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Updated:
23 September, 2024
Various conditions with thrombocytopenia are described here, such as ITP, TTP, and HIT.
Definition of Thrombocytopenia
- Platelet count (PLT) < 150 x 109
- Approximately 50% of ICU patients experience thrombocytopenia at some point
- Associated with higher mortality
- Increased risk of bleeding
- No lower risk of thrombosis
- Thromboprophylaxis at PLT > 30
Facts about Platelets
- Produced in the bone marrow
- Derived from megakaryocytes
- Average lifespan approx. 5-7 days
- About 20% are newly produced daily
Thrombopoietin
- Growth factor primarily produced in the liver
- Increases the number of megakaryocytes, their size, and accelerates their maturation
- Broken down by platelets as negative feedback
- TPO receptor agonists as medication
- Avatrombopag 40 mg/day for 5 days before elective procedures
What is the main function of platelets?
Platelets are part of primary hemostasis and are crucial for repairing small damages in capillaries.
Different Functions of Platelet Inhibitors
What happens if you have too few platelets?
- Platelets are important for repairing small damages in capillaries
- Scattered small bleedings
- Bleeding in the skin – petechiae – “purpura”
What is thrombocytopenia?
- Normal PLT 150-300 x 109
- PLT is generally stable in an individual
- Normal PLT is 15-40 times higher than necessary – functional reserve capacity
- Low – below 50 x 109
- Spontaneous bleedings at PLT under 20 x 109
- Potentially life-threatening at under 10 x 109
Grading of Thrombocytopenia
- In surgical contexts
- Mild PLT 100 – 149
- Moderate – 50-99
- Severe PLT < 50
- The issue is that risk grading is an extrapolation from patients with blood malignancies and risk for spontaneous bleeding.
How does PLT correlate to the risk of spontaneous bleeding?
Thrombocytopenia and Invasive Procedures
- When is it safe to perform various procedures?
- According to international guidelines
- Arterial catheter, CVC, ascites tapping, pleural tapping – PLT over 20
- Diagnostic gastroscopy – PLT over 20
- Spinal anesthesia – PLT over 50
- Epidural anesthesia – PLT over 80
Platelet Transfusion Threshold and Indication
| Transfusion Threshold (Platelet x 10⁹ /L) and Indication | |
|---|---|
| PLT ≤ 20: | Insertion of CVL/CDL (tunneled/non-tunneled) |
| PLT < 30: | Minor surgery Less severe bleeding |
| PLT < 40: | Lumbar puncture |
| PLT ≤ 50: | Major surgery Severe bleeding DIC with bleeding Percutaneous liver biopsy |
| PLT < 80: | Epidural catheter (insertion/removal) Spinal anesthesia |
| PLT ≤ 100: | Neurosurgery or posterior eye surgery Major/multiple trauma Massive bleeding Traumatic/spontaneous brain hemorrhage |
| Condition | Recommendation |
| Reversible/chronic bone marrow failure during intensive chemotherapy: | < 10: if no other risk factors are present < 20: if there are risk factors for bleeding/fever/sepsis/antibiotic use/ICU care/coagulation disorder (DIC without bleeding). |
| Immune-induced thrombocytopenia: | Only in cases of severe bleeding. Before emergency surgery/procedure if there is no response to treatment. |
| ITP, PTP, HIT: | < 50: for epidural catheter placement or spinal anesthesia. For ITP: add IVIG. For PTP: IVIG is the first line of treatment. |
| TTP/HUS: | Contraindicated except in life-threatening bleeding (applies to both adults and children). |
| Acquired platelet dysfunction regardless of Platelets: | First, consider general hemostatic measures, discontinuation of antiplatelet therapy +/- reversal of anticoagulants, and tranexamic acid (Cyklokapron). Consider platelet transfusion in cases of: Significant bleeding after cardiac surgery. Significant bleeding during emergency surgery while on antiplatelet therapy. Platelets < 1 caused by abciximab (ReoPro). |
| Congenital platelet dysfunction (Glanzmann's Thrombasthenia [GT], Bernard-Soulier Syndrome [BSS]) regardless of Platelets: | For bleeding prevention, NovoSeven is used for GT, and tranexamic acid and Octostim for BSS. Consider platelet transfusion if: Drug contraindication/ineffectiveness or high risk of bleeding (for GT and BSS). For GT: administer HLA-matched platelets (contact the blood bank's on-call physician). |
Pseudothrombocytopenia
- Common blood tests use K2-EDTA tubes
- Patients with antibodies that react with EDTA causing platelet aggregation – falsely low PLT
- Retake the test in a heparin or citrate tube
Cyclic Thrombocytopenia
- Related to the menstrual cycle
- Lowest on the day menstruation begins
- Then rapid recovery
Thrombocytopenia from Excessive Alcohol Consumption
- Not due to vitamin deficiency
- Not due to splenomegaly
- Direct inhibition of bone marrow
- Occurs after 5-10 days of consumption
- Normalizes within 1-3 weeks
Transfusion Thrombocytopenia
- Occurs with large transfusions of banked blood
- Risk of thrombocytopenic bleeding
- Therefore, use 4 blood: 4 plasma: 1 BAT (one platelet unit)
Various Thrombocytopenias Involving the Immune System
ITP – Immune-Mediated Thrombocytopenic Purpura
- Most common in women under 40 years
- Insidious onset
- Mucosal bleeding, skin bleeding, menorrhagia, melena
- Most do not have purpura (skin bleeding)
- Intracerebral and subarachnoid hemorrhage is the most feared complication
- Normal bone marrow function
- Autoantibodies targeting glycoproteins on the surface of platelets
- Platelets are covered with antibodies and phagocytosed
- 80% improve after splenectomy
Different Types of ITP
- Primary
- Acute < 3 months
- Persistent 3-12 months
- Chronic 12 months
- Secondary – SLE, viruses, medications, HIV
When is ITP a problem in the ICU, and what can we do?
- ITP is rarely a problem in itself – ITP patients often feel fine
- Often the patient has ITP and another pathology – e.g., trauma, TBI, ICH
- Platelet transfusion to increase PLT
- At least 5 units to stop bleeding
- Always combine with IVIG and steroids
- Thromboprophylaxis as long as PLT is over 20
Principles for Treatment Strategy
- Newly diagnosed or chronic?
- PLT over or under 20?
- Asymptomatic or very mild symptoms?
- Duration over or under 3 months?
- Steroid-refractory?
- Spontaneous improvement within a year?
Possible Therapies
- Steroids for 5 weeks
- Prednisolone 0.5-2 mg/kg per day
- Dexamethasone 40 mg per day for 4 days
- Rituximab
- Thrombopoietin receptor agonist
- Splenectomy
| Newly Diagnosed ITP | Mild symptoms | PLT < 20 | Inpatient | Steroids (5 weeks) |
| Chronic ITP | Mild symptoms | PLT > 30 | Outpatient | Observation |
ITP Treatment
- First-line treatment – steroids for 5 weeks
- Response with PLT up to 50 x 109 within 1-3 weeks
- In case of severe bleeding – platelet transfusion and IVIG in addition
- IVIG 1 g/kg body weight/day for 2 days
- Response to IVIG within 3 days
Second-line Treatments
- Dexamethasone 40 mg/day for 4 days
- Rituximab 375 mg/m2/week for 4 weeks
- Thrombopoietin receptor agonists
- If nothing helps – splenectomy
TTP – Thrombotic Thrombocytopenic Purpura
- Moschowitz syndrome discovered in 1924
- A 16-year-old girl fell ill with fever, low platelets, general malaise, and focal neurology, and died a few days later
- The five cardinal symptoms identified in 1967 – the so-called pentad
- Mortality was over 90 percent
- Plasmapheresis as a possible treatment in 1991 – mortality only 10 percent
- Life-threatening condition requiring urgent diagnosis and treatment
- ALL patients with TTP are initially ICU patients
- Characterized by widespread microthrombosis and organ failure
- Requires rapid investigation and treatment
- Acute treatment – plasmapheresis
- The danger is over when PLT is 150-400 for at least 2 days
Conditions Associated with TTP
- Bacterial infections
- SLE
- Scleroderma renal crisis
- Antiphospholipid syndrome
- Certain medications such as cyclosporine, quinine
Symptoms of TTP
- Classic pentad
- Thrombocytopenia
- Hemolytic anemia
- Neurological symptoms
- Fever
- Impaired kidney function
- But when all 5 symptoms are present, it’s too late!
TTP Pathophysiology
- 80% due to antibodies directed against ADAMTS13
- 10% due to congenital deficiency of ADAMTS13
- The rest are secondary TTP
- ADAMTS13 deficiency – vWF activates platelets – thrombus formation
- Amplified by complement system activation
Thrombotic Microangiopathies
- Endothelial damage + endothelial activation as the starting point
- Platelet aggregation
- Vascular obstruction
- Ischemia
What happens if we miss the diagnosis?
- Multi-organ failure
- Stroke
- Heart attack
- Kidney failure
- Bleeding
Definitive Diagnosis
- Analysis of ADAMTS13 activity
- Specific analysis method
- Coagulation lab in Malmö
- Results once a week
- Transport from Klinkem happens once a day
How do we find these patients faster?
- Low platelets – < 30 x 109
- General malaise
- Neurological symptoms
- Schistocytes in peripheral blood smear
- Schistocytes over 1%
TTP and Differential Diagnoses
- HUS but no neurological symptoms and more pronounced kidney involvement, often children and young people after Shigella infection
- DIC low fibrinogen, elevated PT and APTT
- ITP shows no hemolysis and no neurological, fever, or kidney involvement
- HIT – clear connection to heparin
Plasmapheresis
- Replaces ADAMTS13 – resolves the deficiency
- Washes away antibodies against ADAMTS13
- Large volumes
- If plasmapheresis is unavailable – FFP transfusion can be used
TTP Treatment Beyond Plasmapheresis
- Steroids – to suppress antibody production
- Rituximab, for example in severe neurology – to suppress B cells
- Caplacizumab, an anti–von Willebrand factor humanized immunoglobulin
- ASA when PLT over 50
- LMWH when PLT over 50
- Folic acid due to hemolytic anemia
- Blood transfusion if severe anemia
HIT – Heparin-Induced Thrombocytopenia
- Thrombocytopenia is common – 30-50% of our patients
- Expected on days 1-4 – hemodilution, consumption
- Varies by type of surgery
- It takes about 3 days for the bone marrow to respond to thrombopoietin
- PLT is expected to normalize on day 5 (97% of thoracic patients)
- Days 5-14, PLT should double
- Deviations from this pattern need investigation
Heparin-Induced Thrombocytopenia (HIT)
- Rare condition 0.3-0.5%
- Risk with regular thrombocytopenia – bleeding
- Risk with HIT – thromboses
- Arterial thromboses in cardiovascular patients
- Deep venous thromboses, sinus thromboses, and pulmonary embolism in others
- DVT about 4 times more common
Risk Factors for HIT
While Waiting for Investigation Results…
- If 4T score is between 4-8
- Stop all heparin administration and label the patient’s location with “No heparin”
- Start alternative anticoagulants
- Order immunoassay
- If the result is positive, order a functional analysis
- Order ultrasound of upper and lower extremities
- Be vigilant for bleeding and/or thrombosis
Why Alternative Anticoagulants and for How Long?
- 25% develop thromboses before PLT falls
- 50% develop thromboses up to a month after stopping heparin
- If only thrombocytopenia – anticoagulation for up to four weeks
- If thrombosis – 3-6 months as usual for thrombosis treatment
Anticoagulants
- Argatroban – thrombin inhibitor
- Arixtra – Factor Xa inhibitor
- Orgaran – Factor Xa inhibitor
- Angiomax – Factor Xa inhibitor + thrombin inhibitor
Keep it Simple!
- Stable patient not requiring surgery or CRRT – Arixtra
- Unstable patient with bleeding risk, surgery – Argatroban
- The other agents are uncommon and unavailable
Fondaparinux – Arixtra
- Factor Xa inhibitor
- Once daily subcutaneously
- Long half-life – 17 hours
- Not suitable for impaired renal function
- Okay in liver failure
- An antidote is available
Argatroban – Novostan
- Direct-acting thrombin inhibitor
- Only continuous intravenous administration
- Short half-life
- Rapid onset – about 30 minutes
- Steady state after 1-3 hours
- Independent of renal function and age
- No antibodies
How Fast is the Improvement?
- Within 4 days after stopping heparin
- PLT is expected to normalize within 2 weeks
- The risk of thrombosis persists for at least 4 weeks
Platelet Concentrate
- 350 ml of nutrient solution and plasma
- Contains over 240 x 109 platelets
- Leukocyte-depleted
- Usually pooled from 4-6 donors
- Increases PLT by 15-30 x 109 within 10 minutes
A platelet unit is prepared from whole blood by pooling platelets from 4-6 donors. Platelet concentrates are always leukocyte-depleted and contain < 1 x 106 leukocytes per unit. The concentrate is prepared from buffy coat, which is obtained by centrifugation of whole blood. It also contains 100 ml of plasma.
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