Platelets and Plasma

This chapter begins with a description of thrombocytopenia and platelet therapy in critically ill patients, and then focuses on the transfusion of plasma products, including recommendations for the rapid reversal of warfarin anticoagulation.

I. Thrombocytopenia

Thrombocytopenia is the most common hemostatic disorder in critically ill patients, with a reported incidence of up to 60% (1,2). Although thrombocytopenia is defined as a platelet count <150,000/μL, the ability to form a hemostatic plug is retained until the platelet count falls below 100,000/μL (2), so a platelet count <100,000/μL is more appropriate for identifying clinically significant thrombocytopenia.

A. Bleeding Risk

The risk of major bleeding is not determined by the platelet count alone, but also requires a structural lesion that is prone to bleeding.
In the absence of a structural lesion, platelet counts as low as 5,000/μL can be tolerated, without evidence of major bleeding (3).
The principal risk with a platelet counts <10,000/μL is spontaneous intracerebral hemorrhage, which is uncommon (2).

B. Etiologies

The most likely causes of thrombocytopenia in the ICU setting are listed in Table 12.1.
Sepsis is the most common cause of thrombocytopenia in ICU patients (4), and is the result of increased platelet destruction by macrophages.

Table 12.1 Potential Sources of Thrombocytopenia in the ICU

Nonpharmacological	Pharmacological
Cardiopulmonary Bypass Disseminated Intravascular Coagulation (DIC) HELLP Syndrome Hemolytic-Uremic Syndrome HIV Infection Intra-aortic Balloon Pump Liver Disease/Hypersplenism Massive Transfusion Renal Replacement Therapy Sepsis Thrombotic thrombocytopenia purpura (TTP)	Anticonvulsants: Phenytoin Valproic Acid Antimicrobial Agents: β-Lactams Linezolid TMP/SMX Vancomycin Antineoplastic Agents Antithrombotic Agents Heparin IIb/IIIa Inhibitors Histamine H₂ Blockers Miscellaneous Drugs Amiodarone Furosemide Thiazides Morphine

C. Pseudothrombocytopenia

Pseudothrombocytopenia is a condition where antibodies to EDTA (the anticoagulant in blood collection tubes) produce clumping of platelets in vitro, resulting in spuriously low platelet counts.
This phenomenon has been reported in 2% of platelet counts performed by hospital laboratories (5).
If suspected (e.g., by sudden, unexpected thrombocytopenia), blood collection tubes that use citrate or heparin as an anticoagulant should be used to measure the platelet count.

II. Heparin and Thrombocytopenia

There are two types of thrombocytopenia associated with heparin.

The first is a nonimmune response that results in mild thrombocytopenia (platelet counts often 100,000–150,000/μL) in the first few days after starting heparin. This reaction is reported in 10–30% of patients receiving heparin (6), and it resolves spontaneously without interruption of heparin, and without adverse consequences.
The second (heparin-induced thrombocytopenia, or HIT) is an immune-mediated response that typically appears 5–10 days after starting heparin (6). This reaction is much less common (incidence = 1–3%) but can have serious consequences, with a mortality rate as high as 30% when unrecognized (6).
HIT is the result of heparin binding to a protein (platelet factor 4) on platelets, to form an antigenic complex that induces the formation of IgG antibodies, which bind to
the antigen complex and form cross-bridges between contiguous platelets. This promotes platelet aggregation, which can lead to symptomatic thrombosis (not bleeding) and a consumptive thrombocytopenia. Heparin-associated antibodies usually disappear within 3 months after discontinuing heparin (5).

A. Risk Factors

HIT is not a dose-dependent reaction, and can be triggered by the small amounts of heparin used to flush intravascular catheters, or even heparin-coated pulmonary artery catheters (7).
The type of heparin preparation influences the risk of HIT; i.e., the risk of HIT is ten times greater with unfractionated heparin than with low-molecular-weight heparin (8).
The risk of HIT also varies by patient population; it is highest in patients undergoing orthopedic and cardiac surgical procedures, and lowest in medical patients (6,8).

B. Clinical Features

HIT typically appears 5–10 days after the first exposure to heparin, but it can appear within 24 hours in patients exposed to heparin within the preceding 3 months (8).
Platelet counts are usually between 50,000–150,000/μL, and are rarely below 20,000/μL (6,8).
The major complication of HIT is thrombosis, which precedes the thrombocytopenia in up to 25% of cases (8).
- Venous thrombosis is much more common than arterial thrombosis. Up to 55% of patients with HIT develop deep vein thrombosis in the legs and/or pulmonary embolism, whereas only 1–3% of patients develop arterial thromboses (which can result in limb ischemia, ischemic stroke, or acute coronary syndromes) (8).

C. Diagnosis

Multiple assays are available for detecting HIT antibodies. The most popular is an enzyme-linked immunosorbent assay (ELISA) for antibodies to the platelet factor 4-heparin complex.
A negative antibody assays helps to exclude the diagnosis of HIT, but a positive assay does not confirm the diagnosis because HIT antibodies do not always produce thrombocytopenia or thrombosis (8).
The diagnosis of HIT requires a positive antibody assay and a high index of clinical suspicion.

D. Acute Management

Heparin must be discontinued immediately (don’t forget to discontinue heparin flushes and remove heparin-coated catheters). Therapeutic anticoagulation with one of the direct thrombin inhibitors shown in Table 12.2 should be started immediately, even in cases where HIT is not accompanied by thrombosis (8).

1. Argatroban

Argatroban is a synthetic analogue of L-arginine that reversibly binds to the active site on thrombin. It has a rapid onset of action, and is given by continuous infusion using the dosing regimen in Table 12.2. The therapeutic goal is an activated partial thromboplastin time (aPTT) of 1.5–3 times control values.

The drug is cleared primarily by the liver, and a dose adjustment is required in hepatic insufficiency.
Argatroban is recommended in patients with renal insufficiency (8) because a dose adjustment is not necessary.

Table 12.2 Direct Thrombin Inhibitors for Anticoagulation in HRT

Drug

Dosing Recommendations

Argatroban

Normal:

Infuse at 2μg/kg/min, and titrate dose to achieve aPTT = 1.5–3 × control. Max dose is 10μg/kg/min.

Liver Failure:

Start infusion at 0.5μg/kg/min.

Lepirudin

Normal:

Start with IV bolus of 0.4 mg (for life-threatening thrombosis). Begin infusion at 0.15mg/kg/h and titrate to achieve aPTT = 1.5–3 × control.

Renal Failure:

Reduce IV bolus to 0.2 mg/kg (if needed), and decrease infusion rate as follows:

Serum Creat (mg/dL)	1.6–2.0	2.1–3.0	3.1–6.0	>6.0
% Decrease in Infusion Rate	50%	70%	85%	Avoid

From References 10, 11, and 14. HIT = heparin-induced thrombocytopenia.

2. Lepirudin

Lepirudin is a recombinant form of hirudin, an anticoagulant that binds irreversibly to thrombin. Lepirudin is given by continuous infusion, which can be preceded by a bolus injection in cases of life-threatening thrombosis. The therapeutic goal is the same as with argatroban (aPTT = 1.5–3 × control).

Lepirudin is cleared by the kidneys, and a dose adjustment is necessary when renal function is impaired (see Table 12.2).
Re-exposure to lepirudin can produce life-threatening anaphylactic reactions (8), so treatment with lepirudin is a one-time affair.

3. Duration of treatment

Full anticoagulation with argatroban or lepirudin is recommended until the platelet count rises above 150,000/μL (8). Thereafter, coumadin can be used for long-term anticoagulation if HIT is associated with thrombosis, but there are 2 caveats: 1) coumadin should NOT be started until the platelet count increases beyond 150,000/μL, and 2) the initial coumadin dose should not exceed 5 mg (8). These precautions are intended to reduce the risk of limb gangrene associated with coumadin therapy during the active phase of HIT. The antithrombin agents should be continued until coumadin achieves full anticoagulation.

III. Thrombotic Microangiopathies

The following conditions are characterized by a “consumptive” thrombocytopenia with microvascular thrombosis and dysfunction in one or more vital organs. The hematologic features of these conditions are shown in Table 12.3.

A. Disseminated Intravascular Coagulation

Disseminated intravascular coagulation (DIC) is a secondary disorder that is triggered by widespread tissue injury (e.g., multisystem trauma) and obstetric emergencies (i.e., amniotic fluid embolism, abruptio placentae, eclampsia, retained fetus syndrome). These conditions promote the release of tissue factor from the endothelium, which activates a series of clotting factors in the bloodstream, culminating with the formation of fibrin. This leads to widespread microvascular thrombosis and secondary depletion of platelets and clotting factors, resulting in a consumptive coagulopathy (9).

1. Clinical Features

The microvascular thrombosis in DIC can lead to
multiorgan failure, most often involving the lungs, kidneys, and central nervous system, while depletion of platelets and coagulation factors can promote bleeding, particularly from the GI tract.
DIC can also be accompanied by symmetrical necrosis and ecchymoses involving the limbs. This condition (known as purpura fulminans) is usually seen with overwhelming sepsis, most notably with meningococcemia (4).

2. Laboratory Studies