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CHAPTER 90: Bleeding Disorders 853

ranges from mild to severe requiring renal replacement therapy. Long- DISORDERS OF SOLUBLE COAGULATION FACTORS
term consequences in children and young adults who develop diarrhea-
associated HUS include death or irreversible end-stage renal disease in The precise rate of abnormal coagulation times in critically ill patients
approximately 12%, and mild to moderate renal insufficiency in 25% of has been difficult to establish because of absence of standardization not
survivors. 96 only in the laboratory techniques and assay reagents, but also because of
the timing and frequency of testing in general ICU populations. A sin-
Atypical HUS There has been increased recognition of subsets of patients gle, multicenter study in adult ICU patients in England, Scotland, Wales,
who have typical HUS findings but without a preceding diarrheal illness and Ireland examined the incidence of abnormal coagulation times in
or enterohemorrhagic E coli infection. These patients have an HUS-like 1923 admissions, measuring almost six tests per patient and an average
thrombotic microangiopathy which may be refractory to treatment, frequency of one test per day. In this group of mixed medical, surgical,
2
with persistent thrombocytopenia, hemolytic anemia, and renal failure and trauma patients, 25% had an INR >1.5 on at least one measurement.
despite ongoing plasma exchange. Atypical HUS is characterized by Although the majority of patients had a transient INR elevation, this was
chronic refractory thrombocytopenia and renal failure, usually in children independently associated with ICU mortality particularly when it devel-
or young adults, and often requiring dialysis and renal transplantation. oped after admission. While single-center cohort studies suggest that
A known cause of atypical HUS is mutation in complement regulation the rate of abnormal PT and aPTT may be much higher, reviews suggest
pathways leading to unchecked complement activation. Eculizumab that the rate of abnormal coagulation tests ranges from 14% to 28%. 106,107
86
is a humanized monoclonal antibody to human C5 complement which The most common causes of abnormally prolonged coagulation
blocks complement pathway activation and has been shown to benefit times in ICU patients are acquired disorders. The inherited disorders of
renal function and reduce dialysis requirements in atypical HUS cases. 97 coagulation factor deficiency (eg, Hemophilia A and B) are infrequently
Treatment Patients with TTP and thrombotic microangiopathies may encountered and typically present with a well-established history of
develop shock, respiratory failure, or irreversible neurologic deteriora- prior bleeding episodes. Abnormal coagulation function may be consid-
tion. Untreated, the mortality of TTP in adults without diarrheal illness ered within four broad categories including synthesis defects, increased
approaches 100%. With the exception of children who present with rate of turnover-consumption, dilution, and inhibition. In ICU popula-
typical diarrheal illness-related HUS, the treatment of severe thrombotic tions, the most common associations and causes include chronic liver
microangiopathies requires emergent initiation of plasma exchange. The disease, warfarin therapy, vitamin K deficiency, heparin, sepsis, dis-
basis of treatment is removal of the circulating factor which inhibits seminated intravascular coagulation, dilution in massive transfusion,
ADAMTS13, and replacement of insufficient ADAMTS13 levels. Since antibody inhibitors including lupus anticoagulant, and von Willebrand
the widespread use of plasma exchange, the mortality rate for TTP disease (Table 90-8).
has fallen to 10% to 35%. 98,99 If diagnostic uncertainty exists, plasma
exchange should be initiated until an alternative diagnosis is established. ■ ANTIBODY INHIBITORS OF COAGULATION ENZYMES
Plasma infusion alone is less effective and is limited by the volume of The laboratory features of antibody inhibitors of coagulation include
plasma required to produce clinical effect. 98-100 In addition to plasma prolonged aPTT which does not correct on mixing assays. A mixing
exchange, rituximab has been shown to improve time to therapeutic
response and reduce relapses in patients with acute TTP and should also
be considered for patients with severe disease. 101
Treatment with daily plasma exchange is indicated until platelet count TABLE 90-8 Common Causes of Abnormal Prothrombin and Activated Partial
rise above 150 × 10 /L and anemia, renal failure, and neurologic deficits Thromboplastin Times in ICU Patients
9
improve. Other indicators of therapeutic response include decreases in
serum LDH and resolution of the abnormal peripheral blood smear. PT elevated; aPTT normal
Typically, patients will require 1 to 2 weeks of plasma exchange treat- Factor VII deficiency
ments tapered from daily treatments to every other day to every third day. Mild vitamin K deficiency
Refractory cases, late-responding patients, and relapsed patients may require
treatment for 4 to 6 weeks. Patients who fail to respond to plasma exchange Hepatic disease
should be considered for high-dose steroid therapy or splenectomy. Warfarin effect

Functional Platelet Disorders: Functional platelet disorders occur in the PT normal; aPTT elevated
setting of normal platelet number and appearance but impaired activa- Factor VIII, IX, XI, or XII deficiency
tion, aggregation, or binding. Clinically, functional platelet disorders are Unfractionated heparin
associated with petechiae, ecchymoses, menorrhagia, mucosal bleeding,
and epistaxis. The most common functional platelet disorders result von Willebrand disease
from antiplatelet medications including aspirin, nonsteroidal anti-inflam- Antibody inhibitor of coagulation proteins
matory medications, cyclooxygenase inhibitors, clopidogrel, and the Antiphospholipid antibody
glycoprotein IIb/IIIa inhibitors (abciximab, tirofiban, eptifibatide). Renal PT elevated; aPTT elevated
failure is associated with impaired platelet function and bleeding dur-
ing invasive procedures, as well as mucosal bleeding and bruising. Deficiency of fibrinogen, thrombin, factor V, factor X
102
The bleeding tendency in renal failure patients appears to result from Advanced liver disease, liver failure
decreased platelet aggregation and platelet adhesiveness, likely mediated Severe vitamin K deficiency
by dysfunction of the glycoprotein IIb/IIIa receptor and von Willebrand
factor. Congenital diseases affecting the glycoprotein Ib receptor (Bernard- Full heparin and warfarin effect
103
Soulier syndrome) and IIb/IIIa receptor (Glanzmann thrombasthenia) are Factor Xa inhibition
rare causes of dysfunctional platelets. Finally, von Willebrand disease is Rivaroxaban, apixaban
actually a group of common genetic diseases which affect the level and func-
tion of von Willebrand factor and binding to the Ib receptor. Treatment for Disseminated intravascular coagulation
functional platelet disorders includes platelet transfusion and removal of the Massive hemorrhage
offending agent. For patients with uremia and bleeding, hemodialysis and Reproduced with permission from Lo GK, Juhl D, Warkentin TE, et al. Evaluation of pretest clinical score
an infusion of deamino-8-D-arginine vasopressin (DDAVP) may reduce (4 T’s) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost.
bleeding and be helpful in achieving hemostasis. 104,105 April 2006;4(4):759-765.

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