Complications
The frequency, size, and symptoms of PE are variable. In patients with known DVT, silent PE is detected in about 30% to 40% of patients.[250][251]
PE is treated in the same fashion as DVT unless there is cardiopulmonary compromise with hypotension or evidence of right heart strain with significant pulmonary hypertension. In these cases, pulmonary embolectomy or use of catheter-directed or systemic thrombolytic therapy should be considered. The exact criteria for when to use thrombolysis have not been determined, but certain high-risk groups (e.g., patients with hemodynamic compromise) seem to derive greater benefit.[252] Selected patients with PE are candidates for inferior vena cava filter.
Most episodes of bleeding during anticoagulation result from a previously unknown pathologic lesion, such as duodenal ulcer, angiodysplasia in the colon, microvascular disease (e.g., a striatal intracerebral bleed in a patient with hypertension), or rare conditions, such as amyloid angiopathy in the central nervous system.[255]
If the patient is taking warfarin and experiences major bleeding, inactivated 4-factor prothrombin complex concentrate (PCC) should be given promptly if clinically indicated. Oral or intravenous vitamin K can also be given, either alone or in conjunction with PCC, but the effect of vitamin K on warfarin is delayed and typically sustained for days. Intravenous administration is preferred in the setting of intracranial hemorrhage.[256] The effect of the PCC can be assessed immediately by measuring the international normalized ratio.[257] Fresh frozen plasma (FFP) has also been described as a means of reversing the effect of warfarin, but carries greater risk, is much slower to administer, and confers a much larger volume load than PCC. Guidelines favor PCC over FFP.[190]
Specific reversal agents are available for direct oral anticoagulants. Dabigatran can be reversed with idarucizumab.[171] Recombinant coagulation factor Xa (andexanet alfa) has been approved for patients with major or life-threatening bleeding on rivaroxaban and apixaban. Of note, andexanet alfa is not approved for the reversal of edoxaban in the US and Europe, likely due to low study enrollment of these patients.[258] However, it is approved in Japan.
Protamine should be used to reverse unfractionated heparin and may be used to reverse low molecular weight heparin, although it is not as effective.[259]
Nonspecific reversal strategies have been tested for newer anticoagulants as well, but the level of evidence for these is low. PCC has also been shown to normalize coagulation studies in normal volunteers given high-dose rivaroxaban or apixaban. It is not known if this is the case with edoxaban. Dabigatran does not appear to be reversed by PCC, though anti-inhibitor coagulant complex (also known as factor eight inhibitor bypass activity) may affect dabigatran, and about 60% of dabigatran can be removed by dialysis. Activated charcoal may inhibit absorption of recently taken oral anticoagulants.
Inferior vena cava filter may be indicated in selected patients with acute bleeding during anticoagulation.
Antibodies may develop to heparin-platelet factor IV complexes starting 5-7 days after initial exposure to heparin or as early as <1 day in patients with recent (<30 days prior) heparin exposure.[247][248] The antibodies aggregate platelets, lead to thrombocytopenia, and might result in acute arterial and venous thrombosis as well as bleeding.
If there is a history of recent heparin exposure, development of HIT can be immediate. It develops in between 1% and 2% of patients treated with therapeutic doses of heparin; however, it is rare when heparin is given subcutaneously to patients as a form of prophylaxis, but is possible and should be evaluated in patients receiving prophylactic heparin with an elevated Warkentin Probability Scale ("4T score").
The incidence of HIT is lower in patients treated with low molecular weight heparin (LMWH). Although there have been several reported cases of fondaparinux-associated HIT, it is a rare occurrence.
Due to the risk of HIT, platelet count should be measured at baseline, then on days 3 and 5, to observe for the development of HIT.
Suspected HIT should be managed by promptly discontinuing heparin or LMWH, and substituting a direct thrombin inhibitor such as argatroban, bivalirudin, or fondaparinux, or selecting apixaban, rivaroxaban, or dabigatran. Anticoagulation may be transitioned to warfarin, if a parenteral anticoagulant is initially chosen, when the platelet count returns to baseline.
When anticoagulation is clinically indicated in the presence of definite or moderate/high-probability HIT, a direct thrombin inhibitor (e.g., argatroban) is the generally recommended anticoagulant. Fondaparinux, bivalirudin, apixaban, rivaroxaban, and dabigatran have been suggested, but they do not have regulatory approval for active HIT.[166][167]
The Warkentin Probability Scale (“4T score”) for HIT can be used to estimate the pretest probability of HIT.[249]
[ Pretest Probability of Heparin Induced Thrombocytopenia (4-T's score) Opens in new window ]
Patients might require very large doses of intravenous heparin and never achieve a therapeutic activated partial thromboplastin time (aPTT).[260] This might be caused by very high levels of clotting factors, such as fibrinogen.
In patients who require extremely large daily doses of unfractionated heparin (i.e., >2500 units/hour) without achieving a therapeutic aPTT, it is recommended that the calibrated anti-Xa activity be measured and used to guide heparin dosing.
In certain patients, such as those with antiphospholipid syndrome, the aPTT value may create a result in the target range with only very low doses of heparin (or even no heparin). Calibrated anti-Xa activity should be used to manage heparin in such cases if heparin is the drug chosen.
Due to the risk of HIT, platelet count should be measured at baseline, then on days 3 and 5, to observe for the development of HIT in patients receiving IV unfractionated heparin.
Caused by chronic obstruction of venous outflow and/or destruction of venous valves, resulting in venous hypertension from venous insufficiency and/or venous outflow obstruction.[253]
Up to half of patients develop some signs or symptoms of post-thrombotic syndrome and this usually occurs within 2 years of the acute DVT episode.[254]
The incidence is greatest in the first 3 months of treatment when on warfarin. Most bleeds are minor. Fatality is relatively rare, and the rate is greatest for intracranial bleeds. Age over 75 years is associated with an increase in the incidence of intracranial bleeding. Patients with renal impairment have a higher rate of major bleeding. In general, bleeding is less with direct oral anticoagulants (e.g., apixaban, edoxaban, dabigatran) when compared with warfarin for the management of venous thromboembolism.
While the risk of osteoporotic fracture is as high as 2% if unfractionated heparin is given throughout pregnancy, there are only a handful of cases published where osteoporotic fracture occurred in those on low molecular weight heparin.[261]
There is conflicting evidence as to whether this develops in patients during chronic warfarin therapy.
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