the
effective for preventing bleeding during surgery. One review reported γ-chain [fibrinogen Paris I]) was described in 1964. The actual
that thrombotic episodes (related or unrelated to replacement) incidence of congenital dysfibrinogenemia is not known because the
occurred in 30% of patients. As the half-life of transfused fibrinogen majority of affected individuals are probably asymptomatic.
is approximately 3 days, dosing every 2 to 4 days is usually adequate Congenital dysfibrinogenemias are almost all autosomal dominant
to maintain levels in the absence of consumption. Increased dosing traits due to missense mutations in a fibrinogen gene (www.geht.or/
frequency may be necessary in cases of massive hemorrhage, major databaseand/fibrinogen). 6,9,10 Amino acid substitutions that alter
surgery or advanced pregnancy, and monitoring of the fibrinogen fibrinopeptide release, cross-linking, polymerization, or degradation
level is recommended to facilitate dosing. The utility of thromboelas- have been described. The diagnosis is established by identifying low
tography to provide guidance for patients receiving fibrinogen con- fibrinogen in a rate-based clotting assay relative to immunoreactive
centrate for bleeding is being investigated. fibrinogen. The functional defects most often reported are clearly
Prophylactic fibrinogen administration is recommended to main- influenced by the assays available in clinical laboratories and are
tain pregnancies in afibrinogenemic women and to reduce postpartum unlikely to represent the full spectrum of mutations causing