Primary hemostasis Hemophilias
• Formation of weak platelet plug Hemophilia A (F VIII Deficiency) Hemophilia B (F IX Deficiency)
• Four phases:
1. Vasoconstriction • X-linked recessive, 1/5000 M • X-linked recessive, 1/30000 M
2. Platelet adhesion • Mild (> 5% normal factor level), moderate (1-5%), severe (< 1%) • 50% have severe disease (F IX activity < 1% of normal)
3. Platelet activation
4. Platelet aggregation Clinical presentation: Clinical presentation and investigations same as F VIII
• Prolonged mucocutaneous bleeding
• Umbilical stump bleeding, oral hematoma with breast feeding MANAGEMENT
• F IX concentration for prophylaxis, on demand
INVESTIGATIONS Mixing study: • Anti-fibrinolytic agents (tranexamic acid)
• aPTT prolonged, PT/INR N • Mix patient’s plasma with normal donor plasma – even
• Decreased F VIII If 50% coag factor will have normal coag
• Mixing study N • If there’s an inhibitor it will cross-react with factor in
• Assess for concomitant VWD donor plasma and you won’t get normalization of aPTT
Factor XI Deficiency (“Hemophilia C”)
MANAGEMENT
• Desmopressin (DDAVP) in mild • AR, Ashkenazi Jewish population
• F VIII concentrates for prophylaxis, on demand Note: DDAVP induces release of vWF from platelets (a • F XI level doesn’t correlate with bleeding risk
• Anti-fibrinolytics agents (tranexamic acid) granules) and endothelial cells (released into plasma) • Bleeding risk correlates with previous bleeding Hx and FHx
DDAVP (vasopressin/ADH)
Note: older patients have HIV or HCV from contaminated blood products Clinical presentation:
• Usually mild, diagnosed in adulthood
Acquired Hemophilia A (AHA)/Acquired F VIII Deficiency MANAGEMENT
• Autoantibodies against F VIII • F XI concentrate
Steps: • Very rare • Anti-fibrinolytics (tranexamic acid)
1. Endothelial damage
2. vWF secreted by endothelial cells and binds to exposed collagen = platelet adhesion
• Post-partum, other autoimmune disorders, elderly (think malignancy) • Frozen plasma
3. Platelets bind to vWF via GPIb receptor and become activated = platelet activation • Variable clinical presentation
4. Activated platelets change shape to increase surface area and express GPIIb/IIIa (fibrinogen receptor) • **isolated prolonged aPTT
5. Platelets secrete: • Factor levels and mixing study
• a granules, which contain additional vWF and PDGF for long-term wound healing • Tx:
• Dense granules, which contain ADP and thromboxane A2 (TXA2)
• ADP binds to P2Y12 receptors and TXA2 binds to TP receptors to recruit/activate other platelets
• Stop acute bleeding with alternative factors: F VIIa or activated PCC
6. Fibrinogen, produced by the liver, binds to platelets via GPIIb/IIIa and links platelets = platelet aggregation (prothrombin complex concentrate), porcine F VIII
• Eradicate inhibitor: prednisone +/- cyclophosphamide, 2nd line rituximab,
Hemostasis and Disorders of Hemostasis
7. Actin and myosin proteins in platelets cause contraction of the platelet plug
calcineurin inhibitors, other immune modulating agents
Immune Thrombocytopenic Purpura (ITP) Note: have to do Hep B serology prior to ritux b/c possible re-activation; may need to treat concomitantly Thrombotic Thrombocytopenic Purpura (TTP)
Increased destruction à immune-mediated Increased destruction à immune and non-immune mediated
HEME EMERGENCY
• MC cause of thrombocytopenia in children; can be in adult Fever
MANAGEMENT
• Often presents 1-3 weeks after viral illness • Pathophys: deficiency of ADAMTS-13 (vWF cleaving protease (decreases vWF activity))
NOT BLEEDING/MILD MUCOCUTANEOUS BLEEDING + PLAT > 30
• Think infection as trigger • Plat aggregation and coagulation in small blood vessels = RBC hemolysis
• Watch and wait
• Autoantibody-mediated (commonly GPIIb/IIIa or Ib-IX; IgG)
• Pathophys: opsonization and phagocytosis by splenic macrophages and liver Kupffer cells; NOT BLEEDING + PLAT < 30 CAUSES
damage to megakaryocytes; possible impaired production of thrombopoietin • Congenital mutation in ADAMTS-13
• Prednisone 0.5-2 mg/kg OR Dex 40 mg x 4 days
• Primary vs. Secondary: SLE, CLL, NHL, viral infections (Hep C, HIV) • Acquired = autoantibodies?
• IVIG
• Secondary (40%):
• Anti-D Hemolytic anemia
Clinical presentation: • Cancer
• Asymptomatic/purpura/bleeding/hemorrhage
• 2nd line: splenectomy, TPO-R agonists (romiplostim, eltrombopag), rituximab
• BMT
TTP Thrombocytopenia
• Essentially plat < 100 x 109/L in absence of other causes • Pregnancy
ACTIVE BLEEDING
• Medications: ticlopidine, clopidogrel, acyclovir, quinine, tacrolimus, bevacizumab
• Steroids
INVESTIGATIONS • HIV
• Tranexamic acid
• No gold standard; dx of exclusion • Pathogenesis of 2ndary poorly understood
• +/- IVIG
• CBC, blood film • Life threatening: plat transfusion +/- splenectomy Note: TTP is associated w SLE
• HBV/HCV/HIV serology Triggers: infections, meds, autoimmune dz (SLE), pregnancy
• H. pylori
PREGNANCY
Clinical presentation: *only need 2 to make diagnosis
• Treat if bleeding and plat < 30 OR plat < 50 at > 36 weeks GA
• Pentad of thrombocytopenia, microangiopathic hemolytic anemia*, renal failure, altered mental status, fever
Onset of response: GPIb • Steroids or IVIG (Dex crosses placenta)
• IVIG 1-3 days GPIIb/IIIa • Plat > 50 for delivery, > 80 for neuraxial anesthesia
INVESTIGATIONS Renal failure
• Corticosteroids 2-14 days • CBC and blood film (schistocytes)
• Rituximab (anti-CD20) 7-56 days Note: • PT, aPTT, fibrinogen (N) Neurological symptoms
TPO-R agonist increases plat numbers • Increased markers of hemolysis (increased unconjugated bili, increased LDH, decreased haptoglobin)
Secondary ITP: Ritux, IVIG targets abs/ab production • Cr, urea
• Bleed and HCV use IVIG Steroids suppress immune system: binds to Fc of ab, reduces plasma cells, • ADAMTS-13 activity
• Bleed and HIV use steroids or IVIG reduces Fc receptor expression on macrophages
Splenectomy removes site of most macrophages (RES), prevents plat destruction MANAGEMENT
• Plasmapheresis
Note: Evan’s Syndrome = ITP + hemolytic anemia
Note: • Corticosteroids
Dry purpura = cutaneous hemorrhage (bruising or petechiae) • IVIG
Wet purpura = MM hemorrhage (GI, mouth, nose, eyes) • Rituximab
Note: Admit if new diagnosis and plat < 20
Note: anti-RhD thought to work by blocking Fc receptors within reticuloendothelial system Note: DO NOT transfuse plats
,
, Primary hemostasis
• Formation of weak platelet plug
• Four phases:
1. Vasoconstriction
2. Platelet adhesion
3. Platelet activation
4. Platelet aggregation
Steps:
1. Endothelial damage
2. vWF secreted by endothelial cells and binds to exposed collagen = platelet adhesion
3. Platelets bind to vWF via GPIb receptor and become activated = platelet activation
4. Activated platelets change shape to increase surface area and express GPIIb/IIIa (fibrinogen receptor)
5. Platelets secrete:
• a granules, which contain additional vWF and PDGF for long-term wound healing
• Dense granules, which contain ADP and thromboxane A2 (TXA2)
• ADP binds to P2Y12 receptors and TXA2 binds to TP receptors to recruit/activate other platelets
6. Fibrinogen, produced by the liver, binds to platelets via GPIIb/IIIa and links platelets = platelet aggregation
7. Actin and myosin proteins in platelets cause contraction of the platelet plug
• Formation of weak platelet plug Hemophilia A (F VIII Deficiency) Hemophilia B (F IX Deficiency)
• Four phases:
1. Vasoconstriction • X-linked recessive, 1/5000 M • X-linked recessive, 1/30000 M
2. Platelet adhesion • Mild (> 5% normal factor level), moderate (1-5%), severe (< 1%) • 50% have severe disease (F IX activity < 1% of normal)
3. Platelet activation
4. Platelet aggregation Clinical presentation: Clinical presentation and investigations same as F VIII
• Prolonged mucocutaneous bleeding
• Umbilical stump bleeding, oral hematoma with breast feeding MANAGEMENT
• F IX concentration for prophylaxis, on demand
INVESTIGATIONS Mixing study: • Anti-fibrinolytic agents (tranexamic acid)
• aPTT prolonged, PT/INR N • Mix patient’s plasma with normal donor plasma – even
• Decreased F VIII If 50% coag factor will have normal coag
• Mixing study N • If there’s an inhibitor it will cross-react with factor in
• Assess for concomitant VWD donor plasma and you won’t get normalization of aPTT
Factor XI Deficiency (“Hemophilia C”)
MANAGEMENT
• Desmopressin (DDAVP) in mild • AR, Ashkenazi Jewish population
• F VIII concentrates for prophylaxis, on demand Note: DDAVP induces release of vWF from platelets (a • F XI level doesn’t correlate with bleeding risk
• Anti-fibrinolytics agents (tranexamic acid) granules) and endothelial cells (released into plasma) • Bleeding risk correlates with previous bleeding Hx and FHx
DDAVP (vasopressin/ADH)
Note: older patients have HIV or HCV from contaminated blood products Clinical presentation:
• Usually mild, diagnosed in adulthood
Acquired Hemophilia A (AHA)/Acquired F VIII Deficiency MANAGEMENT
• Autoantibodies against F VIII • F XI concentrate
Steps: • Very rare • Anti-fibrinolytics (tranexamic acid)
1. Endothelial damage
2. vWF secreted by endothelial cells and binds to exposed collagen = platelet adhesion
• Post-partum, other autoimmune disorders, elderly (think malignancy) • Frozen plasma
3. Platelets bind to vWF via GPIb receptor and become activated = platelet activation • Variable clinical presentation
4. Activated platelets change shape to increase surface area and express GPIIb/IIIa (fibrinogen receptor) • **isolated prolonged aPTT
5. Platelets secrete: • Factor levels and mixing study
• a granules, which contain additional vWF and PDGF for long-term wound healing • Tx:
• Dense granules, which contain ADP and thromboxane A2 (TXA2)
• ADP binds to P2Y12 receptors and TXA2 binds to TP receptors to recruit/activate other platelets
• Stop acute bleeding with alternative factors: F VIIa or activated PCC
6. Fibrinogen, produced by the liver, binds to platelets via GPIIb/IIIa and links platelets = platelet aggregation (prothrombin complex concentrate), porcine F VIII
• Eradicate inhibitor: prednisone +/- cyclophosphamide, 2nd line rituximab,
Hemostasis and Disorders of Hemostasis
7. Actin and myosin proteins in platelets cause contraction of the platelet plug
calcineurin inhibitors, other immune modulating agents
Immune Thrombocytopenic Purpura (ITP) Note: have to do Hep B serology prior to ritux b/c possible re-activation; may need to treat concomitantly Thrombotic Thrombocytopenic Purpura (TTP)
Increased destruction à immune-mediated Increased destruction à immune and non-immune mediated
HEME EMERGENCY
• MC cause of thrombocytopenia in children; can be in adult Fever
MANAGEMENT
• Often presents 1-3 weeks after viral illness • Pathophys: deficiency of ADAMTS-13 (vWF cleaving protease (decreases vWF activity))
NOT BLEEDING/MILD MUCOCUTANEOUS BLEEDING + PLAT > 30
• Think infection as trigger • Plat aggregation and coagulation in small blood vessels = RBC hemolysis
• Watch and wait
• Autoantibody-mediated (commonly GPIIb/IIIa or Ib-IX; IgG)
• Pathophys: opsonization and phagocytosis by splenic macrophages and liver Kupffer cells; NOT BLEEDING + PLAT < 30 CAUSES
damage to megakaryocytes; possible impaired production of thrombopoietin • Congenital mutation in ADAMTS-13
• Prednisone 0.5-2 mg/kg OR Dex 40 mg x 4 days
• Primary vs. Secondary: SLE, CLL, NHL, viral infections (Hep C, HIV) • Acquired = autoantibodies?
• IVIG
• Secondary (40%):
• Anti-D Hemolytic anemia
Clinical presentation: • Cancer
• Asymptomatic/purpura/bleeding/hemorrhage
• 2nd line: splenectomy, TPO-R agonists (romiplostim, eltrombopag), rituximab
• BMT
TTP Thrombocytopenia
• Essentially plat < 100 x 109/L in absence of other causes • Pregnancy
ACTIVE BLEEDING
• Medications: ticlopidine, clopidogrel, acyclovir, quinine, tacrolimus, bevacizumab
• Steroids
INVESTIGATIONS • HIV
• Tranexamic acid
• No gold standard; dx of exclusion • Pathogenesis of 2ndary poorly understood
• +/- IVIG
• CBC, blood film • Life threatening: plat transfusion +/- splenectomy Note: TTP is associated w SLE
• HBV/HCV/HIV serology Triggers: infections, meds, autoimmune dz (SLE), pregnancy
• H. pylori
PREGNANCY
Clinical presentation: *only need 2 to make diagnosis
• Treat if bleeding and plat < 30 OR plat < 50 at > 36 weeks GA
• Pentad of thrombocytopenia, microangiopathic hemolytic anemia*, renal failure, altered mental status, fever
Onset of response: GPIb • Steroids or IVIG (Dex crosses placenta)
• IVIG 1-3 days GPIIb/IIIa • Plat > 50 for delivery, > 80 for neuraxial anesthesia
INVESTIGATIONS Renal failure
• Corticosteroids 2-14 days • CBC and blood film (schistocytes)
• Rituximab (anti-CD20) 7-56 days Note: • PT, aPTT, fibrinogen (N) Neurological symptoms
TPO-R agonist increases plat numbers • Increased markers of hemolysis (increased unconjugated bili, increased LDH, decreased haptoglobin)
Secondary ITP: Ritux, IVIG targets abs/ab production • Cr, urea
• Bleed and HCV use IVIG Steroids suppress immune system: binds to Fc of ab, reduces plasma cells, • ADAMTS-13 activity
• Bleed and HIV use steroids or IVIG reduces Fc receptor expression on macrophages
Splenectomy removes site of most macrophages (RES), prevents plat destruction MANAGEMENT
• Plasmapheresis
Note: Evan’s Syndrome = ITP + hemolytic anemia
Note: • Corticosteroids
Dry purpura = cutaneous hemorrhage (bruising or petechiae) • IVIG
Wet purpura = MM hemorrhage (GI, mouth, nose, eyes) • Rituximab
Note: Admit if new diagnosis and plat < 20
Note: anti-RhD thought to work by blocking Fc receptors within reticuloendothelial system Note: DO NOT transfuse plats
,
, Primary hemostasis
• Formation of weak platelet plug
• Four phases:
1. Vasoconstriction
2. Platelet adhesion
3. Platelet activation
4. Platelet aggregation
Steps:
1. Endothelial damage
2. vWF secreted by endothelial cells and binds to exposed collagen = platelet adhesion
3. Platelets bind to vWF via GPIb receptor and become activated = platelet activation
4. Activated platelets change shape to increase surface area and express GPIIb/IIIa (fibrinogen receptor)
5. Platelets secrete:
• a granules, which contain additional vWF and PDGF for long-term wound healing
• Dense granules, which contain ADP and thromboxane A2 (TXA2)
• ADP binds to P2Y12 receptors and TXA2 binds to TP receptors to recruit/activate other platelets
6. Fibrinogen, produced by the liver, binds to platelets via GPIIb/IIIa and links platelets = platelet aggregation
7. Actin and myosin proteins in platelets cause contraction of the platelet plug
