Silverstein and Hopper Chapter 103: Platelet Disorders

What are the steps that platelets undergo following vascular injury?

Adhesion, activation, and aggregation

Enables the formation of the platelet plug and facilitates thrombin generation

What is the most common initial presenting sign in dogs with platelet disorders?

Mucocutaneous bleeding leading to petechiae, cutaneous ecchymosis, and melena

What are clinical signs that have been documented in cats in addition to mucocutaneous bleeding?

Hematomas, epistaxis, and hematuria

What may cause thrombocytopenias to arise?

Decreased production

Increased consumption

Increased destruction

Sequestration

Causes of Increased Consumption of Platelets

Disseminated intravascular coagulation

Acute/severe blood loss

Platelet activation/aggregation

Sepsis

Thrombotic microangiopathies

Massive thrombosis

What can cause iatrogenic thrombocytopenia?

Hemodialysis

Postcardiopulmonary bypass

Hemodilution including massive transfusion

EDTA-mediated

What can cause thrombocytopenia due to increased destruction?

Primary immune mediate thrombocytopenia

Secondary immune mediated thrombocytopenia

• Anaplasmosis

• Babesiosis

• Ehrlichiosis

• Neoplasia

What can cause thrombocytopenia due to decreased production?

Bone marrow disease

Chemotherapy

What can cause thrombocytopenia due to increased sequestration?

Splenic sequestration

Sepsis/systemic inflammatory response syndrome

What is the most severe form of thrombocytopenia?

Primary or secondary immune-mediated destruction of platelets

Often results in life-threatening hemorrhage

What platelet count can lead to spontaneous hemorrhage? What platelet count indicates the highest risk of fatal bleeding?

Spontaneous hemorrhage can occur when the platelet count is <30 ×10⁹/ml

The highest risk of fatal bleeding occurs when the platelet count is <10 × 10⁹/ml

Does initial platelet concentration correlate with survival in dogs with immune-mediated thrombocytopenia?

No

What does presence of melena at the time of hospital admission associated with in dogs with ITP?

Increased transfusion requirement and mortality

DOGiBAT Score for Dogs with ITP

• Novel ITP bleeding score called DOGiBAT was developed to provide an objective and standardized way to clinically assess ITP dogs

  • Comprises site-specific grades (0 - none, 1 - mild, 2- severe) of nine different anatomic sites

  • DOGiBAT score is correlated with transfusion requirements and inversely correlated with platelet count

What is the proposed mechanism of ITP in dogs and cats?

Increased phagocytosis by splenic macrophages due to autoantibodies bound to platelet integrin aIIbB3 (fibrinogen receptor) or glycoprotein Ib-IX (von Willebrand factor receptor)

Thrombocytopenia in Sepsis

• Thrombocytopenia is a common finding in sepsis and its severity is associated with mortality

  • Causes of sepsis-mediated thrombocytopenia are multifactorial

    • Direct microbial-platelet interactions

      • Bacteria such as E coli and Streptococcus can directly interact with platelets leading to platelet activation and aggregation

      • Canine platelets directly interact with pathogens by expressing functional TLR 4 which augments platelet activation in the presence of LPS and ADP

      • Once activated, platelets interact with circulating neutrophils to form platelet-neutrophil aggregates and NETs

        • Overzealous production of NETs can further exacerbate organ dysfunction and thrombocytopenia by accelerating thrombus formation and reducing fibrinolysis

    • Platelet-leukocyte aggregate formation

    • Increased platelet sequestration secondary to microvascular thrombosis

How can acquired platelet disorders manifest?

As platelet dysfunction or hyperactivity resulting in bleeding diathesis or thrombosis

• In small animal medicine, acquired platelet dysfunction is more common

Uremia Associated Platelet Dysfunction

• Uremia-associated platelet dysfunction is multifactorial

  • Due to defects in platelet adhesion, secretion, and aggregation

• Underlying mechanism in dogs and cats unclear

  • Dogs with CKD and clinical bleeding were found to have normal platelet aggregation and activation with compromised platelet adhesion

  • Uremia may directly alter the function of vWF producing a phenotypic resemblance of type II von Willebrand disease in humans

  • Because vWF supports shear-induced platelet adhesion and aggregation by interacting with platelet glycoprotein (GP) 1ba, defects in vWF may manifest more profoundly in the microcirculation, where shear forces are high

Platelet Disorders Associated with Liver Disease

• Associated with both thrombocytopenia and platelet dysfunction

• Dogs with hepatic malignancy and cirrhosis have lower platelet counts than those with hepatitis

• Decreased platelet aggregation in response to collagen and arachidonic acid has previously been documented in dogs with liver disease but underlying mechanism is unknown

Platelet Disorders Associated with Heart Disease

Studies suggest that cats with occult or overt HCM have hypercoagulable platelets that may predispose them to thrombosis

Platelet Dysfunction due to NSAIDs

• COX is a rate-limiting enzyme that converts arachidonic acid to eicosanoids

  • Platelets express mainly COX-1 which is irreversibly inhibited by acetylsalicylic acid, thereby modulating the biosynthesis of thromboxane A2 (TXA2) and prostaglandin

  • In theory, COX-2 selective NSAIDs should not inhibit platelet function

    • There are data suggesting that COX-2 selective NSAIDs possess antiplatelet effects in small animals

    • A small amount of CO-2 is constitutively expressed in platelets under normal physiologic conditions, it is upregulated during thrombopoiesis or hematopoietic hyper-regenerative conditions (post chemotherapy) and might play a prominent role in the biosynthesis of TXA2

      • Selective COX-2 inhibitors may induce clinically significant platelet dysfunction in these conditions

Effect of Anticoagulants and Fibrinolytic Drugs on Platelet Function

• Anticoagulants and fibrinolytic drugs have been documented to have a direct or indirect impact on platelet function

  • Elevation in plasmin activity by strepotokinase or tPA may impair platelet aggregation by direct degradation of fibrinogen, which mediates platelet-to-platelet aggregation, or by cleavage of integrin a1IbB3

  • Activation of plasmin, a protease enzyme, also cleaves thrombin receptors and thus induces platelet aggregation

How can drugs that elevate intracellular cyclic nucleotides affect platelet function?

Drugs that elevate intracellular cyclic nucleotides such as cAMP or GMP, both critical inhibitory secondary messengers that modulate fundamental platelet pathways, can inhibit platelet receptor activation, degranulation, shape change, and aggregation

How can phosphodiesterase inhibitors affect platelet function?

Platelets express three isoforms of phosphodiesterase (2, 3, and 5) and thus in theory, platelet function can be inhibited by nonselective or isoenzyme-selective phosphodiesterase inhibitors

Mechanisms of Platelet Dysfunction Secondary to Hydroxyethyl Starch (HES)

• Mechanisms of platelet dysfunction secondary to hydroxyethyl starch (HES) administration are multifactorial

  • Binding of colloidal molecules on the extracellular domains of integrin aIIbB3 or glycoprotein 1b inhibits their conformational changes and subsequently, platelet aggregation and adhesion

  • Binding of colloidal molecules also interferes with factor VIII/vWF complex formation causing their accelerated elimination

    • Can further inhibit platelet adhesion upon vascular injury

  • Slowly degradable HES may further exert its inhibitory effects in platelets by interfering with intracellular signaling function

• Clinicians should weight the risks and benefits when administering HES in patients and should avoid HES in those with preexisting platelet disorders

Congenital Platelet Disorders - Classification A

Defect in platelet receptors for adhesion

Congenital Platelet Disorders - Classification B

Defect in platelet receptors for agonists

Congenital Platelet Disorders - Classification C

Platelet granule defect

Congenital Platelet Disorders - Classification D

Defect in signal transduction

Congenital Platelet Disorders - Classification E

Defect in formation of procoagulant membrane

Recommendations for Discontinuation of Antiplatelet Therapy Prior to Elective Procedures

Not recommended in patients at high risk of thrombosis due to the potential rebound of platelet reactivity and acute thrombotic events

Discontinuation of one antiplatelet drug (preferably clopidogrel) 5-7 days prior to elective procedures is recommended in patients considered high risk of surgical bleeding receiving dual antiplatelet therapy

Antiplatelet drugs should be discontinued at least 5-7 days prior to elective procedures in animals with low to moderate risk of bleeding

What are the two general principles of the treatment of platelet disorders?

Prevention of bleeding diathesis

Control of major hemorrhagic events

Prevention to Avoid Catastrophic and Life-Threatening Hemorrhages in Animals with Platelet Disorders

• Avoid IM injections

• Discontinue medications with confirmed antiplatelet or antithrombotic properties

  • Commonly prescribed antiplatelet drugs have short half-lives but their irreversible inhibitory effects on platelet function can persist beyond the reported platelet life span (4-6 days)

• Hemorrhage is rare following SQ injections but direct pressure should be applied following injections

• To prevent bleeding diatheses in patients with congenital platelet disorders, discourage animals from engaging in strenuous exercise or high impact activities that may result in unnecessary trauma

• Preventative treatments may be indicated prior to invasive or surgical procedures

Indications for Whole Blood-Derived Platelets

Thrombocytopenia

• Prophylaxis in patients with severe thrombocytopenia (10×10⁹/L or less) or requiring invasive procedures (50 × 10⁹/L or less)

• Severe thrombocytopenia causing anemia, shock, or intracranial/pulmonary hemorrhage

Congenital/acquired platelet disorders

• Severe or uncontrolled bleeding

• Prophylaxis in animals prior to invasive procedures

Indications for Trehalose Stabilized Cryopreserved Platelet Concentrate

Severe thrombocytopenia causing anemia, shock, or intracranial/pulmonary hemorrhage

Indications for Fresh Whole Blood with Platelet Dysfunction

Hemorrhage due to severe thrombocytopenia, congenital/acquired platelet disorders, and vWD with concurrent anemia

Indications for Cryoprecipitate

Type 1, 2, or 3 vWD

Indications for Desmopressin with Platelet Disorders

Congenital or acquired platelet disorders

• Mild bleeding

• Adjunctive therapy with platelet transfusions

• Aspirin-induced platelet dysfunction

• Platelet dysfunction caused by liver disease ± uremia

Type 1 or 2 vWD

Indications for Antifibrinolytic Drugs (Epsilon-aminocaproic acid and tranexamic acid) with Platelet Disorders

Thrombocytopenia

• Associated hemorrhage

Congenital or acquired platelet disorders

• Prophylactic treatment prior to elective noninvasive procedures

• Mild to severe bleeding diathesis

• Adjunctive therapy with platelet transfusions

Indications for Fresh Frozen Plasma

Platelet disorders with concurrent consumptive coagulopathy and hypofibrinogenemia

Types 1, 2, or 3 vWD

What can you use to control hemorrhagic events due to acquired and congenital platelet disorders?

Platelet transfusions, antifibrinolytic therapy, desmopressin (DDAVP), and fresh frozen plasma transfusion

What should platelet transfusions be reserved for?

• Patients with major hemorrhagic events including intracranial and pulmonary bleeding secondary to severe thrombocytopenia, irreversible antiplatelet drugs, and severe platelet disorders

  • May temporarily stop or slow down bleeding in dogs with severe ITP to allow time for immunosuppressive therapies to take effect

What are alternatives to fresh platelet products?

• Cryopreserved or lyophilized platelet products using either dimethylsulfoxide or trehalose have been extensively studied in human medicine

  • Trehalose prevents cell damage caused by lyophilization that induces temperature-mediated membrane reorganization, calcium fluxes, and morphological changes