Section 4: Vascular Disorders Flashcards
List hereditary vascular disorders
- Hereditary Hemorrhagic Telangiectasia
- Ehlers-Danlos Syndrome
List acquired vascular disorders
- allergic and drug-induced purpuras
- Henoch-Schonlein Purpura
- scurvy
- senile purpura
List disorders of platelet adhesion
- Bernard-Soulier Syndrome
- von Willebrand Disease (Types I, II, III, and Platelet Type)
- Autoimmune disorders (IgG anti-plt Ab)
- Myeloproliferative disorders
- MM and Waldenstrom’s
- Chronic liver disease (alcohol)
- Drugs
List disorders of platelet aggregation
- Glanzmann’s Thrombasthenia
- Hereditary afibrinogenemia
- Uremia
- Aspirin therapy
List disorders of release reaction
- Aspirin therapy
- Storage pool diseases (Delta SPD, Hermansky-Pudlak Syndrome, Gray Platelet Syndrome, Wiskott Aldrich Syndrome, Chediak Higashi…etc)
List disorders of decreased platelet production
- Congenital hypoplasia
- Fanconi hypoplasia
- Wiskott-Aldrich
- May Hegglin
- Neonatal hypoplasia
- Acquire hypoplasia (irradiation, drugs, ethanol, infections, pernicious anemia/folate deficiency…etc)
- Immune mechanisms
Hereditary hemorrhagic telangiectasia
- Vessel walls reduced to single EC layer -> inadequate support -> fragile vessels
- Bleeding: epistaxis, GIT, UG tract, possible in any organ
- Mouth, tongue, face dilated superficial vessels that blanche with pressure (telangiectasia)
Ehlers-Danlos Syndrome
- Indian rubber man with hypermobile joints and stretchy skin
- Collagen disorder
Allergic and drug-induced purpuras
- Autoimmune vascular injury or
- Drug causes Ab to form against vessel walls
Henoch-Schonlein Purpura
- Usually kid following upper resp infection
- IgA deposits in vessels
- Concerned about meningitis-associated rash (diff diagnosis)
- Rash, abdominal/joint pain, proteinuria/hematuria
- Small % advance to renal disease
Scurvy
- Vit C deficiency
- Reduced collagen synthesis leads to weakened capillary walls
- Bruising on back of legs
Senile purpura
- Elderly
- Usually forearms and back of hands
- Loss of collagen and subcut. fat/elastic fibers to support small blood vessels
Bernard-Soulier Syndrome
- Platelet function issue
- Lack of GpIb on platelet
Bernard-Soulier Syndrome lab findings
- Increased bleeding time or PFA
- Decreased platelets
- Large platelets
- Plt aggregation normal with all agents except ristocetin bc ristocetin causes agglutination via GpIb
von Willebrand disease Type I
- Platelet adhesion issue
- most common
- decreased amount of all multimers
- possibly due to abnormal release
- structure is normal
Where is vWF made and stored?
- Made in ECs and megakaryocytes
- Stored in alpha granules, present in plasma
vWF associated with ___
Factor VIII
Which coag function test depends on Factor VIII?
APTT
not PT
vWF Type I FVIII:C level
Low or normal
vWF Type I APTT
Prolonged or normal
bc no FVIII
vWF Type I PT
Normal
PT (prothrombin time)
PT testing measures how long it takes for blood to clot. It’s used to assess the function of certain clotting factors in the blood, specifically factors I, II, V, VII, and X. PT is often used to monitor patients on anticoagulant therapy (like warfarin) and to diagnose bleeding disorders
APTT (Activated Partial Thromboplastin Time)
measures the time it takes for blood to clot through the intrinsic and common pathways of the coagulation cascade. It primarily evaluates factors VIII, IX, XI, XII, and other components involved in clot formation. APTT is useful in diagnosing and monitoring patients with hemophilia and other clotting factor deficiencies
PFA (platelet function assay)
PFA testing assesses the function of platelets, which are crucial for blood clotting. It measures how well platelets stick together and form clots in response to certain chemicals or conditions. PFA tests are used to diagnose platelet function disorders and to assess the effectiveness of antiplatelet medications (like aspirin) in inhibiting platelet function (measures in time it takes for clot to form)
FVIII:C
measures the functional activity of Factor VIII in the blood. This test assesses how well Factor VIII is functioning in facilitating blood clotting, rather than simply measuring its presence. It is a crucial diagnostic test for conditions like hemophilia A, where there is a deficiency or dysfunction in Factor VIII coagulant activity.
“C” stands for coag activity
vWF disease Type II
- Decrease in high MW multimers only possibly due to instability
vWF disease Type III
- Most severe
- All multimers absent possibly due to reduced synthesis or rapid breakdown at site of synthesis
vWF disease platelet type
- GpIb has increased affinity for vWF
- Platelets agglutinate and are removed
List assays that quantitate plasma vWF or separate multimers on basis of molecular size
Quantitate
- ELISA
- Chemiluminescence immunoassay
- Automated method - latex particles
Separate
- Agarose gel electrophoresis
- Crossed immunoelectrophoresis
List assays that measure vWF activity
- Ristocetin induced plt agglut (RIPA)
- Ristocetin cofactor (vWF:Rco)
T/F
RIPA uses pt plasma and donor platelets
False
RIPA uses PRP-pt own plts and plasma
vWF:Rco uses pt plasma and donor plt
List other platelet adhesion disorders
- autoimmune disorders (IgG anti-platelet Ab)
- Myeloproliferative disorders
- MM and Waldenstrom’s
- Chronic liver disease (alcohol)
- Drugs
Glanzmann’s thrombasthenia
Platelets lack GpIIb/IIIa receptor for fibrinogen-mediated aggregation (platelet issue)
Glanzmann’s thrombasthenia lab findings
- Increased PFA
- PT normal
- APTT normal
- Plt count normal
- Plt aggregation only normal with ristocetin bc agglutination is fine (GpIb present)
Hereditary afibrinogenemia
No plt aggregation bc no fibrinogen
Uremia
- Toxins interfere with platelet function
- No adhesion or aggregation
Aspirin therapy
- Inhibits cyclooxygenase needed for TXA2 production - so no aggregation
- Could also be called Disorder of Release Reaction
How do up to 22% of pts taking aspirin respond?
Resistant to anti-plt effect
Aspirin resistance associated with what?
- Thrombosis
- Higher risk of myocardial infarction and stroke
How to detect aspirin resistance
Plt aggregation studies (arachidonic acid curve more sensitive)
Describe storage pool diseases
- Lack plt dense or alpha granules
- Release reaction defect
- Abnormal aggregation
Delta SPD
Lack dense granules
Hermansky-Pudlak Syndrome
- Plt dense granule deficiency
- Dilation of canicular system on plt surface
- Swiss cheese plts
- Results in deficient release reaction
Gray Platelet Syndrome
- Marked decrease in platelet alpha granules
- Hypo or agranular platelets
Wiskott Aldrich Syndrome
- Micro plts
- Decreased alpha and dense granules in plts
- Plt sequestration - decreased plt count
- Recurrent infections due to B and T cell dysfunction -> reduced serum IgM
- Immunodeficiency in males
- Enhancement of surface phospholipid involved in apoptosis signals macrophage engulfment
Chediak Higashi
Platelets lack normal dense granules
List disorders that feature thrombocytosis
- Reactive thrombocytosis
- Myeloproliferative disorders (polycythemia vera, CML, primary myelofibrosis, essential thrombocythemia)
Reactive thrombocytosis
Response to blood loss, majory surgery, childbirth, tissue necrosis, inflammatory disease, exercise…etc
Hallmark of chronic myelocytic leukemia
High plts (thrombocytosis)
Describe ET microscopic traits
- BM: increased megakaryocytes
- Plt > 600k, often >1 million
- Large pt aggregates
- Giant/bizarre/small plts
- Spontaneous plt clumping and functional defects resulting in thrombotic/hemorrhagic complications
Decreased plt production IPF value
Decreased bc BM can’t make plts to begin with
Increased plt destruction IPF value
Increased bc BM still working properly
Fanconi syndrome (congenital hypoplasia)
Aplastic anemia with decreased plt production
May Hegglin
- Ineffective thrombopoiesis w large bizarre platelets
- Dohle-like bodies
- Most pt asymptomatic, some have bleeding infections
Neonatal hypoplasia
- Newborns born w rubella lack megakaryocytes
- drugs ingested by mom toxic to fetal megakaryocytes
- Recover few weeks postpartum
List increased platelet destruction immune mechanism disorders
- Immune thrombocytopenia purpura (ITP)
- Drug induced immune effects
- Neonatal allo or auto-immune thrombocytopenia
- Post-transfusion alloimmune thrombocytopenia
- Secondary autoimmune thrombocytopenia (CLL/SLE)
ITP lab findings
- Plt count often < 20,000
- Plt large (var size and shape)
- BM megakaryocyte hyperplasia
- Bleeding time or PFA increased
- Deficient clot retraction
Chronic ITP
- Most 20-50 y/o pt
- Fluctuating course
- Bleeding episodes days or weeks
- Spontaneous remissions uncommon
- May be seen as an early manifestation of AIDS
Acute ITP
- Most in kids
- Most have history of infection 2-21 days previous (most viral)
- Sometimes happens after vaccination
- Usually self limiting, 80% spont remission
ITP treatment
- Limit contact sports/activities
- If plt < 30,000 -> steroids, plt transfusion, TPO, splenectomy…etc
Drug-induced immune effects - mechanisms
- A true auto-Ab that is not dependent on the presence of the drug
- Hapten linkage of drug to plt, then Ab forms
- Drug-Ab complex attaches to plt
Common drugs that cause Ab formation
- Heparin
- Quinine
- Quinidine (gin/tonic)
Most common drug that causes Ab formation
Heparin
When to suspect heparin
30-50% drop in plt count
Heparin-associated thrombocytopenia (HAT)
- Direct, non-immune mediated plt activation
- NOT associated with risk of thrombosis
Heparin-induced thrombocytopenia (HIT)
- Pt presents with thrombosis
- Heparin prescribed
- Plt count drops within 7 days
- Develop Ab to Platelet Factor 4-Heparin complex
- Plt count then falls
Type I HIT
- Develops 1-3 days into treatment and is benign
- Plt count rarely falls below 100 X 10^3/mm3
Type II HITTS
- Subgroup of pt have plt count as low as 20 X 10^3 + thrombosis
- Etiology no well understood
Other disorders associated with HITTS
- Heparin induced skin necrosis
- Venous gangrene
T/F
In HIT/HITTS, the Ab is only active in the presence of heparin, so take the pt off heparin and plt count will increase
True
If anticoag must be used in HIT/HITTS pt, then use:
- Coumadin
- Low MW heparin (not ideal sub)
- Fondaparinux
- Newer agents lepthirudin and argatroban
List lab testing methods for HIT
- Serotonin release SRA (reference method)
- HIPA
- ELISA
- PIFA
HIPA tests for what?
- Tests for presence of heparin-induced Ab in pt plasma
- Pt must be off heparin for 8 hr
T/F
HIPA uses pt plt + pt plasma + heparin dilutions
False
Normal donor plts and pt PPP + heparin dilutions
Neonatal alloimmune thrombocytopenia
- Appear normal at birth then get petechiae and purpura
- Pathophysiology same as HDN from Rh Ag
- Plt HPA-1a Ag absent in mom but present in baby, so mom makes Ab against baby plt Ag
Mother with ___ or ____ commonly develops neonatal autoimmune thrombocytopenia
ITP
SLE
How to determine if baby should undergo vaginal delivery or C-section
Fetal scalp platelet manual plt count
Mechanism of post transfusion alloimmune thrombocytopenia/purpura
- 3-12 days after transfusion have rapid onset of thrombocytopenia
- Most common anti-HPA-1a Ab caused by transfusion or pregnancy and then response after re-exposure to Ag positive blood product
How to confirm post transfusion purpura?
- ID Ab by ELISA
- Demonstrate pt Ag negative by flow cytometry
List increased plt destruction non-immune mechanisms
- Incidental thrombocytopenia of pregnancy
- Preeclampsia/Eclampsia (HELLP syndrome)
- Thrombotic thrombocytopenic purpura (TTP)
- Hemolytic Uremic Syndrome (HUS)
HELLP stands for
Hemolysis
Elevated Liver enzyme
Low Plt count
What is HELLP syndrome
- Life threatening pregnancy complication, variant of preeclampsia
Preeclampsia
Pregnancy induced hypertension in association w either edema or proteinuria after 20 wk gestation
Eclampsia
Severe form of preeclampsia in which there is also seizures or coma
Etiology of HELLP syndrome
- Intravascular plt activation
- Microvascular endothelial damage
- TXA2 release
- Vasospasm
- Vascular lesions in multiple organs
T/F All HELLP pt have preeclampsia
False
HELLP symptoms
- hypertension
- nausea
- malaise
- epigastric pain
- right upper quadrant tenderness
- edema
- cerebral/visual disturbances
- proteinuria
- oliguria
HELLP lab findings
- Hgb/hct and haptoglobin decreased
- LDH and bilirubin increased
- Schistocytes
- Plt count less than 200,000/mm3
HELLP hepatic dysfunction chemistry findings
- AST > 48 IU/L
- ALT > 24 IU/L
- LDH > 164 IU/L
TTP mechanism
- Endothelial cell injury
- Plt microthrombi form
- Unusually large vWF and small plt clumps that occlude capillaries in organs
- Auto-Ab against ADAMTS13 or rare inherited ADAMTS13 deficiency
TTP lab findings
- Hemolytic anemia w schistocytes
- Thrombocytopenia (hemorrhage)
- Fluctuating neurological dysfunction
- Fever
- Progressive renal disease
HUS typically found in which demographic?
young children 6 mth-4yrs
HUS triad of findings
- MAHA
- Thrombocytopenia
- Acute renal failure (RBCs, protein, and casts in urine)
How to distinguish TTP and HUS
Based on severity of renal failure and absence of neurological symptoms
