CMAP summary
4.1 Primary Hemostasis
-Endothelin - powerful vasoconstrictor
-NO and prostacyclin (prostaglandin I2)- vasodialator
-What happens in platelet adhesion?
3.
Platelet adhesion - VWF (von willieband factor) is a glue that binds to exposed collagen in damaged tissue. It then binds to glycoprotein VIII, and then glycoprotein IB (integrin IB) on
platelet. VWF mainly comes from endothelial cells storage unit -Weibel Palade body(HY), but are also found in alpha granules platelets. (another important factor in weibel palade body is P-selectin)
-What happens in platelet activation (aka degranulation)?
4.
thromboxane A2 (very powerful degranulator made by cyclooxygenase (COX)),
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alpha granules (contain fibrinogen and VWF),
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delta granules (contain SAC - serotonin for vasoconstriction, ADP which is necessary for expression of GP IIB/IIIA receptor by platelet and stimulates degranulation, and calcium that helps in secondary hemostasis)
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Platelet changes shape after adhesion and is activated. It secretes
-What happens in platelet aggregation?
5.
A single fibrinogen is linked to multiple platelets via their glycoprotein IIB/IIIA. This creates platelet plug. Platelet plug is weak and needs secondary hemostasis (coagulation cascade) for stabilization.
-What are 2 classification of platelet disorders?
6.
4.1 Primary Hemostasis
What are 2 classification of platelet disorders?
6.
Qualitative disorders - bad platelet
-Quantitative disorders - good platelet but too few in numbers (petechiae (spots in skin due to bleeding) seen in thrombocytopenia and not usually in qualitative disorder)
-What are common features of pt with problem in primary hemostasis ? 6.
Key sign is mucosal and skin bleeding; intracranial bleeding with severe thrombocytopenia (low platelet) (can kill you).
-Mucosal bleeding - epistaxis (nose bleeding), hemoptysis (coughing blood), GI bleeding, hematuria, and menorrhagia (heavy menses)
-Skin bleeding - petechiae (bleeding spots on skin), purpura (>3mm bleeding spots), ecchymoses (>1cm), easy bruising.
-What are some useful lab studies for platelet?
7.
Platelet count (normal is 150k-400k per microliter of blood)
-Bleeding time - prick patient and see how long it takes to stop bleeding - normal is 2-7 minute
-Blood smear - look under microscope
-Bone marrow biopsy - look at megakaryocytes (they make platelets)
-What is idiopathic thrombocytopenic purpura (ITP)?
8.
Most common cause of thrombocytopenia in kids and adults. Autoimmune production of IgG against platelet antigens (ex- GP IIB/IIIA)
-Antibodies are made in spleen, and tagged platelets are phagocytosed by spleen macrophages.
Low platelets cause purpura (bleeding spots in skin)
-Describe acute form of ITP?
9.
Seen in children weeks after viral infection or immunization.
-Self-limited disorder - resolves within weeks of presentation
-Quantitative disorders
Describe chronic form of ITP?
10.
Classically seen in child bearing age woman
-May be primary (idiopathic) or secondary (strong association with lupus- remember antibodies against blood is a common feature in lupus)
-IgG can cross placenta and cause short-lived thrombocytopenia in children
-What do we see in labs in ITP?
11.
Platelet count <50K/microliter
-Normal PT/PTT
-Hyperplasia of megakaryocytes on bone marrow biopsy
-What are treatment choices of ITP?
12.
Corticosteroids Kids respond well to corticosteroids, adults may show early response but usually relapse
usually relapse IVIG (IV
immunoglobulins)
Used for symptomatic bleeding. spleen macrophages will eat them instead of immunoglobulins bound to platelets.
Splenectomy for severe cases
Recall that spleen is the source of Ab production and site of phagocytosis
What is microangiopathic hemolytic anemia (hemolysis in small blood vessels)? What 2 disease is it commonly seen in?
11.
Platelet microthrombus are formed in small blood vessels that cut RBC as it passes through. This results in hemolytic anemia with Schistocytes aka helmet cells (cut RBC).
-Thrombocytopenia is seen because of formation of tons of microthrombi.
-It's a symptom commonly seen in thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS)
-Microangiopathic hemolytic anemia
Fig - schistocyte - the two pointy things at the end is classic appearance of cut RBC What is thrombotic thrombocytopenic purpura?
12.
There are lots of thrombus in blood vessels that result in low platelet (thrombocytopenia) and purpura (skin bleeding due to low platelet).
-What causes thrombotic thrombocytopenic purpura (HY)?
13.
Caused due to deficiency ADAMTS13 enzyme. ADAMTS13 normally cleaves VWF multimers into smaller monomers for eventual degradation. Bad ADAMTS13 = too much VWF = more platelet adhesion resulting in microthrombi.
-Low ADAMTS13 is usually due to acquired autoantibody and most commonly seen in adult females
-What is hemolytic uremic syndrome (HUS)?
13.
Platelet microthrombi causes hemolysis. This mainly occurs in kidney leading to uremia and in brain.
-What causes HUS (HY)?
14.
Classically seen in children with E Coli 015:H7 dysentery - results from exposure to undercooked beef. Dysentery = bloody diarrhea
-E Coli verotoxin damages endothelial cells in kidney and also reduces ADAMTS13 resulting platelet microthrombi
-What are clinical findings of TTP and HUS?
15.
Skin and mucosal bleeding
-Microangiopathic hemolytic anaemia
-Microangiopathic hemolytic anaemia
-Renal insufficiency - predominant problem in HUS
-CNS abnormality - predominant problem in TTP
-What do we see in labs in TTP and HUS?
16.
Thrombocytopenia with increased bleeding time
-Normal PT/PTT
-Anemia with schistocytes
-Increased megakaryocytes on bone marrow biopsy
-How do we treat TTP?
17.
Plasmapheresis (process by which we remove protein from blood - removes Ab against ADAMTS13)
-Corticosteroids - reduce production of AB.
-What is bernard soulier syndrome? How do we diagnose?
18.
Genetic GP1b deficiency; platelet adhesion is impaired
-Blood smear shows mild thrombocytopenia (platelet don't live as long because they lack GP1b) with enlarged platelet. See big suckers in Bernard Soulier- big platelets
-Fig: arrow points to big platelets in Bernard Soulier syndrome What is Glanzmann thrombasthenia?
19.
Genetic GIIB/IIIA deficiency; platelet aggregation is impaired.
-Qualitative disorders of platelet
How do uremia affect platelet?
20.
It impairs adhesion and aggregation of platelets.
-It creates fibrin mesh via coagulation cascade to stabilize platelet plug.
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It creates thrombin (factor IIa). Thrombin converts fibrinogen to fibrin (factor Ia). Fibrin is then cross linked.
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1. What does secondary hemostasis do?
They occur due to factor abnormalities.
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2. What causes disorders of secondary hemostasis?
Deep bleeding in muscles and joints (recall that disorders of primary hemostasis has bleeding in skin and mucosal surface)
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Rebleeding after surgical procedures
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3. What is clinical presentation of disorders of secondary hemostasis?
Intrinsic pathway - Starts with factor 12 which is activated by subendothelial collagen (SEC).
Measured by PTT lab test. Heparin results is better measured by PTT (PTT measures Hep - 3 letters each)
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Extrinsic pathway - starts with factor 7 which is activated by tissue thromboplastin. Measured by PT lab test. PT measures coumadin results.
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4. How do extrinsic and intrinsic pathway of coagulation cascade start? What lab tests measures intrinsic and extrinsic pathways? What lab test is better is coumadin vs heparin?
Hemophilia A
Caused by genetic factor 8 deficiency
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x- linked recessive.
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Can arise from new mutation without any family history
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Deep tissue, joint and post-surgical bleeding.
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9. What causes hemophilia A (think hemophilia 8)? What is it's clinical presentation?
Elevated PTT, normal PT (factor 8 is a part of intrinsic pathway and PTT measures intrinsic pathway)
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Low factor 8
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Normal platelet count and bleeding time
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10. What are lab findings in hemophilia A?
Give recombinant factor 8.
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11. How do you treat hemophilia A?
Hemophilia B
Caused by genetic deficiency in factor 9.
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Clinically resembles hemophilia A.
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Lab values - same as hemophilia A except low factor 9 instead of factor 8.
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12. What causes hemophilia B (aka christmas disease)? What are its clinical features? What are the lab values?
Coagulation factor inhibitor disease
Patient acquires antibody against coagulation factor which impairs factor function. Anti-factor 8 antibody most common.
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Clinical presentation same as hemophilia A.
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13. What is coagulation factor inhibitor disease? What factor is most commonly inhibited?