Page 2294 - Hematology_ Basic Principles and Practice ( PDFDrive )

2036 Part XII Hemostasis and Thrombosis

gene mutations such as Gly284Arg (fibrinogen Brescia), Arg375Trp (54% and 72%, respectively), but were less frequent (25%) in another
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(fibrinogen Aguadilla), or Thr314Pro (fibrinogen Al DuPont) are study. Hemarthrosis-related arthropathy appears to be less pro-
associated with accumulation of the mutant γ-polypeptide in hepa- nounced than in hemophilia A or B. Intracranial bleeding occurs in
tocytes, leading to hepatic dysfunction and cirrhosis similar to the up to 10% of patients, and is a major cause of death, providing a
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process associated with α 1-antitrypsin deficiency (endoplasmic reticu- justification for prophylaxis. Afibrinogenemic patients are prone to
lum [ER] storage disease). spontaneous rupture of the spleen. Hypofibrinogenemic patients are
Acquired hypofibrinogenemia occurs in disseminated intravascu- usually asymptomatic, but may have excessive bleeding with trauma
lar coagulation (DIC) and primary fibrinolysis (see Chapter 139). or surgery, particularly if the fibrinogen level is below 0.5 g/L. In the
Fibrinogen levels are usually normal or increased in liver disease, but absence of factor replacement, pregnancy loss is common in afibrino-
2,7
levels less than 1 g/L may be seen in cirrhosis with hepatic failure or genemic women, usually occurring in the first trimester. Fibrinogen-
fulminant hepatic necrosis, and indicate a poor prognosis. Patients deficient mice also have difficulty sustaining pregnancy, confirming
receiving L-asparaginase for hematologic malignancies may develop the importance of maternal fibrinogen to fetal viability. Pre- and
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severe hypofibrinogenemia (<0.2 g/L), while other coagulation postpartum bleeding is common, and intraabdominal bleeding from
factors are normal or only slightly reduced. ruptured corpus luteal cysts has been reported.
Hemorrhagic symptoms in fibrinogen deficiency are most signifi- Curiously, arterial and venous thromboses occur in afibrinogen-
5,6
cant when the plasma level is less than 0.5 g/L. Data from the emic patients, and there may actually be an increased risk of myocar-
EN-RBD database indicate spontaneous bleeds rarely occur when dial infarction. While some events are likely precipitated by known
levels are over 0.7 g/L, while bleeding even with surgery is unusual risk factors or by factor replacement, no identifiable cause is evident
with levels over 1.0 g/L. Most (85%) afibrinogenemic patients bleed in most instances. Fibrinogen and fibrin downregulate thrombin
6
from their umbilical cord and mucosal surfaces. Menorrhagia and activity, providing a possible explanation for these events.
6
bleeding from the skin, GI tract and genitourinary tract are common. Assays such as the PT, aPTT, and thrombin time will be infinitely
Hemarthroses and muscle hematomas were common in one series prolonged in afibrinogenemia. In hypofibrinogenemia, the thrombin
time is often prolonged, but the PT and aPTT are insensitive to low
fibrinogen and may be normal. Results for the template bleeding time
40 36 28 32 and standard platelet aggregometry are usually abnormal. However,
the aperture closure times in the PFA-100 platelet function screen
% of all rare factor deficiencies 20 8 8 8 15 8 10 23 is most commonly used for measuring fibrinogen, based on determin-
are usually normal, as this test depends on von Willebrand factor and
not fibrinogen to support platelet function. The von Clauss method
30
ing the time to clot formation after addition of thrombin to plasma.
The assay is not reliable at low fibrinogen levels (<10 mg/dL) and
may give falsely low readings with fibrinogen variants that polymerize
slowly (dysfibrinogenemia), if high levels of substances that interfere
with fibrin polymerization (paraproteins, fibrin degradation products)
10
borns, liver disease). Thus it is important to demonstrate the absence
of immune-reactive fibrinogen to confirm a diagnosis of afibrinogen-
0 2 2 7 2 5 7 are present, or if the sialic acid content of fibrinogen is high (new-
emia. In hypofibrinogenemia functional and antigenic fibrinogen
Fib FII FV FV VIII FVII FX FXI FXIII levels are proportionately decreased. A disproportionately low func-
Fig. 137.2 WORLDWIDE PREVALENCE OF RARE BLEEDING DIS- tional level suggests dysfibrinogenemia. Afibrinogenemic patients
ORDERS. Shown are data for each factor deficiency as a percentage of total have low erythrocyte sedimentation rates and develop little indura-
rare bleeding disorders from data collected by the World Federation of tion with skin tests for delayed hypersensitivity because of the absence
Hemophilia (WFH, blue bars) and the International Rare Bleeding Disorders of fibrin deposition.
Database (RBBD, purple bars). The difference in percentage for combined Fibrinogen is the main component of cryoprecipitate, the prepara-
factor V and factor VIII deficiency between the surveys may reflect cases of tion used most often in the United States to treat fibrinogen deficiency
factor V deficiency with mild hemophilia A being classified as combined (Table 137.3). Fresh frozen plasma (FFP) contains fibrinogen, but
deficiencies in the RBDD survey. (Adapted from Peyvandi F, Menegatti M, Palla large volumes are required to correct significant deficiency. Each unit
R: Rare bleeding disorders: worldwide efforts for classification, diagnosis and manage- of cryoprecipitate has approximately 300 mg of fibrinogen. For a
ment. Semin Thromb Haemost. 39:579, 2013, with permission.) patient with a normal hematocrit, the plasma volume is approximately

TABLE Plasma Factor Levels Based on European Network of Rare Bleeding Disorders Categories.
137.2
EN-RBD Severity Category
Clinical Correlation
Disorder Severe Moderate Mild With Factor Level
Fibrinogen deficiency Undetectable 0.1–1.0 g/dL >10 g/dL Strong
Prothrombin deficiency Undetectable ≤0.1 IU/mL (≤10%) >0.1 IU/mL (>10%) Strong
Factor V deficiency Undetectable <0.1 IU/mL (<10%) ≥0.1 IU/mL (≥10%) Weak
Factor VII deficiency <0.1 IU/mL (<10%) 0.1–0.2 IU/mL (10%–20%) >0.2 IU/mL (>20%) Weak
Factor X deficiency <0.1 IU/mL (<10%) 0.1–0.4 IU/mL (10%–40%) >0.4 IU/mL (>40%) Strong
Factor XI deficiency – – – Very weak
Factor XIII deficiency Undetectable <0.3 IU/mL (≤30%) ≥0.3 IU/mL (>30%) Strong
Combined factor V and VIII deficiency <0.2 IU/mL (<20%) 0.2–0.4 IU/mL (20%–40%) >0.4 IU/mL (>40%) Weak
Vitamin K–dependent factor deficiencies – – – Weak
EN-RBD, European Network of Rare Bleeding Disorders.