In the patient with thrombocytopenia, examination of the blood smear can quickly reveal whether pseudothrombocytopenia (artifactual platelet clumping) [9] is present and verify the degree of thrombocytopenia (Table 109.2). Although exceptions do exist, the magnitude of thrombocytopenia can be an aid in the differential diagnosis of low platelet counts (Table 109.3). Heparin-induced thrombocytopenia and thrombotic microangiopathy (including thrombotic thrombocytopenic purpura, TTP) often present with modest thrombocytopenia (50 to 100 × 10⁹ per L). The smear should be carefully reviewed for presence of fragmented red cells (schistocytes). Laboratory assessment of liver function and renal function also should be assessed. A markedly elevated level of lactate dehydrogenase level (LDH) out of proportion to other liver function abnormalities characteristically occurs in TTP and hantavirus infection [10,11]. If there is any suspicion of HIT, all heparin should be stopped and alternative antithrombotic agents should be started [12,13]. Assessment of platelet function can be difficult and must be based largely on clinical judgment. The bleeding time or the platelet function assay (PFA) is rarely useful in the evaluation of a thrombocytopenic patient, because the low platelet count leads to prolongations in the test endpoint [14].

The reason for the ICU admission is a very important indicator in evaluation of thrombocytopenia (Table 109.4) [15]. For example, thrombocytopenia in patients who present with sudden-onset multiorgan system failure may indicate TTP or sepsis. In long-term critical care patients, new-onset thrombocytopenia may be a manifestation of HIT, drug-induced thrombocytopenia, occult or established sepsis, or bacteremia [16].

HIT occurs due to the formation of antibodies directed against the complex of heparin and platelet factor 4 [12,20]. This complex in a minority of cases binds to the Fcγ RIIA receptor, activating platelets and macrophages. The frequency of HIT is 1% to 5% when unfractionated heparin is used but less than 1% with low-molecular-weight heparin [21]. HIT is more common in women and more common in surgery patients than medical patients [22].

HIT should be suspected when there is a sudden onset of thrombocytopenia with either at least a 50% drop in the platelet count from baseline or the platelet count falling to less than 100 × 10⁹/L in a patient receiving heparin in any form. HIT usually occurs at least 4 days after starting heparin but may occur suddenly in patients with recent (less than 3 months) exposure [23]. An often overlooked feature of HIT is recurrent thrombosis in a patient receiving heparin despite a normal platelet count [24]. Recently, a scoring system—the four Ts—has been validated in several critical care studies as a means of assessing the pretest probability of HIT [25,26] (Table 109.5).

Patients with very low scores are very unlikely to have HIT and can forgo PF4-heparin antibody testing and empiric therapy. A biphasic pattern of thrombocytopenia following cardiac surgery—namely, recovery from the postsurgical thrombocytopenia followed by recurrent thrombocytopenia—is strongly predictive for HIT [27].

The diagnosis of HIT can be challenging in the critical care patient who has multiple reasons for being thrombocytopenic.
In this situation, the laboratory assay for HIT may be helpful. Two levels of HIT testing exist. Increasingly, an ELISA assay that detects the presumed pathogenic antiheparin-platelet factor 4 antibodies is evaluated initially [13]. This test is very sensitive but in some populations not specific. For example, 25% to 50% of cardiac surgery patients will show positive results (presumably due to platelet activation in the bypass circuit) [28,29]. A negative test rules out HIT in all but the highest-risk patients.

A second type of test, a (functional) platelet aggregation assay, such as the serotonin release assay, comprises patient plasma, donor platelets, and heparin. If added heparin induces platelet aggregation, the test is considered to be positive. The test is technically demanding, but if performed carefully can be sensitive and specific [12,13,30]. One caveat is that early in the HIT disease process, the test can be negative but then turns positive 24 hours later as the antibody titer increases. Due to substantial frequency of false positivity of PF4-heparin ELISA among cardiovascular, dialysis, and vascular surgery patients, a diagnosis of HIT should be confirmed by a serotonin release assay, even if treatment for HIT already has been initiated.

The first step in therapy of HIT consists of stopping all heparin. Low-molecular-weight heparins cross-react with the HIT antibodies and therefore these agents are also contraindicated. Institution of warfarin therapy alone following a diagnosis of HIT has been associated with an increased risk of thromboses and is also contraindicated. Due to the high risk of thrombosis (53% in one study) [21] among HIT patients, antithrombotic therapy should be administered to all patients [12]. For immediate therapy of HIT patients, several antithrombotic agents are available [12,20,31] (Table 109.6).

Argatroban is a synthetic thrombin inhibitor with a short half-life of 40 to 50 minutes [12,32]. Dosing is 2 μg per kg per minute with the infusion adjusted to keep the aPTT 1.5 to 3 times normal. One advantage of argatroban is that it is not renally excreted and no dose adjustment is necessary in renal disease [33]. These characteristics make it the most useful agent for patients in the critical care unit. However, argatroban
must be used with caution in patients with severe liver disease by using an initial dose of 0.5 μg per kg per minute [32]. Also metabolism appears to be decreased in patients with multiorgan system failure and these patients should receive a dose of 1 μg per kg [34]. Argatroban (like all thrombin inhibitors) prolongs the prothrombin time/INR (PT/INR) making initiation of warfarin therapy difficult. If available, the chromogenic Xa assay can be used to adjust warfarin therapy [35]. Also, if the patient is on a drip of 2 μg per kg per minute or less, one can simply aim for a PT/INR of more than 4.0 as therapeutic. Unfortunately, there is no agent that can reverse argatroban.

Lepirudin, another direct inhibitor of thrombin, is also monitored using the aPTT. The half-life of lepirudin is short, but the drug accumulates in renal insufficiency with the half-life increasing to more than 50 to 100 hours. Recent data indicate that a lower dosing regimen that is recommended on the package insert may result in lower bleeding rates [12]. There is no antidote for lepirudin. Patients with even slight renal insufficiency (creatinine greater than 1.5) must have their lepirudin doses adjusted to avoid overanticoagulation [36]. Up to 80% of patients receiving long-term lepirudin therapy will develop antibodies that reduce the metabolism of hirudin and increase the therapeutic effect of lepirudin [37,38]. Patients on long-term (> 6 days) lepirudin therapy should still continue to have monitoring to avoid overanticoagulation.

Bivalirudin is a semisynthetic direct thrombin inhibitor. Its indication involves patients undergoing percutaneous coronary intervention, but other patients may receive it as a treatment for HIT.

The indirect anti-Xa inhibitor fondaparinux does not cross-react with HIT antibodies [12,39], suggesting a potential role in therapy of HIT [40]. However, it has not been studied as extensively in HIT as have the DTIs. Additionally, exposure to fondaparinux has been rarely associated with a syndrome similar to delayed-onset HIT [41]. In the future, newer agents such as dabigatran and rivaroxaban may be suitable for management of patients with HIT.

The issue of platelet transfusion remains controversial [42]. Patients with HIT rarely bleed, which reduces clinical concern over the potential for platelet transfusions, but a prudent
approach would be to reserve transfusion of platelets for the rare patient with severe thrombocytopenia who also has life-threatening bleeding.

As mentioned earlier, initiation of warfarin as the sole antithrombotic agent in the initial treatment of HIT has been associated with limb gangrene. In patients receiving a direct thrombin inhibitor, warfarin can be started in small doses (2 to 5 mg daily) once the platelet count has recovered. These often malnourished patients tend to have a dramatic response to warfarin therapy and excessive anticoagulation can easily occur. One should overlap warfarin and parental therapy by 2 to 3 days as there is evidence that patients may do worse if therapy with a DTI is truncated [32].

Patients with HIT should be carefully screened for any thrombosis, at least by performing lower extremity Doppler ultrasound. If thrombosis is present, at least 3 months of therapeutic anticoagulation are required, whereas HIT without thrombosis usually is treated with 30 days of therapeutic anticoagulation.

TTP should be suspected when any patient presents with thrombocytopenia and microangiopathic hemolytic anemia (as evidenced by schistocytes on the blood smear and biochemical evidence of hemolysis); end-organ damage, mostly manifesting as renal insufficiency or neurologic phenomena, and fever also may occur, although the minority of patients with TTP present with all of the aforementioned features [43,44,45]. Critical care patients with TTP most often present with intractable seizures, strokes, or sequela of renal insufficiency. Postsurgical TTP may occur 1 to 2 weeks after major surgery, and is heralded by decreasing platelet counts and renal insufficiency [46]. Many patients who present to the critical care unit with TTP have been misdiagnosed as having sepsis, “lupus flare,” or vasculitis.

Evidence is strong that many patients with the classic form of TTP have an inhibitor against an enzyme that is responsible for cleaving newly synthesized von Willebrand factor (vWF) [45,47,48]. vWF is synthesized as an ultra large multimer that can spontaneously aggregate platelets. The enzyme, ADAMTS13, cleaves vWF into a smaller form that can circulate [48,49]. Presumably when ADAMTS13 is inhibited in TTP, the ultra large multimers can spontaneously aggregate platelets leading to the clinical syndrome of TTP. However, many patients with classic TTP have normal activity of ADAMTS13 and reduced levels are found in other diseases implying other factors are important in pathogenesis of TTP [50,51,52].

There is currently not a single diagnostic test for TTP but rather the diagnosis is based on the clinical presentation [43,45]. Patients uniformly will have a microangiopathic hemolytic anemia with the presence of schistocytes on the peripheral smear. Renal insufficiency and not frank renal failure is the most common renal manifestation. Thrombocytopenia may range from a mild decrease in platelet number to platelets being undetectable. The findings of thrombocytopenia with a relative normal prothrombin time help eliminate DIC from the differential [53]. The LDH is often extremely elevated and is a prognostic factor in TTP [54]. Finding very low levels of ADAMTS13 due to an inhibitor may also be a negative prognostic factor [55]. However, lack of standardization and slow turnaround time still make this assay difficult to use clinically.

Untreated TTP is rapidly fatal. Mortality in the preplasma exchange era ranged from 95% to 100%. Today plasma exchange therapy is the cornerstone of TTP treatment and has reduced mortality to less than 20% [11,43,56,57,58].

Glucocorticoid therapy, either 1 to 2 mg per kg of methylprednisolone until remission or 1 g of methylprednisolone initially, may be given to patents presumed to have TTP, although this intervention is not practiced in all centers [45]. The glucocorticoid may be continued until the patient has fully recovered and perhaps longer, given the presumed autoimmune nature of the disease and the high relapse rates. Plasma infusion is beneficial but [47] plasma exchange has been shown to be superior to simple plasma infusion in therapy of TTP [56]. This may be due to the ability of plasma exchange to give very large volumes of fresh frozen plasma and removal of inhibitory antibodies. In patients who cannot be immediately exchanged, plasma infusions should be started at a dose of one unit every 4 hours. Patients with all but the mildest cases of TTP should receive 1 to 1.5 plasma volume exchange each day for at least 5 days [43]. Daily plasma exchange should be continued daily until the LDH has normalized, at which point the frequency of exchange may be taped, starting with every-other-day exchange. If the platelet count falls or LDH level rises, daily exchange should be reinstated [59]. Since the platelet count can be affected by a variety of external influences, the LDH level tends to be the most reliable marker of disease activity [60]. There is increasing evidence that the use of the anti-CD20 therapy may reduce the incidence of relapses and shorten the duration of therapy in refractory disease [48].

Renal insufficiency should be managed in the typical fashion. About 50% of patients require renal replacement therapy.

Classically, hemolytic uremic syndrome (HUS) comprises the triad of renal failure, microangiopathic anemia, and thrombocytopenia [61,62]. Two major forms are recognized: a “typical” form, which occurs in young children with an antecedent diarrheal illness, and an “atypical” form.

TTP/HUS syndromes can complicate a variety of therapies [70,71]. TTP/HUS can be associated with medications such as cyclosporine, tacrolimus, gemcitabine, and clopidogrel. Cyclosporine/tacrolimus-associated TTP/HUS occurs within days after the agent is started manifesting as a falling platelet count, falling hematocrit, and rising serum LDH level [71,72]. Some cases have been fatal but often the TTP/HUS resolves with decreasing the dose of the calcineurin inhibitor or changing to another agent.

In the past TTP/HUS was most commonly seen with the antineoplastic agent mitomycin C, with a frequency of 10% when a dose of more than 60 mg was used [73]. Anecdotal reports indicated that treatment with staphylococcal A columns was useful for this condition [74]. Now, the most common antineoplastic drug causing TTP/HUS is gemcitabine [75,76,77,78]. Like with mitomycin, the appearance of the TTP/HUS syndrome associated with gemcitabine can be delayed, and the condition often is fatal. Severe hypertension often precedes the clinical appearance of the TTP/HUS [79]. The use of plasma exchange is controversial [80], since advanced cancer itself can be associated with a TTP-like syndrome that is typically poorly responsive to plasma exchange. The increasing use of vascular endothelial growth factor (VEGF) inhibitors such as bevacizumab and sunitinib has been associated with observation of related TTP/HUS syndromes as well [81,82,83].

TTP/HUS has been reported with other drugs including the thienopyridines, ticlopidine, and clopidogrel [84]. The frequency of ticlopidine-associated TTP may be as high as 1:1,600, and since this drug was often prescribed for patient with vascular disease, these patients may have been initially misdiagnosed as having recurrent strokes or angina [75,78]. The frequency of TTP using clopidogrel is much less—0.0001%—but since it is widely prescribed, it is the second most common cause of drug-induced TTP [84]. Almost all cases of clopidogrel-induced TTP occur within 2 weeks of starting the drug. All patients with thienopyridine-associated TTP should receive plasma exchange.

TTP/HUS can complicate both autologous and allogeneic hematopoietic stem cell transplants [85,86,87,88,89]. The frequency ranges widely, depending on the criteria used to diagnose TTP/HUS, but it is in the range of 15% for allogeneic and 5% for autologous hematopoietic stem cell transplantation procedures [86,87]. One type, characterized by fulminant multiorgan failure occurs early after transplantation (e.g., within 20 to 60 days), has multiorgan system involvement, is often fatal, and has been associated with severe cytomegalovirus (CMV) infection. Another type of TTP/HUS is similar to cyclosporine/tacrolimus-associated HUS. TTP/HUS that is associated with the conditioning regimen used in the transplantation protocol occurs 6 months or more after total body irradiation, and is associated with primary renal involvement. Finally, patients with systemic CMV infections may present with a TTP/HUS syndrome related to vascular infection with CMV. The etiology of hematopoietic stem cell transplantation-related TTP appears to be different from that of “classic” TTP since alterations of ADAMTS13 have not been found in bone marrow transplant-related TTP implicated in therapy-related vascular damage [90]. The best management of hematopoietic stem cell transplantation-related TTP/HUS is uncertain. Patients should have doses of cyclosporine or tacrolimus decreased, if taking calcineurin inhibitors. Although plasma exchange is often tried, patients with fulminant or conditioning-related TTP/HUS or those with TTP/HUS and concomitant acute graft versus host disease typically do not respond [91,92,93].