CONTENTS

general approach to thrombocytopenia

• Overview & definition
• General differential diagnosis
• Clinical clues & specific situations:
  • Thrombocytopenia + thrombosis
  • Platelets <20,000
  • Thrombocytopenia + sepsis
  • Thrombocytopenia + cardiac patient
  • Thrombocytopenia + pregnancy
  • Mean platelet volume
• APPROACH of thrombocytopenia
• Platelet transfusion
  • Transfusion-refractory or no platelets available

HIT (heparin-induced thrombocytopenia)

• Epidemiology
• HIT evaluation:
  • [1] Initial evaluation & 4T score
  • [2] PF4 titer
  • [3] Serotonin release assay
• Management

other causes of thrombocytopenia

• Drug-induced immune thrombocytopenia (D-ITP)
• Transfusion-related thrombocytopenia

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overview & definition

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overview

• Thrombocytopenia (<150,000 platelets) is extremely common in the ICU. It is often a poor prognostic sign that is associated with systemic inflammation.
• Most cases of thrombocytopenia 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:
• [1] Severe thrombocytopenia (<50,000 platelets).
• [2] Features of HIT (e.g., abrupt drop in platelet count by >50%, skin necrosis at the site of heparin injection). A discussion of when to evaluate for HIT is below: ⚡️
• [3] Clinical thrombosis.
• [4] The underlying disease process is unclear, raising the 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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[1/5] pseudothrombocytopenia

• Clues suggesting pseudothrombocytopenia:
  • Clumped platelets may be seen on the blood smear. Platelets may also coat the surface of neutrophils (platelet satellitism). (30579402)
  • MPV ⚡️ (mean platelet volume) may increase.
• Pseudothrombocytopenia is an artificially low platelet count due to in vitro aggregation induced by EDTA in blood tubes.
• A definitive diagnosis is based on measuring a higher platelet count when blood is drawn in a citrated blood tube (“blue top platelet tube”).
• Pseudothrombocytopenia is usually meaningless but can be associated with lupus, vasculitis, or lymphoma. (28808508)

[2/5] reduced platelet production

• Clinical clues:
  • This is often subacute/chronic and frequently present before critical illness. However, the average platelet lifespan is ten days, so acutely reduced synthesis can cause thrombocytopenia within days.  
  • Concurrent leukopenia and/or anemia. 
• Infection:
  • EBV, VZV.
  • HIV.
  • Parvovirus.
• Drugs & toxins:
  • Alcohol (direct marrow toxicity; can be suggested by macrocytosis; platelets should rise within 2-5 days of cessation). (31269407)
  • Antimicrobial agents:
    • Antiviral agents (some).
    • Linezolid.
    • Penicillins/cephalosporins.
    • Trimethoprim/sulfamethoxazole.
  • Chemotherapy.
  • NSAIDs.
  • Thiazides.
• Nutritional deficiency:
  • B12 deficiency.
  • Folate deficiency.
  • Iron deficiency (rare; iron deficiency usually causes thrombocytosis). (31444663)
• Primary bone marrow disorder:
  • Myelodysplastic syndrome.
  • Infiltration of the bone marrow.
• Cirrhosis (reduced thrombopoietin production).

[3/5] non-immune consumption

• Clinical clues: Often gradual decrease over several days, adequate response to platelet transfusion.
• Disseminated intravascular coagulation (DIC).
• Large PE or DVT.
• Sepsis, especially due to:
  • Anaplasmosis/ehrlichosis.
  • Babesiosis.
  • Rocky Mountain spotted fever.
  • Hantavirus pulmonary syndrome.
  • Leptospirosis.
• Surgery, trauma.
• Devices:
  • Intra-aortic balloon pump.
  • Impella.
  • Hemodialysis.
  • ECMO.
• Thrombotic microangiopathies, e.g.: 📖
  • TTP.
  • HUS.
  • HELLP.
• HLH (hemophagocytic lymphohistiocytosis).
• CAPS (catastrophic antiphospholipid antibody syndrome).

[4/5] immune consumption

• Clinical clues:
  • It often occurs several days after ICU admission.
  • The fall in platelets is abrupt (>50% fall in 24-48 hours).
  • There is often severe thrombocytopenia, which is poorly responsive to platelet transfusion
• HIT.
• Drug-induced immune thrombocytopenia (D-ITP).
• Post-transfusion purpura.
• Passive alloimmune thrombocytopenia.
• Idiopathic thrombocytopenic purpura (ITP) is a diagnosis of exclusion.

[5/5] abnormal distribution or dilution

• Massive transfusion.
• Splenic sequestration.
• Hypothermia (platelets are sequestered in the spleen and peripheral tissues).

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clinical clues & specific situations

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The differential diagnosis of thrombocytopenia is broad. Below are some clues that may help you 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.

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thrombocytopenia with (paradoxical) clinical thrombosis

• HIT (heparin-induced thrombocytopenia).
• Spontaneous HIT (without heparin exposure):
  • Rare, usually following major surgery, especially orthopedic procedures.
  • Anti-PF4 antibodies are positive (may react with endogenous heparins).
• DIC of a pro-thrombotic type, including:
  • Acute DIC/liver necrosis/limb necrosis syndrome: Shock liver causes depletion of protein C and antithrombin, with subsequent microvascular thrombosis of extremities. (26539932)
  • Associated with malignancy (similar to marantic endocarditis).
  • Associated with sepsis.
• Cirrhosis.
• APLS (antiphospholipid antibody syndrome), including CAPS (catastrophic antiphospholipid antibody syndrome 📖).
• Massive clot thrombocytopenia – Venous thromboembolic disease itself may cause mild thrombocytopenia. (28808508, 27982413)
• TTP (thrombotic thrombocytopenic purpura).
• Paroxysmal nocturnal hemoglobinuria (rare)

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

• Immune-mediated thrombocytopenia of any cause:
  • D-ITP (drug-induced immune thrombocytopenia).
  • HIT causes severe thrombocytopenia in ~10% of cases (generally, when HIT causes simultaneous DIC). (25590528)
  • Transfusion-related (post-transfusional purpura, passive alloimmune thrombocytopenia)
  • 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). (29222318)

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thrombocytopenia in septic-appearing patient

• DIC due to infection.
• Specific infections have a proclivity for causing thrombocytopenia (ehrlichiosis, babesiosis, anaplasmosis, rocky mountain spotted fever, hantavirus, leptospirosis, dengue).
• Hemophagocytic lymphohistiocytosis (HLH) – either mimicking sepsis or HLH secondary to infection.📖
• Drug-induced thrombocytopenia (including various antibiotics).

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thrombocytopenia in the cardiac patient

• HIT (heparin-induced thrombocytopenia).
• Devices and procedures:
  • Cardiopulmonary bypass.
  • ECMO.
  • IABP (intra-aortic balloon pump).
  • Impella.
• Drug-induced thrombocytopenia, including:
  • TTP (thrombotic thrombocytopenic purpura) related to clopidogrel.
  • GPIIb/IIIa inhibitors.

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thrombocytopenia in pregnant patient

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

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MPV (mean platelet volume)

basics

• MPV is often reported with routine complete blood counts (even without a differential order).
• Normal MVP is 9.5-12.7 fL.
• Younger platelets tend to have a higher MPV and greater pro-thrombotic activity.
• Numerous factors affect mean platelet volume so that the trends may be more useful than absolute values.

interpretation of mean platelet volume

• MPV may be most useful in the evaluation of thrombocytopenia: (38033118)
  • Elevated MPV suggests a consumptive thrombocytopenia, which may increase platelet production. (30579402) A transient elevation of MPV may also occur in patients with pseudothrombocytopenia due to platelet clumping.  
  • Reduced MPV suggests impaired bone marrow production of platelets, leading to an increased fraction of older platelets.
• Inflammation may increase mean platelet volume (cytokines, especially IL6, stimulate platelet release from the bone marrow).

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approach to thrombocytopenia

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chart review

• Chronicity?
• Medication review: innumerable medications can cause thrombocytopenia, but common offenders in the modern ICU include:
  • Acetaminophen. (rare; D-ITP).
  • Antibiotics:
    • Amphotericin.
    • Linezolid.
    • Penicillin, methicillin.
    • Rifampin.
    • Trimethoprim-sulfamethoxazole.
    • Vancomycin.
  • Cardiac medications:
    • Amiodarone.
    • Digoxin.
  • Diuretics: chlorothiazide, hydrochlorothiazide.
  • Heparin (HITT ⚡️).
  • Neurologic:
    • Carbamazepine.
    • Haloperidol.
    • Phenytoin.
    • Valproic acid.
• Recent events known to cause thrombocytopenia:
  • Massive transfusion?
  • Surgery?
  • Hemodialysis?
  • Intra-aortic balloon pump or impella?
  • ECMO?
  • Transfusion?
• Calculate the 4T score for HIT: ⚡️

physical examination

• Evaluate for petechiae or purpura (especially on the legs, around the blood pressure cuff, and in the mouth). (31269407) Substantial petechiae/purpura has several implications:
  • [1] This supports that the thrombocytopenia is real (not spurious).
  • [2] This argues against processes that promote thrombosis (e.g., HIT).
  • [3] This may support the benefit of platelet transfusion. 📖

basic thrombocytopenia lab panel

• [1] Platelet count in a citrated tube to exclude pseudothrombocytopenia (blue top tube).
• [2] INR, PTT, fibrinogen, D-dimer.
• [3] Blood smear: 📖
  • Platelet clumps or satellitism (platelets clumped around neutrophils) suggests pseudothrombocytopenia.
  • Schistocytes may suggest thrombotic microangiopathy. 📖
  • Blasts may reveal acute leukemia.
  • Atypical lymphocytes may suggest unusual infections. 📖
  • Spherocytes may suggest autoimmune hemolytic anemia with Evan's syndrome.

additional studies to consider

• Consider the parameters of the CBC:
  • Abnormal MPV (mean platelet volume) may occasionally provide some clues about etiology. ⚡️
  • Abnormal MCV could rarely provide information regarding impaired platelet count due to nutritional deficiency (elevated MCV suggests folate or B12 deficiency; reduced MVC may suggest iron deficiency).
• Heparin-PF4 antibody to evaluate for HIT only if the 4T score is 4-8.
• Ferritin, if concern for hemophagocytic lymphohistiocytosis (HLH). 📖
• Liver function tests, if concern for cirrhosis.
• Thromboelastography (TEG) may be useful, especially for patients with DIC or cirrhosis. (29595638)
• Folate level.
• Ultrasonography:
  • Ultrasonography to evaluate for DVT (if HIT or other thrombogenic forms of thrombocytopenia are possible).
  • Splenomegaly evaluation. 📖

immediate management concerns:

• [1] Consider the immediate risk of hemorrhage:
  • Review all anticoagulating medications and consider discontinuation (especially antiplatelet agents).
  • Consider platelet transfusion. 📖
• [2] Emergent causes of thrombocytopenia to always consider:
  • HIT. 📖
  • TTP. 📖

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platelet transfusion

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relative contraindications to platelet transfusion

• HIT.
• Thrombotic microangiopathy (e.g., TTP, HUS).
• DIC with clinical thrombosis.

platelet transfusion targets?

• Limitations in the concept of platelet transfusion target:
  • (1) Clinical bleeding doesn't track well with platelet count. Numerous other factors affect the risk of bleeding (e.g., age, uremia, use of anticoagulant/antiplatelet agents).
  • (2) Platelet targets for various procedures are based primarily on convention than actual evidence.
• Conventional transfusion targets:
  • Target >100 if:
    • Active intracranial hemorrhage.
    • Pre-operative before neurosurgery/ophthalmic surgery.
  • Target >50 if:
    • Active hemorrhage.
    • Pre-operative (non-neurological surgery).
  • Target >20 if:
    • Other coagulopathies (e.g., severe renal failure).
    • The patient is receiving platelet inhibitors or anticoagulants.
    • Pre-operative before bronchoscopy with bronchoalveolar lavage. (29222318, 23860341)
  • Target >10 if:
    • None of the above criteria apply.
• An alternative approach is to use a TEG-based transfusion strategy. Patients with thrombocytopenia often have a preserved maximal amplitude (MA), suggesting that platelet transfusion is unnecessary. 📖 Ultimately, the risks and benefits of transfusion should be considered for each individual patient.

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approach to the platelet-refractory patient or exhaustion of the hospital's platelet supply

diagnosis: 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.
  • 💡 A more precise approach to determine whether the platelet count has increased appropriately is to use the Corrected Count Increment (CCI). 🧮
• 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.
  • If the 1-hour platelet level increases appropriately and then the platelet count falls over the following day, this indicates non-immune platelet consumption (causes listed above).

strategies to improve the response to platelet transfusion

• Evaluate and treat for other causes of thrombocytopenia (especially immune etiologies such as drug-induced immune thrombocytopenia, HIT, or post-transfusion purpura).
• HLA-matched platelets: If the patient has HLA antibodies, a transfusion of HLA-matched platelets may be helpful. However, this may fail to work in 20-70% of patients. (Irwin & Rippe 9th ed)
• Platelet drip: consider a continuous infusion of platelets at a rate of 1 U over 6 hours. (Irwin & Rippe 9th ed)

strategies to improve platelet function and hemostasis (other than platelet transfusion)

• Restoring platelet counts using transfusion may be the ideal solution to thrombocytopenia, but this is not always feasible for several reasons:
  • Platelets may be rapidly consumed.
  • The hospital may lack compatible platelets.
  • Some smaller hospitals may lack immediate access to platelet transfusion.
• Alternative approaches to improve hemostasis may include the following:
  • Desmopressin (DDAVP) may cause a temporary improvement in platelet function and hemostasis. 📖 (30579402)
  • Targeting unusually high fibrinogen levels (e.g., >200 mg/dL) may be considered. Platelets and fibrinogen function together to physically form a clot. To a certain extent, one deficiency may be compensated for by an excess in the other.
  • Antifibrinolytic therapy may be considered (either tranexamic acid or aminocaproic acid).

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heparin induced thrombocytopenia

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introduction

• HIT results from autoantibodies which react to an antigen created by the combination of heparin plus platelet factor 4 (PF4). These antibodies cause activation of platelets, leading to arterial and venous thrombosis. Consumption of activated platelets leads to thrombocytopenia.
• HIT is rare, yet important to recognize early. HIT is challenging to diagnose, because the vast majority of patients with DVT or thrombocytopenia won't have HIT.
• In ~10% of cases, HIT 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 HIT and DIC can be difficult to diagnose, because the unusually low platelet count will confound diagnostic algorithms for HIT.

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epidemiology of HIT

• [1] Clinical context:
  • Surgical ICU (especially cardiothoracic and orthopedic surgery) has the highest rate, up to ~2%.
  • Cardiac ICU: Intermediate rate, may approach ~1%.
  • Medical ICU: Lowest rate, <<1%.
  • Obstetric patients: Rare. (34288442)
• [2] Unfractionated heparin is almost ten times higher risk than low molecular weight heparin. (32904403) At one center, efforts to avoid unfractionated heparin successfully reduced the HIT rate. (AVOID heparin initiative; 26817956)
• [3] Therapeutic heparin dosing is much more likely to cause HIT than prophylactic dosing (risk of 0.76% versus <0.1% in one study). (17400685)
• [4] Additional risk factors:
  • Female sex (odds ratio ~2).
  • Older age (less common <40 years old; rare in very young patients).
  • Higher risk with duration of heparin exposure >5 days. (37601013)

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[1] initial HIT evaluation & 4T score

evaluate for HIT if one of the following is noted: 

• Platelet count suddenly drops by >50%.
• New-onset thrombocytopenia with platelet count <100,000. (Irwin & Rippe 9th Ed)
• Skin necrosis at sites of heparin injection.
• Anaphylactoid response to systemic heparin infusion.
• Venous and/or arterial thrombosis, including:
  • DVT and/or PE.
  • Ischemic stroke.
  • Myocardial infarction.
  • Limb necrosis.

4T score

• Thrombocytopenia:
  • % drop is calculated using the peak platelet count after heparin was started (i.e., not necessarily the day heparin started). (37601013)
  • 2 points: >50% drop AND nadir >20,000.
  • 1 point: 30-50% drop OR nadir 10-19,000.
  • 0 points: <30% drop OR nadir <10,000.
  • ~90-95% of patients with HIT have platelets <150,000. HIT with a normal platelet count may occur if the baseline platelet count is high.  
  • The nadir is often ~60,000.
  • Platelets <20,000 is rare and casts some doubt on the diagnosis of HIT. However, ~10% of HIT patients also have DIC, which may push the platelets below <20,000.  
• Timing:
  • In many patients, platelet fall is biphasic: an initial decline results from non-HIT illness (e.g., surgery), followed by a rebound and a second, HIT-induced sharp decline. (37601013)
  • 2 points:
    • Fall 5-10 days after starting heparin.
    • Fall 1 day after starting heparin in a patient exposed within the past month.
  • 1 point:
    • Platelets fall after >10 days.
    • Fall 1 day after starting heparin & exposure to heparin in the past 30-100 days.
    • Fall possibly 5-10 days after starting heparin (data incomplete).
  • 0 points:
    • Fall <5 days without exposure to heparin in the past 100 days.
• Thrombosis:
  • This only includes thrombosis that occurred or progressed after heparin exposure.
  • 2 points:
    • New arterial or venous thrombosis, e.g.:
      • DVT/PE.
      • MI.
      • Acute ischemic stroke.
      • Limb ischemia.
    • Skin necrosis at the site of heparin injection.
    • Anaphylactoid reaction to IV heparin bolus.
    • Adrenal hemorrhage.
  • 1 point:
    • Recurrent or progressive venous thrombosis.
    • Suspected thrombosis awaiting imaging.
    • Erythematous skin lesion at the site of heparin injection.
  • 0 points: No thrombosis.
• oTher explanation:
  • 2 points: No alternative explanation.
  • 1 point: Possible alternative explanation.
  • 0 points: Definite alternative explanation. (28808508)

interpretation of the 4T score:

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

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[2] heparin-PF4 antibody titer as measured using ELISA

interpretation of anti-PF4 antibody titer

• <0.6 = Negative
  • The likelihood ratio for having HIT is ~0.04
  • This generally excludes HIT.
  • If the 4T score is 6-8 and there is an unusually strong clinical concern regarding HITT, it might be reasonable to check a serotonin release assay.
• 0.6-1.5 = Indeterminant
  • The likelihood ratio for having HIT is ~1.2.
  • This result provides no information about the risk of HITT.
  • This is commonly misconstrued as “positive” for HITT – but it’s actually not.
  • If the 4T score is 4-5, the post-test probability of HIT is 10-15%.
  • If the 4T score is 6-8, the post-test probability of HIT is ~60%.
• 1.5-2 = Positive
  • The likelihood ratio for having HIT is ~7
  • If the 4T score is 4-5, the post-test probability of HIT is ~50%.
  • If the 4T score is 6-8, the post-test probability of HIT is ~90%.
• >2 = Strongly positive
  • The likelihood ratio for having HIT is ~70.
  • If the 4T score is 4-5, the post-test probability of HIT is ~91%.
  • If the 4T score is 6-8, the post-test probability of HIT is ~99%. (37601013, 24363239, 28622439)

background on the heparin-PF4 antibody

• This test detects any antibodies that bind the heparin-PF4 complex. However, most antibodies that bind this complex don't cause clinical HIT. Only IgG antibodies are pathologic (due to binding platelet surface Fc receptors), so assays specific for IgG anti-PF4 antibodies may have slightly higher specificity. (31069988)
• The heparin-PF4 antibody generally has a high sensitivity with a poor specificity. Therefore, a negative result largely excludes HIT, but a positive result doesn't prove the diagnosis of HIT. Care should be taken to avoid ordering this test indiscriminately because that will generate false-positive results (e.g., it shouldn't be ordered if the 4T score is 0-3).
• The heparin-PF4 test must be interpreted using the precise antibody titer combined with the 4T score (in a Bayesian fashion; see the section above). However, precise levels can vary somewhat between different assays, so some caution is required. (37601013, 24363239, 28622439)

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[3] SRA (serotonin release assay)

• 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 HIT is indicated while waiting for the serotonin release assay to result.
• The sensitivity of the serotonin release assay isn't perfect. Thus, if a patient has a very high anti-PF4 antibody titer and a negative serotonin release assay result, HIT may remain possible. (34288442) Ticagrelor and possibly other antiplatelet agents might lead to false-negative serotonin release assay results. (33578859)

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management

[1] stop heparin and place a heparin allergy in the computer

• The heparin allergy will prevent inadvertent administration of heparin.

[2] consider anticoagulation

• Indications for anticoagulation:
  • For patients with clinical thrombosis (e.g., DVT/PT) on therapeutic heparin anticoagulation, heparin should be switched to a non-heparin agent.
  • For patients without clinical thrombosis who have a high likelihood of HIT (e.g., ~50%), empiric anticoagulation with a non-heparin agent should generally be started empirically before the diagnosis is confirmed. Delaying therapy for HIT carries a significant risk of thrombosis, so anticoagulation is generally rational in high-likelihood patients. (26847066)
  • For patients without clinical thrombosis who have an intermediate likelihood of HIT (e.g., ~10-15%), management is controversial. (30502310) If the patient is thrombocytopenic due to another cause, then anticoagulation could compound thrombocytopenia to cause major bleeding. (29253554) Thromboelastography might theoretically be helpful here because HIT seems to be associated with a hypercoagulable pattern, whereas a hypocoagulable pattern would argue against HIT and potentially signal harm from anticoagulation. (18056152, 17632008) A sensible compromise might be to use a DVT-prophylactic dose of fondaparinux in this situation (2.5 mg sq. daily). (26539932, 32904403) Ultrasonography of upper and lower extremities should be performed to exclude DVT if this hasn't already been done. Ongoing evaluation for HIT should be expedited, with further management depending on additional testing results.
• Non-heparin anticoagulants:
  • Argatroban 💉 is perhaps the most commonly used.
  • Bivalirudin 💉 might have an advantage among patients with hepatic dysfunction. 
  • Fondaparinux 💉 could be considered in intermediate-likelihood situations at a reduced dose (2.5 mg sq daily).

discontinue warfarin and give IV vitamin K in acutely ill patients

• Warfarin may cause protein C deficiency, especially early after initiation. Consequently, warfarin shouldn't be initiated in the context of acute HIT (until the disorder has clinically improved with a non-heparin anticoagulant).
• For patients with acute HIT who recently started warfarin, consider the reversal of warfarin to avoid any deficiencies of protein C or S.

IVIG (intravenous immunoglobulin)

• IVIG is hypothesized to competitively inhibit the binding of anti-PF4/heparin antibody to platelet Fc-receptors.
• This may be considered for the treatment of severe and/or refractory HIT. (28622439)

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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 (but can occur within a day, if previously sensitized to the medication).
• Immune consumption often causes severe thrombocytopenia (e.g., <10,000-20,000) with bleeding.
• Often causes systemic symptoms, including fever and chills.(27982413)
• Antibodies may also damage megakaryocytes, reducing the capacity to produce more platelets.

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:
  • Amphotericin B.
  • Beta-lactams (esp. penicillin/ampicillin/piperacillin, ceftriaxone).
  • 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:
  • Acetaminophen.
  • Aspirin.
  • Danazol.
  • Famotidine.
  • NSAIDs (esp. Diclofenac, Ibuprofen, Indomethacin, Naproxen).
  • Pantoprazole.
  • Quinine (found in tonic water and mixed drinks).
• More information, including more detailed, up-to-date lists, is here. Bolded drugs seem to be more common causes of D-ITP.

treatment

• Discontinuation of the drug will usually lead to resolution within 4-8 days. (31498668)
• It may require platelet transfusion (however, ongoing consumption will typically cause patients to be refractory to platelet transfusion).
• Intravenous immunoglobulin (IVIG) may be used in severe cases (e.g., 1 gram/kg on two consecutive days).
• Steroids don't seem to help. (30579402)

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transfusion related thrombocytopenias

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post-transfusion purpura (PTP)

• Mechanism:
  • It usually occurs in patients who lack the platelet antigen PLA-1 and were previously sensitized to this antigen. Transfusion leads to antibodies against PLA-1, which ends up destroying the patient's own platelets as well.
• Epidemiology:
  • Usually, mothers (previously sensitized at pregnancy).
  • Patients with a history of transfusion or transplantation.
• Clinical presentation:
  • Occurs ~5-10 days after transfusion of platelets, packed RBCs, or whole blood.
  • 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 alloantibodies in the patient's serum.
• Treatment:
  • IV immunoglobulin may be the front-line therapy, possibly combined with steroids. (33707107)
  • Avoid unmatched platelets. Transfusion of platelets from compatible donors may be more effective (HPA-1a antigen-negative platelets).

passive alloimmune thrombocytopenia

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

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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 HIT labs if the 4T score is 0-3 points. These patients are at very low risk for HIT, 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 HIT. 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 HIT compared to low molecular weight heparin (e.g. enoxaparin) or fondaparinux.(25590528)
• Don't assume that a “positive” anti-PF4 antibody proves a diagnosis of HIT. 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, see section above.(28622439)

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