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• Bleeding disorders are classified into quantitative and qualitative disorders

Thrombocytopenia

• Platelet count is less than 100,000/uL

• Most common cause of clinically important bleeding

• Clinical presentation: petechiae, purpura, and ecchymoses

• Causes of thrombocytopenia include decreased production (ineffective thrombopoiesis, megakaryocyte hypoplasia, aplastic anemia, congenital/acquired hypoplasia, BM infiltration, TAR syndrome, hereditary macrothrombocytopenia)

• Thrombocytopenias can result from impaired or decreased platelet production

• Can be congenital (May-Hegglin anomaly, Bernard-Soulier syndrome, Fechtner syndrome, Sebastian syndrome, Epstein syndrome, Montreal platelet syndrome, Fanconi anemia, Wiskott-Aldrich syndrome, TAR syndrome) or acquired (viral/bacterial infections, drug-induced, neonatal)

• Thrombocytopenia can also be caused by increased destruction, either immune (acute/chronic ITP, drug-induced, heparin-induced, neonatal alloimmune, neonatal autoimmune, post-transfusion purpura, secondary autoimmune) or nonimmune (gestational, HIV infection, hemolytic disease of the newborn, thrombotic microangiopathies, DIC, bacterial infection, drug-induced)

• Another cause of thrombocytopenia is distribution or dilution (splenic sequestration, Kasabach-Merritt syndrome, hypothermia, loss of platelets from massive transfusions)

• Sequestration is found in spleens

• Platelet dilution is found in multiple blood transfusions

Immune Thrombocytopenic Purpura

• Acute ITP presents in children ages 2-6 and chronic ITP presents in adults ages 20-50
• Sex predilection: None in acute, female > male (3;1) in chronic
• Acute ITP typically follows an infection
• Onset of bleeding: Sudden in acute and gradual in chronic
• Platelet count: <20,000/uL in acute, 30,000-80,000/uL in chronic
• Duration: 2-6 weeks in acute, months to years in chronic
• Spontaneous remission: 90% of patients in acute, uncommon in chronic
• Seasonal pattern: Higher incidence in winter and spring in acute
• Therapy: Steroids are used to treat the disorder. Splenectomy required to treat

Immunologic Drug-Induced Thrombocytopenia

• Drug-dependent antibodies typically occur after 1 to 2 weeks of exposure to a new drug
• Mechanism: drug-dependent auto-Ab, hapten-induced Ab, and immune complex-induced thrombocytopenia

Post-Transfusion Purpura

• Rare disorder, typically develops about 1 week after a transfusion of platelet-containing blood products

• (+) anti-HPA-1a (platelet antibodies) from recipient

Isoimmune Neonatal Thrombocytopenia

• Mother lacks a platelet-specific antigen, fetus has inherited from the father. Maternal IgG Abs attach the fetal platelet antigen

Thrombotic Thrombocytopenic Purpura

• Rare disorder
• Related to accumulation of ultra large vWF multimers in plasma due to deficient ADAMTS-13

Increased Platelet Consumption

• Disseminated Intravascular Coagulation (DIC): Rare but serious condition causing abnormal blood clotting throughout the body

• Hemolytic uremic syndrome (HUS): Damages blood vessels in the kidneys and can cause acute kidney failure

Thrombocytosis

• Increase in circulating platelets (>450,000/uL)
• Reactive thrombocytosis causes an elevation in platelet count secondary to inflammation, trauma, or other underlying conditions
• The platelet count can range from 450,000-800,000/uL

Reactive thrombocytosis

• Related to blood loss and surgery
• Postsplenectomy
• Iron deficiency anemia
• Reactive thrombocytosis (such as infection or infection plus surgery)
• Stress
• Rebound after myelosuppressive chemotherapy

Myeloproliferative disorders

• Polycythemia vera
• Chronic myelogenous leukemia
• Chronic myelomonocytic leukemia
• Myelodysplastic syndrome variants
• Primary myelofibrosis
• Essential thrombocythemia

Qualitative Disorders

• Clinical presentation includes excessive bruising and superficial (mucocutaneous) bleeding

Platelet Aggregation disorders

• Glanzmann thrombasthenia
• Hereditary afibrinogenemia
• Acquired defects of platelet aggregation. Acquired von Willebrand disease, or acquired uremia.

Disorders of Platelet Adhesion

• Bernard-Soulier syndrome
• Von Willebrand disease
• Acquired VWD.
• Myeloproliferative and lymphoproliferative disorders, dysproteinemias
• Antiplatelet antibodies
• Cardiopulmonary bypass surgery
• Chronic liver disease
• Drug-induced membrane modification

Disorders of Platelet Secretion

• Storage pool diseases
• Thromboxane pathway disorders
• Hereditary aspirin-like defects:
  • Cyclooxygenase or thromboxane synthetase deficiency
• Drug inhibition of the prostaglandin pathways/platelet phosphodiesterase activity

Changes in Membrane Phospholipid Distribution

• Scott syndrome

• Stormorken syndrome

• Hyperactive Prothrombotic Platelets

• Bernard-Soulier syndrome is characterized by ADP receptor definciency

• Storage pool disease is characterized by gray platelets

• Glanzmann Thrombasthenia is characterized by aggregation defects

• Scott Syndrome is characterized by procoagulant activity defects

• Platelet Type VWD and GP6 Deficiency have defects related to Thromboxane A2 receptors and PAR-r defects

• LAD III Syndrome is the aggregation defect associated to these

• Hermansky-Pudlak syndrome and Chediak Higashi syndrome have storage pool defects.

Glanzmann Thrombasthenia (Platelet Aggregation Defects)

• Bleeding disorder
• Abnormal in-vitro clot retraction test and normal platelet count
• Population with high consanguinity
• Deficient/abnormal (GP) IIb/IIIa complex

Bernard-Soulier Syndrome (Platelet Adhesion Defects)

• Manifests during infancy and childhood
• Ecchymoses, epistaxis, and gingival bleeding
• GP Ib/IX/V complex is missing from platelet surface, exhibits abnormal function
• Giant Platelets

Alpha Granueles Deficiency

• gray platelet syndrome is Autosomal recessive, and causes an absence of granules
• Platelets appear large and grey

Dense Granules Deficiency

• Decreased dense granules are found in Wiskoot Aldrich Syndrome. It is a X-linked disease. Mutations in the WAS gene. Immunodeficiency, thrombocytopenia, microthrombocytes.
• Quebec platelet disorder - Autosimal Dominant, a multimeric protein that is stored complexed with factor V in a-granules

Acquired Platelet Problems

• Uremia
• Paraproteinemia Multiple Myeloma and Waldenstrom Macroglobulinemia
• AML, Myeloproliferative Disorder
• PNH
• Drug (Aspirin)
• Chronic Liver Disease
• Anemia
• CABG
• Autoimmune Disease (Collagen Vascular Disease)

Vascular Disorders

• Hereditary Vascular Disorder includes Hereditary Hemorrhagic Telangiectasia, Hemangioma Thrombocytopenia Syndrome, and Ehler-Danlos Syndrome
• Hereditary Hemorrhagic Telangiectasia is also called Rendu-Osler-Weber Syndrome
• Aquired Vascular Disorder includes Allergic Purpura/henoch Schonlein Purpura, Paraprotenemias, Senile Purpura, and Scurvy
• Purpuras include Purpura Simplex and Psychogenic Purpura

Coagulation Disorders

• Hereditary - quantitative or qualitative defect in single coagulation factor
• Acquired - deficiency of multiple coagulation factors
• Common Presentations: Large ecchymosis and hematomas – delayed bleeding Bleeding from the nose, gums, GIT, GUT Joint bleeds, muscle bleeds Excessive bleeding (post-dental, post-surgical, trauma).

Coagulation Tests

• APTT
• Thrombin.

Hemophilia A

• X-linked recessive disorder
• Due to defective deficient factor VIII molecules.
• Incidence is 1 in 10,000
• Aka the "Royal Disease"
• Symptoms: Bleeding usually last up to 8 hours and as late as 1-3 days after trauma. Can occur in Joints, Urinary Tract, Intracranial (major cause of dead), and Deep muscle.

Hemophilia B (Christmas disease)

• Clinically indistinguishable from Hemophilia A and needed to perform specific assays to distinguish disorder.
• Deficiency of factor IX
• Incidence 1 in 25,000-30,000

Von Willebrand Disease (VWD)

• Quantitative or qualitive abscence of VWF
• Symptoms: bleeding, bruising, epistaxis, menorrhagia
• Lab Results: VWF (plasma), factor VIII activity, Bleeding time, Normal Platelet count

VWD Type 1, MOST COMMON

• Partial quantitative deficiency of VWF
• Autsomal Dominant. Prolonged Bleeding time, normal platelet count

VWD Type 2

• Qualitative Alterations in the VWF structure and function

VWD Type 3

• Lease Common
• Complete abscence of VWF
• Autsomal Recessive
• Acquired VWD
• Occurs as a secondary complication

Disseminated Intravascular Coagulation (DIC)

• Defibrination syndrome/consumptive coagulopathy
• Conditions associated with DIC include Infections, Intravascular Hemolysis, Acute Liver Disease, Tissue injury, Obstetric, Malignancy, Cardiovascular, Hypo/Hyperthermia .
• Acquired Coagulation Disorders

Clinical Manifestations of DIC

• Includes Ischemic and hemorrahagic symptoms.

Microscopic Findings

• fragments, schistocytes, paucity of platelets.

Evaluation of DIC

• lab evaluation includes D dimer, Antithrombin I, PP.

Hereditary Coagulation Factors

• Hemophilia A
• Hemophilia B
• Von Willebrand Disease
• Afibrinogenemia
• Factor V Leiden mutation
• Prothrombin G20210A mutation
• Protein C deficiency
• Protein S deficiency
• Antithrombin deficiency
• Dysfibrinogenemia
• Factor XIII deficiency

Acquired Coagulation Factors

• Vitamin K deficiency
• Liver Disease
• Warfarin therapy
• Acquired inhibitors of coagulation factors
• Disseminated Intravascular Coagulation (DIC)
• Thrombotic Thrombocytopenic Purpura (TTP)
• Hemolytic Uremic Syndrome (HUS)
• Heparin-Induced Thrombocytopenia (HIT)
• Antiphospholipid Syndrome (APS)
• Acquired hemophilia A