Thrombocytopenia and Platelets

1 What are two principal functions of platelets in effecting hemostasis?

Platelets function to effect hemostasis by the following:

The initial platelet plug is due to loose aggregation of platelets in an area of injury and requires the presence of von Willebrand factor. Heparin does not affect this primary hemostasis, which explains why hemostasis can still occur in heparinized patients.

2 What is the most common congenital platelet deficiency?

von Willebrand disease. The absence of von Willebrand factor disrupts the formation of platelet aggregates (see question 1).

3 Define thrombocytopenia

No single value for platelet count universally defines thrombocytopenia; however, conventionally, platelet count of less than 100,000/mm³ is considered to constitute thrombocytopenia.

4 What are the basic mechanisms of thrombocytopenia?

Thrombocytopenia can be caused by decreased platelet production (marrow failure or replacement by cancerous cells or fibrosis), disordered platelet distribution or sequestration (hypersplenism), or increased platelet destruction (antibody mediated, prosthetic valves, extracorporeal bypass, disseminated intravascular coagulation [DIC]). These mechanisms can occur in isolation or in combination.

5 How prevalent is thrombocytopenia in critically ill patients, and what are the most common causes of thrombocytopenia in the intensive care unit (ICU)?

Thrombocytopenia has a prevalence of 30% to 50% of patients in the ICU. Some of the most common causes of thrombocytopenia in the ICU are recent surgery and hemorrhage, blood transfusions, drug-induced thrombocytopenia, intravascular catheters or aortic balloon pumps and vascular grafts, sepsis, renal replacement therapy, DIC, and myelodysplastic and metastatic disease. Most patients who have thrombocytopenia in the ICU have multifactorial causes or idiopathic thrombocytopenia.

6 What are the most common agents used in the ICU that cause drug-induced thrombocytopenia?

7 What is heparin-induced thrombocytopenia (HIT)?

HIT is a life- and limb-threatening prothrombotic complication of heparin administration (risk of 0.6% with unfractionated heparin and 0.3% with low-molecular-weight heparin in a recent large multicenter trial of ICU patients). It results from an immune response triggered by the interaction of heparin with a specific platelet protein, platelet factor 4 (PF4). Certain patient populations are at higher risk than others for development of HIT, with patients after cardiac surgery having a risk of HIT that can be greater than 2%. HIT with thrombotic complication has a mortality rate of 20%, with approximately 20% to 30% having permanent disability (i.e., amputations, stroke).

8 When should a patient have a work-up for HIT?

The diagnosis must be considered in any patient in whom thrombocytopenia develops, who has an unexplained fall in platelet count of 50%, or who has thrombotic complication 5 to 10 days (may be as late as 20 days) after heparin exposure.

9 How is HIT diagnosed?

Almost all the patients with HIT have circulating antibodies to complexes between PF4 and heparin. However, in most of the patients who have circulating antibodies, HIT does not develop clinically. Therefore it is currently not indicated to screen patients without symptoms for these antibodies. Two different types of assays are available:

10 Is repeating HIT testing useful?

Testing should be repeated for negative but borderline ELISA results. The chances of a negative test turning positive 3 days later depends on the titer levels. Approximately 45% of high-titer negative (almost positive) may turn positive, whereas approximately 15% and 5% of the medium- and low-titer results respectively are likely to turn positive.

11 How is HIT treated?

Diagnosis of HIT requires immediate withdrawal of all heparin and treatment with anticoagulation agents. The Warkentin criteria may be used to determine the patient’s pretest probability of HIT (Table 55-1). All patients (with or without thrombosis) with HIT must be anticoagulated, as the risk of thrombosis is >50% without anticoagulation. Do not transfuse platelets unless clearly indicated, as platelet transfusion actually increases the amount of PF4 and may exaggerate the antigen response. If continued anticoagulation is required, a vitamin K antagonist (warfarin) should be initiated after the patient is fully treated with one of the following agents:

12 How should you monitor warfarin effect when it is coadministered with argatroban?

Chromogenic factor X assay can be helpful in determining when the patient is therapeutically anticoagulated with warfarin while receiving argatroban (which in itself elevates the INR value). Switch to the measurement of INR 3 hours after discontinuation of argatroban to be certain that a therapeutic level is maintained after discontinuation of argatroban.

13 What are different treatment options for patients with immune thrombocytopenic purpura (ITP)?

ITP is caused by immunoglobulin G antibodies against the platelet GPs (GPIIb/IIIa and GP Ib/IX). Corticosteroids have been the mainstay of therapy for a long time, but alternative therapies are now commonly prescribed. These include intravenous gamma globulins (IVIG) and intravenous anti-D (IV anti-D). Both cause Fc receptor blockade as an important mechanism of acute platelet increase. IVIG works fast (24 hours) and can be used in Rh-negative patients and patients after splenectomy, whereas IV anti-D causes a slower rate of platelet increase (72 hours) and is relatively ineffective in Rh-negative patients and patients after splenectomy. It is, however, effective in patients positive for the human immunodeficiency virus. Patients who initially respond to medical management but have a relapse within 1 to 3 months may be considered candidates for splenectomy. For refractory ITP, combination chemotherapies are used (cyclophosphamide, hydroxydaunomycin, Oncovin, and prednisone [CHOP]-like; vincristine–IVIG–Solu-Medrol) followed by maintenance therapy (using combinations of steroids, danazol, Imuran, CellCept, cyclosporin among others).

14 How do you differentiate between thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS)?

TTP and HUS share thrombocytopenia, hemolytic anemia, and thrombotic occlusions in terminal arterioles and capillaries. Differentiating clinical features are the presence of focal neurologic symptoms in TTP and renal impairment in HUS. In addition, levels of plasma von Willebrand factor–cleaving protease are low in TTP and normal in HUS.

15 What are some causes of platelet dysfunction in the ICU?

The principal causes of platelet dysfunction and thrombocytopenia in the ICU are due to drug side effects (e.g., aspirin, clopidogrel), uremia, and sepsis. Antibiotics, nitrates, local anesthetics, α- and β-adrenergic blockers, xanthine derivatives, diuretics, H₂ receptor blockers, and dextran are some examples of drugs that can impair platelet activity.

16 What are the indications for platelet transfusion?

The platelet counts that should serve as a trigger for platelet transfusion continue to evolve. Although somewhat controversial, the following threshold levels have been proposed in the literature:

There is no specific count at which bleeding is completely prevented. In addition to the count, the quality and function of the platelets are also important. However, life-threatening bleeding can occur with platelet counts less than 5000/mm³ and spontaneous bleeding with counts less than 10,000 to 20,000/mm³.

17 How does aspirin affect platelet function?

Aspirin irreversibly inhibits platelet cyclooxygenase, resulting in a functional defect that lasts the duration of the platelet’s life span (8-9 days).

18 What laboratory test measures platelet function?

Bleeding time is a sensitive indicator of overall platelet function.

19 How are platelet disorders managed?

The patient’s drug regimen should be carefully scrutinized, eliminating or substituting medications implicated in thrombocytopenia. Platelet transfusion may be required (see answer to question 16). Uremia-associated thrombocytopenia can be treated with hemodialysis. Cryoprecipitate, 1-desamino-8-D-arginine vasopressin, and conjugated estrogens have also been used with good results.