Pocket Oncology (Pocket Notebook Series), 1st Ed.

PLATELET DISORDERS

Neil M. Iyengar and Rekha Parameswaran

Normal Platelet Function – Hemostasis

• Production: Regulated by hormone Tpo secreted from liver; 1 × 1011 produced daily, circulate for 7–10 d

• Adhesion: Endothelial injury → plt activation & binding via vWF & GPIb-IX to endothelium

• Aggregation (cohesion): Activated GPIIb-IIIa binds vWF & fibrinogen to form clumps → ADP & serotonin release from granules → additional plt recruited

• Pseudothrombocytopenia: Falsely ↓ count due to plt clumping; collect blood in non-EDTA, citrate- or heparin-containing tube

• Etiologies:

Thrombocytopenia (plt count <150000/mL)

Heparin-induced Thrombocytopenia (HIT)

• Nonimmune (type I): Transient thrombocytopenia; plt nadir >100000/μL ∼1–4 d after starting heparin; may continue heparin, caution to not confuse w/immune HIT w/earlier fall due to prior exposure to heparin in prior 3 mos

• Immune (type II): Median plt nadir 50–60K, 5–7 d after starting heparin, earlier fall if prior exposure to heparin in 3 mos, bovine > porcine UFH > LMWH, Ab to PF4/heparin Ab complex → thrombocytopenia & prothrombotic state w/life- & limb-threatening arterial & venous clots

• Labs: +HIT Ab (PF4/heparin ELISA, ∼90% specific); may confirm by functional plt activation (serotonin release) assay (>90% specific)

• Treatment of immune HIT(NEJM 2006;355:809): D/c all heparin products; alternative anticoag. (argatroban) until plt rise to nl count

• Once plts nl can transition to coumadin from argatroban until INR >4

• Tx duration = DVT tx duration

• If no thrombus, treat for 6 wks (highest risk period for clot) to 3 mos (Abs persist for 3 mos)

Immune Thrombocytopenia (ITP)

• 1° immune plt destruction; dx of exclusion

• Presentation: Variable bleeding sx, may be asymptomatic

• Dx: R/o 2° etiologies esp. HIV; CBC: Isolated ↓ plt, large plt on peripheral smear; BM bx: Not routinely recommended; perform in adults >60 y to r/o MDS or if refractory disease

• Consider observation if asymptomatic & plt count >30 × 109/L; tx required if plt count <20 × 109/L and/or bleeding

• Emergency tx of bleeding: Plt transfusion + IVIg 1g/kg/d × 2–3 d + methylprednisolone 1 g/d × 3 d; ± adjunctive aminocaproic acid (inhibits plasmin activation & stabilizes thrombus); if refractory consider emergency splenectomy

Thrombotic Microangiopathies

• Vasoocclusive disorders that cause ↓ plts & mechanical injury to RBCs, ie, MAHA

• HUS: A/w enterohemorrhagic E. coli & bloody diarrhea usu in children; shiga toxin binds/activates renal endothelium & plt → intrarenal microthrombi HUS Triad: Thrombocytopenia + MAHA + renal failure

• TTP: Deficient ADAMTS13 → uncleaved large vWF multimers bind plt & form thrombi; etiology usu idiopathic/immune or drugs (quinine, ticlopidine, clopidogrel, cyclosporine, tacrolimus, MMC, GEM), pregnancy, HSCT, HIV, autoimmune diseases, familial

TTP Pentad: Thrombocytopenia + MAHA ± renal failure ± fever ± ΔMS; presence of MAHA & thrombocytopenia w/o other apparent course sufficient to diagnose TTP

• Dx: ↓ plt (usu <20k) + MAHA (schistocytes, ↑↑ LDH, ↑ unconjug. bili., ↓↓ haptoglobin); –Coombs, nl PT/PTT & fibrinogen; ADAMTS-13 deficiency

• Ddx: DIC, vasculitis/connective tissue disorders, scleroderma renal crisis, APS, malignant HTN, preeclampsia/HELLP syndrome, disseminated malignancy

• Treatment of TTP: Emergent plasma exchange (1–1.5 plasma volumes) daily until plt count >150K, LDH nl, & sx resolve (NEJM 1991;325:393); if delay in initiating pheresis, transfuse FFP; may consider glucocorticoids if refractory

• Treatment of HUS: Supportive if E. coli associated, avoid abx; consider plasma exchange for atypical HUS; use of eculizumab reported in sev. 2011 HUS outbreak in Europe (NEJM 2011;364:2561)

Thrombocytopenia in The Critically Ill

• Multifactorial etiology; occurs in ∼5% ICU pts

• Plt transfusion a/w ↑ thrombosis risk (J Crit Care 2005;20:348)

• Avoid plt transfusion unless bleeding, procedure, or <20K

Qualitative Platelet Disorders

von Willebrand Disease (vWD)

• Most common inherited bleeding disorder (1% of population); may also be acquired

• vWF involved in plt adhesion & carries factor VIII in plasma

• Dx: ↓ vWF Ag (except type 2N); ↓ vWF activity (ristocetin cofactor assay) in types 1, 2A, 2M, & 3; ↑ vWF activity in type 2B; nl vWF activity in type 2N; ↓ factor VIII level ± ↑ PTT; ± ↓ plt; vWF multimer analysis to confirm type

• Treatment:

Desmopressin (DDAVP): Nasal spray or IV; useful for type 1, variable for type 2, not helpful for type 3; do therapeutic trial before procedure

vWF concentrates: Give prior to & after surgery; duration/dose dependent on severity of bleeding/deficiency & type of surgery

Antifibrinolytic agents (aminocaproic acid): Useful as adjunctive tx for mucosal bleeding

Emergency tx: May give cryoprecipitate, factor VIII concentrates