24th July 2024

Thrombocytopenia

Overview of thrombocytopenia

Key causes of low platelets can be categorised as follows:

Microangiopathic haemolytic anaemia is defined by the destruction of red blood cells within the small arteries of the body. Schistocytes can be seen on blood film. The following causes of MAHA will be discussed in detail:

• Haemolytic uraemic syndrome (HUS)
• Thrombotic thrombocytopenic purpura (TTP)
• Disseminated intravascular coagulopathy (DIC)

Other causes include metallic valve haemolysis, malignant hypertension, paroxysmal nocturnal haemoglobinuria and eclampsia.

Immune thrombocytopenic purpura

The pathophysiology of ITP is not entirely understood, but it is thought that sensitised antibodies destroy platelets.

Clinical features of ITP

ITP typically presents with purpura, bruising and bleeding. Mucocutaneous bleeding is common.

A low platelet count with unaffected haemoglobin and white cell count is suggestive of ITP; a blood film can show that other blood lines are not affected and will demonstrate thrombocytopenia. In difficult cases, bone marrow biopsy may be indicated. ITP is a diagnosis of exclusion and it is important to rule out other causes of thrombocytopenia.

Management of ITP

Most patients are treated conservatively with regular monitoring of platelet count. If bleeding symptoms persist and platelet counts are low (<30 x109), prednisolone can be used. If a quicker increase in platelet count is indicated such as before a procedure or surgery or in active bleeding, then IVIG plus steroids is indicated. Platelet transfusion can also be given in bleeding. Second line treatments involve immunosuppression or novel treatments such as thrombopoietin receptor agonists (e.g. eltrombopag).

ITP can also occur secondary to an underlying condition, for example CLL, HIV, HCV, APLS and H. Pylori infection; the treatment of secondary ITP is that of the underlying disease.

Microangiopathic haemolytic anaemias

Microangiopathic haemolytic anaemia is defined by the destruction of red blood cells within the small arteries of the body. It encompasses all three of DIC, HUS and TTP but also includes conditions such as metallic valve haemolysis, malignant hypertension, paroxysmal nocturnal haemoglobinuria and eclampsia. On blood film, all of the above conditions will demonstrate schistocytes.

Metallic valve haemolysis can be managed medically with folate, iron replacement and EPO injections, however redo surgery may be indicated if the anaemia is poorly controlled.

Haemolytic uraemic syndrome

HUS typically occurs in children and is associated with shiga-producing toxin which causes bloody diarrhoea. Cases presenting without diarrhoea can be labelled atypical HUS.

Clinical features of HUS

HUS is characterised by a triad of findings:

• Microangiopathic haemolytic anaemia
• Thrombocytopenia
• AKI

FBC will show low Hb and low platelet count; U&E will demonstrate renal dysfunction. A blood film is vital, as it will have evidence of haemolysis such as schistocytes. A clotting screen is useful to distinguish HUS from disseminated intravascular coagulation (DIC): PT and APTT are normal in HUS. A haemolysis screen should also be ordered, including haptoglobins (low), LDH (high), Coomb’s test (negative). If diarrhoea is present, a stool test should be ordered.

Management of HUS

Management is supportive, with IV fluids and blood pressure control. Around 50% of patients may need renal replacement therapy.

Thrombotic thrombocytopenic purpura

TTP is defined by reduced activity of the vWF-inactivating protein ADAMTS13. This leads to platelet aggregation within vessels, microangiopathic haemolytic anaemia and organ damage.

Clinical features of TTP

Traditionally, TTP has been thought of as a pentad consisting of:

• Thrombocytopenia
• Microangiopathic haemolytic anaemia
• AKI
• Fever
• Neurological symptoms

However, due to earlier treatment, the complete pentad is much rarer nowadays. Symptoms can vary and typically affect the neurological system (confusion, headache, weakness and stroke), gastrointestinal tract (pain, nausea, vomiting and diarrhoea), kidneys (this may manifest as rises in creatinine that are not necessarily diagnostic for AKI; anuria is rare) and cardiac (arrhythmias, MI). Patients can vary from ambulant to moribund.

Investigations are similar to those in HUS. ADAMTS13 levels should be checked, however results may take some time.

TTP can be secondary to HIV, medications such as clopidogrel and pregnancy.

Management of TTP

Due to the potential rapid deterioration with TTP it is a medical emergency. Plasma exchange is the first line treatment along with steroids, followed by monoclonal antibody infusions such as rituximab.

Disseminated intravascular coagulation

In normal homeostasis, coagulation and fibrinolysis are under control and activated in an ordered fashion. In DIC, these processes are overactive, leading to both increased coagulability and increased bleeding. There is release of large volumes of tissue factor, which activates the clotting cascade. Coagulation factors are used up quicker than they are able to be produced. Fibrin degradation products are produced and interfere with clot formation and platelet aggregation, leading to an increased bleeding state. DIC can present acutely or chronically.

DIC can be caused by infection, cancer (importantly APML), trauma and obstetric complications such as preeclampsia.

Clinical features of DIC

FBC will show low Hb and platelets; schistocytes will be present on blood film; coagulation studies will show prolonged PT and APTT; fibrinogen can be low and d-dimer elevated.

Management of DIC

Treatment of the underlying cause of DIC is paramount. Blood products to correct clotting derangements are indicated when patients are actively bleeding. This includes platelets, FFP and cryoprecipitate.

Heparin-induced thrombocytopenia/with thrombosis

This is a rare complication of heparin therapy, more common with UFH than LMWH.

Antibodies are produced against platelet factor 4 (PF4)-heparin complex. This leads to thrombocytopenia and, conversely, thrombosis.

Clinical features of HIT/T

HIT/T should be suspected with new thrombocytopenia, venous or arterial thrombosis or necrosing skin lesions at the site of heparin injection. There are assays to detect the presence of PF4-heparin antibodies and their ability to bind and activate platelets.

Management of HIT/T

Heparin should be discontinued and a non-heparinoid anticoagulant considered such as argatroban, danaparoid or bivalirudin.

Liver disease

Liver disease is a heterogeneous condition with complex interplay between different bleeding and thrombotic mechanisms. It is no longer thought that patients with liver disease are only more prone to bleeding – there is often both a prothrombotic and concomitant pro-bleeding state.

Common haematological derangements in liver disease include:

Platelets are often transfused once below 50 x 10-9 but INR is not routinely corrected.

For common procedures encountered in liver disease such as paracentesis, pre-procedure prophylaxis is not routinely recommended owing to the low bleeding risk. Prior to invasive procedures, a discussion between haematologists and hepatologists is advised to assess the overall bleeding/coagulable state of a given patient.

References

• Andreoli S. Haemolytic uraemic syndrome [Internet]. BMJ Best Practice. 2019 [cited 4 January 2022]. Available from: https://bestpractice.bmj.com/topics/en-gb/470
• George J, Cuker A. Diagnosis of immune TTP [Internet]. Leung L, Mandel J, editors. UpToDate. 2021[cited Jan 4 2022]. Available from: https://www.uptodate.com/contents/diagnosis-of-immune-ttp
• George J, Cuker A. Immune TTP: Initial treatment [Internet]. Leung L, Mandel J, editors. UpToDate. 2021[cited Jan 4 2022]. Available from: https://www.uptodate.com/contents/immune-ttp-initial-treatment
• Intagliata N, Shah N. Hemostatic abnormalities in patients with liver disease [Internet]. Leung L, Tirnauer J, editors. UpToDate. 2021 [cited 26 December 2021]. Available from: https://www.uptodate.com/contents/hemostatic-abnormalities-in-patients-with-liver-disease
• Leung L. Evaluation and management of disseminated intravascular coagulation (DIC) in adults [Internet]. Mannucci P, Tirnauer J, editors. UpToDate. 2021 [cited 5 January 2022]. Available from: https://www.uptodate.com/contents/evaluation-and-management-of-disseminated-intravascular-coagulation-dic-in-adults
• Linkins L. Heparin induced thrombocytopenia. BMJ. 2015;350(jan08 7):g7566-g7566. [cited 5 January 2022] DOI: 10.1136/bmj.g7566
• Scully M. Immune thrombocytopenia [Internet]. BMJ Best Practice. 2019 [cited 4 January 2022]. Available from: https://bestpractice.bmj.com/topics/en-gb/138