Page 2343 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 140 Hypercoagulable States 2085

fulminans require protein C or protein S concentrates or sufficient
When to Perform a Thrombophilia Screen
amounts of plasma to increase the levels of protein C or protein S.
Clinical Scenario Patients with severe antithrombin deficiency can usually be
• First episode of unprovoked venous thromboembolism in managed with LMWH or unfractionated heparin, although some
individuals younger than 40 years of age patients may require considerably higher doses to achieve therapeutic
• Thrombosis in an unusual site (e.g., cerebral or mesenteric anticoagulation. Some individuals may require antithrombin concen-
thrombosis) trates to increase plasma levels of antithrombin to a point where
• Two or more first-degree relatives with unprovoked thrombosis heparin or LMWH can be used for treatment. Antithrombin con-
• Three or more early pregnancy losses, or one or more fetal centrates are commercially available in plasma-derived and recombi-
deaths after 10 weeks gestation nant forms. The aim of treatment with antithrombin concentrate is
to initially increase antithrombin activity to greater than 120% of the
normal level (based on an expected 1.4% increase above baseline
activity level per IU/kg of antithrombin administered) and to then
Essential Tests for Thrombophilia Screening
maintain antithrombin activity at over 80% of the normal level.
Basic coagulation screen Plasma antithrombin levels need to be monitored to ensure that levels
International normalized ratio (INR): to exclude warfarin effect— over 80% are maintained; antithrombin has a half-life of 2 to 4 days.
warfarin will lower protein C and S levels The role of the non–vitamin K antagonist oral anticoagulants, such
Activated partial thromboplastin time (aPTT): to exclude heparin as dabigatran, rivaroxaban, apixaban, or edoxaban, in patients with
effect—heparin will lower antithrombin levels antithrombin deficiency and thrombosis is uncertain.
Functional assay for antithrombin (with heparin to detect type II Treatment of heparin-induced thrombocytopenia involves discon-
defects) tinuation of heparin (including heparin flushes of indwelling central
Functional assay for protein C venous catheters) and the initiation of an alternative anticoagulant,
Functional assay for protein S (immune assays for total and free such as argatroban or fondaparinux.
protein S)
APC resistance assay: with genetic test for factor V Leiden for The management of acute venous thromboembolism in patients
confirmation of abnormal results with APS is similar to that in other patients. However, monitoring
Genetic test for FIIG 20210A gene mutation treatment with heparin or vitamin K antagonists can be problematic
Anticardiolipin and β 2-glycoprotein-1 antibodies (IgG and IgM) and because the aPTT or INR may be prolonged at baseline. Under these
lupus anticoagulant assay circumstances, heparin can be monitored using an antifactor Xa assay
and warfarin can be monitored using a factor X assay. Alternatively,
LMWH or fondaparinux can be used in place of heparin because
these agents do not require coagulation monitoring. Although the
protein C resistance using the modified APC sensitivity ratio with non–vitamin K antagonist oral anticoagulants may be reasonable
DNA testing for the factor V Leiden mutation if the screening test is alternatives to warfarin, clinical data on their effectiveness in APS
positive, DNA testing for the FIIG 20210A gene mutation, phos- patients are lacking. In asymptomatic subjects with laboratory evi-
pholipid-based clotting tests to detect a lupus anticoagulant and dence of ACL or LA, but no history of venous or arterial thrombosis,
enzyme immunoassay for ACL (see box on Essential Tests for Throm- appropriate thromboprophylaxis should be given at time of throm-
bophilia Screening). The benefits and potential harms of thrombo- botic challenge, such as major surgical procedures, prolonged
philia testing should always be discussed in advance with the patient immobilization, or pregnancy and the puerperium. There is no
because the psychological impact of knowing that they are a carrier indication for primary preventive treatment with anticoagulants or
of a genetic defect is one of the disadvantages of testing, and because antiplatelet agents in such individuals.
test results may also impact on the cost of life insurance.
The timing of thrombophilia screening is critical. Levels of natural
anticoagulants may be lower at the time of an acute thrombotic event; Extended Therapy
additionally, heparin can reduce the level of antithrombin, while
vitamin K antagonists, such as warfarin, reduce the levels of protein Extended treatment of thrombosis in patients with hypercoagulable
C and protein S. Therefore testing is best performed after the acute states is similar to that of patients without these underlying disorders.
event and when anticoagulant treatment has stopped. During preg- Caution is needed when starting patients with protein C or protein
nancy, protein S levels fall, which complicates the diagnosis of protein S deficiency on warfarin or other vitamin K antagonists to prevent
S deficiency. skin necrosis. Warfarin should not be started in these patients until
therapeutic anticoagulation has been fully achieved with heparin or
MANAGEMENT OF THROMBOSIS IN PATIENTS WITH LMWH. Once started, low doses of warfarin should be given to
prevent precipitous decreases in the levels of protein C or protein S;
HYPERCOAGULABLE STATES the heparin or LMWH should only be stopped when the INR has
been therapeutic for at least two consecutive days.
Thrombosis treatment is usually divided into two overlapping stages, Randomized trials have shown that usual-intensity warfarin
initial treatment and extended therapy. The impact of hypercoagu- (target INR of 2.0 to 3.0) is as effective as higher-intensity warfarin
lable states on these two stages is discussed separately as is their impact in patients with antiphospholipid syndrome. The risk for major
on duration of anticoagulant therapy and recommendations for bleeding is lower with usual-intensity warfarin than it is with higher-
prevention of recurrence. intensity regimens. A target INR of 2.5 with an INR range from
2.0 to 3.0 is appropriate for patients with other hypercoagulable
states.
Initial Treatment Patients with thrombosis who have a history of metastatic cancer
may do better with extended treatment with LMWH. Randomized
With few exceptions, management of initial thrombotic events in clinical trials have shown that, compared with warfarin, LMWH
patients with hypercoagulable states is no different from the manage- reduces the risk for recurrent venous thromboembolism without
29
ment of these events in patients without underlying hypercoagulable increasing bleeding. Furthermore, LMWH simplifies treatment
disorders. The exceptions are purpura fulminans in newborns with because it can be given subcutaneously once-daily without coagula-
homozygous protein C or protein S deficiency, warfarin-induced skin tion monitoring. The drug can be held before invasive procedures,
necrosis, heparin-induced thrombocytopenia and thrombosis in and the dose may be reduced if thrombocytopenia is present. The
patients with severe antithrombin deficiency. Newborns with purpura major drawbacks of LMWH are cost and its requirement for