Primary Hemostasis Related Disorders
What are the general notable signs and symptoms of immune thrombocytopenia?
sudden appearance of petechial rash, easy bruising, bleeding
IVIG are indicated in ITP. What is the mechanism of action of IVIG?
IVIG (intravenous immunoglobulin) presents a "second" choice to splenic macrophages... basically, splenic macrophages will become attracted to IVIG instead of the auto-IgG on platelets...leading to fewer platelets destroyed
There are 2 forms of immune thrombocytopenia purpura. What are the two forms?
Acute ITP... Chronic ITP
What is Glanzmann thrombasthenia? What is its pathogenesis?
qualitiatve disorder related to primary hemostasis due to... Deficiency of GP2b3a receptor on platelets... recall Gp2b3a facilitates PLATELET AGGREGATION... Gp2b3a is induced by ADP and TXA2 and receptors from platelets are linked by fibrinogen... Decreased ability to facilitate platelet aggregation
What is plasmapheresis?
removal, treatment, and retrun or exchange of blood plasma or component thereof from and to blood circulation... extracorporeal therapy (medical procedure done outside of body)... Basically, remove autoantibodies against ADAMSTS13 from blood plasma
What assay clinically tests for GpIb function?
ristocetin agglutination assay
How does the ristocetin agglutination assay tests for GpIb function?
ristocetin agglutination assay induces VWF binding to GpIb... in pts. with Bernard Souiler Syndrome... platelets do NOT agglutinate in presence of ristocetin
What is acute immune thrombocytopenia?
self-limited (i.e. resolves on its own) ITP 1-2 weeks post-viral infection or immuniztaion in children... children, self-limited, post-viral infection 1-2 weeks
What are shistocytes?
sheared RBCs... "helmet cells" in the context of microangiopathic hemolytic anemia; the platelet-thrombus shears RBCs turning them into shistocytes
What is a peripheral blood smear or blood film?
thin layer of blood smeared on glass microscope slide and then stained...to look for abnormalities in blood cells... 3 blood cells visualized and assess are... RBCs, WBCs, and Platelets
What patient population presents with Hemolytic Uremic Syndrome most commonly? What symptoms are present?
1. Young children exposed to undercooked beef... 2. gastrointestinal illness with dysentery/inflammatory diarrhea
What are the clinical findings of patients with Bernard Soulier Syndrome?
1. bleeding diatheses... 2. thrombocytopenia...(platelets without GpIb apoptose)... 3. enlarged platelets (secreted immaturely from bone marrow megakaryocytes)...
There are 3 ways to treat ITP. What are the 3 ways to treat Immune Thrombocytopenia?
1. corticosteroids... 2. Intravenous Immunoglobulin IVIG... 3. splenectomy
[rx] Glanzmann thrombasthenia 1. definition 2. labs 3. smear
1. defect in platelet integrin GP2b3a; no platelt plug formation 2. no platelet count; incrased BT... 3. no platelet clumping
[rx] Bernard-Soulier Syndrome 1. Definition 2. Labs 3. smear
1. defect platelet plug formation; decreased GpIb; decreased platelet to vWF adhesion... 2. decreased platelet count; increased BT... 3. enlarged platelets
[rx] Immune Thrombocytopenia... 1. Definition 2. etiologies ... 3. labs 4. Treatments
1. Anti-Gp2b3a autoantibodies trigger splenic macrophage destruction of platelets 2. idiopathic or seconday to autoimmune disorder, viral illness, malignancy, drug reaciton, pregnancy... 3. increased megakaryocytes BM biopsy, large platelets smear, thrombocytopenia, normal PT PTT. 4. IVIG, corticosteroids, splenectomy for refractory cases
[rx] MAHA: Thrombotic Thrombocytopenic Purpura... 1. Definition 2. Labs 3. Symptoms 4. Treatment:
1. Autoantibodies anti-ADAMST13; increased vWF multimers; MAHA 2. Labs: increased LDH, BT, megakaryocytes on BM biopsy, anemia with shistocytes, thrombocytopenia, normal PT and PTT 3. fever, thrombocytopenia, MAHA, CRAFT 4. plasmapheresis, steroids
What are 4 Qualitative Insults related to Primary Hemostasis?
1. Bernard Soulier Syndrome... 2. Glanzmann thrombasthenia... 3. Uremia... 4. Aspirin consumption
CRAFT stands for the pentad of neurological and renal symptoms in TTP... What does CRAFT stand for?
1. CNS [more in TTP than HUS]... 2. Renal [more in HUS than TTP]... 3. Anemia with shistocytes... 4. Fever... 5. Thrombocytopenia
Thrombotic Thrombocytic Purpura and Hemolytiuc Uremic Syndrome are types of Microangiopathic Hemolytic Anemias; thus, they have similar Clinical Findings. What are the 5 Clinical Findings of both TTP and HUS...CRAFT?
1. CNS [more in TTP than HUS]... 2. Renal [more in HUS than TTP]... 3. Anemia with shistocytes... 4. Fever... 5. Thrombocytopenia
What are 3 usual, general causes of thrombocytopenia?
1. Decreased bone marrow production... decreased megakaryocyte...decreased platelets... 2. Sequestration (usually in spleen)... 3. Increased platelet consumption or destruction
What 2 mechanisms lead to hemolytic uremic syndrome HUS?
1. Infection... 2. Drugs
Primary Hemostasis Disorders can be classified into 2 categories. What are these two categories?
1. Quantitative disorders... 2. Qualitative disorders
What are the secondary causes of immune thrombocytopenia? 1. Autoimmune 2. Viral 3. Malignancies 4. Misc
1. SLE, antiphospholipid antibody syndrome... 2. HIV, HC 3. lymphoproliferative disorders... 4. pregnancy
What are 6 laboratory findings of microangiopathic hemolytic anemias TTP and HUS?
1. Thrombocytopenia (platelet consumption)... 2. increased bleeding (due to thrombocytopenia) 3 Increased serum lactate dehydrogenase (LDH)...high to extremely high levels... 4. Normal PT/INR (prothrombin time) and normal PTT (partial thromboplastin time)... 5. Increased megakaryocytes on bone marrow biopsy... 6. anemia with shistocytes on peripheral blood smear
What are the 2 types of microangiopathic hemolytic anemia?
1. Thrombotic Thrombocytopenia Purpura (TTP)... 2. Hemolytic Uremic Syndrome
What are 5 signs/symptoms associated with chronic immune thrombocytopenia?
1. epistaxis... 2. easy bruising... 3. gingival hemorrhage... 4. menorrhagia... 5. soft tissue hemorrhage from minor trauma
What are the 2 treatment options for Thrombotic Thrombocytopenia Purpura?
1. plasmapheresis... 2. corticosteroids
What are the 4 laboratory findings of Immune Thrombocytopenia Purpura?
1. thrombocytopenia = low platelet count... 2. increased megakaryocytes on bone marrow biopsy... 3. large platelets on peripheral blood film... 4. Normal PT and PTT time (prothrombin and partial thromboplastin time)...coagulation cascade not messed up
[rx] Hemolytic-Uremic Syndrome HUS... 1. Definition... 2. population 3. presentation 4. treatment
1. thrombocytopenia, MAHA, acute renal failure... 2. kids undercooked beef EHEC O157:H7 esp following GI illness with inflammatory or bloody diarrhea [HUS in adults does NOT present with diarrhea]... 3. CRAFT...[more renal in HUS than CNS...compare to TTP]... 4. plasmapheresis
What are the 5 clinical features associated with thrombotic thrombocytopenia purpura?
1. thrombocytopenia... 2. microangiopathic hemolytic anemia... 3. fever... 4. Transient neurological deficits... 5. Renal failure (inability to filter blood of wastes)
Uremia is considered a qualitative insult related to primary hemostasis. What is uremia? How does it inhibit primary hemostasis?
1. uremia is condition associated with renal failure and characterized by build-up of toxic metabolites in blood (due to renal failure)... 2. toxic metabolites leads to inhibition of... a. platelet adhesion... b. platelet aggregation
What is enzmye is deficient in thrombotic thrombocytopenia purpura TTP? What is its function? Why is it deficient?
ADAMSTS13 (von Willebrand factor metalloprotease) cleaves and degrades VWF multimers... Most common, female patients have autoantibodies against ADAMSTS13
CNS abnormalities are more common in which of the types or causes of microangiopathic hemolytic anemias? Thrombotic Thrombocytopenic Purpura or Hemolytic Uremic Syndrome?
CNS abnormalities = Thrombotic Thrombocytopenic Purpura because thrombi are in CNS
Corticosteroids are used in treatment of ITP. What are corticosteroids and their mechanism of action?
Cortisone, prednisone, hydrocortisome... Decreases inflammation by suppression of migration of polymorphonuclear leukocytes and reversal of increased capillary permeability... i.e. stops platelet destruction via splenic macrophages AND... INHIBIT FORMATION OF AUTOANTIBODIES
E. coli O157-H7 causes Hemolytic Uremic Syndrome. What toxin does E. coli O157:H7 secrete? How does this toxin lead to hemolytic uremic syndrome, a type of microangiopathic hemolytic anemia?
E. coli O157:H7 secretes Verotoxin... Vertoxin leads to endothelial damage... Endothelial damage leads to Platelet-thrombus formation... Platelet thrombus formation leads to RBC shearing to shistocytes... All in all, classic triad 1. thrombocytopenia... 2. anemia... 3. uremia/renal failure is observed
Infection leads to Hemolytic Uremic Syndrome. What bacterial infection is most closely associated to HUS?
EHEC: enterrohemorrhagic E. coli... E. coli O157:H7; shiga-like toxin producing type of E. coli...
Autoantibodies of immune thrombocytopenia are IgG. Why is immune thrombocytopenia even more concerning in women of child-bearing age or women already pregnant?
IgG crosses placenta and causes short-lived thrombocytopenia in infants... Short-lived because IgG autoantibodies will get used up and infant's antibody production will rev up so that mother's is no longer needed
What is the most common cause of thrombocytopenia in both children and adults?
Immune Thrombocytopenia Purpura, which is also known as... Idiopathic thrombocytopenic purpura or immune thrombocytopenia
Uremia is one finding in the clinical triad of Hemolytic Uremic Syndrome. What is uremia?
Uremia: condition involving abnormally high levels of waste products in blood... consequence of renal failure
Microangiopathic Hemolytic Anemia is another cause of thrombocytopenia. What is microangiopathic hemolytic anemia?
Microangiopathic hemolytic anemia: 1. consumption of platelets via platelet thrombus formation in microvasculature... 2. shearing of RBCs by platelet-thrombus leading to shistocytes and, ultimately, hemolytic anemia
Renal insufficiency is more common in which of the types or causes of microangiopathic hemolytic anemias? Thrombotic Thrombocytopenic Purpura or Hemolytic Uremic Syndrome?
Renal insufficiency = HUS because thrombi damaged in kidney... renal insufficiency: inability of kidneys to remove waste and balance fluids
Splenectomy is indicated in treatment of ITP. Why is splenectomy an option, the last option, for patients with ITP?
Splenectomy: removal of spleen... Performed in patients with refractory conditions (do not respond to other treatments)... Splenectomy removes splenic plasma cells producing auto-IgG and removes splenic macrophages
Why is secondary chronic immune thrombocytopenia associated with SLE?
Systemic Lupus Erythematosus SLE produces autoantibodies against several targets... Blood cells like RBCs, WBCs, and platelets are targeted... The association comes from the fact that SLE targets platelets for destruction
What are Qualitiative Disorders related to Primary Hemostasis?
The characteristics (as opposed to number) of platelets is aberrant... (i.e. missing receptors, missing components, etc.)
What are quantitative disorders related to Primary Hemostasis?
Thrombocytopenia and its causes... 1. Immune thrombocytopenia purpura... 2. Microangiopathic hemolytic anemia via... a. thrombotic thrombocytopenic purpura and... b. hemolytic uremic syndrome
Hemolytic uremic syndrome is another type or cause of microangiopathic hemolytic anemia. What is hemolytic uremic syndrome HUS?
a condition characterized by the following triad: 1. thrombocytopenia (platelet-thrombus formation)... 2. anemia (RBC to shistocytes)... 3. uremia (indicator of renal failure)
What is the mechanism of immune thrombocytopenia purpura?
autoIgG antibodies produced by plasma cells in spleen target... platelet antigen like Gp2b3a (i.e. fibrinogen, platelet aggregation) for destruction by... splenic macrophages... lowering platelet count = thrombocytopenia
What is thrombotic thrombotic thrombocytopenia purpura?
deficiency of ADAMSTS13 enzyme leads to undegraded VWF (von willebrand factor)... undegraded VWF mediates excessive platelet adhesion... excessive platelet adhesion leads to platelet-thrombus...leads to... Platelet consumption and RBC shearing evident in microangiopathic thrombocytopenia purpura
Children with inflammatory diarrhea (dysentery, bloody diarrhea) due to EHEC (E.coli O157:H7) should NOT be given antibiotics... Why shouldn't children suspected of EHEC be given antibiotics?
killing EHEC would release shiga-like toxin (verotoxin) exacerbating Hemolytic Uremic Syndrome
What is chronic immune thrombocytopenia? What 2 types of chronic immune thrombocytopenia exist?
long-lasting immune thrombocytopenia in adults... Primary and Secondary chronic thrombocytopenia... Secondary is associated with SLE...
What is thrombocytopenia?
low platelet count
Menorrhagia is seen in ITP. What is menorrhagia?
menstrual bleeding with abnormally heavy or prolonged bleeding
How does a blood smear of patients with Glanzmann thrombasthenia present?
no platelet aggregation...
Aspirin, acetylsalicylic acid, is considered a qualitative insult related to primary hemostasis. What is Aspirin? How does it inhibit primary hemostasis?
non-steroidal anti-inflammatory drug treats pain, fever, and inflammation... irreversible inhibitior of platelet-cyclooxygenase leads to decrease prostaglandin Thromboxane (TXA2)... TXA2 stimulates platelet aggregation...therefore... Aspirin prevents platelet aggregation by inhibiting synthesis of TXA2 via platelet-cyclooxygenase block
What is Bernard Soulier syndrome? What is its pathogenesis?
qualitative disorder... Mutation in G1Pb receptor prevents platelet adhesion... Recall G1Pb on platelets binds to VWF (after VWF binds to subendothelial collagen)... PREVENTS platelet adhesion
Soft tissue hemorrhage from minor trauma is associated with ITP. What is soft tissue?
tissues connect support or surround structures and organs of the body... 1. tendons, ligaments, synovial membranes 2. fascia, skin, fibrous tissue, fat... 3. nerves, muscles, blood vessels... Everything but hard bone and organs
Patients with Bernard Soulier Syndrome experience bleeding diatheses... What is bleeding diatheses in hematological terms?
unusal susceptibility to bleed (hemorrhage) due to hypocoaguability caused by defect in coagulation system (i.e. lack of GpIb; lack, etc.)
