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2276 Part XII: Hemostasis and Thrombosis Chapter 133: Venous Thrombosis 2277

Therefore, patients with VTE associated with concurrent cancer should alternative anticoagulant, such as danaparoid, bivalirudin, or argatroban,
be treated with LMW heparin for the first 3 to 6 months of long-term should be initiated. The DOACs have potential to be useful for anticoag-
treatment. 9,57,58 The patients then should receive anticoagulation indef- ulant therapy in patients with heparin-induced thrombocytopenia, but
initely or until the cancer resolves. The regimens of LMW heparin that their use has not been evaluated by clinical trials in this patient group.
are established as effective for long-term treatment are dalteparin 200 Heparin-Induced Osteoporosis Osteoporosis may occur as
U/kg once daily for 1 month, followed by 150 U/kg daily thereafter, or a result of long-term treatment with heparin or LMW heparin (usu-
tinzaparin 175 U/kg once daily. ally after more than 3 months). The earliest clinical manifestation of
heparin-associated osteoporosis usually is nonspecific low back pain
Anticoagulant Therapy During Pregnancy primarily involving the vertebrae or the ribs. Patients also may pres-
LMW heparin or adjusted-dose subcutaneous heparin are the options for ent with spontaneous fractures. Up to one-third of patients treated
anticoagulant therapy of pregnant patients with VTE. 94–96 LMW heparin with long-term heparin may have subclinical reduction in bone den-
is preferred because it has the safety advantages of causing less thrombo- sity. Whether these patients are predisposed to future fractures is not
cytopenia and probably less osteoporosis than unfractionated heparin An known. The incidence of symptomatic osteoporosis in clinical trials of
additional advantage is that LMW heparin is effective when given once LMW heparin treatment for 3 to 6 months was very low and are not
daily, whereas unfractionated heparin requires twice-daily injection. A increased compared to warfarin treatment. Patients with osteoporosis
study indicates no major change in the peak anti–factor Xa levels over or fractures often had other risk factors such as bone metastases.
the course of pregnancy in most patients treated with a once-daily thera- Other Side Effects of Heparin Heparin or LMW heparin
96
peutic LMW heparin regimen (tinzaparin 175 U/kg). Measurement of may cause elevated liver transaminase levels. These elevations are of
the anti–factor Xa level may provide reassurance that major drug accu- unknown clinical significance and usually return to normal after the
mulation is not occurring. However, the appropriate dose adjustments in heparin or LMW heparin is discontinued. Awareness of this biochemi-
response to a decreased anti–factor Xa level are uncertain. The DOACs cal effect is important so as to avoid unnecessary interruption of hepa-
have not been evaluated in pregnant patients. Evidence-based guidelines rin therapy and unnecessary liver biopsies in patients who may develop
for antithrombotic therapy during pregnancy are available. 94 elevated transaminase levels during heparin or LMW heparin therapy.
Additional rare side effects of heparin include hypersensitivity and skin
Side Effects of Anticoagulant Therapy reactions, such as skin necrosis, alopecia, and hyperkalemia occurring
Bleeding Bleeding is the most common side effect of anticoagulant as a result of hypoaldosteronism.
therapy. Bleeding can be classified as major or clinically relevant non-
major according to standardized international criteria. Major bleeding is THROMBOLYTIC THERAPY
defined as clinically overt bleeding resulting in a decline of hemoglobin Thrombolytic therapy is indicated for patients with PE who present
of at least 2 g/dL, transfusion of at least 2 U of packed red cells, or bleed- with hypotension or shock, and for select patients with PE who have
ing that is retroperitoneal or intracranial, or occurs into other critical evidence of right ventricular dysfunction and are at high risk of hemo-
30
spaces. The rates of major bleeding in contemporary clinical trials of ini- dynamic collapse. Thrombolytic therapy provides more rapid lysis of
tial therapy with intravenous heparin, LMW heparin, or fondaparinux pulmonary emboli and more rapid restoration of right ventricular func-
are 1 to 2 percent. 65,66,73–78 Patients at increased risk of major bleeding are tion and pulmonary perfusion than does anticoagulant treatment. 30,98,99
those who have undergone surgery or experienced trauma within the Effective regimens are 100 mg of recombinant tissue plasminogen
previous 14 days; those with a history of gastrointestinal or intracranial activator by intravenous infusion over 2 hours (50 mg/h), or 30 to 50
bleeding, peptic ulcer disease, or genitourinary bleeding; and those with mg (depending on body weight) of tenecteplase given as a single bolus
miscellaneous conditions predisposing to bleeding, such as thrombocy- injection. 98,99 Heparin then is given by continuous infusion once the
topenia, liver disease, and multiple invasive lines. thrombin time or aPTT is less than twice the control value. 98,99 The
Major bleeding occurs in approximately 1 to 2 percent of patients starting infusion dose is 1000 U/h. Chapters 25 and 135 provide further
during the first 3 months of oral anticoagulant treatment using a vita- details of thrombolytic therapy.
min K antagonist and in 1 to 3 percent per year of treatment thereafter. The recently reported PEITHO trial evaluated the effectiveness
97
99
A meta-analysis suggests the clinical impact of major bleeding during and safety of thrombolysis with tenecteplase followed by anticoagulant
long-term oral vitamin K antagonist treatment is greater than widely therapy compared with anticoagulant therapy alone in 1006 patients
97
appreciated. The estimated case fatality rate for this major bleeding with PE and evidence of both right ventricular dysfunction by echocar-
is 13 percent, and the rate of intracranial bleeding was 1.15 per 100 diography or CT scan, and evidence of myocardial injury by the results
patient-years. These risks are important considerations in the decision of troponin I or troponin T measurement. The primary outcome of death
about extended or indefinite anticoagulant therapy in patients with or hemodynamic compensation (or collapse) within 7 days occurred in
VTE. As noted above, clinical trials of the DOACs and meta-analysis 13 of 506 patients (2.6 percent) given thrombolysis, compared with 28
indicate clinically important lower rates of bleeding, including major, of 499 (5.6 percent) receiving anticoagulant therapy alone (p = 0.02).
99
intracranial, and fatal bleeding than the vitamin K antagonists. 73–79 Stroke occurred in 12 patients (2.4 percent) in the thrombolysis group,
Heparin-Induced Thrombocytopenia (See also Chap. 118.) compared with one (0.2 percent) in the anticoagulant alone group
Heparin or LMW heparin may cause thrombocytopenia. In large clini- (p = 0.003). Extracranial bleeding occurred in 32 patients (6.3 percent)
cal studies of acute VTE treatment, thrombocytopenia occurred in less given thrombolysis, and in six patients (1.2 percent) receiving anti-
than 1 percent of more than 2000 patients treated with unfractionated coagulant therapy alone (p <0.001). At day 7, death had occurred in
66
heparin or LMW heparin. Nevertheless, heparin-induced thrombocy- six patients (1.2 percent) given thrombolysis and in nine patients
topenia can be a serious complication when accompanied by extension or (1.8 percent) given anticoagulant therapy alone; the corresponding rates
recurrence of VTE or the development of arterial thrombosis. Such com- at day 30 were 2.4 percent and 3.2 percent, respectively. The findings
99
plications may precede or coincide with the fall in platelet count and are indicate thrombolytic therapy prevented hemodynamic decompensa-
associated with a high rate of limb loss and a high mortality. Heparin in tion, but increased the risk of major bleeding and stroke. The study was
all forms should be discontinued when the diagnosis of heparin-induced not large enough to resolve the key question of whether thrombolysis
thrombocytopenia is made on clinical grounds, and treatment with an will improve survival. At present, the risk of thrombolysis outweighs

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