CHAPTER 1 - HEMOSTASIS PART 6 Flashcards
From an external substance
ACQUIRED DEFECTS OF PLATELET FUNCTION
- Drug-related
• Aspirin
• NSAIDs and other COX-2 inhibitors (naproxen and ibuprofen)
• Other Antiplatelet medications: ticlopidine and clopidogrel
• Dextran
acytelate the cyclooxygenase enzyme
Aspirin
adding/removin one cpd to make it nonfuncitonal
acytelate
– secretes thromboxane and prostaglandin
cyclooxygenase enzyme
(stimulates the activation of plt and aggregation)
thromboxane and prostaglandin
blood donation: deferral after 14 days; plasma and plt are nonfuncitonal
NSAIDs and other COX-2 inhibitors (naproxen and ibuprofen)
.Prevent blood clotting by preventing plt aggregation
ticlopidine and clopidogrel
Administered to enhance fibrinolysis (plt clot – stabilization of coagulation – agglutinates in the bv to arrest bleeding – interacts w/ bf = not healthy)
Dextran
Side effect: reduce plt adhesion to vWF (interference to plt plug formation)
Dextran
Normal:
140-450 x 109/uL
: transient thrombocytopenia
100-150 x 109/uL
(due to medication but can go back as soon as it is eliminated)
: transient thrombocytopenia
- abnormally low
• ≤ 100,000/ pL
- bleeding possible
• 30,000-50,000/ pL
- spontaneous bleeding
• ≤ 30,000
- severe spontaneous bleeding
• ≤ 5,000/pL
-decrease in circulating platelets
THROMBOCYTOPENIA
-less than 100,000/uL
THROMBOCYTOPENIA
-increase in circulating platelets
THROMBOYTOSIS /THROMBOCYTHEMIA
-more than 450,000/uL
THROMBOYTOSIS /THROMBOCYTHEMIA
-bleeding -
THROMBOCYTOPENIA
hallmark for myeloproliferative diseases
Primary Thrombocytosis
- polycythemia vera: thrombocytosis is in sync w/ an abnormality of the rbc
THROMBOYTOSIS /THROMBOCYTHEMIA
THROMBOCYTOPENIA
- Decreased production
- Blood Transfusion
- Increased Destruction or Consumption
- Decreased production
a. Megakaryocyte hypoproliferation
b. Ineffective thrombopoiesis
c. Marrow replacement (infiltration) by abnormal cells
a. Megakaryocyte hypoproliferation
a.1) Inherited/Congenital Hypoplasia
a.2) Acquired/Drug induced Hypoplasia
Inherited/Congenital Hypoplasia:
- May Hegglin Anomaly
- TAR Syndrome
- Fanconi Anemia
- Neonatal Thrombocytopenia
- Bernard Soulier Syndrome
- Wiskott Aldrich
-Large plt (20 um); dohle like bodies (neutrophils, monocytes)
May Hegglin Anomaly
-Mutation in MYH9 gene
May Hegglin Anomaly
Encodes for myosin heavy chain
May Hegglin Anomaly
– contractile protein in plt (imp for activation)
Thrombostenin
Causing thrombocytopenia (abnormally large plt but low in level)
May Hegglin Anomaly
-absence/hypoplasia of radial bones (small arm)
TAR Syndrome
-Mutation in RBM8A gene
TAR Syndrome
-occurs in neonates
Fanconi Anemia
-bone and visceral organ abnormalities
Fanconi Anemia
-pancytopenia (decrease in all blood cells)
Fanconi Anemia
-onset: w/in 72 hours of birth
Neonatal Thrombocytopenia
- associated with infections with TORCH
Neonatal Thrombocytopenia
Toxoplasma, Rubella, CMV, HIV, Herpes
Neonatal Thrombocytopenia
-small platelets
Neonatal Thrombocytopenia
-absence of megakaryocytes
Neonatal Thrombocytopenia
: directly affect the fetal BM megakaryocyte
chlorthiazide and tolbutamide
-Large plt but few
- Bernard Soulier Syndrome
-Dense granules; small platelets
- Wiskott Aldrich
-suppresses BM megakaryocyte production and other cells.
Acquired/Drug induced Hypoplasia
Acquired/Drug induced Hypoplasia Examples:
-methotrexate, busulfan, cytosine, arabinoside, cyclosphamide, cisplatin
– assoc. w/ specific gene chromosomal abnormality
Inherited/Congenital Hypoplasia
: HIV treatment
-Zidovudine
side effect – severe thrombocytopenia
-Zidovudine
eliminates infection but negatively affects the healthy cells
-Zidovudine
: thrombocytosis treatment
-Anagrelide
(eliminating some platelet to go back to normal level by increasing sequestration or affecting the life span of plt)
-Anagrelide
improper administration causes thrombocytopenia
-Anagrelide
: long-term consumption may lead to thrombocytopenia
-Ethanol
bleeding may not be arrested easily
-Ethanol
: after chemotherapy, there will be pancytopenia, destroying some healthy cells
-Recombinant IL-2
restores platelet
-Recombinant IL-2
chemotherapy-induced thrombocytopenia treatment
-Recombinant IL-2
• Seen in megaloblastic anemias
Ineffective thrombopoiesis
Pernicious anemia, Folic acid deficiency and Vitamin B 12 deficiency
Ineffective thrombopoiesis
: affects maturation stage of cell; immature cells remained large; nucleus continue to divide but the cytoplasm will not; main cause
Folic acid deficiency and Vitamin B 12 deficiency
: response will follow after 1-2 weeks
Vitamin replacement
-impaired DNA synthesis = BM produce abnormal megakaryocytes
Ineffective thrombopoiesis
-Platelets: decreased survival time and abnormal function
Ineffective thrombopoiesis
-abnormality in the division and maturation of the megakaryocyte – even plt shedding is affected (ineffective)
Ineffective thrombopoiesis
-due to infiltration of abnormal cells, inhibitors of thromobopoiesis are produced contributing to thrombocytopenia
Marrow replacement (infiltration) by abnormal cells
Suppression of normal cell/megakaryocyte production - Affecting thrombopoiesis
Marrow replacement (infiltration) by abnormal cells
-inhibits maturation of the megakaryocyte
Marrow replacement (infiltration) by abnormal cells
: lost of platelet containing blood products and coagulation
factors
• Donor
: may have alloantibodies directed against the antigens of blood products
• Recipient
: dilution of px platelet
• Recipient
- Increased Destruction or Consumption
a. non-immune (premature activation & consumption)
b. Immune destruction
a. non-immune (premature activation & consumption)
Thrombotic Thrombocytopenic Purpura (TTP)
DIC
HUS
Infections (eg. Dengue)
Secondary
non-immune (premature activation & consumption)
caused by mechanical trauma
non-immune (premature activation & consumption)
due to inflammation, infection, or gene mutation
non-immune (premature activation & consumption)
does not involve the immune system
non-immune (premature activation & consumption)
Gene that produces enzyme, which controls the VWF
(ADAMTS-13)
responsible for cutting VWF to interact w/ plt in a normal size
(ADAMTS-13)
- has uncontrolled and very large VWF
Thrombotic Thrombocytopenic Purpura (TTP)
VWF is unfolded, multimer, and hyper adhesive (creating a thrombus)
Thrombotic Thrombocytopenic Purpura (TTP)
: composed of 1 VWF + plt
- Hyaline thrombi
- thrombocytopenia: circulating plt decreases due to thrombi formation
Thrombotic Thrombocytopenic Purpura (TTP)
- aka Moschcowitz Symdrome
Thrombotic Thrombocytopenic Purpura (TTP)
- thrombocytopenia: due to simultaneous coagulation
Disseminated Intravascular Coagulation (DIC)
: composed of fibrinogen + plt (plt is trapped in agglutination during coagulation concerning fibrinogen)
- DIC thrombi
: invasive bacteria in the colon that destroys mucosa lining
- S.dysentiriae/E.coli 0157:H7 serotype
- thrombocytopenia: as soon as the colon is damaged, the endothelium of the colon releases VWF creating thrombi that may go to the renal structure
Hemolytic Uremic Syndrome (HUS)
Involves the immune system, Abs, and auto-Abs
b. Immune destruction
- Acute: onset after 1-3 weeks
Immune (Idiopathic) Thrombocytopenic Purpura (ITP)
Ab and Ag forms an immune complex that binds w/ plt = elimination of Gp IIb-IIIa
Immune (Idiopathic) Thrombocytopenic Purpura (ITP)
-after plt is destroyed, it will be removed by the reticuloendothelial cells from the circulation
Immune (Idiopathic) Thrombocytopenic Purpura (ITP)
- unfractioned heparin administration: destroys PF4, affecting aggregation and plt destruction
Heparin-Induced Thrombocytopenia
: used to test platelet aggregation
- Ristocetin
in vivo/unfractioned form administration will facilitate interaction of VWF + Gp Ib-IX causing adhesion, aggregation, and in vivo agglutination
- Ristocetin
: can cause transient tmrombocytopenia
- Hematin
: induces thrombocytopenia
- Rotamine sulfate (for parasitic infection) and Bleomycin ( for bacterial infection)
Deficiency: disintegrase + ADAMTS-13
TTP
-platelets are trapped in fibrin clots
DIC
-VWF involvement
HUS
Disease triad: Microangiopathic Hemolytic Anemia, thrombocytopenia and neurologic abnormality
TTP
onset with platelet consumption, factor V,VIII and fibrinogen reduced level
-acute DIC
Due to S.dysentiriae/E.coli 0157:H7 serotype
HUS
Onset on children
HUS
Life threatening
DIC
Characterized by: erosive damage to the colon + bloody diarrhea
HUS
-no apparent cause
ITP
-presence of anti-platelet ab (IgG)
ITP
-develops IgG antibody specific for heparin plt factor 4 complex
HIT
-due to unfractioned heparin administration
HIT
abrupt onset, usually on children
Acute: ITP
mumps, chicken pox, small pox, and measles
ITP
Characterized by bruising, petechiae and epistaxis
ITP
Drugs affecting thrombocytopenia:
- Ristocetin
- Hematin
- Rotamine sulfate
- Bleomycin
HIT
: any age onset
Chronic ITP
rubella, chicken pox, ruboela
ITP
Characterized by: menorrhagia, epistaxis and bruising
ITP
Splenic sequestration Seen in:
hypersplenism/splenomegaly
(Gaucher’s, Hodgkin, Cirrhosis, Sarcoidosis, Lymphoma)
hypersplenism
more plt can be sequestered, reducing the circulating plt (thrombocytopenia)
hypersplenism
– removal of the spleen = low plt (thrombocytopenia)
splenomegaly
THROMBOYTOSIS/THROMBOCYTHEMIA
- Primary Thrombocytosis
- Secondary/Reactive Thrombocytosis
-hallmark of myeloproliferative disorders
Primary Thrombocytosis
-unregulated plt production
Primary Thrombocytosis
-variable size (small and large) affecting function
Primary Thrombocytosis
-increased megakaryocyte production in the bm
Primary Thrombocytosis
-myeloproliferative disorders: pcv, chronic myelogenous leukemia, myelofibrosis
Primary Thrombocytosis
plt can exceed up to 1 million/uL
Primary Thrombocytosis
-aka Essential Thrombocytopenia
Primary Thrombocytosis
-does not exceed 800,000/uL
Secondary/Reactive Thrombocytosis
-secondary to inflammation and trauma
Secondary/Reactive Thrombocytosis
-occurs to compensate for the lost platelet (betterment of the body)
Secondary/Reactive Thrombocytosis
-Ex. Childbirth, splenectomy, tissue necrosis, IDA
Secondary/Reactive Thrombocytosis
-exists for a short period of time
Secondary/Reactive Thrombocytosis
-normal plt morphologyand responds to normal stimuli
Secondary/Reactive Thrombocytosis
→ Excessive plasma proteins lead to hyperviscosity syndrome
Paraproteinemias (Multiple myeloma and Waldenstrom macroglobulinemia)
→ uremia: leads to decreased thromboxane synthesis, decreased adhesion, decreased platelet release, and decreased aggregation
Renal disease
May-Hegglin
Megakaryocyte hypoproliferation
in-utero exposure to certain drugs (particularly chlorothiazide diuretics and the oral hypoglycemic tolbutamide)
Neonatal Thrombocytopenia
• caused by a deficiency of a disintegrin an metalloproteinase with a thrombospondi type 1 motif, member 13 (ADAMTS-13).
TTP
involves the activation of both coagulation and fibrinolysis at the same time due to liberation of thromboplastic substance by damaged or abnormal cells
DIC
Associated with mild febrile illnesses, certain immunizations, and gastrointestinal disturbances
HUS
E. coli 0157:H7 or other Shiga/Vero toxin-producing bacteria
HUS
due to presence of anti-platelet antibodies of the IgG type
ITP
Most common in young females <15 y/o
ITP
patient develops IgG antibody specific for heparin-platelet factor 4 complexes
Heparin-Induced Thrombocytopenia
A. common side effect of unfractionated heparin administration
Heparin-Induced Thrombocytopenia
seen in myeloproliferative disorders
Primary Thrombocytosis
seen in splenic mobilization and in hemolytic anemias
Secondary/Reactive Thrombocytosis
(deformed with dumbbell shaped nuclei; could be reversed)
Ineffective thrombopoiesis
