LABORATORIO DE URGENCIAS

Thrombocytopenia in Critical Patients

Oyvind Bruserud; Knut Mosevoll; Einar Kristoffersen Reidar Kvale; Hakon Reikvam

Tidsskr Nor Laegeforen; Jan 2021, 141 (1) (review)

In the intensive care area, it is presented as a marker of poor prognosis for which the cause must be detected to indicate the correct treatment.
The condition arises as a result of reduced production or increased destruction or consumption of platelets.
Thrombocytopenia in critically ill patients can often be a consequence of multiple pathophysiological mechanisms. These must be identified to determine the prognosis and provide appropriate treatment.
This article provides an overview of thrombocytopenia in critically ill patients, including its pathophysiological mechanisms, course, evaluation, and treatment.
The work is based on literature identified through a non-systematic search of the PubMed database and the authors' own clinical experience.
In a recent clinical study of patients in intensive care and observation units, thrombocytopenia was defined as:
     * Mild (100-149 × 109/L), with an incidence of 15.3%
     * Moderate (51-99 × 109/L), with an incidence of 5.1%
    * Severe (<50 × 109/L), with incidences of 1.6%.

The incidence of new-onset thrombocytopenia among intensive care patients ranges from 14% to 44%.
More than half of those who spend more than two weeks in intensive care develop thrombocytopenia, which is associated with high mortality.

PATHOPHYSIOLOGICAL MECHANISMS
Platelets are produced in the bone marrow from megakaryocytes, have a lifespan of 8 to 10 days, and are destroyed primarily in the spleen.
They are essential for hemostasis and also contribute to angiogenesis and innate immunity.
The causes of thrombocytopenia can be divided into three main categories:
     A. Reduced production (bone marrow disease, chemotherapy or radiotherapy, acute and chronic viral infections, poisoning)
     B. Increased dynamism of destruction (physiological activation of platelets during surgery/trauma/bleeding, pathological activation of platelets as in disseminated intravascular coagulation (DIC) with high frequency triggered by severe infection/sepsis)
     C. Increased platelet consumption (hypersplenism, immunologically mediated drug hypersensitivity reactions, autoantibody formation, inflammatory diseases such as hemophagocytic lymphohistiocytosis, platelet aggregation in the microcirculation, as in cases of thrombotic microangiopathy).

> Production reduction
It is unclear to what extent reduced platelet production contributes to thrombocytopenia in critically ill patients. Individuals who have undergone cytotoxic chemotherapy show reduced production, as do those with bone marrow disease or acute alcohol toxicity. Both acute and chronic viral infections, including hepatitis C, cytomegalovirus, Epstein-Barr virus, and parvovirus B19, can inhibit platelet production. Thrombocytopenia has also been described in patients with severe COVID-19.
> Increase in consumption
Platelets can be activated by leukocytes, the complement system, coagulation factors, microorganisms, and tissue damage. They also play a key role in the immune response. Thrombin-mediated platelet activation may be physiological, for example, in response to major surgery, trauma, or blood loss. Pathological activation of platelets occurs in cases of disseminated intravascular coagulation (DIC), which can be triggered, for example, by sepsis or malignancy. Activated platelets are rapidly removed from the circulation, resulting in thrombocytopenia. Patients receiving extracorporeal membrane oxygenation treatment also show increased platelet consumption.
> Greater destruction
Both antiplatelet drugs and antibiotics have been reported to cause immune-mediated adverse reactions that can lead to thrombocytopenia.
Together, they represent about 15% of cases in intensive care units. The formation of antibodies can also cause thrombocytopenia. The most common example of this is the formation of antibodies against the heparin-platelet factor 4 (PF4) complex; These antibodies cause heparin-induced thrombocytopenia (HIT) when heparins are used as anticoagulants. However, this is relatively rare and is reported in <5% of patients with thrombocytopenia in intensive care units.
It is worth mentioning that thrombocytopenia may occur as a result of a dilution effect after a massive transfusion of volume resuscitation solutions or blood products.
A patient may often exhibit more than one of these pathophysiological mechanisms simultaneously.
Platelet dysfunction is relatively common in critically ill patients and may be due to uremia, liver failure, the use of medications, or a heart-lung machine.

ASSESSMENT, DIAGNOSIS AND CLINICAL EVOLUTION
The underlying cause of thrombocytopenia can often be identified by taking a complete medical history, monitoring the clinical course, and performing specific laboratory diagnostic tests.
In about 25% of critically ill patients with thrombocytopenia, the condition has more than one underlying cause.
It is essential to obtain an overview of the patient's medical history, comorbidities and medications and view the current clinical status in light of this information. An attempt should be made to determine whether thrombocytopenia is the result of the current critical illness and associated organ dysfunction, or a preexisting underlying condition, such as severe hematologic malignancy.
The absolute platelet count should also be considered, along with the development and progression of thrombocytopenia. Specific patterns often become evident that may reveal the underlying cause, examples:
1. Low platelet count that persists throughout the course.
    Probable cause: Bone marrow failure, hypersplenism
2. Platelet count drops rapidly and normalizes quickly
    Probable cause: surgery, heart-lung machine, transfusions massive without platelet
    contribution
3. Progressive drop in platelets and normalization with improvement of the clinical picture.
    Probable cause: septicemia, pancreatitis, SIRS
4. Low platelet count without normalization with the patient's improvement.
    Probable cause: drug-induced thrombocytopenia
5. Low platelet count that persists over time in patients with persistent severe organ failure
    Probable cause: septicemia, disseminated intravascular coagulation (DIC), circulatory
    insufficiency.

In general, thrombocytopenia will be more severe (< 50 x 109/L) if a chronic underlying cause is accompanied by additional new etiologic factors; platelet transfusion may then fail to increase the platelet count. Because of high platelet turnover, low counts in critical illness likely present a lower hemostatic risk than thrombocytopenia caused by bone marrow failure.
You should also consider other factors that may contribute to a low platelet count. Examples include pseudothrombocytopenia due to EDTA-induced platelet aggregation, hemodilution due to fluid infusion, massive transfusions of other blood components without platelets, or accumulation of platelets in the spleen in cases of splenomegaly or liver disease with portal hypertension.
Patients with thrombocytopenia who develop thromboembolic disease should be tested for procoagulant conditions

TREATMENT
The patient's underlying condition must be treated. Infection control and organ supportive therapy should be prioritized if thrombocytopenia is caused by sepsis, while hemostasis and blood transfusions are appropriate if thrombocytopenia is the result of massive hemorrhage.
Providing the correct treatment depends on identifying the causes. Platelet transfusion may be the correct approach in patients with conditions that reduce production or increase consumption/destruction of platelets, but may be potentially harmful in conditions where there is increased intravascular activation, such as heparin-induced thrombocytopenia, thrombotic thrombocytopenic purpura, or prothrombotic disseminated intravascular coagulation. These factors justify a conservative approach to the use of platelet transfusions, with more emphasis on treating the underlying condition.
>Therapeutic transfusión
To avoid severe thrombocytopenia and hemodilution of coagulation factors, severe bleeding should be treated with a balanced transfusion of red blood cells, plasma, and platelets. According to international guidelines, platelet transfusion should be considered for critically ill patients with bleeding and a platelet count < 50 x 109/L, or in whom reduced platelet function is suspected/confirmed.
>Prophylactic transfusión
Clinical practice varies considerably, but international guidelines recommend platelet transfusion if the count is < 10 x 109/L.
It is estimated that transfusion increases the platelet count by about 15 x 109/L per unit of transfusion, although this can vary to a relatively large extent.
>Transfusion related to procedures
Platelet transfusion is recommended to minimize the risk of bleeding during certain procedures, for example, during implantation of a central venous catheter in patients with a platelet count of < 20 x 109/L. Likewise, there are guidelines and recommendations for the absolute platelet count in patients undergoing lumbar puncture or epidural anesthesia (> 50 x 109/L), major surgery (> 50 x 109/L) or neurosurgery (> 100 x 109/L) . However, these recommendations are largely based on clinical experience and the evidence base is limited.
> Other treatment methods
Drugs can affect the production and destruction of platelets. In the critically ill, steroids may be administered if a low platelet count is suspected to be of immunological origin.

CONCLUSIONS
• Thrombocytopenia is common in critically ill patients. It often results from an interaction between several different pathophysiological mechanisms that together reduce platelet production and/or increase their consumption or destruction. The most significant cause of thrombocytopenia is sepsis/infection.
• Thrombocytopenia is a marker of poor prognosis and increased risk of mortality in intensive care patients. Careful consideration of the medical history and clinical course, along with specific laboratory diagnoses, is often sufficient to identify the underlying cause. This is necessary to determine the likely prognosis and provide appropriate treatment.
• Treatment of the underlying cause should be the priority, with platelet transfusions being used primarily to avoid bleeding-related complications until the platelet count has increased and hemostasis has normalized.

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