Platelet Abnormalities Flashcards
Thrombosis results from, and in turn causes, three interrelated factors (hypercoaguable state/activation of blood coagulation, vascular endothelial injury/inflam of bv, circulatory stasis/decreased blood flow
Virchow’s Triad (1854)
Hypercoagulable states or conditions are usually associated with a?
predisposition to venous
thrombosis and/or arterial thrombosis (acquired or inherited)
Hypercoagulable states are secondary to
• Secondary to: → Malignancy → Pregnancy and pre-partum period → Estrogen therapy → Trauma or surgery of lower extremities, hips, abdomen, or pelvis → Sepsis → Thrombophilia → Inflammatory bowel disease* → Nephrotic syndrome*
Vascular endothelial injury involves abnormalities in?
endothelium (ie atherosclerosis, assoc. vascular inflam)
This is secondary to atrial fibirillation, left ventricular dysfunction, immobility or paralysis, venous insufficiency or varicose veins, venous obstruction from tumor, obesity or pregnancy
Circulatory Stasis
*Abnormalities of haemorheology and turbulence at vessel
bifurcations and stenotic regions
This is secondary to: → Trauma or surgery → Venipuncture → Chemical irritation → Heart valve disease or replacement → Atherosclerosis → Indwelling catheters*
Vascular endothelial injury
Formation of an abnormal mass within the vascular system which comes from RBCs, WBCs, platelets leading to improper circulation (=necrosis/gangrene)
Thrombosis
*Arterial: comp. of platelet aggregates/ white thrombus
Venous: cons. of fibrin and RBC/red thrombus (see table 1: a vs v thrombus)
Acquired predisposing risk factors for venous thrombosis (can be prevented)
- Increasing age
- Pregnancy (due to hormonal factor; risk:2-6x higher)
- DIC
- Elevated levels of microparticle tissue factor (membrane vesicles that can be shed from many cell types)
- malignant neoplasms
- surgery/trauma
- prolonged immobilization
- smoking
- obesity
- arteriosclerotic CVD
venous thrombosis partly due to increasing age is associated with what?
increase in procoagulant factors:
→ D-dimer
→ Fibrinogen
→ Factor VIII
What are the risk factors for venous thromboembolism in pregnancy?
→ Obstruction of venous return by the gravid uterus
→ Venous astonia caused by hormonal factors
→ Acquired prothrombotic changes in hemostatic proteins (increased plasma levels of VWF, fibrinogen, and factors VII, VIII, and X, essentially unchaged Factors II, V, IX, and XII and declined Factor XIII)
An increase in procoagulant factors due to perturbed endothelial cells and activated mononuclear cells, which may produce proinflammatory cytokines that mediate coagulation activation is associated with which factor for venous t.?
DIC
→ Activation of coagulation is initiated by tissue factor expression on activated mononuclear cells and endothelial cells
→ Downregulation of physiologic anticoagulant mechanisms
→ Inhibition of fibrinolysis by endothelial cells
• DIC is an end-complication of infection or sepsis
→ When you have DIC, the resulting event will be death
Elevated levels of microparticle tissue factor can be seen in
Atherosclerotic vascular disease, severe infections and
malignancy
refers to a group of conditions where blood clots more easily than normal which may lead to thrombosis
thrombophilia or thrombocytosis
[thrombophilia or thrombocytosis] homozygous state can be incompatible with life or present at a very early age
Hereditary thrombophilia
*Most common: • Activated protein C (APC)-resistant factor V Leiden mutation (APC is a natural anticoagulant) • Elevated prothrombin levels caused by the prothrombin G20210A (or Factor II) polymorphism • Increased Factor VIII Level • Homozygous C677T • Polymorphism in Methylenetetrahydrofolate reductase
[thrombophilia or thrombocytosis]
→ Usually become apparent in adulthood
→ Can happen as a result of other medical problems that have developed or problems with the immune system
Acquired Thrombophilia
rarely seen in hereditary thrombophilia
Rare: • Protein C deficiency • Protein S deficiency • Antithrombin deficiency Very Rare: • Dysfibrogenemia • Homozygous homocystinuria
Other acquired risk factors for venous thrombosis
- Long flights
- Myeloproliferative diseases
- Superficial vein thrombosis
- Previous venous thrombosis
- Pregnancy & puerperium
- Use of female hormones
- Antiphospholipid antibodies
- Hyperhomocysteinemia
- Activated Protein C resistance unrelated to Factor V Leiden
- Varicose veins
laboratory examination for thrombophilia (screening test NA)
APC resistance where Partial Thromboplastin Time (PPT)
More expensive specific assays
- Factor V Leiden
- Protein C and S Assay
- Anti-thrombin assay
abnormal results associated with APC resistance (Decreased ratio) test
Pregnancy, use of oral contraceptives, stroke, presence of lupus anticoagulant, increased Factor VIII levels, autoantibodies against activated protein C, use of anticoagulants
abnormal results associated with decreased level of protein C
Liver disease, use of oral anticoagulants,
Vitamin K deficiency, childhood, DIC,
presence of autoantibodies against protein
C
abnormal results associated with Hyperhomocysteinemia
Deficiencies of folate, Vitamin B12, or B6,
old age, renal failure, excessive
consumption of coffee, smoking
abnormal results associated with dysfirbinogenemia
neonates, liver disease
abnormal results associated with decreased level of antihtrombin
Use of heparin, thrombosis, DIC , liver disease, Nephrotic syndrome
abnormal results associated with Increased Factor VIII levels
Pregnancy, use of oral contraceptives,
exercise, stress, older age, Acute phase
response, liver disease, Hyperthyroidism
abnormal results associated with Presence of
Lupus Anticoagulant and Increased Titer
of Anticardiolopin
Antibody
Systemic lupus erythematosus,
Antiphospholipid syndrome, autoimmune
diseases, liver disease, Hyperthyroidism
(anticardiolipin ab: + infectious diseases)
abnormal results associated with increased level of fibrinogen
acute phase rxn, pregnancy, old age, atherosclerosis, smoking
abnormal results associated with decreased level of protein s
Liver disease, use of oral anticoagulants, Vitamin K deficiency, pregnancy, use of oral contraceptives, nephrotic syndrome, childhood, presence of autoantibodies against Protein S, DIC
(see trans for treatment of thrombophilia)
(see trans for treatment of thrombophilia)
• Most common symptom is bleeding • Usually caused by → Decreased production of platelets → Increased destruction of platelets → Sequestration → Pseudothrombocytopenia
Thrombocytopenia
may be secondary to marrow failure which is secondary to aplastic anemia, chemotherapy and toxin
decreased platelet rpoduction
Other conditions which cause decreased platelet prod
• B12, folate or, rarely, iron deficiency • Viral infection • Drugs (Alcohol, Estrogens, Thiazides, Chlorpropamide, Interferon) • Amegakaryocytic thrombocytopenia → Myelodysplasia (pre-leukemia) → Immune (related to apalastic anemia) • Cyclic thrombocytopenia (rare) • Inherited thrombocytopenia
• Congenital aplastic anemia (Fanconi’s anemia)
• Congenital amegakaryocytic thrombocytopenia
• Thrombocytopenia with absent radius syndrome (recessive)
• Bernard-Soulier syndrome (recessive, giant platelets, defective function, GPlb defect)
• May-Hegglin anomaly and related disorders (dominant,
leukocyte inclusions, giant platelets, MYH-9 mutation)
• Other autosomal dominant syndromes (platelets may be normal or giant)
• Wiskott-Aldrich syndrome (X-linked, immunodeficiency,
eczema)
Inherited Thrombocytopenia
accounts for about 75% of thrombocytopenia
Benign thrombocytopenia of pregnancy (5% in term pregnancies, Asymptomatic, mild, occurs late in gestation)
increases in incidence during pregnancy
Idiopathic thrombocytopenia (increased incidence in pregnancy
*Microangiopathy (preeclampsia/eclampsia, HELLP) may also lead to thrombocytopenia in pregnancies
increased platelet CONSUMPTION in thrombocytopenia are due to
- Immune destruction
- Intravascular coagulation (DIC or localized)
- Microangiopathy
- Damage by bacterial enzymes, etc.
Immune platelet DESTRUCTION in thrombocytopenia may result from
- Immunologic destruction of platelets resulting when antibodies coat platelets that are then destroyed by macrophages [LabCE]
- Autoimmune (ITP) (Childhood/adult)
- Drug-induced (Heparin, Quinine (anti-malarial drug))
- Immune complex (infection, etc.)
- Alloimmune (Post-transfusion purpura, Neonatal purpura) → Possibly due to coating of patient’s platelet by donor platelet microparticles
Caused by re-exposure to foreign platelet antigen via blood product transfusion which typically presents as sudden onset of severe thrombocytopenia (<10K) 5-7 days after transfusion
Post-transfusion purpura
*Almost all cases in multiparous women
→ HPA-1a antigen most commonly involved (98% of the
population) [diagnosis by anti-hpa-1a alloabs in serum]
This is treated by
→ IVIg
→ Avoid giving HPA-1a positive platelets
→ Wash RBC to remove passenger platelets
Post-transfusion purpura
What is involved in thrombocytopenia during infection?
• Immune complex-mediated platelet destruction
→ Childhood ITP, Bacterial sepsis, Hepatitis C, other viral infections
• Activation of coagulation cascade (Sepsis with DIC)
• Vascular/endothelial cell damage
→ Viral hemorrhagic fevers (e.g. Dengue Fever)
→ Rocky Mountain Spotted Fever
• Damage to platelet membrane components by bacterial
enzymes (e.g. S. pneumoniae sialidase)
• Decreased platelet production
→ Viral infections (EBV, measles)
• Mixed production defect/immune consumption
→ HIV infection
In Heparin Type drug which induces typically mild to moderate thrombocytopenia, What complex forms on platelet surface?
Heparin-platelet factor 4 complex
*antibody binds to this complex
In Heparin type drug which is associated with thrombosis in many patients, fc portion of antibody binds to where on platelet?
platelet/monocyte Fc receptor
In Heparin type drug, what is triggered?
Platelet and monocyte activation
Type of drug which binds to platelet membrane and causes typically severe thrombocytopenia with bleeding. Some patients develop microangiopathy with renal failure (HUS)
Quinine type
*Antibody binds to drug
In quinine type drug, what does the exposed fc portion do?
Exposed Fc portion targets platelet for destruction
Directly destroys platelets
How is ITP diagnosed?
by exclusion (no known cause)
Forms of ITP?
see epidemiology
Childhood form (may follow viral infxn, vaccination) Adult form (non-prodromal, chronic, recurrences common, spontaneous remission rate about 5%)
What are present in most cases of ITP (often specific for platelet membrane glycoprotein; usually autoimmune)?
(mech still not clear)
Platelet-reactive autoantibodies
*coat platelets wc are then cleared by tissue macrophages and destroyed in spleen
Some patients wc experience impaired platelet production in ITP undergo?
- Intramedullary destruction
* Enhanced thrombopoietin clearance
most common manifestation in ITP?
mucosal bleeding
[others: petechiae, purpura, major internal/intracranial bleeding (rare; results in death), no consti symptoms or splenomegaly, normal blood counts and coag parameters]
T or F: ITP blood smears exhibit schistocytes and platelet clumps
False
T or F: Marrow in ITP shows abnormal megakaryocytes
normal or increased megakaryocytes (compensation for decreased platelet count)
T or F: confirmatory lab testing for itp is necessary
*diagnosis mainly based on clinical history
false
(methods: serum antiplatelet antibody assay [poor sensitivity and expensive], test for specific anti-platelet gp abs [more specific])
How is ITP managed in children with platelets >20-30K and no bleeding?
no treatment
**generally for ITP in children: platelet transfusion (if needed)
How is ITP managed in children with platelets <10-20K with bleeding?
intravenous immunoglobulin (IVIg) or corticosteroids • Prednisone, 1-2mg/kg/day • Single dose IVIg 0.8-1g/kg as effective as repeated dosing
How is ITP managed in children with chronic ITP (>12 mos.) or refractory disease with life-threatening bleeding?
Splenectomy
• Pre-immunize with pneumococcal, H. influenza and meningococcal vaccines (vaccines for encapsulated
bacteria) because spleen is responsible for eliminating encapsulated bacteria
usual treatment for ITP in Newly-Diagnosed adults
→ Indications:
• Platelets <20-30K (you may do platelet transfusion)
• Active bleeding or high bleeding risk, platelets <50K
platelet transfusion or steroids and ig
see first line treatment of ITP
When is emergency treatment of ITP (platelet transfusion + high dose steroids/continuous IVIg, rVIIa, antifibrinolytics, emergency splenectomy) done?
when the patient is severely bleeding (platelet <10,000)
it is not a true condition wherein there is an artificially low platelet count due to in vitro clumping of platelets (involves chemical factors ie chelating agents such as EDTA)
Pseudothrombocytopenia
*Seen in healthy individuals and in a variety of disease states
→ Marked fluctuations in platelet count without apparent cause
→ Thrombocytopenia disproportionate to symptoms
→ Clumped platelets on blood smear
→ “Platelet satellitism”- platelets stuck to WBC
→ Abnormal platelet/ leukocyte histograms
→ Platelet count varies with different anticoagulants
Pseudothrombocytopenia
