#24 Thrombocytopenia in Critical Illness
Thrombocytopenia is a puzzling, yet common problem in the ambulatory setting, on the wards and in critically ill patients! Having an understanding of why it happens, why it matters, and what we should do about it, is of paramount importance. Given that patient care is first and foremost for us at Critical Care Time, we’ve teamed up - once again - with hematologist extraordinaire Matthew Rendo (X: RendOncology) to help us develop a pragmatic approach to managing the patient with thrombocytopenia. Please give it a listen and let us know what you think!
Show Notes:
Platelets 101
What are platelets?
Small, disc shaped cellular fragments that adhere to foci in vasculature when endothelial damage occurs.
Circulate in the blood and spleen, derived from megakaryocytes.
TPO signals the production of platelets, signal derived from liver.
Thrombocytopenia
Mild: 100-149
Moderate: 50-99
Severe: <50
Platelets are only part of the story as it related to bleeding risk – need to consider underlying disease process(es) and assess for presence of coagulopathy.
No safe platelet count for all – needs to be tailored to the patient.
Pseudothrombocytopenia:
Sampling error – clot forms in the sample, consumes platelets, the portion of the sample tested may suggest “thrombocytopenia” in that case.
Clumping – occurs in 1/1000 patients when EDTA anticoagulant 🡪 platelet clumping around WBCs (rosettes)
Repeat study w/ citrated or heparinized tube.
Causes for thrombocytopenia
Increased destruction
Immune: ITP, anti TPO Ab, amegakaryocytic thrombocytopenia (Ab 🡪 TPO receptor)
Non-Immune: Thrombotic destruction --? Diffuse vascular endothelia damage (DIC, TMA)
Decreased production
Bone marrow dysfunction: Toxins (alcohol), infiltration / fibrosis (myelofibrosis), myelodysplasia, metastatic disease to bone marrow.
Primary platelet dysfunction syndrome: Bernard-Soulier. Gray Platelet Syndrome.
Reduced TPO production: Cirrhosis
Sequestration
Seen in portal hypertension, usually due to cirrhosis.
Platelet transfusion goals
GENERAL platelet transfusion goals. These are based on fairly low-quality evidence, not uniformly followed across the globe.
>10K for all-comers
>20K in febrile patients
>50K in a bleeding patient, patent with suspected bleeding
>100K for a patient pending CNS surgery
Case 1: Sepsis and thrombocytopenia
Bacterial infections / sepsis can cause direct bone marrow suppression, often in association with other cytopenias.
May occur in the setting of DIC – will be accompanied by other coagulation abnormalities, low fibrinogen.
Consumption and destruction of platelets can also be seen, independent of DIC.
Infectious diseases that cause liver dysfunction may lead to decreased TPO production (hepatitis, rickettsial diseases)
Treatment: Treat the underlying infection
Beware of treatments CAUSING thrombocytopenia (TMP-SMX, Linezolid, etc.)
Case 2: Heparin Induced Thrombocytopenia (HIT)
When to suspect HIT?
In anyone with new onset thrombocytopenia!
Conversely: Convince yourself that you are NOT missing HIT!
PLT count drop by >50%, even if PLT is still > 150
Presence of clots or skin necrosis at heparin injection site(s)
Systemic symptoms: fevers/chills, tachycardia, hypertension, dyspnea, (rarely can present with cardiopulmonary arrest)
Cause?
Antibody against endogenous platelet-factor-4 complex with heparin.
Antibody leads to platelet activation, causing arterial and venous thrombi.
Mortality: ~20% if untreated
How common?
20,000 cases per year in the United States or 1/1500 hospitalizations
Less common in those treated with low-molecular weight heparin, however, the data is not consistent and of poor quality (i.e. the belief that LMWH cannot cause HIT has been refuted)
Trauma / trauma surgery, extracorporeal membrane oxygenation seem to be risk factors for development of HIT
4T Score
If you suspect HIT calculate a 4T score
Interpretation
< 3 = unlikely
4-5 = intermediate
> 5 = probable/likely
HIT Work Up
ELISA test: detects antibodies against PF4/heparin.
Does not test ability of these antibodies to activate platelets.
If ELISA is intermediate, proceed with a functional platelet activation assay to confirm = SRA or serotonin release assay (detects antibodies that induce heparin-dependent platelet activation)
Approach to treatment
Stop heparin
Extremity U/S (upper if IVs are in place, lower for all patients)
Utilize a non-heparin anticoagulant
Argatroban, bivalirudin, fondaparinux (which does not trigger formation of the antibody/PF4 complex despite molecular similarities to heparin).
DOACs such as dabigatran, apixaban, rivaroxaban, edoxaban.
Warfarin: May be an option, but must be used in concert with another non-heparin anticoagulant given that warfarin therapy causes a pro-thrombotic state in the first few days of therapy due to inhibition of protein C & S production (which naturally protect against dysregulated blood clotting)
Duration of therapy for HIT:
At least 3 months, with absence of clot x at least 4 weeks
Differential / alternative diagnoses to consider:
DIC (low fibrinogen), sepsis/infection 🡪 BM suppression
ITP (no association with heparin or clotting), drug induced ITP (consider if on vancomycin, pip-tazo, NSAIDs, APAP, sulfonamides)
Post-transfusion purpura (PTP, prior pregnancy with recent transfusion)
Won’t usually see clots, skin necrosis present, PLT less than 20
Thrombotic microangiopathic angiopathy (TTP, HUS, Drug-Induced aka DITMA)
Will typically see schistocytes on peripheral smear, hemolysis.
Antiphospholipid syndrome, lupus – typically mild thrombocytopenia with arterial and venous clots
Bonus Resource!
Check out this excellent visual resource on HIT.
Case 3: The Liver & Thrombocytopenia
Thrombocytopenia is very common in liver disease.
Reduction in TPO in moderate-to-advanced liver disease
Acutely worsened due to acute alcohol ingestion and BM toxicity – mechanism is not well understood
Decreased synthetic function may 🡪 decreased fibrinogen, thrombin, factors V, VII, IX, X, XI
Portal venous changes and portal hypertension 🡪 increased splenic sequestration.
Portal venous thrombosis risk is higher in cirrhosis, can cause some degree of consumption.
Cirrhosis portends and increased risk of GI bleeds, also can be consumptive.
Recognize: cirrhosis is associated with thrombocytopenia, but also coagulopathy and not necessarily an overt tendency to bleed
INR is not a reliable indicator of “increased tendency towards bleeding” in cirrhosis – it is a test designed to assess warfarin function, not sufficient to assess the complexities of bleeding & clotting in cirrhosis
Case 4: Thrombocytopenia associated with acute illness & hemolysis
If you see hematochezia and fevers with thrombocytopenia, ? airway bleeding & elevated LDH think about a marked coagulopathy and/or hemolytic anemia
DIC DAT SMEAR
DIC: Consider this diagnosis, especially in a critically ill patient with bleeding/clotting occurring simultaneously, thrombocytopenia, perhaps liver enzyme abnormalities, low fibrinogen, high d-dimer, schistocytes on peripheral smear
DAT: Direct antiglobulin test (Coomb’s Test) to assess for circulating antibodies that could cause a hemolytic anemia
Smear: Peripheral smear with anemia and schistocytes concerning for a microangiopathic hemolytic anemia (MAHA) – which could include DIC (that diagnosis would be supported by additional findings as reference above)
MAHA & Thrombocytopenia
Think about common etiologies… start Droppin’ DIMESS
D: DIC
I: Infections
M: Malignancies
E: Eclampsia
S: SEVERE Hypertension
S: SEVERE Rheumatic Diseases
Thrombocytopenia & other disease
TTP (Think about TTP with anemia + schistocytes + normal coags in a critically ill patient)
ADAMTS13 deficiency – this enzyme cleaves VWF multimers in the vasculature, deficiency 🡪 propagation of multimers allowing for formation of platelet microthrombi.
Kidney injury is UNCOMMON in TTP, fever is also not commonly seen.
Neurologic symptoms: 1/3 have none, 1/3 have mild symptoms, 1/3 have severe neurologic findings.
PLASMIC Score can help determine likelihood of TTP:
Score = 5 is intermediate
Score = 6+ is high
Treatment
PLEX until an ADSMTS13 assay returns (<10% is diagnostic)
Can also use steroids, rituximab can be added once ADAMTS13 assay returns and is <10%.
Caplacizumab: Monoclonal antibody fragment that binds VWF and prevents it from interacting with platelet glycoproteins, preventing microthrombi formation.
Response to therapy = PLT count > 150 x2 days (or plateaus for 3 days)
ST-HUS (Shiga Toxin Associated Hemolytic Uremic Syndrome)
Hx: Exposure to farm animals, undercooked meat. Usually occurs several days prior to symptoms which occur due to Shigella dysenteriae and E. coli (O157:H7 strain) here toxins 🡪 kidney epithelial damage and vascular endothelial cell damage.
Sxs: Prodrome of bloody diarrhea + kidney injury and evidence of MAHA and thrombocytopenia, which typically occurs days after the onset of GI symptoms.
Treatment: Mostly supportive with transfusions and dialysis if/when necessary.
Complement Mediated Thrombotic Microangiopathy (CM-TMA)
Consider this if a patient has severe AKI as eculizumab – a terminal complement blocking agent – may prevent end-stage kidney disease.
Occurs commonly due to autoantibody against complement factor H 🡪 uncontrolled activation of complement on cell membranes, including the vascular endothelium.
Immune Thrombocytopenic Purpura (ITP)
Autoimmune disease characterized by thrombocytopenia, purpura and hemorrhagic episodes due to antiplatelet antibodies.
Treatment: usually steroids, B-Cell targeted agents meant to counter the production of these antibodies.
Could consider Eltrombopag, Avatrombopag or Romiplostim in refractory disease – these are TPO analogs. Also used in the setting of aplastic anemia in conjunction with immunosuppressive therapy, and in chronic hepatitis C associated thrombocytopenia.
Audio
Video
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Teran F, Prats MI, Nelson BP, et al. Focused transesophageal echocardiography during cardiac arrest resuscitation: jacc review topic of the week. J Am Coll Cardiol. 2020;76(6):745-754.
Arntfield R, Lau V, Landry Y, Priestap F, Ball I. Impact of critical care transesophageal echocardiography in medical-surgical icu patients: characteristics and results from 274 consecutive examinations. J Intensive Care Med. 2020;35(9):896-902.
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Undifferentiated Shock
Cardiac Arrest