Page 1245 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

852 PART 7: Hematologic and Oncologic Disorders

discontinuation of all heparin exposures and immediate initiation of platelet aggregation and activation. The accumulation of large von
non-heparin anticoagulation treatment. Thrombocytopenia should Willebrand multimers results from deficiency or inhibition of the von
not be treated with platelet transfusion unless clinically significant Willebrand factor cleaving protease ( ADAMTS13, a disintegrin and metal-
bleeding is also present. Recommended initial treatment should be an loprotease with thrombospondin 1–like domains). The activation of soluble
intravenous direct thrombin inhibitor such as argatroban or bivalirudin. factor coagulation pathways, consumption of fibrinogen, and accumulation
Treatment should be monitored with activated partial thromboplastin of fibrin degradation products are not features of thrombotic microangiopa-
time. Platelet counts should be followed until return to baseline. HIT thies, allowing differentiation from disseminated coagulation.
patients with and without thrombosis remain at significant increased While TTP and HUS have been considered a single spectrum of
risk for new thrombosis for weeks following recovery. For this reason closely related diseases, there is increasing recognition of multiple,
they should receive an oral agent such as warfarin. Warfarin should not unique disease mechanisms that give rise to similar clinical features.
be initiated until the platelet count returns to baseline because of the risk Evidence for different pathophysiologic mechanisms in the thrombotic
of protein C depletion and secondary thrombosis. Initial intravenous microangiopathies includes subsets of patients with inherited deficiency
antithrombin anticoagulant and warfarin should be continued together of ADAMTS13, wide variations in levels and activity of ADAMTS13, as
until the warfarin is fully therapeutic. Patients with no evidence of HIT- well as the identification of thrombomodulin and complement protein
associated thrombosis may be treated for 4 to 6 additional weeks while mutations. 86-88 Even within the subgroup of patients who specifically
those with thrombosis should receive a minimum 3 months therapy. 70-72 have classic TTP features, different mechanisms of disease exist and may
include congenital deficiency of ADAMTS13, acquired autoimmune
Posttransfusion Purpura: Posttransfusion purpura (PTP) may occur 3 to 89,90
12 days following transfusion with any platelet-containing blood prod- inhibition of ADAMTS13, or its autoimmune-mediated destruction.
Thrombotic microangiopathies may be categorized as primary or sec-
uct (platelets, RBCs). PTP is caused by antibody development to human
platelet antigens such as HPA-1a usually in women who have been sen- ondary and have been described as idiopathic and secondary to medica-
tions, infections, and autoimmune disorders.
sitized to platelet antigens through prior pregnancy and in nulliparous
The clinical features of the thrombotic microangiopathies result from
women and men who have been sensitized by prior transfusions. 77,78 PTP vascular occlusion and damage caused by platelet-based microthrombi.
may produce severe thrombocytopenia and bleeding that can last for
days to weeks. The major differential diagnosis of PTP includes drug- Organ damage is often clinically evident in the brain and kidneys, but
ischemic damage may occur in any organ. The degree of thrombocy-
induced thrombocytopenia and immune thrombocytopenic purpura.
Treatment for severe PTP is intravenous immune globulin (IVIG) and topenia in the thrombotic microangiopathies is often very severe, with
platelet counts less than 30 to 50 × 10 /L. In the most severe cases of
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corticosteroids or exchange transfusion in refractory cases. 79,80
TTP, the platelet counts can be less than 10 × 10 /L. Other laboratory
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Immune Thrombocytopenia: Immune thrombocytopenia is also called findings include schistocytes on peripheral blood smear, low serum
idiopathic thrombocytopenic purpura and immune thrombocytope- haptoglobin, elevated serum lactate dehydrogenase, and negative direct
nic purpura. Immune thrombocytopenia (ITP) results from immune- antiglobulin (Coomb) test. The initial degree of anemia is often mild
mediated destruction and inhibition of megakaryocyte production by with hemoglobin concentration 7 to 9 g/dL, but refractory patients may
immunoglobulins directed toward platelet surface glycoproteins. The require red cell transfusion to maintain adequate hematocrit. The initial
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diagnosis of ITP is by exclusion and only when isolated thrombocytope- degree of new renal impairment also tends to be mild with creatinine
nia is present and other etiologies have been excluded, including spurious less than two times normal; however, patients may quickly progress
thrombocytopenia-pseudothrombocytopenia, hematologic malignancy, to renal failure requiring hemodialysis, particularly in classic HUS.
and viral infections including HIV and hepatitis C. In ITP there are no Prothrombin time and activated partial thromboplastin time remain
other detectable abnormalities in coagulation, red blood cells, or white normal or near normal since coagulation factors are not consumed.
blood cells. ITP is considered a primary immune disorder; immune-
mediated destruction of platelets by drug-induced mechanisms, infec- TTP Classic TTP has been characterized by the clinical pentad of hemo-
tions, and thrombocytopenia due to autoimmune rheumatologic diseases lysis, thrombocytopenia, neurologic defects, low-grade fever, and renal
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such as systemic lupus erythematosus must be excluded. Given that a dysfunction. However, the most important findings are hemolysis and
large number of antiplatelet antibodies may result in thrombocytopenia, thrombocytopenia. Only a minority of patients have all findings simulta-
antiplatelet testing has not been recommended for confirmation. 82,83 neously. Common symptoms of TTP include nausea, vomiting, abdomi-
Clinically, ITP usually presents with insidious thrombocytopenia nal pain, headache, seizures, and fluctuating neurologic deficits, all of
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although acute and abrupt episodes can occur. ITP does not usually which develop over days to weeks prior to diagnosis. TTP and throm-
result in life-threatening hemorrhage; however, petechia, purpura, easy botic microangiopathies in adults may be idiopathic, congenital, or
bruising, epistaxis, gingival bleeding, and menorrhagia are common. occur secondarily in systemic infections. TTP-like thrombotic micro-
Treatment for ITP is indicated for any patient at risk for bleeding and for angiopathies have also been well described in postpartum patients,
those with severe thrombocytopenia with platelet counts ≤30 to 50 × patients with recent viral infection including HIV, organ transplant
10 /L. Initial treatment includes glucocorticoids or intravenous immune patients receiving immunosuppression, cancer patients receiving che-
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globulin. Refractory cases have been treated with splenectomy and motherapy, and those with collagen vascular disease. Drug-induced
immunosuppressive drugs including azathioprine, cyclophosphamide, TTP may occur following quinine treatment, chemotherapy agents,
and cyclosporine. Newer therapies with thrombopoietin receptor ago- and with thienopyridine derivatives including ticlopidine, clopidogrel, and
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nists/activators eltrombopag and romiplostim also demonstrate efficacy prasugrel. The likely mechanism of drug-induced TTP is through the
and may promote sustained clinical remission. 84,85 drug-mediated induction of antibodies to ADAMTS13. The differential
diagnosis for TTP includes preeclampsia; eclampsia; and the hemolysis,
Thrombotic Microangiopathies: Thrombotic Thrombocytopenic Purpura and elevated liver enzymes, and low platelet syndrome (HELLP, see below).
Hemolytic Uremic Syndrome: The thrombotic microangiopathies includ-
ing thrombotic thrombocytopenic purpura (TTP), hemolytic uremic HUS HUS has been classically described as the triad of thrombocytope-
syndrome (HUS), and atypical HUS are defined by the simultaneous nia, hemolytic anemia, and renal failure. Classic HUS occurs in children
presence of thrombocytopenia and intravascular hemolysis. Thrombotic following diarrheal illness, but may also affect adults. HUS occurs most
microangiopathies are characterized by platelet activation, microvascular commonly within days following gastroenteritis from enterotoxin-
platelet thrombi, and accumulation of fractured, damaged circulating red producing, enterohemorrhagic bacteria including E coli O157 : H7, E coli
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blood cells (schistocytes). The primary disease mechanism of thrombotic O104 : H4, or Shigella. Other bacterial infections, including those due
microangiopathies results from accumulation of large von Willebrand fac- to nonhemorrhagic gram-negative bacteria, have also been associated
tor multimers which subsequently bind to circulating platelets and cause with thrombotic microangiopathy in adults. Renal failure in TTP-HUS
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