Page 2298 - Hematology_ Basic Principles and Practice ( PDFDrive )

2040 Part XII Hemostasis and Thrombosis

not sensitive to heparin or direct thrombin inhibitors. The apparent to 60% normal activity. Approximately 50 prothrombin gene muta-
plasma concentration of fibrinogen as determined by the von Clauss tions have been described in patients with prothrombin deficiency,
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method (see section on Fibrinogen Deficiency) may be low in some three-quarters of which are missense mutations. In dysprothrom-
types of dysfibrinogenemia. Levels of immunoreactive fibrinogen are binemia, missense mutations typically cause defects in prothrombin
usually normal, but are decreased in cases of hypodysfibrinogenemia. conversion to thrombin (e.g., prothrombin pArg457Gln [Puerto
With some variants, serum fibrin degradation products may appear Rico I] and pArg271Cys [Madrid]), or result in functionally defective
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to be elevated because the variant fibrinogen is incompletely incor- thrombin (e.g., prothrombin pArg418Trp [Tokushima]). Pro-
porated into the clot. This can lead to the false impression that DIC thrombin deficiency can be inherited in combination with deficien-
is present. cies of other vitamin K–dependent proteins (see Combined Deficiency
Most dysfibrinogenemic patients are asymptomatic, and symp- of Vitamin K–Dependent Proteins).
toms correlate poorly with coagulation assay abnormalities, making Acquired prothrombin deficiency occurs with warfarin therapy,
it difficult to make general therapeutic recommendations. The poisoning with rodenticides such as brodifacoum, vitamin K defi-
patient’s personal and family histories are useful for guiding therapy. ciency, liver disease, and DIC. Cephalosporins, particularly those
Active bleeding can be treated with replacement therapy as in afi- with N-methyl-thiotetrazole side chains, can decrease prothrombin
brinogenemia, and such treatment may be indicated in some patients levels. Antiprothrombin antibodies are common phospholipid-
before invasive procedures. In general, patients with thrombosis and dependent antibodies in patients with lupus anticoagulants or the
dysfibrinogenemia should be treated in the same manner as other antiphospholipid syndrome. More rarely, patients with a lupus
patients with thrombosis. There are no data on which to formulate anticoagulant or systemic lupus erythematosus have antibodies that
recommendations as to duration of therapy; thus past history, family enhance prothrombin clearance causing true deficiency. This acquired
history, coexisting conditions, and the nature (idiopathic, pregnancy- hypoprothrombinemia occurs primarily in children under 10 years
related or surgery-related) and seriousness of the thrombotic event of age, usually in association with lupus anticoagulants after a viral
are taken into consideration. As with any thrombotic event, the risk illness. These episodes typically resolve spontaneously but excessive
for bleeding associated with prolonged therapy must be considered. bleeding can occur. There are no reports of neutralizing antibodies
Recurrent spontaneous abortions have been associated with dysfi- forming after replacement therapy in congenital prothrombin defi-
brinogenemia in several families, and pregnancies have been carried ciency, consistent with patients having at least a trace of circulating
to term using replacement therapy. While some investigators recom- prothrombin.
mend replacing fibrinogen starting early in pregnancy, as in afibrino- Severe hypoprothrombinemia is inevitably associated with bleed-
genemic patients, the prothrombotic nature of the peripartum period ing that may be life threatening. In the EN-RBD survey prothrombin
may dictate against this approach in certain patients. deficiency is classified as severe (<1% or normal), moderate (1% to
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10%) or mild (> 10%) (Table 137.2). CNS hemorrhage was
reported in 8% to 12% of patients, and in 20% with prothrombin
PROTHROMBIN DEFICIENCY (OMIM 176930) levels less than 1% of normal activity. 11,12 Soft tissue hematomas,
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bruising (60%), and hemarthroses (42%) are common. The bleed-
More than a century ago Morawitz proposed that insoluble fibrin is ing diathesis can present at circumcision in neonates, with trauma or
formed from fibrinogen through the activity of fibrin ferment or surgery, or as easy bruising, epistaxis, menorrhagia, or GI hemor-
thrombin. Thrombin was generated from a precursor, prothrombin, rhage. Heterozygotes occasionally have excessive bleeding with
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by thrombokinase (probably factor Xa). Prothrombin and thrombin surgery or tooth extraction, but most are asymptomatic. Bleeding
are designated factors II and IIa. Total prothrombin deficiency is tends to be less severe in dysprothrombinemia, and some variants are
probably not compatible with life. Complete absence of the protein particularly mild. For example, homozygosity for pArg67His causes
has not been observed in a human, and prothrombin-deficient mice severe reduction in plasma prothrombin activity (<20% of normal)
succumb to bleeding in utero or shortly after birth. Severe deficiency but causes relatively few symptoms.
associated with reduced plasma prothrombin antigen (hypopro- In the PT and aPTT assays, prothrombin is converted to thrombin
thrombinemia) or circulating dysfunctional prothrombin (dyspro- by factor Xa in complex with factor Va on phospholipid surfaces (Fig.
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thrombinemia) affects about 1 in 2 million people (Table 137.1). 137.1B), and severe prothrombin deficiency will prolong the clotting
Prothrombin deficiency is the third most common coagulation factor time in both tests. Some PT and aPTT reagents are relatively insensi-
disorder in Puerto Rico (carrier frequency about 1 in 700), account- tive to reductions in prothrombin, and mild deficiencies may be
ing for 6% of congenital bleeding disorders other than von Willebrand missed. The diagnosis is usually confirmed, and the degree of defi-
disease at the University of Puerto Rico Hemophilia Center. In the ciency established, by a modified PT assay using prothrombin-
North American Rare Bleeding Disorder Registry, 62% of patients deficient plasma. A prothrombin antigen level is needed to distinguish
with prothrombin deficiency were Latino, possibly reflecting the between hypoprothrombinemia (activity and antigen are equivalent)
prevalence of the pArg457Gln variant prothrombin Puerto Rico I. and dysprothrombinemia (activity is less than antigen). Prothrombin
Globally almost 70% of patients with prothrombin deficiency are of deficiency must be distinguished from deficiencies of fibrinogen,
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Latin or Hispanic origin. Prothrombin is a 72,000-Da protein that factor V, or factor X, which also prolong the PT and aPTT.
is converted to thrombin by factor Xa in complex with factor Va on Prothrombin complex concentrate (PCC) approved for use in
phospholipid surfaces (Fig. 137.1A). Thrombin is the pivotal protease factor IX deficiency typically contains an amount of prothrombin
in hemostasis, with multiple procoagulant activities including cleav- comparable to, or higher than, the factor IX activity. It is the preferred
age of fibrinopeptides A and B from fibrinogen to form fibrin (Fig. product for treating prothrombin deficiency (Table 137.3). PCC is
137.3), activation of factors V, VIII, XI, and XIII, and cleavage of derived from human plasma and undergoes viral inactivation. Hemo-
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protease activated receptors on a variety of cells including platelets. static levels of prothrombin are estimated to be 20% to 40% of
Thrombin forms a complex with thrombomodulin on endothelial normal for major surgery or trauma, but 10% to 15% may be adequate
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cells that downregulates fibrinolysis by activating thrombin-activatable for milder hemostatic challenges. A PCC dose of 20 to 30 factor
fibrinolysis inhibitor (TAFI) and downregulates coagulation by IX units/kg usually produces plasma prothrombin levels of 20% to
activating protein C. 30% of normal in a severely deficient patient. The half-life of pro-
Prothrombin deficiency is an autosomal recessive disorder thrombin is about 3 days, and dosing every 2 to 3 days can maintain
manifested as hypoprothrombinemia (reduced activity and antigen; adequate levels until healing is complete. Alternatively, one-fourth of
cross-reactive material [CRM]–negative [CRM–] deficiency), dyspro- the loading dose each day should keep the level therapeutic. Prophy-
thrombinemia (activity reduced relative to antigen; CRM+ deficiency) lactic infusion of PCC every 5 to 6 days prevented spontaneous
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or a combination of both. Plasma prothrombin activity is typically bleeding in one severely deficient patient. PCC administration has
1% to 10% of normal in hypoprothrombinemia and 1% to 20% in been associated with thrombosis, although a meta-analysis of studies
dysprothrombinemia. Heterozygotes for either condition have 40% using PCC to reverse the effect of warfarin suggests the risk is