Platelets in critical illness

Thrombocytopenia: Platelet count < 140K. In the absence of qualitative platelet defects or vascular damage, spontaneous bleeding does not typically occur with Plt counts >30K.

HIT

• • Heparin combines with heparin-binding protein (PF4) on plts to form an ag-complex that induces the formation of IgG abs. These abs then bind to Plt and form cross-bridges that result in plt aggregation. If severe enough, this process can result in a consumptive thrombocytopenia and clinically apparent thrombosis.

  • Thrombocytopenia during heparin Tx by any route (including heparin flushes), and prompt recovery after DC heparin.

  • Plt <150,000 or decrease in Plt count of 50% or more from baseline in Pts on heparin, usually begins 5 - 14 days after the first exposure to heparin (onset is earlier in patients with prior exposure to heparin). Sometime it can be delayed and occurs after stopping heparin.

  • 5-10% with HIT will develop erythematous lesions surrounding the injection site

  • HIT complications include venous (30%-70%)and arterial thromboses, skin necrosis at injection sites, and acute systemic reactions after IV bolus administration. Systemic allergic responses can follow an IV bolus administration of heparin characterized by fever, hypotension, and cardiac arrest.

  • HIT is low with LMWH

  • HIT rarely occurs in association with fondaparinux.

Check:

• Nucleated RBCs, tear drop cells, immature myeloid forms on peripheral smear = myelophthisic process.

  • Infectious processes: HIV, fungal, mycobacterial, HHV-6, H. pylori.

  • Prolonged Vit B12, and folate def

  • ITP 2° to SLE, Hep-C, HIV, APA syndrome, or lymphoproliferative d/o.

Unfractionated heparin assay

• • Functional (plt. aggregometry or serotonin release assay): more specific

  • Serological enzyme immunoassays (heparin-PF4 complexes PF4 EIA): more sensitive.

  • For low test pretest probability of HIT, a functional test should confirm a positive PF4 EIA result.

  • Thrombosis can develop in ~50% of HIT pts, and the risk can persists for upto ~6 wks after DC of heparin. Screen for LE doppler to r/o DVT.

  • Plt count <50,000 - bleeding, <20,000 - <10,000: CNS, GI bleeding occur spontaneously.

Avoid ASA, NSAIDs, Heparin, LMWH, quinidine, quinine, rifampin, TMP/SMX, methyldopa, ethanol (directly inhibits thrombopoiesis), anti-retrovirals, clopidogrel (Plavix), THZ, digoxin, furosemide, H2 blockers, APAP, b-lactam Abx

Management of HIT:

D/c heparin, d/c heparin flushes and remove any heparinized coated intravascular catheters.

Use direct thrombin inhibitors: Lepirudin and Argatroban. These agents inhibit clot bound thrombin, and they do not cross-react with heparin antibodies.

• • Since P4 antibody test results rarely become immediately available, clinical assessment is important for initial management. A scoring system based on 4Ts improves diagnostic accuracy: thrombocytopenia, timing, thrombosis, and other explanation for thrombocytopenia.

• When HIT is strongly suspected, begin treatment by eliminating all heparin

• exposure.

  • Patients with and those at high risk for thrombosis require alternative anticoagulation with a parenteral direct thrombin inhibitor (DTI) (argatroban or lepirudin)

  • Lepirudin, prophylactic dose 0.10 mg/kg IV or 25 mg sc q12. Therapeutic dose: 0.4 mg/kg IV bolus, then 0.15 mg /kg/hr (max wt = 110 kg). Adjust dose to PTT = 1.5 x 3 control

  • Argatroban, hepatic clearance. No prophylactic dose. Therapeutic dose: 2 mcg/kg/min and adjust dose to PTT = 1.5-3 x control. Max rate = 10 mcg/kg/min. No dose adjustment in renal failure. Decrease initial dose rate to 0.5 mcg/kg/min.

  • The safety and efficacy of prophylactic or therapeutic fondaprinux therapy in HIT patients is controversial.

  • Although it lacks supportive evidence from clinical trials and it does not have FDA approval for the indication of HIT, clinicians could consider using fondaparinux for treatment of HIT if a parenteral DTI is not available. Do not substitute LMWH for UFH

  • due to high rates of cross-reactivity with HIT antibodies.

• Screen (e.g., lower extremity venous compression ultrasound [US]) to assess for asymptomatic venous thromboembolism, which mandates longer duration anticoagulation.

  • Start warfarin only after the platelet count normalizes, at an initial low dose, overlapping with a DTI for 5 days, to reduce the risk of limb gangrene due to ongoing hypercoagulable conditions and depletion of proteins C and S.

• DTIs prolong the INR and require careful monitoring when transitioning from DTI to warfarin.

  • Oral DTI and anti-Xa inhibitors (dabigatran and rivaroxaban) have not been evaluated for safety and efficacy in HIT patients with or without thromboses.

• The recommended duration of anticoagulation therapy for HIT depends on the clinical scenario: 4 weeks for isolated HIT (without thrombosis) and 3 months for HIT-associated thrombosis.

Platelets are cytoplasmic remanants of megakaryocytes

Life span: 10 d

Thrombosis: Damage to vascular endothelium > exposure of the collagen in subendothelium. Plt stick to subendothelium. Release calcium, and this activates GP IIb/IIIa rcp on the plt surface. These rcp bind irreversibly to vWF in the surrounding endothelium, and this anchors the developing plt plug. The GP IIb/IIIa rcp also bind fibrinogen, and fibrinogen bridges between plts result in plt aggregation. The released Ca also activates the coagulation cascade, and this results in the production of fibrin strands that form an interlacing mesh work with the plt to produce a thrombus.

Thrombocytopenia: plt <140 - 150K. Becomes clinically significant at <100K, bleeding tendency depends on presence of structural lesion prone for bleeding. If such a lesion is absent Plt <5K can be tolerated without evidence of bleeding.

Pseudothrombocytopenia: clumped plt due anticoagulant EDTA. Collect samples in sodium citrate as the anticoagulant.

Platelet adhesion: Ability of platelet to adhere to the subendothelium is diminshed as in uremia, the risk of H'ge is increased despite plt counts >100,000.

Causes of thrombocytopenia in ICU: sepsis, DIC, TTP, HELLP syndrome, APAP, heparin, quinidine, rifampin, TMP-SMX

Thrombocytopenia is almost always present in systemic sepsis.

AIDs causes increased plt destruction which is immune-mediated.

Drug-Induced Platelet Defects

• • Antiplatelet Agents

    • ASA

    • Plavix

    • Dipyridamole

    • GP IIb/IIIa inhibitors

    • Ticlodipine

    • NSAIDs

  • Antihistamines

    • Chlorpheniramine

    • Diphenhydramine

  • Antithrombotic Agents

    • Alteplase

    • Heparin

  • Beta-lactam ABx

    • PCN

    • Cephalosporins

  • Cardiovascular Drugs

    • CCB

    • NTG

    • Nitroprusside

  • Others

    • Hetastarch

    • Dextran

    • Haloperidol

    • Ketorolac

Classification of Thrombocytopenia

• Decreased Platelet production

  • • Marrow failure syndromes

      • Congential

      • Acquired: aplastic anemia, PNH

    • Hematological malignancies

    • Marrow infiltration: cancer, granuoloma

    • Fibrosis: primary or secondary

    • Nutritional: Vit B12 and folate deficiencies

    • Physical damage: radiation, alcohol, chemotherapy

• Increased Platelet sequestration

  • • Portal HTN

    • Felty's syndrome

    • Lysosomal storage disorders

    • Infiltrative hematological malignancies

    • Extramedullary hematopoiesis

• Increased Platelet clearance

  • • Immune mediated mechanisms

      • ITP

      • TTP

      • Post-transfusion purpura

      • HIT

    • Non-immune mediated mechanisms

      • DIC

      • Local consumption (aortic aneurysm)

      • Acute Hg'e

• Infections associated with thrombocytopenia

  • • HIV, HHV-6, ehrlichiosis, rickettsia, malaria, hepatitis C, CMV, EBV, H. pylori, E. coli O157:H7