Page 2162 - Williams Hematology ( PDFDrive )

2136 Part XII: Hemostasis and Thrombosis Chapter 124: Inherited Deficiencies of Coagulation Factors II, V, V+VIII, VII, X, XI, and XIII 2137

platelets and other cells. Two forms of thrombin are generated: meizoth- Undetectable plasma prothrombin probably is incompatible with
rombin, if prothrombin is cleaved at residue 320, and α-thrombin, if life, as inferred from the partial embryonic and neonatal lethality of
cleavage occurs first at residue 271, removing prothrombin fragment prothrombin knockout mice, which do not survive to adulthood. 62,63
1.2, and subsequently cleaved at residue 320. The α-thrombin A-chain
(residues 272 to 320) formed by factor Xa cleavage is encoded by exons THERAPY
8 and 9. The B-chain (residues 321 to 579) containing the catalytic site
and regulatory elements is encoded by exons 9 to 14. Thrombin is a Replacement therapy is needed only in severe patients, in case of bleed-
multifunctional serine protease. In addition to converting fibrinogen to ing or to ensure adequate prophylaxis before surgical procedures. In
fibrin, thrombin also exerts functions in the coagulation cascade, con- severe clinical settings, higher levels of prothrombin may be achieved
54
sisting of both pro- and anticoagulant effects and activates platelets by with FFP, or with PCCs, which avoids the risk of volume overload
64
cleavage of the protease-activated receptor (PAR)-1 and PAR-4, initiat- sometimes associated with the use of FFP. However, PCCs contain
ing signals leading to platelet adhesion and aggregation. 55,56 Thrombin other vitamin K–dependent coagulation factors (VII, IX, and X) and
also stimulates wound healing through its action as a growth factor and small amounts of their activated forms, which could potentially induce
its proangiogenic activity. 57 thrombotic complications; those containing an amount of factor VII
below 10 percent are commonly known as three-factor PCCs. These
concentrates are heated or treated with solvent–detergent, processes
GENETICS that remove HIV, hepatitis B, hepatitis C, and other viruses, but which
The prothrombin gene is located on the short (p) arm of chromosome do not remove parvovirus B19 or hepatitis A virus 65–67 ; the latter viruses
68
11. It is 20-kb long and consists of 14 exons separated by 13 introns. can be effectively removed by dry heat and nanofiltration. However,
58
Fifty-four mutations that cause prothrombin deficiency have been iden- transmission of other possible bloodborne agents, such as prions
tified, of which 42 are missense, three nonsense, seven deletions/inser- causing Creutzfeldt-Jakob disease and its new variant, have not been
tions, and two splicing mutations (see mutation database on the ISTH totally eliminated. Bruises and mild superficial bleeding generally do
website, http://www.isth.org/?MutationsRareBleedin and Ref. 9). Type not require replacement therapy. Antifibrinolytic agents (tranexamic
II deficiency (dysprothrombinemias) results from missense mutations acid and gabexate mesylate) have also been used for minor surgical
that are located throughout the gene. As expected, many mutations are procedures. The oral contraceptives have been shown to exert bene-
in the catalytic domain, imparting catalytic dysfunction on thrombin. ficial effects on menometrorrhagia in women characterized by proth-
9
Other mutations give rise to abnormally slow activation of proth- rombin coagulant levels less than 3 percent. Thromboprophylaxis in
rombin. Only about 10 mutations were identified in patients with type dysprothrombinemic patients considered at high risk for a thrombotic
I deficiency, of which five were present in homozygotes. Globally, there event (e.g., orthopedic surgery) is a controversial issue. It is likely that
is a clear prevalence of patients with a Latin/Hispanic origin, as nearly administering low-molecular-weight heparin prophylactically to sur-
70 percent of all patients with thrombin gene defects come from such gical patients at the same doses and schedules as those recommended
areas (Barcelona, Padua, Segovia, and Puerto Rico). 9 for nondefect patients having similar procedures may be a valuable and
A number of polymorphisms have been identified in the proth- safe procedure after correction of factor II deficiency by FFP or PCC
rombin gene. One of these polymorphisms, a G>A change at nucleotide infusion.
20210 in the 3′ untranslated region of the prothrombin gene, is asso-
ciated with increased plasma levels of prothrombin and an increased FACTOR V DEFICIENCY
tendency to venous thrombosis (Chap. 130). 59
DEFINITION AND HISTORY

CLINICAL MANIFESTATIONS Hereditary factor V deficiency was initially termed parahemophilia
69
According to a recent classification by the SSC of the ISTH, proth- because of its similarities with classical hemophilia. In most of the
affected individuals the phenotype is characterized by the concomitant
rombin deficiency may be classified as severe, moderate, and mild deficiency of factor V activity and antigen (type I deficiency); however,
corresponding to blood levels of less than 5 percent, 5 to 10 percent, approximately 25 percent of the patients have normal antigen levels
24
and greater than 10 percent, respectively. In severely prothrombin- (type II deficiency), thus indicating the presence of a dysfunctional
deficient patients, bleeding may be marked, including spontaneous protein. 70
hemarthroses; less-severe patients may show mild to moderate mucocu-
taneous and soft-tissue bleeding that usually correlates with the degree
of functional prothrombin deficiency. Heterozygous subjects, having PROTEIN
plasma prothrombin levels between 30 and 60 percent of normal, are Factor V is synthesized by the liver and its plasma concentration is
71
usually asymptomatic; however, occasionally, excessive bleeding after approximately 20 nM (7 mcg/mL). 72–74 Factor V is a high-molecular-
moderate-intensity trauma, tooth extractions, or after surgical proce- weight (Mr ~330,000), single-chain, large glycoprotein that consists of
dures may occur. Patients with dysprothrombinemias show a variable 2196 amino acids that bears significant, regional sequence homology
bleeding tendency that is usually less severe than in type I deficiency. to factor VIII. Analysis of the approximately 7-kb factor V comple-
Women with prothrombin deficiency may suffer from menorrhagia. mentary DNA showed that the protein is organized according to the
Because of the extreme rarity of such deficiency, reports on event dur- following domain structure: A -A -B-A -C -C . The A and C domains
1
2
3
1
2
ing pregnancy/delivery are very scarce, being only one describing in have approximately 40 percent homology with analogous domains
four of eight pregnancies in a hypoprothrombinemic woman. In the in factor VIII. 74,75 The large B domain shows no homology with the
60
same report, one postpartum hemorrhage (PPH) episode on the four- corresponding B domain of factor VIII. Factor V is converted to its
term pregnancies was reported, despite administration of clotting fac- activated form following several proteolytic cleavages by thrombin
76
60
tor concentrate ; however, this data was not confirmed by a following or factor Xa. These cleavages remove the B domain and yield factor
77
Iranian series, including a total of 14 patients with the same deficiency Va, which consists of a heavy chain (A -A domains) associated by
1
2
(coagulant activity levels 4 to 10 percent). 61 Ca with a light chain (A -C -C domains). The light chain contains
2+
3 1 2
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