Page 1247 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

854 PART 7: Hematologic and Oncologic Disorders

assay is performed by adding standardized, normal plasma to the sample. with VWS include aortic stenosis, ventricular septal defect, hypertrophic
The presence of an antibody inhibitor of coagulation will also inhibit the obstructive cardiomyopathy, and extracorporeal blood circulation. 121-123
function of the added factors. This feature distinguishes inhibitors from The specific association of aortic stenosis, acquired von Willebrand
simple factor deficiencies which may also produce prolonged aPTT, but syndrome, and bleeding secondary to gastrointestinal angiodysplasia
instead correct with mixing of normal plasma. The presence of antibody has been termed Heyde syndrome. Heyde syndrome is associated with
inhibitors and factor deficiency must be distinguished from heparin decreased VWF collagen binding activity and loss of large VWF multim-
contamination which also prolongs the aPTT. When an abnormal aPTT ers in 67% to 92% of patients with severe aortic stenosis and correlates
is obtained, every effort to exclude heparin contamination should be with the severity of the stenosis. Treatment considerations in acquired
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made and, if necessary, the test repeated if the results are uncertain. VWS should focus on correction of the underlying disorder including
Antiphospholipid antibodies are identified by the addition of phospho- chemotherapy for malignancies, vascular correction, and valve replace-
lipid to the mixed plasma. If antiphospholipid antibodies are present, ment. Acute bleeding should be managed similarly to congenital VWD
the aPTT will correct. with DDAVP and factor VII concentrates.
The presence of antibody inhibitors may lead to significant bleeding ■
or, in the case of antiphospholipid antibody, a hypercoagulable state and PHARMACOLOGIC ANTICOAGULANTS
clinical thrombosis. Bleeding manifestations may be severe and include Given the high frequency of therapeutic and prophylactic anticoagulant
postpartum, severe mucosal, or postprocedure bleeding. The most com- use in patients with risk factors for ICU admission, management of bleed-
mon acquired antibody inhibitors are against factor VIII and can occur ing and coagulopathy in these patients is a common clinical problem. In
spontaneously in a large variety of disorders or through induced antibody general, therapy of anticoagulant-related bleeding should focus on risk
formation in hemophilia patients chronically receiving factor replace- factors for bleeding, the presence of continued active bleeding, the half-life
ment. While acquired hemophilia A and factor VIII inhibitors may be of the anticoagulant, and whether or not specific antidotes are available.
idiopathic, specific disease associations and potential causes for acquired The risk of bleeding correlates with dose of agent (particularly heparins),
factor VIII inhibitors include malignancies, postpartum status, and concurrent antiplatelet therapy, severity of concurrent major organ
autoimmune disorders including lupus and rheumatoid arthritis. 108-110 dysfunction, age, and recent surgery, trauma, or invasive procedures. 125,126
Treatment recommendations for patients with bleeding associated
with antibodies to factor VIII include factor VIII concentrates, recom- Heparins and Heparin-Like Compounds: Unfractionated heparin and, to
binant human factor VIIa, desmopressin (DDAVP), and activated a significantly lesser degree, low-molecular-weight heparins have vari-
prothrombin complex concentrates. 111,112 Long-term management of able and difficult-to-predict dose-response rates. Predictors of bleeding
antibody inhibitors should include consideration for immunosuppres- include concurrent use of antiplatelet medications, increased heparin
sion including corticosteroids and cyclophosphamide to suppress anti- dose, advanced hepatic disease, concurrent administration of throm-
body production. 113 bolytic medications, invasive procedures, female gender, and presence
■ VON WILLEBRAND DISEASE AND HEYDE SYNDROME bleeding in the setting of heparin anticoagulation, the initial approach
of anemia on admission.
For patients with clinically significant
125,127
Deficiency of von Willebrand factor (VWF) is the most common inher- must include immediate discontinuation of the medication and local,
physical control of the bleeding source if possible. Unfractionated hepa-
ited coagulopathy. In less common instances, VWF deficiency may be rin may be reversed by treatment with protamine sulfate. Protamine is a
acquired. VWF circulates as high-molecular-weight multimers which naturally occurring protein derived from fish which binds heparin and
bind to platelet glycoprotein receptors IIb/IIIa and Ib/IX/V. VWF defi- is rapidly cleared from the circulation. Protamine is given as an intrave-
ciency directly limits effective binding of platelets to injured vascular nous infusion at a dose of 1 mg per every 100 units of heparin adminis-
endothelium and to other platelets. Von Willebrand disease (VWD) has tered and its effect is monitored with the aPTT. Because of the protein
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multiple subtypes including autosomal dominant and autosomal reces- structure of protamine, it is antigenic and may cause allergic reac-
sive variants as well as quantitative and qualitative defects of VWF. tions, anaphylaxis, hypotension, and bradycardia. While other agents
114
The most common clinical presentation of VWD includes easy bruising, including recombinant activated factor VII and heparinases have been
or skin, oropharyngeal, nasal, gastrointestinal, or menstrual bleeding. tested, routine use of these agents for reversal of heparin anticoagulation
Patients with VWD have normal platelet counts (with some exceptions is not approved or recommended by regulatory agencies.
for patients with rare variants) and normal PT. The aPTT in VWD may While protamine is effective in binding and clearing heparin bound
be normal or prolonged and depends on the association of concurrent in thrombin-antithrombin enzyme complexes, it has variable effective-
factor VIII levels. The diagnosis of VWD is established by specialized ness in reversing the specific anti-Xa activity of low-molecular-weight
testing including direct measurement of VWF, factor VIII activity, ris- heparins. There is little information from human studies to convincingly
tocetin cofactor activity, and VWF collagen binding. Initial treatment demonstrate the effectiveness of protamine in management of LMWH
for patients with clinically significant bleeding and VWD includes anticoagulation. Despite this, consensus guidelines from the American
DDAVP, which releases VWF from vascular endothelial cells. For College of Chest Physicians for life-threatening bleeding associated
115
refractory bleeding and for patients with severe VWF deficiency, factor with LMWH anticoagulation are for protamine infusion to attenuate
VIII concentrates (which also contain VWF) or recombinant human the heparin effect. Case reports also describe combined use of prot-
125
VWF should be administered. 116,117 Other options for refractory bleed- amine and recombinant activated factor VII in an LMWH overdose
ing include the antifibrinolytic agents, epsilon aminocaproic acid and patient. 128,129 Although the synthetic heparin analogue fondaparinux and
tranexamic acid, as well as human recombinant factor VIIa. 118 the heparin-containing glycosaminoglycan mixture danaparoid sodium
Acquired von Willebrand disease, also termed von Willebrand syndrome share anticoagulant mechanisms with heparin, they are not reversed by
(VWS), results from increased proteolysis, antibody-mediated clearance, protamine.
or antibody-mediated functional inhibition of VWF. Conditions associated
with acquired VWS include malignant diseases such as lymphoprolif- Vitamin K Antagonists: Vitamin K antagonists, specifically warfarin,
erative and myeloproliferative disorders, autoimmune diseases includ- are the most commonly used anticoagulants for treatment of venous
ing systemic lupus erythematosus, hemoglobinopathies, and drugs. 119,120 thrombosis and prevention of thrombotic complications in patients at
A specific subset of patients with acquired VWS has cardiovascular risk. Supratherapeutic effect and bleeding related to warfarin are among
disease with shear stress within the bloodstream. The mechanism of the most common coagulation problems in hospitalized patients. Risk
VWF deficiency in these conditions is believed to be increased clear- factors for an INR greater than target range include febrile illness, diar-
ance of VWF induced by flow-related binding of VWF to platelets in the rhea, heart failure, and liver disease. The bleeding risk in patients
130
absence of coagulation activation. Cardiovascular conditions associated receiving warfarin treatment correlates directly with elevation in the

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