Platelet Disorders

Qualitative:

• Defects in membrane glycoproteins

  • Bernard-Soulier Syndrome (GPIb/IX/V)

  • Glanzmann Thrombasthenia (GPIIB/IIIa)

  • Collagen Defects (GPVI and GPIa/IIa)

• Defect in platelet granules

  • Storage Pool Deficiency

  • Gray Platelet Syndrome

  • Quebec Platelet Disorder

  • Hermanksy Pudlak syndrome

• Defects in platelet secretion and signaling

• Defects in platelet coagulant activity

• Defects of transcription factors

  • RUNX1

• Defects of cytoskeletal/structural proteins

  • Wiskott-Aldrich Syndrome

  • B1-Tubulin Deficiency

  • Kindlin Defect

• Acquired (iatrogenic)

  • Medications

  • Uremia

  • Cardiopulmonary Bypass

Quantitative:

• Thrombocytosis

  • Essential Thrombocythemia (ET)

• Thrombocytopenia

  • Decreased bone marrow production

  • Sequestration

  • Hemodilution

  • Increased consumption

  • Increased clearance

  • Alloimmune

  • Pseudothrombocytopenia

Platelet Function Tests:

• Arachidonic acid: Tests the thromboxane pathway

• Epinephrine: Tests receptor binding leading to ADP release

• Ristocetin: Tests for the functional vWF receptor/GP1b/IX complex

• Thrombin: Tests full platelet aggregation independent of both the ADP and prostaglandin pathway

• Aggregation studies:

  • Primary wave/aggregation: Initial and reversible clumping of platelets stimulated by exogenous agonists like ADP/epinephrine/collagen

  • Secondary wave/aggregation: subsequent often irreversible aggregation caused by the release of internal platelet agonists, such as ADP/epinephrine

    
    

Defects in membrane glycoproteins:

• Bernard-Soulier Syndrome (GPIb/IX/V: receptor for vWF):

  • Autosomal recessive

  • Platelets are unable to bind to vWF on endothelial surface → no platelet adhesion to the vessel walls

  • Platelets increased in size

  • Prolonged bleeding time

  • No aggregation in response to ristocetin 

  • Normal response (with primary and secondary wave) to ADP/epinephrine/collagen

  • Treatment for acute bleeding: platelet transfusion

• Glanzmann Thrombasthenia (GPIIB/IIIa):

  • Autosomal recessive

  • Heterozygotes without bleeding

  • Platelets are unable to bind with fibrinogen and aggregate with other platelets

  • Impaired clot retraction

  • Normal platelet appearance

  • Normal aggregation with ristocetin

  • No primary or secondary wave with ADP/epinephrine/collagen

  • Treatment: platelet transfusion

    • If refractory to platelet transfusion: use recombinant factor VIIa (NovoSeven)

• Collagen Defects (GPVI and GPIa/IIa)

Defects in platelet granules

• Storage Pool Deficiency

  • Deficiency of dense or alpha granules

  • Normal aggregation with ristocetin

  • No secondary wave with ADP/epinephrine/collagen

    • Robust aggregation to primary ADP but much less with secondary ADP

• Gray Platelet Syndrome

  • Deficiency of alpha granules

    • VWF, factor V, multimerin, fibrinogen, fibronectin, thrombospondin

  • Gray appearance of platelets on PBS

  • No significant abnormality in aggregation studies

  • Mutations in NBEAL2 (responsible for vesicle trafficking)

  • Predisposed to myelofibrosis and elevated Vit B12

• Quebec Platelet Disorder

  • Autosomal dominant

  • Normal to reduced platelet counts

  • Decreased alpha granule proteins due to abnormal proteolysis due to increased urokinase plasminogen activator (PLAU)

  • Platelet transfusion does not provide benefit.

• Hermanksy Pudlak syndrome

  • Autosomal recessive

  • Defect in dense granules

  • Presents with mild bleeding diathesis (avoid anticoagulants), oculocutaneous albinism, and pulmonary fibrosis

Defects in platelet secretion and signaling

Defects in receptors and signaling

• Abnormalities in arachidonic acid pathways and TXA synthesis

• Normal aggregation with ristocetin

• Reduced secondary wave with ADP/epinephrine

Defects in platelet coagulant activity

Defects of transcription factors

• RUNX1: familial platelet defect 

  • Autosomal dominant

  • Impaired megakaryopoiesis

  • Predisposed to AML

Defects of cytoskeletal/structural proteins

• Wiskott-Aldrich Syndrome

  • X-linked

  • Deficiency of dense granules

  • Immunodeficiency, eczema, and thrombocytopenia

• B1-Tubulin Deficiency

• Kindlin Defects

Acquired (iatrogenic)

• Medications

• Uremia

  • Leads to platelet dysfunction through increased nitric oxide production

  • Treated with hemodialysis and DDAVP

• Cardiopulmonary Bypass

  • Platelets being exposed to different surfaces/substances can activate them and lose their function

  • Should recover in a few days after surgery

Thrombocytosis

• Reactive

• Essential Thrombocythemia (ET):

  • Associated with increased risk of thrombosis

  • Very high levels of platelets can be associated with acquired vWD → bleeding

  • Small percentage will progress to post-ET myelofibrosis or leukemic transformation

  • Risk criteria:

    • Very low risk: 

      • age <60 + no JAK2 mutation + no history of thrombosis

    • Low risk:

      • age <60 + JAK2 mutation + no history of thrombosis

      • Treatment: Aspirin

    • Intermediate risk: 

      • age >60 + no JAK2 mutation + no history of thrombosis

      • Treatment: Aspirin +/- Hydroxyurea

    • High risk:

      • (age >60 + JAK2 mutation) or (History of thrombosis)

      • Treatment: Aspirin + Hydroxyurea

        • Consider addition of anticoagulation if history of DVT/PE

Thrombocytopenia

• Platelet type bleeding involves skin or mucous membranes

  • Petechiae, ecchymoses, epistaxis, menorrhagia, GI hemorrhage

  • Usually when platelet count less than 20,000

• Decreased bone marrow production

  • Congenital disorders:

    • MYH9 thrombocytopenias (May-Hegglin anomaly)

      • Large platelets, thrombocytopenia, nephropathy, deafness

    • Mediterranean macrothrombocytopenia

    • RUNX1 mutation Paris-Trousseau thrombocytopenia

    • DiGeorge Syndrome

    • Congenital amegakaryocytic thrombocytopenia

      • MPL mutation which encodes TPO receptor

    • Wiskott-Aldrich Syndrome

    • GATA-1 mutation

    • Bernard-Soulier Syndrome

  • Acquired disorders:

    • Leukemias, lymphoma, myeloma

    • Aplastic anemia

    • Fanconi anemia

    • Medications

• Hemodilution

  • Pregnancy: Blood volume increased by up to 30%

• Sequestration

  • Hypersplenism

  • Kasabach-Merritt syndrome

    • Linked to giant cavernous hemangioma- when hemangioma grows rapidly, trapping platelets causes thrombocytopenia (platelet sequestration)

    • Also associated with DIC (plt consumption)

• Increased consumption

  • DIC

    • Treat underlying cause: Pancreatitis, trauma/shock, infection, hepatic necrosis

  • Sepsis

  • Cardiovascular disease (ECMO, artificial heart valves)

  • Vasculitis

    • SLE

    • Wegener's disease (Granulomatosis with polyangiitis)

  • Thrombotic microangiopathy

    • Thrombotic thrombocytopenic purpura (TTP)

    • Hemolytic Uremic Syndrome (HUS)

      • Typically patient has diarrhea (from E.coli strains produce Shiga toxin) and renal failure

        • Shiga toxin PCR in stool helps diagnosis

      • Triad of MAHA, thrombocytopenia, AKI

      • Treat infection, plasmapheresis, supportive care

        • 25% mortality without PLEX

        • 50% of patients with permanent renal failure on HD

    • aHUS

      • Complement mediated, leads to renal failure

      • Diagnosis of exclusion

        • Rule out HUS and TTP

      • Treat with anti-C5 therapy (eculizumab, ravulizumab)

    • Pregnancy complications

      • Pre-eclampsia

      • HELLP syndrome

    • Medications

      • Gemcitabine, ticlopidine, clopidogrel, zosyn, sulfa drugs, vancomycin

      • Heparin induced thrombocytopenia (HIT)

      • Vaccine induced thrombocytopenia (VITT)

        • Similar mechanism to HIT without heparin

        • Treat with: DOAC (could also use bivalirudin, argatroban, fondaparinux), IVIG, Steroids, PLEX can be considered

• Increased clearance

  • Immune thrombocytopenia purpura (ITP)

• Alloimmune

  • Neonatal alloimmune thrombocytopenia (NAIT)

    • Fetal platelet antigen leads to material antibodies that transfer the placenta and induce thrombocytopenia in fetus

  • Post-transfusion purpura

    • Parous females form high titer anti-HPA-1a (anti Gp2b3a) alloantibodies that destroy autologous platelets

  • Passive alloimmune thrombocytopenia

    • Transfused platelets contain Ab against recipient platelets

  • Transplantation associated alloimmune thrombocytopenia

    • Patient is refractory to platelet transfusion due to residual host lymphocytes

  • Platelet transfusion refractoriness

    • Alloimmunization due to heavy transfusion history

• Pseudothrombocytopenia

  • EDTA in the collecting blood tubes can cause platelet clumping

  • Repeat the lab but collect the blood sample in a heparin or citrated tube

Conditions with giant platelets:

• Bernard-Soulier Syndrome (GPIb/IX/V)

• Gray platelet syndrome

• ITP

• May-Hegglin anomaly

• Montreal platelet syndrome (Type IIb vWD)

Heparin Induced Thrombocytopenia (HIT)

• Heparin binds to platelets and releases PF4 eventually causes heparin-PF4 complexes. Heparin-dependent Ab attaches to complex which activates platelets.

• Usually cause 50% drop in platelet count between 3-30 days after heparin exposure

  • Median plt count is 60K

  • Not associated with plt count <10K

• Spontaneous HIT:

  • No prior heparin exposure

  • Happens after orthopedic surgeries (usually knee replacement surgery)

  • Also associated with monoclonal gammopathies

• Should know 4T score:

  • Degree of thrombocytopenia

  • Timing of thrombocytopenia

  • Presence of thromboses

  • Any other cause of thrombocytopenia?

• Lab tests: Serotonin release assay, Heparin-PF4 antibody

• Management:

  • Stop heparin and start anticoagulant with direct thrombin inhibitor

    • Bivalirudin is preferred in abnormal hepatic function

    • Argatroban is preferred in abnormal renal function

  • Transition to warfarin, fondaparinux, or DOAC at discharge

    • Plt count should increase to >150K before transitioning to warfarin (bridging). Also, there should be at least 5 days of overlap between direct thrombin inhibitor and warfarin before the former medication is discontinued. Target INR is 2-3.

    • Fondaparinux is contraindicated if CrCl<30

  • Duration of AC dependent on if clot present

    • If present: 3-6 months

    • If NOT present: unknown (4 weeks usually offered)

• Platelet transfusion is associated with higher odds of arterial thrombosis and mortality in patients with HIT and TTP.

Immune Thrombocytopenia Purpura (ITP)

• Ab bind to platelet surface (GP2b3a or GP1ba) → splenic/hepatic clearance

• Peak incidence in childhood (2-10 years) and adult

• Causes sudden onset bruising and petechiae and sometimes mucosal bleeding

• Sometimes preceded by viral illness or immunization/vaccination, also associated with H.pylori infection

• Smear shows normal RBCs but no platelets

  • Could also see giant platelets

• Bone marrow biopsy should show megakaryocytes

• Treat only if plt <20K and/or major bleeding and/or preoperative management

• Treatment:

  • Acute setting:

    • Dexamethasone vs. prednisone

    • IVIG

  • Secondary Treatment (long term): 

    • Rituximab

    • TPO agonists (Eltrombopag)

    • Splenectomy

  • Tertiary Treatment:

    • Cyclophosphamide, azathioprine, prednisone, anti-D antigen therapy (WinRho), danazol. Vyvgart 

    • Fostamitinib (spleen tyrosine kinase, Syk inhibitor)

    • Splenectomy (if unresponsive to steroids and IVIG)

• Pregnancy:

  • Treatment is the same as in non-pregnant patients.

    • Steroids are preferred in the first trimester but IVIG is recommended if the patient is close to delivery (IVIG acts more quickly)

Thrombotic Thrombocytopenic Purpura (TTP)

• Mechanism:

  • Lack of ADAMTS13 (normally cleaves vWF multimers) usually due to inhibitor → vWF multimers persist → adhesion/aggregation of platelets → Shearing/clotting

• Classic pentad:

  • Microangiopathic hemolytic anemia (Jaundice, purpura)

  • Thrombocytopenia

  • Renal insufficiency

  • Neurologic abnormalities

  • Fever

• Treatment:

  • Initially treated with PLEX + prednisone

  • If refractory: PLEX (daily) + prednisone + Rituximab ± Caplacizumab

• Some medications can cause TTP-HUS in rare cases:

  • Quetiapine

  • Oxaliplatine

  • Gemcitabine

  • Bactrim

  • Quinine

• Congenital TTP is called Upshaw-Schulman syndrome

  • Autosomal recessive

  • Can give regular plasma infusion or recombinant ADAMTS13 since disease is characterized by lack of ADAMTS13 protein