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Written by ms. Worldwide, edited by Nikolas

Immune thrombocytopenia

Introduction and epidemiology

Immune thrombocytopaenia (ITP), also called immune thrombocytopaenic purpura, is an immune-mediated cause of thrombocytopaenia. It is caused by the formation of autoantibodies against thrombocytes and is relatively common. Other cell lines are unaffected.

It usually either affects children <5 or older adults >55 years, but the disorder is a bit different in the two populations. In children, it’s typically acute and self-limiting. In adults, it’s typically chronic and persisting.

Classification

Primary immune thrombocytopenia: autoimmune disorder characterized by isolated thrombocytopenia with no known cause. In other words, idiopathic. Often follows a viral infection.

Secondary immune thrombocytopenia: Isolated thrombocytopenia due to an autoimmune hematologic disorder with a known trigger. It is associated with lymphoma, leukaemia (especially CLL), SLE, HIV, HCV, and drug reactions.

Persistent ITP means that it has lasted 3 – 12 months, while chronic ITP means that it has lasted for more than 12 months.

Pathophysiology

IgG antiplatelet antibodies bind to the surface proteins on platelets. They get sequestrated by the spleen and liver, leading to a decreased platelet count. This will lead to an increased megakaryocyte production, and therefore platelet production on the bone marrow.

Clinical features

Many patients are asymptomatic. Those with symptoms usually present with minor bleedings such as petechias, purpuras and epistaxis. Severe bleedings are rarely seen, and examples of this are GI bleedings or intracranial haemorrhage.

Spontaneous bleedings usually don’t occur unless the platelet level is <30 G/L, and serious bleeding usually don’t occur unless it’s <20.

Diagnosis and evaluation

It’s a diagnosis of exclusion, so we must exclude other causes of thrombocytopaenia like drug side effects, infections, autoimmune disorders, lymphoproliferative disorders, etc. In ITP, there is isolated thrombocytopaenia, so the other cell lines are normal. The platelet count can be very low, even < 10 G/L (normally 140 – 440).

Platelets have normal morphology on blood smear. Bone marrow biopsy can be performed in case of uncertain cases, which will show increased number of megakaryocytes. Patients should be tested for HIV and HCV. Testing for antiplatelet antibodies is not indicated.

Treatment

For children with no symptoms or mild mucocutaneous bleedings, observation is enough as it usually resolves by itself. This applies to adults with no symptoms or minor bleedings with platelet counts above 30 G/L as well. They should be advised to not do contact sports as it is a bleeding risk.

If spontaneous bleedings occur or platelets are <30, pharmacological treatment is indicated. First-line medical therapy consists of glucocorticoids or IVIG. Second line is thrombopoietin receptor agonists such as romiplostim, or splenectomy.

Thrombotic microangiopathies

Thrombotic microangiopathies (TMA) are characterised by the presence of thrombocytopaenia, microangiopathic haemolysis (haemolysis in the small vessels), and microvascular thrombi. The main TMAs are haemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP).

Microthrombi cause ischaemic organ dysfunction. In HUS this is mostly seen in the glomeruli and may lead to acute kidney injury, while TTP involves the neurological endothelial cells and cause neurological symptoms. However, TTP and HUS are often considered together as they have similar aetiology and have overlaps in symptoms. Many patients are best fit for the diagnosis TTP-HUS as they can suffer from seizures or coma and AKI.

Thrombotic thrombocytopenic purpura

Introduction and epidemiology

Thrombotic thrombocytic purpura (TTP) is characterised by thrombocytopaenia, microangiopathic haemolysis, neurological abnormalities, renal abnormalities, and low levels of a protein called ADAMTS-13.

It is primarily seen in adults and is typically caused by acquired autoantibodies against the enzyme cleaving von Willebrand factor, vWF, known as ADAMTS13. Deficiency of ADAMTS13 leads to excess vWF which in turn leads to microthrombus formation. These microthrombi also damage RBCs, causing haemolytic anaemia.

Rapid diagnosis and treatment are important to improve prognosis. It has high mortality untreated. It’s a rare disease, affecting 10 per million. Most cases are idiopathic, but some may be secondary to drugs, autoimmune disorders, etc.

Clinical features

The patients are typically previously healthy patients that acutely present with mental status changes, fever, petechiae and pallor. There is a pentad of symptoms to remember, but very few patients present with all five. Pentad of clinical findings:

1. Neurological symptoms (dizziness, seizures, coma)
2. Fever
3. Renal damage:
   1. Haematuria/proteinuria
   2. Oliguria or anuria
4. Symptoms of microangiopathic haemolytic anaemia:
   1. Jaundice
   2. Fatigue
   3. Dyspnoea
   4. Pallor
5. Symptoms of thrombocytopenia:
   1. Petechiae, purpuras
   2. Mucosal bleedings
   3. Prolonged bleeding after minor cuts

(Mnemonic for this: Nasty Fever Ruined My Tubes)

Diagnosis:

• Laboratory
  • Thrombocytopaenia
  • Haemolytic anaemia
  • Increased urea/BUN and creatinine
  • Normal leukocyte count
  • Elevated LDH
• Negative Coombs test
• Peripheral blood smear
  • Schistocytes – fragmented RBCs

Diagnosis can be confirmed by an ADAMTS13 activity assay, but it’s not necessary for the diagnosis. However, this test can take days, but treatment should begin immediately if there is clinical suspicion of TTP, as TTP can be a medical emergency.

Treatment

TTP requires urgent treatment, and therefore there is no time to delay treatment waiting for confirmation of for example ADAMTS13 deficiency.

The first-line treatment is plasma exchange, sometimes given together with glucocorticoids. Plasma exchange is very efficacious.

Haemolytic uremic syndrome

Introduction and epidemiology

Haemolytic uraemic syndrome (HUS) is characterised by thrombocytopaenia, microangiopathic haemolysis, and renal abnormalities. Levels of ADAMTS-13 is normal.

HUS predominantly affects children <5 and is caused by bacterial toxins. The condition might result in renal failure and must be treated immediately. It’s more common than TTP.

Etiology

Over 90 % of cases occur due to infection by Shiga-like toxin produced by bacteria like EHEC. It is especially associated with the serotype O157:H7. Approximately 10 % of children with EHEC infection develop HUS.

The remaining cases are caused by gene mutations or pneumococcal infection.

Classification

• Primary HUS – previously called atypical HUS (aHUS)
  • Those cases caused by genetic mutations
• Secondary HUS – previously called typical HUS (90% of cases)
  • Those cases caused by infections
  • Shiga toxin HUS
    • EHEC – O157:H7
    • Shigella dysenteriae
  • Pneumococcal HU

Clinical features

Shiga toxin HUS is usually preceded by bloody diarrhoea in the past 5 – 10 days. HUS presents with the following three clinical features, all of which are also features of TTP:

• Thrombocytopaenia
  • Petechiae
  • Purpura
• Microangiopathic haemolytic anaemia
• Impaired renal function
  • Oliguria

Renal symptoms are more severe in HUS than in TTP.

Diagnosis

• Laboratory
  • Thrombocytopaenia
  • Haemolytic anaemia
  • Increased urea/BUN and creatinine
• Negative Coombs test
• Peripheral blood smear
  • Schistocytes – fragmented RBCs

Stool culture for EHEC or Shigella in case of secondary HUS.

Treatment

Supportive treatment is usually enough, but 50% of the patients might require dialysis due to the development of AKI. Plasma exchange is given in refractory cases. Immediate treatment is needed to prevent permanent kidney injury.

In case of primary (atypical HUS) Eculizumab is very effective.

Avoid antibiotics and antimotility agents when treating Shigella or EHEC as they can increase the risk for the development of HUS.