CONTENTS

• Overview & definition
• Differentials
  • Overall classification of thrombocytopenia in the ICU
  • Clinical clues & specific situations
• Additional comments on specific causes of thrombocytopenia:
  • Drug-induced immune thrombocytopenia (D-ITP)
  • Transfusion related thrombocytopenia
  • Heparin-Induced Thrombocytopenia & Thrombosis (HITT)
• Investigation of thrombocytopenia
• Platelet transfusion
• Algorithms
• Podcast
• Questions & discussion
• Pitfalls
• PDF of this chapter (or create customized PDF)

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overview & definition

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overview

• Thrombocytopenia is extremely common in the ICU.  It is often a poor prognostic sign which is associated with systemic inflammation.
• Most cases will resolve in parallel with the patient's overall recovery.

when to initiate an evaluation?

• Most ICU patients with mild thrombocytopenia don't require an exhaustive evaluation.  Potential indications to evaluate further might include:
  • Severe thrombocytopenia (e.g. below ~50,000).
  • Features of HITT (abrupt drop in platelet count by >50%, skin necrosis at site of heparin injection).
  • Clinical thrombosis.
  • Underlying process is unclear, raising a possibility of an underlying hematologic disorder (e.g. thrombotic thrombocytopenic purpura or hemophagocytic lymphohistiocytosis).

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common causes of thrombocytopenia in the ICU

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Thrombocytopenia in critical illness may be divided into roughly four classes:

subacute/chronic thrombocytopenia:  often present before critical illness.

• Cirrhosis, alcoholism
• Bone marrow dysfunction (e.g. myelodysplastic syndrome)
• Bone marrow suppression (chemotherapy, alcoholism, some antiviral agents, linezolid, some penicillins/cephalosporins, NSAIDs, thiazides)
• HCV, HIV

non-immune consumption:  often gradual decrease over several days, adequate response to platelet transfusion.

• Microangiopathic hemolytic anemia (TTP/HUS, HELLP, malignant hypertension)
• Disseminated intravascular coagulation (DIC)
• Catastrophic antiphospholipid antibody syndrome (CAPS)
• Sepsis:  Can occur with any pathogen, but especially occurs with specific pathogens (ehrlichiosis, babesiosis, anaplasmosis, rocky mountain spotted fever, hantavirus, dengue)
• Surgery, trauma
• Hemophagocytic lymphohistiocytosis (HLH)
• Devices:  intra-aortic balloon pump, hemodialysis, ECMO

immune consumption:  often occurs several days after ICU admission, decrease is rapid (>50% fall in 24-48 hours), often with severe thrombocytopenia which is poorly responsive to platelet transfusion.

• HITT
• Drug-induced immune thrombocytopenia (D-ITP; see section below)
• Post-transfusional purpura
• Passive alloimmune thrombocytopenia
• Idiopathic thrombocytopenic purpura (ITP)¹

other

• Obvious causes
  • Massive transfusion
  • Hypothermia
• Pseudo-thrombocytopenia
  • Artificially low platelet count due to in vitro aggregation induced by EDTA in blood tubes.
  • Diagnosed by finding clumped platelets on blood smear and higher platelet count when measured in a citrated blood tube (blue top platelet tube).
  • Usually meaningless, but can be associated with lupus, vasculitis, or lymphoma.²

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clinical clues & specific situations

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The differential diagnosis of thrombocytopenia is broad.  Below are some clues which may help point in the right direction.  These shouldn't be used to narrow the differential diagnosis, but rather merely to highlight possibilities that deserve particular attention.

thrombocytopenia with (paradoxical) clinical thrombosis

• Heparin-Induced Thrombocytopenia and Thrombosis (HITT)
• Disseminated intravascular coagulation (DIC) of a pro-thrombotic type (e.g. associated with malignancy or sepsis)
  • Acute DIC/liver necrosis/limb necrosis syndrome:  Shock liver causes depletion of protein C and anti-thrombin, with subsequent microvascular thrombosis of extremities.³
• Catastrophic antiphospholipid antibody syndrome (CAPS)
• “Massive clot thrombocytopenia” – Venous thromboembolic disease itself may cause mild thrombocytopenia.^2,4
• Thrombotic thrombocytopenic purpura (TTP)
• Antiphospholipid antibody syndrome (APLS)
• Cirrhosis, in some patients
• Paroxysmal nocturnal hemoglobinuria (rare)

severe thrombocytopenia (e.g., <20,000)⁵

• Immune-mediated thrombocytopenia of any cause:
  • Drug-induced immune thrombocytopenia (D-ITP)
  • Transfusion-related (post-transfusional purpura, passive alloimmune thrombocytopenia)
  • HITT causes severe thrombocytopenia in ~10% of cases (generally when HITT causes simultaneous DIC).⁶
  • Idiopathic thrombocytopenic purpura (ITP)
• Thrombotic thrombocytopenic purpura (TTP)
• Hemophagocytic lymphohistiocytosis (HLH)
• Severe marrow failure (e.g. chemotherapy or leukemia).  Will usually see neutropenia here as well.
• (Usually not due solely to sepsis or DIC)

thrombocytopenia in septic-appearing patient 

• Disseminated intravascular coagulation (DIC) due to the infection.
• Specific infections (ehrlichiosis, babeosis, anaplasmosis, rocky mountain spotted fever, hantavirus, dengue).
• Hemophagocytic lymphohistiocytosis (HLH) – either mimicking sepsis or HLH secondary to infection.

thrombocytopenia in the cardiac patient

• Heparin-Induced Thrombocytopenia and Thrombosis (HITT)
• Cardiopulmonary bypass, ECMO, intra-aortic balloon pump (IABP)
• GPIIb/IIIa inhibitors
• Thrombotic thrombocytopenic purpura (TTP) related to clopidogrel

thrombocytopenia in pregnant patient

• Pre-eclampsia and/or HELLP syndrome (Hemolysis, Elevated LFTs and Low Platelets)
• Acute fatty liver of pregnancy
• Thrombotic microangiopathy (including TTP, pregnancy-induced atypical HUS)
• Disseminated intravascular coagulation (may result from various obstetric catastrophes)
• Idiopathic thrombocytopenia (ITP)
• Gestational thrombocytopenia

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drug-induced immune thrombocytopenia (D-ITP)

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clinical features

• Typically begins 1-3 weeks after starting new medication (can occur within a day if previously sensitized to medication).
• Immune consumption often causes severe thrombocytopenia (e.g. <10,000-20,000) with bleeding.
• Often causes systemic symptoms including fever and chills.⁴

commonly implicated medications

• Cardiac:  Abciximab, Amiodarone, Amlodipine, Captopril, Digoxin, Diltiazem, Eptifibatide, Hydralazine, Procainamide, Quinidine, Simvastatin, Tirofiban,
• Heme/onc:  Bleomycin, Fludarabine, Gemcitabine, Checkpoint inhibitors? (Ipilimumab), Oxaliplatin, Rituximab, Trastuzumab
• Infectious disease:  Amphotercin B, Beta-lactams (esp. ampicillin, ceftriaxone, penicillin, piperacillin), Clarithromycin, Fluconazole, Fluoroquinolones (Ciprofloxacin, Levofloxacin, Moxifloxacin), Indinavir, Interferon-alpha, Linezolid, Rifampin, Trimethoprim/Sulfamethoxazole, Vancomycin
• Nephrology:  Acetazolamide, Chlorothiazide, Desmopressin, Hydrochlorothiazide,
• Neuro/Psych:  Carbamazepine, Clozapine, Diazepam, Fluoxetine, Haloperidol, Lamotrigine, Levetiracetam, Olanzapine, Ondansetron, Phenytoin, Quetiapine, Valproic acid
• Rheum:  Allopurinol, Cyclosporin, Methotrexate, Tacrolimus, TNF-inhibitors (Adalimumab, Etanercept, Infliximab)
• General/Misc:  Acetaimonphen, Aspirin, Danazol, H2 blockers (Famotidine, Ranitidine),  NSAIDs (esp. Diclofenac, Ibuprofen, Indomethacin, Naproxen), Pantoprazole, Quinine (found in tonic water, mixed drinks)
• More information including more detailed up-to-date lists here.  Bolded drugs seem to be more common causes of D-ITP.

treatment

• Discontinuation of drug.
• May require platelet transfusion (however, ongoing consumption can be refractory to platelet transfusion).
• IVIG may be used in severe cases (e.g. 1 gram/kg on two consecutive days).

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transfusion related thrombocytopenias

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post-transfusion purpura (PTP)

• Mechanism
  • Patient was previously sensitized to platelet antigens (especially HPA-1a).
  • Transfusion leads to antibody against HPA-1a, which ends up destroying patient's own platelets as well.
• Epidemiology
  • At-risk host:  Usually mothers (previously sensitized at pregnancy) or patients with history of transfusion or transplantation
• Clinical presentation
  • Occurs ~5-10 days after transfusion of platelets or packed RBCs
  • Abrupt fall in platelets to <20,000 which can cause life-threatening bleeding.
  • May be refractory to platelet transfusion
• Investigation
  • Diagnosis supported by anti-HLA allo-antibodies in patient's serum.
•  Treatment
  • IV immunoglobulin and/or steroids should be considered early.
  • Avoid un-matched platelets; ideally, transfusion of platelets from compatible donor.

passive allo-immune thrombocytopenia

• Rare, results from passive transfer of anti-HPA-1a antibodies.
• Immediate, severe thrombocytopenia occurs within hours of transfusion.
• Treatment unclear, but IV immunoglobulin has been used.

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heparin induced thrombocytopenia and thrombosis (HITT)

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introduction

• Rare, yet important to recognize early.  HITT is challenging to diagnose, because the vast majority of patients with DVT or thrombocytopenia won't have HITT.
• In ~10% of cases, HITT leads to overt DIC.  These cases are distinguished by unusually low platelet counts (e.g. <20,000), lab derangements of DIC (e.g. elevated INR and low fibrinogen), and often microvascular thrombosis.  This combination of HITT and DIC can be difficult to diagnose, because the unusually low platelet count will confound diagnostic algorithms for HITT.

epidemiology of HITT

• Rare, with incidence varying, depending on the type of unit:
  • Surgical ICU (especially cardiothoracic surgery) has highest rate, up to ~2%.
  • Cardiac ICU:  Intermediate rate, may approach 1%.
  • Medical ICU:  Lowest rate, <<1%.
• Risk varies depending on drugs and dosages:
  • Unfractionated heparin is higher risk than low molecular-weight heparin
  • Heparin infusion is higher risk than DVT prophylactic doses of heparin
• Additional risk factors:  Female sex, older age, obesity, hemodialysis.
• Overall, HITT causes at most ~1% of thrombocytopenia which is seen in an ICU (so the vast majority of thrombocytopenia isn't HITT).⁶

when to evaluate for HITT

• Consider HITT in a patient recently treated with heparin and with:
  • New-onset thrombocytopenia or a platelet count that suddenly drops by 50%.
  • Skin necrosis at sites of heparin injection.
  • Anaphylactoid response to systemic heparin infusion.
  • Venous and/or arterial thromboses.
• Evaluation begins with risk-stratification using the 4T score.²

interpretation of the 4T score:

• 0-3 points:  Low probability (<<1%)
  • No further workup of HITT is indicated (avoid checking heparin-PF4 antibodies).
• 4-5 points:  Intermediate probability (~10%)
  • Stop heparin & check anti-PF4 antibody titer
  • Consider therapeutic anticoagulation with non-heparin agent (more on this below).
• 6-8 points:  High probability (50%)
  • Stop heparin & check anti-PF4 antibody titer
  • Initiate therapeutic anticoagulation with a non-heparin agent

PF4 antibody titer (ELISA for Heparin-PF4 antibody complex)

• This test detects any antibodies that bind the heparin-PF4 complex.  However, most antibodies that bind this complex don't cause clinical HITT.
• Overall heparin-PF4 has high sensitivity but poor specificity (it's positive in ~15% of ICU patients).⁷  Therefore, a negative result largely excludes HITT, but a positive result doesn't prove the diagnosis of HITT.  Care should be taken to avoid ordering this test indiscriminately, because that will increase the generation of false-positive results.
• PF4 is often treated as a binary test (positive/negative) but this is a gross over-simplification.  In reality, the risk of HITT increases with increasing antibody titer as shown above.
• The best way to interpret the PF4 level is in combination with the 4T score, using Bayesian analysis:

Serotonin Release Assay (SRA) 

• This is the gold-standard diagnostic test with excellent sensitivity and specificity.
• Unfortunately, this test is expensive and usually takes several days to return.  In some cases, empiric therapy for HITT is indicated while waiting for the serotonin release assay to result.

when to initiate empiric anticoagulation therapy for HITT

• (1) For patients with clinical thrombosis (e.g. DVT/PT) on therapeutic heparin anticoagulation, heparin should be switched to a non-heparin agent such as argatroban (more on this below).
• (2) For patients without clinical thrombosis who have a high likelihood of HITT (e.g. ~50%), empiric anticoagulation with a non-heparin agent should generally be started empirically before the diagnosis is confirmed.  Delaying therapy for HITT carries a significant risk of thrombosis, so anticoagulation is generally rational in high-likelihood patients.⁸
• (3) For patients without clinical thrombosis who have an intermediate likelihood of HITT (e.g. ~10-15%), management is controversial.⁹  If the patient is thrombocytopenic due to another cause, then anticoagulation could compound thrombocytopenia to cause major bleeding.¹⁰  Thromboelastography might theoretically be helpful here, because HITT seems to associate with a hyper-coagulable pattern whereas hypo-coagulability would argue against HITT and potentially signal harm from anticoagulation.^11,12  A sensible compromise might be to use a DVT-prophylactic dose of fondaparinux in this situation (2.5 mg sq. daily).³  Ultrasonography should be performed to exclude DVT if this hasn't already been done.  Ongoing evaluation for HITT should be expedited, with further management depending on the results of additional testing.

non-heparin anticoagulants for HITT 

• Argatroban is the most commonly used agent.¹³
  • Small molecule which directly inhibits thrombin (figure above).
  • Cleared by the liver with ~45-minute half-life.  Coagulation will normalize two hours after holding the infusion, if hepatic function is normal.
  • Monitored with aPTT level, targeting aPTT 1.5-3 times baseline.
  • Make sure to obtain a baseline aPTT before starting the argatroban infusion.  If the PTT is elevated at baseline and this is unrecognized, it may lead to subtherapeutic argatroban dosing (“PTT confounding”).⁶
  • Starting dose is a 2 ug/kg/min infusion, possibly lower in multi-organ failure (1 ug/kg/min) or hepatic dysfunction (0.5 ug/kg/min).
  • Medscape monograph on argatroban.
• Fondaparinux is another option
  • Full-dose fondaparinux is often avoided in the ICU, because in case of bleeding it is impossible to reverse and it has a relatively long half-life  (~20 hours).
  • The DVT prophylactic dose of fondaparinux may be reasonable for patients with possible HITT and with no evidence of thrombosis, as explored above (2.5 mg sq daily).
  • Fondaparinux is cleared by the kidneys, so this cannot be used in patients with significant renal dysfunction.
  • Medscape monograph on fondaparinux.

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investigation of thrombocytopenia

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chart review

• Chronicity of thrombocytopenia?   (Obtaining baseline CBC from prior admissions or from other hospitals may be extremely helpful.)
• Medication review?  (Many drugs can cause thrombocytopenia, not all of which are listed above.)
• Calculate the 4T score for HITT (see above)
• Recent events known to cause thrombocytopenia (e.g. massive transfusion, surgery, hemodialysis, intra-aortic balloon pump, ECMO, transfusion)?

thrombocytopenia tests to consider:  

• Core investigations
  • Platelet count in citrated tube to exclude pseudothrombocytopenia (blue top tube)
  • Blood smear
  • Coagulation studies (INR, PTT)
  • DIC labs (fibrinogen, D-dimer)
• Additional studies to consider
  • Heparin-PF4 antibody to evaluate for HITT if the 4T score is 4-8
  • Ferritin, if concern for hemophagocytic lymphohistiocytosis (HLH)
  • Ultrasonography to evaluate for DVT (if HITT or other thrombogenic forms of thrombocytopenia are possible)
  • Liver function tests, if concern for cirrhosis
  • Thromboelastography (TEG) may be considered in selected cases.¹⁴

immediate management steps to consider (while awaiting labs)

• Discontinue heparin if there is concern for HITT.
• Discontinue other potentially causative drugs if possible.
• Review all anti-coagulating medications and consider holding them, if there is concern for possible hemorrhage (especially anti-platelet drugs).
• Consider platelet transfusion (next section).

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platelet transfusion

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indications & contraindications to platelet transfusion 

• Relative contraindications to platelet transfusion:
  • HITT
  • TTP/HUS
  • DIC with clinical thrombosis
• Conventional transfusion targets:
  • Target >100 if active intracranial hemorrhage or pre-operative before neurosurgery/ophthalmic surgery.
  • Target >50 if active bleeding or pre-operative (non-neurologic surgery).
  • Target >20 possibly in patients with other coagulopathies (e.g. DIC, severe renal dysfunction).⁵
  • Target >10 in most patients.

response to platelet transfusion

• Platelets may be given in one of the forms listed below, which are functionally equivalent.  Either one should increase platelet count by roughly 30,000-60,000.
  • 4-6 pack of pooled platelets from multiple donors.
  • One unit of platelets obtained using apheresis from a single person.
• If the patient doesn't respond appropriately to platelet transfusion, this may be investigated by checking a platelet level one hour after the next platelet transfusion.
  • If the 1-hour platelet level fails to increase appropriately, this implies immune platelet consumption.   In addition to the causes of immune platelet consumption listed above, this can also be due to alloimmunization (antibodies against donor platelet antigens).  Alloimmunization may be managed by obtaining HLA-matched platelets (with the help of the blood bank).
  • If the 1-hour platelet level increases appropriately and then platelet count falls over the following day, this indicates non-immune platelet consumption (causes listed above).

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algorithms

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Approach to thrombocytopenia

Approach to HITT

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podcast

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Follow us on iTunes

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• Avoid checking HITT labs if the 4T score is 0-3 points.  These patients are at very low risk for HITT, so if the heparin-PF4 test is positive it is probably a false-positive.
• Avoid platelet transfusions unless truly indicated.  Platelet transfusion has a significant side-effect profile, and transfused platelets often don't last long anyway.
• Warfarin is contraindicated in the acute (thrombocytopenic) phase of HITT.  Initiation of warfarin in this context may cause depletion of endogenous anticoagulants (proteins C and S), leading to ischemic limb necrosis.
• Avoid the use of unfractionated heparin for DVT prophylaxis if possible, given that unfractionated heparin causes a substantially higher risk of HITT compared to low molecular weight heparin (e.g. enoxaparin) or fondaparinux.⁶
• Don't assume that a “positive” anti-PF4 antibody proves a diagnosis of HITT.  The significance of a positive result depends on the antibody titer.  A validated Bayesian algorithm incorporating the 4T score and anti-PF4 antibody titer is probably the best way to approach this:¹⁵

Going further: 

• Thrombocytopenia
  • Thrombocytopenia (Chris Nickson, LITFL)
  • Thrombocytopenia (WikEM)
• HITT
  • Heparin Induced Thrombotic Thrombocytopenia (Chris Nickson, LITFL)
  • HIT overview (PulmCCM)

References