Thrombocytopenia

Acquired Platelet Dysfunction

Thrombocytosis

Although not as common as thrombocytopenia, reactive thrombocytosis (splenectomy, surgery, or bleeding) may be seen in the ICU. Reactive thrombocytosis does not have an increased risk of thrombosis. Antiplatelet therapy is not needed even for platelet counts higher than 1,000,000/µL.

Heparin-Induced Thrombocytopenia

Although commonly looked for, HIT is an uncommon cause of thrombocytopenia in the ICU.2,16 HIT is a paradoxical condition in which modest thrombocytopenia may be associated with devastating heparin-induced thrombocytopenia thrombosis (HITT). Thus, the entire health care team needs to be vigilant for the development of HIT in any patient receiving heparin. HIT has been associated with all types of heparin (unfractionated [UFH] and low-molecular-weight [LMWH]), at any dose, and by any route, including flushes and heparin-coated catheters.^1,17 The incidence of HIT has been estimated to be less than 1% of patients in the ICU.^2,16,18 HIT occurs in three time intervals. Classic HIT occurs 5 to 15 days after the initiation of heparin. Rapid-onset HIT develops hours to 1 to 2 days after heparin is started in individuals who have preformed circulating antibodies from a previous exposure to heparin, usually in the last 2 months. Classic and rapid-onset HIT may be manifested as thrombocytopenia with or without thrombosis [HIT(T)]. Delayed-onset HIT occurs an average of 12 days after the discontinuation of heparin and is manifested as isolated thrombosis. The thrombocytopenia of HIT is usually modest with an average platelet count of 50,000 to 60,000/µL.¹⁹ Severe thrombocytopenia (<10,000/µL) should suggest an alternative diagnosis. HIT may be associated with a normal platelet count if there is a baseline thrombocytosis (e.g., postoperatively). HIT may be manifested as isolated thrombocytopenia or thrombocytopenia with potentially devastating thrombosis. Venous complications include deep venous thrombosis (DVT), pulmonary embolism (PE), cerebral sinus thrombosis, infarctive adrenal hemorrhage, and skin necrosis at the heparin injection site. Arterial complications include iliofemoral artery thrombosis, digital ischemia, myocardial infarction, stroke, and mesenteric artery thrombosis.

HIT is an immune-mediated process in which the heparin–platelet factor 4 complex becomes immunogenic. Antibodies are formed that activate platelets, causing the release of thrombogenic microparticles.16,19 The antibodies can also activate monocytes and endothelial cells.

The diagnosis of HIT is clinicopathologic. HIT should be thought of in appropriate clinical situations (Box 78.3). The “4T” score has been used to predict the likelihood (pretest probability) of HIT (Table 78.1).^16,20 The HEP score, devised by an expert consensus panel, has recently been validated.²¹ Although the decision to initiate therapy should be based on the clinical likelihood of HIT, laboratory testing should be used for the retrospective confirmation of the pretest likelihood of HIT. The complexities of HIT antibody testing are reviewed elsewhere.^16,22 In general, a strongly positive HIT enzyme-linked immunosorbent assay (ELISA) and strongly positive serotonin release assay (SRA) with a high pretest probability confirm the diagnosis of HIT, whereas a negative ELISA and SRA make the diagnosis of HIT unlikely with a low pretest probability. In other situations, clinical judgment prevails in establishing or excluding a diagnosis of HIT, especially because ELISA and SRA testing from commercial labs has not been validated in clinical studies.^1,16,22

Once the diagnosis of HIT is thought to be likely, all heparin should be discontinued. Heparin-coated pulmonary artery catheters should be replaced with noncoated catheters. Catheters for dialysis or apheresis should be locked with 4% citrate or tissue plasminogen activator. The patient’s chart and bedside should be labeled heparin allergy. Platelet transfusions should be avoided except for life-threatening bleeding, given the anecdotal observations of acute thrombosis occurring after platelet transfusion. A patient with life- or limb-threatening arterial thrombosis should be evaluated for surgical intervention. Anticoagulation with a DTI (Table 78.2) should be initiated in all patients unless contraindicated. LMWH is contraindicated in HIT caused by UFH. Conversion to warfarin can be considered after a minimum of 5 days of DTI therapy if the platelet count has returned to normal (suggesting that the process has cooled off and the patient is no longer hyperprothrombotic) and no future invasive procedures are planned. Simply discontinuing heparin therapy and not starting a DTI is inappropriate because occult thrombosis may have already developed.²³ Starting or continuing warfarin monotherapy is also contraindicated because of the risk of venous limb gangrene.²⁴ If warfarin has been given at the time HIT is diagnosed, vitamin K should be given to replenish proteins C and S. If invasive procedures are needed (e.g., tracheostomy, pacemaker), it is best to delay them, if medically safe, until the platelet count is normal to minimize the risk of developing thrombosis during the time that DTI therapy is withheld. Inferior vena cava (IVC) filters should be avoided because of the risk of vena cava thrombosis. Patients with active HIT may need percutaneous coronary intervention (PCI). Argatroban has been approved by the Food and Drug Administration (FDA) for use during PCI in patients with HIT.²⁵ Though not FDA approved, bivalirudin has been used safely in this situation.²⁶ In a patient who has active HIT or persistent HIT antibodies and who needs open heart surgery, medical management is recommended until the antibody becomes negative. If urgent surgery is needed, bivalirudin is most commonly used.²⁷ For the patient with a past history of HIT who needs open heart surgery and is currently HIT antibody negative, heparin can be used during bypass and a DTI started as soon as it is surgically safe postoperatively.²⁸

Thrombotic Thrombocytopenic Purpura

Thrombotic thrombocytopenic purpura (TTP) is a relatively rare disorder whose hallmarks are thrombocytopenia, microangiopathic hemolytic anemia (MAHA), and neurologic dysfunction. The diagnosis of TTP should be considered in any patient with unexplained thrombocytopenia and MAHA.²⁹ TTP is the clinical manifestation of a heterogeneous group of underlying disorders driven by different pathophysiologic processes. Although most cases of TTP are idiopathic, TTP may be associated with exposure to drugs (e.g., ticlopidine, clopidogrel, quinine, mitomycin C, gemcitabine, cyclosporine), pregnancy, HIV infection, and bone marrow transplantation.³⁰ The morphologic hallmark of TTP is hyaline thrombi in precapillary arterioles composed primarily of platelets. Classic TTP is due to an immune-mediated deficiency of the metalloproteinase ADAMTS13, which cleaves ultralarge multimers of von Willebrand factor (vWF) into smaller forms that are less platelet reactive.³¹ Deficiency of this enzyme allows ultralarge forms of vWF that are normally sequestered in the endothelium to bind platelets and form microthrombi in the circulation. Conversely, ADAMTS13 activity is normal in TTP associated with bone marrow transplantation and the hemolytic-uremic syndrome.^30,31 Organ dysfunction is due to microvascular thrombosis. Commonly involved organs are the brain, kidneys, heart, and pancreas. It is critical to establish the diagnosis quickly because TTP can be rapidly fatal if not properly treated.

The core laboratory features of TTP are those of MAHA (more than two schistocytes per oil immersion field on a peripheral smear, increased lactate dehydrogenase, and very low haptoglobin). The differential diagnosis includes disseminated intravascular coagulation (DIC), severe vasculitis, eclampsia, HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome, malignant hypertension, sepsis, and malignancy.

Once the diagnosis of TTP is thought to be likely, therapy should be initiated quickly because of the proclivity of the disease to progress rapidly. All patients should initially be treated in the ICU. Platelet transfusions should be avoided except for life-threatening bleeding because of anecdotal reports of acute decompensation after platelet transfusions. A large-bore catheter will need to be placed, even in the face of severe thrombocytopenia, because the mainstay and only evidence-based component of therapy for TTP is plasma exchange.32,32a Most commonly, 1.5 plasma volumes are exchanged daily with FFP. A clue that TTP is the correct diagnosis is the color of the plasma removed from the first plasmapheresis. A red or brown color suggests free hemoglobin from intravascular hemolysis. If plasma exchange cannot be initiated in a timely manner, infusion of 30 mL/kg of FFP daily can be a temporizing maneuver.³² Corticosteroids (e.g., prednisone, 1 mg/kg/day) are commonly used as well.^32a The use of antiplatelet agents, which may increase the risk of bleeding, and vincristine is controversial.³³ In patients who do not respond to initial therapy, rituximab is an attractive second-line therapy.^30,34

Hemolytic-Uremic Syndrome

Hemolytic-uremic syndrome (HUS), the triad of thrombocytopenia, MAHA, and acute kidney injury, is most commonly due to infection with Shiga toxin–producing Escherichia coli in children.³⁵ Adult atypical HUS (aHUS) is not Shiga toxin associated. It may be idiopathic or associated with calcineurin inhibitors (cyclosporin, tacrolimus), pregnancy, and HIV. aHUS is associated with low C3 and is a complement deposition disease. Mutations in complement factor H (CFH) are found in a minority of cases. Although not as efficacious as when used for TTP, plasma exchange is used for aHUS. The anti-C5 antibody eculizumab (Soliris) has been FDA approved for the treatment of aHUS.³⁶ Plasma exchange should be initiated while waiting to obtain eculizumab. Supplemental eculizumab dosing is required after each plasma exchange.³⁷ Patients need to receive quadravalent meningococcal vaccine before starting eculizumab.