Complications
The frequency, size, and symptoms of PE are variable. Among patients with proven thrombosis, lung scans at the start of antithrombotic treatment showed a high probability of PE in 51% of patients.[147]
PE is treated in the same fashion as DVT, unless there are signs of haemodynamic instability (e.g., cardiac arrest, obstructive shock, persistent hypotension); these patients should be treated with primary reperfusion. Selected patients with PE are candidates for inferior vena cava filter.
Most episodes of bleeding during anticoagulation result from a previously unknown pathological lesion, such as duodenal ulcer, angiodysplasia in the colon, microvascular disease (such as a striatal intracerebral bleed in a patient with hypertension), or rare conditions, such as amyloid angiopathy in the central nervous system.[150]
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 phytomenadione (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 haemorrhage.[151] The effect of the PCC can be assessed immediately by measuring the international normalised ratio.[152] 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 favour PCC over FFP.[153]
Specific reversal agents are available for direct oral anticoagulants. Dabigatran can be reversed with idarucizumab.[111] Recombinant coagulation factor Xa (andexanet alfa) has been approved in the UK for patients with major or life-threatening bleeding on rivaroxaban and apixaban, although it is only approved for gastrointestinal bleeding in England. Of note, andexanet alfa is not approved for the reversal of edoxaban in the UK, likely due to low study enrollment of these patients.[154]
Protamine should be used to reverse unfractionated heparin and may be used to reverse low molecular weight heparin, although it is not as effective.[155]
Non-specific 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 normalise 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 factor VIII inhibitor bypassing fraction (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 to 7 days after initial exposure to heparin or as early as <1 day in patients with recent (<30 days prior) heparin exposure.[146] 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% to 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 or confirmed HIT should be managed by promptly discontinuing heparin or LMWH, and substituting a direct thrombin inhibitor such as argatroban or danaparoid.[26] Bivalirudin, desirudin, and fondaparinux have also been suggested as suitable options, but are not licensed for active HIT in the UK.[26]
IHI: anticoagulant toolkit – reducing adverse drug events
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Anticoagulation may be transitioned to warfarin, if a parenteral anticoagulant is initially chosen, when the platelet count returns to baseline.
The Warkentin Probability Scale ('4T score') for HIT can be used to estimate the pretest probability of HIT.[99]
Patients might require very large doses of intravenous heparin and never achieve a therapeutic activated partial thromboplastin time (aPTT).[156] 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.
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.[148]
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.[149]
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.[157]
There is conflicting evidence as to whether this develops in patients during chronic warfarin therapy.
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