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01. Hemostasis and Related Disorder > 1. Disorders of primary hemostasis > Flashcards

1. Disorders of primary hemostasis Flashcards

1
Q

Definition of primary hemostasis

A

Processes involved in the formation of a platelet plug (white thrombus) following endothelial injury

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2
Q

Disorders of primary hemostasis

A
  1. Platelet disorders:

a. Platelet deficiency (thrombocytopenia)
b. Platelet dysfunction (thrombocytopathy): disorders that lead to dysfunctional adhesion or aggregation of platelets
- Inherited conditions:
i. Von Willebrand disease
ii. Bernard-Soulier syndrome
iii. Glanzmann thrombasthenia
- Acquired:
i. Drug-induced: e.g., aspirin, NSAID, clopidogrel
ii. Immune thrombocytopenic purpura
iii. Chronic kidney disease (due to uremia)
- —————————————————————————
2. Disorders affecting the vessel wall:

a. Vascular hemorrhagic diathesis (e.g., IgA vasculitis, hereditary hemorrhagic telangiectasia)
b. Thrombotic microangiopathy (e.g., HUS and TTP)
c. Conditions with impaired collagen synthesis (e.g., scurvy, Ehlers-Danlos syndrome)

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3
Q

What is the onset of bleeding with disorders of primary hemostasis?

A

Immediately after trauma

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4
Q

Clinical manifestations with disorders of primary hemostasis?

A
  1. Bleeding of mucous membranes
    a. Epistaxis
    b. Bleeding gums
    c. Gastrointestinal bleeding
  2. Cutaneous and subcutaneous bleeding
    a. Petechiae (1-2mm)
    b. Purpura (>3mm)
    c. Superficial ecchymoses (>1cm)
    d. Easy bruising
  3. Menorrhagia
  4. Prolonged and excessive bleeding after surgery
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5
Q

Definition of thrombocytopenia

A

Thrombocytopenia is a platelet count below the normal range (< 150,000/mm3) that is most commonly due to either impaired platelet production in the bone marrow or increased platelet turnover in the periphery

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6
Q

Etiology of thrombocytopenia

A
  1. Impaired platelet production in bone marrow
    a. Bone marrow failure: aplastic anemia, paroxysmal nocturnal hemoglobinuria
    b. Bone marrow suppression (chemotherapy, antibiotics like linezolid, daptomycin)
    c. Congenital (Bernard-Soulier syndrome, von Willebrand disease)
    d. Infection (CMV, EBV, parvovirus B19)
    e. Malignancy (leukaemia, lymphoma)
    f. Nutritional deficiency (Vit B12 and/or folate deficiency)
  2. Increased platelet turnover in the periphery
    a. Immune thrombocytopenia (ITP) and other autoimmune disease (SLE, RA)
    b. DIC & sepsis
    c. Thrombotic thrombocytopenia purpura (TTP) and haemolytic uremic syndrome (HUS)
    d. Pregnancy: preeclampsia and HELLP syndrome
    e. Mechanical damage due to artificial cardiac valves or extracorporeal circulation (e.g., dialysis)
  3. Redistribution, dilution, and other causes
    a. Liver disease
    b. Splenomegaly
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7
Q

Definition of Von Willebrand disease

A

Von Willebrand disease (vWD) is a bleeding disorder characterized by a deficiency or dysfunction of von Willebrand factor (vWF)

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8
Q

Epidemiology of Von Willebrand disease

A

Most common congenital bleeding disorder

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9
Q

Pathophysiology of Von Willebrand Disease

A

Deficiency or dysfunction of vWF leads to:

  • Dysfunctional platelet adhesion → impaired primary hemostasis
  • Reduced binding of factor VIII → increased degradation → ↓ factor VIII activity → impaired intrinsic pathway of secondary hemostasis
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10
Q

Lab studies for Von Willebrand Disease

A
  1. ↑ Bleeding time
  2. Normal or ↑ aPTT (may be prolonged as a result of factor VIII deficiency)
  3. Normal PT and platelet count
  4. ↓ Factor VIII
  5. ↓ vWF antigen levels
  6. Ristocetin cofactor assay: failure of platelet aggregation
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11
Q

Pathophysiology of Bernard-Soulier Syndrome

A
  1. Adhesion disorder: deficient platelet GPIb receptor

2. Autosomal recessive

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12
Q

Clinical presentation of Bernard-Soulier Syndrome

A

Asymptomatic or presenting with petechiae, purpura, epistaxis, menorrhagia, gingival bleeding

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13
Q

Lab studies for Bernard-Soulier Syndrome

A
  1. Giant platelets
  2. ↓ Platelets
  3. Abnormal ristocetin cofactor assay
  4. Normal PT and aPTT
  5. Normal d-dimer, fibrin degradation products
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14
Q

Pathophysiology of Glanzmann thrombasthenia

A
  1. Aggregation disorder: deficient platelet GPIIb-IIIa receptor
  2. Autosomal recessive
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15
Q

Clinical presentation of Glanzmann thrombasthenia

A

Asymptomatic or presenting with petechiae, purpura, epistaxis, menorrhagia, gingival bleeding

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16
Q

Lab studies for Glanzmann thrombasthenia

A
  1. Normal platelets
  2. Abnormal results on platelet aggregation testing confirm the diagnosis.
  3. Normal PT, aPTT
  4. Normal d-dimer, fibrin degradation products
17
Q

Definition of Immune thrombocytopenia (ITP)

A

Immune thrombocytopenia (ITP) is a type of thrombocytopenia involving the formation of autoantibodies against platelets

18
Q

Epidemiology of Immune thrombocytopenia

A
  1. ♀ > ♂
  2. Children
    - Highest prevalence in children < 5 years of age
    - Typically self-limiting after a viral infection; 80% of cases resolve within 12 months
  3. Adults
    - Highest prevalence in individuals > 55 years of age
    - 80% of patients develop chronic ITP
    - An incidental finding on a routine CBC in 25% of cases
19
Q

Etiology of Immune thrombocytopenia

A
  1. Primary ITP: idiopathic (most common)
  2. Secondary ITP associated with:
    a. Autoimmune disorders: SLE, antiphospholipid syndrome
    b. Malignancy: lymphoma, leukemia (particularly CLL)
    c. Infection: HIV, HCV
    d. Drugs: e.g., quinine, beta-lactam antibiotics, heparin, sulfonamides, TMP-SMX
20
Q

Pathophysiology of Immune thrombocytopenia

A

Antiplatelet antibodies (mostly IgG directed against, e.g., GpIIb/IIIa, GpIb/IX) bind to surface proteins on platelets → sequestration by spleen and liver → ↓ platelet count → bone marrow megakaryocytes and platelet production increase in response (in most cases)

21
Q

Clinical presentation of Immune thrombocytopenia

A
  1. Most commonly
    a. Asymptomatic
    b. Splenomegaly is typically absent.
  2. Minor mucocutaneous bleeding (less common)
    a. Subcutaneous: e.g., bruising, petechiae, purpura
    b. Mucosal: e.g., mild epistaxis, gingival bleeding
22
Q

Lab studies for Immune thrombocytopenia

A
  1. CBC: ↓ platelet count (< 100,000/mm3)
  2. Coagulation panel: usually normal
  3. Bleeding time: may be prolonged
  4. Peripheral blood smear: normal to large platelets

ITP is a diagnosis of exclusion!

23
Q

What are the 2 kinds of thrombotic microangiopathy that can result in primary hemostatic disorders?

A
  1. Hemolytic uremic syndrome

2. Thrombotic thrombocytopenic purpura

24
Q

Definition of Hemolytic uremic syndrome

A

HUS is a thrombotic microangiopathy, a condition characterized by the formation of microthrombi occluding the microvasculature.

25
Q

Epidemiology of Hemolytic uremic syndrome

A

Mainly children < 5 years of age

26
Q

Etiology of Hemolytic uremic syndrome

A
  1. Bacterial exotoxins
    a. Shiga-like toxin (verotoxin)
    - From enterohemorrhagic E. coli (EHEC) strain O157:H7
    - Usually transmitted via contaminated foods (e.g., undercooked beef or raw leafy vegetables)
    b. Shiga toxin produced by Shigella dysenteriae
  2. Streptococcus pneumoniae infection
  3. Atypical hemolytic uremic syndrome: Complement dysregulation (hereditary or acquired)
27
Q

Pathophysiology of Hemolytic uremic syndrome

A
  1. Infection with enterohemorrhagic E. coli (EHEC) or another causative organism
  2. Mucosal inflammation facilitates bacterial toxins entering systemic circulation.
  3. Toxins cause endothelial cell damage (especially in the glomerulus).
  4. Damaged endothelial cells secrete cytokines that promote vasoconstriction and platelet microthrombus formation at the site of damage (intravascular coagulopathy) → thrombocytopenia (consumption of platelets)
  5. RBCs are mechanically destroyed as they pass through the platelet microthrombi occluding small blood vessels (i.e., arterioles, capillaries) → hemolysis (schistocytes), and end-organ ischemia and damage, especially in the kidneys → decreased glomerular filtration rate (GFR)
28
Q

Clinical presentations in Hemolytic uremic syndrome

A

A diarrheal illness (usually bloody) for the past 5–10 days precedes the onset of HUS symptoms in many children.

The triad of clinical findings occurring in HUS consists of:

a. Thrombocytopenia
- Petechiae, purpura
- Mucosal bleeding
- Prolonged bleeding after minor cuts

b. Microangiopathic hemolytic anemia
- Fatigue, dyspnea, and pallor
- Jaundice

c. Impaired renal function
- Hematuria, proteinuria
- Oliguria, anuria

29
Q

Lab studies for Hemolytic uremic syndrome

A
  1. Hematology
    a. Hemolytic markers:
    ↓ Hemoglobin
    ↓ Haptoglobin
    ↑ Indirect bilirubin
    ↑ Reticulocytes
    ↑ LDH
    ↑ Schistocytes on blood smear (up to 10% of RBCs)
    b. Coagulation profile:
    ↓ Platelets
    - Normal/slightly elevated PT and aPTT in contrast to DIC
    - Normal/slightly elevated Fibrin degradation products and D-dimer levels
    c. ↑ WBC count
    d. Negative Coombs test
  2. Serum chemistry: ↑ BUN and ↑ creatinine (impaired renal function)
  3. Urinalysis: hematuria, proteinuria
30
Q

Complications of Hemolytic uremic syndrome

A

HUS can result in microthrombus formation and complications in various organs:

  1. CNS: seizures, paresis, stroke & coma
  2. GI tract: hemorrhagic colitis, bowel necrosis, perforation, stricture, peritonitis, intussusception
  3. Heart: ischemia and fluid overload
  4. Pancreas: transient or permanent diabetes mellitus
  5. Liver: hepatomegaly, transaminase elevations
  6. Kidney: hypertension, chronic kidney disease (CKD), end-stage renal disease (ESRD)
31
Q

Definition of Thrombotic thrombocytopenic prupura

A

TTP is a thrombotic microangiopathy, a condition in which microthrombi form and occlude the microvasculature

32
Q

Epidemiology of Thrombotic thrombocytopenic purpura

A
  1. Primarily adult individuals

2. More common in women and in black populations

33
Q

Etiology of Thrombotic thrombocytopenic purpura

A
  1. ADAMTS13 deficiency/inhibition
    a. Acquired TTP (∼ 95%): autoantibodies against ADAMTS13
    b. Congenital TTP (∼ 5%): gene mutations resulting in deficiency of ADAMTS13
  2. Risk factors
    a. Drugs
    b. Pregnancy
    c. Systemic disease: cancer, HIV, SLE, infections
34
Q

Pathophysiology of Thrombotic thrombocytopenic purpura

A
  1. Autoantibodies or gene mutations → deficiency of ADAMTS13 (a metalloprotease that cleaves von Willebrand factor)
  2. ↓ Breakdown of vWF multimers → vWF multimers accumulate on endothelial cell surfaces
  3. Platelet adhesion and microthrombosis
  4. Microthrombi → fragmentation of RBCs with schistocyte formation → hemolytic anemia
  5. Arteriolar and capillary microthrombosis → end-organ ischemia and damage, especially in the brain and kidneys (potentially resulting in acute kidney injury or stroke)
35
Q

Clinical presentation in Thrombotic thrombocytopenic purpura

A

The pentad of clinical findings consists of:

  1. Fever
  2. Neurological signs and symptoms
    - Altered mental status, delirium
    - Seizure, focal defects, stroke
    - Headache, dizziness
  3. Low platelet count (i.e. thrombocytopenia)
    - Petechiae, purpura
    - Mucosal bleeding
    - Prolonged bleeding after minor cuts
  4. Microangiopathic hemolytic anemia
    - Fatigue, dyspnea, and pallor
    - Jaundice
  5. Impaired renal function
    - Hematuria, proteinuria
    - Oliguria, anuria
Nasty Fever Ruined My Tubes 
N - Neurological 
F - Fever
R - Renal function impairment 
M - Microangiopathic haemolytic anemia 
T - Thrombocytopenia
36
Q

Lab studies for Thrombotic thrombocytopenia purpura

A 
1. Hematology
↓ Platelets 
↓ Hemoglobin 
↑ Reticulocytes
↓ Haptoglobin 
- Normal or mildly prolonged PT and aPTT
- Normal or mildly elevated fibrin degradation products and D-dimer levels
- Negative Coombs test
  1. Peripheral blood smear
    - Large number of schistocytes (up to 10% of RBCs)
    - Low number of platelets
  2. Serum chemistry
    - ↑ LDH, ↑ indirect bilirubin (hemolytic anemia)
    - ↑ BUN and ↑ creatinine (impaired renal function)
  3. Urinalysis
    - Hematuria, proteinuria
  4. ADAMTS13 activity and inhibitor testing
    - ↓ ADAMTS13 activity
    - Not a routinely available test and should be used for confirmation only
  5. Identification of secondary causes (e.g., tests for pregnancy, SLE, HIV, malignancy)
37
Q

Complications of Thrombotic thrombocytopenic purpura

A

TTP can result in microthrombus formation and complications in many organs of the body.

  1. CNS: seizures, coma, stroke, paresis
  2. GI tract: hemorrhagic colitis; bowel necrosis, perforation, stricture; peritonitis; intussusception
  3. Heart: ischemia and fluid overload
  4. Pancreas: transient or permanent diabetes mellitus
  5. Liver: hepatomegaly, transaminase elevations
  6. Kidney: hypertension, chronic kidney disease (CKD), end-stage renal disease (ESRD)

01. Hemostasis and Related Disorder (3 decks)

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