Section 4: Disorders of Primary Hemostasis (Vasculature & Platelets)

Megan F7

Hereditary Hemorrhagic Telangiectasia

- vessel walls reduced to single layer of endothelial cells

- inadequate support structures resulting in fragile vessels

- dilated superficial vessels that Blanche with pressure

- bleeding: epistaxis, GI tract, UG tract, possible in any organ

- classified as Hereditary Vascular Disorder

Ehlers-Danlos Syndrome

- collagen disorder - problems with platelet adhesion

- symptoms may include hypermobile joints & stretchy skin

- classified as a Hereditary Vascular Disorder

Allergic & Drug-Induced Purpuras

- autoimmune vascular injury (antibody attacks blood vessels) or drug causes development of antibody to vessel walls

- classified as an Acquired Vascular Disorder

Henoch-Schönlein Purpura

- usually in children following upper respiratory infection

- IgA deposits in vessels

- causes rash, abdominal pain, joint pain, proteinuria/hematuria

- small percentage advance to renal disease, but most recover if damage is not permanent

- classified as Acquired Vascular Disorder

Scurvy

- vitamin C deficiency

- decreased synthesis of collagen because vitamin C necessary for synthesis of collagen

- results in weakened capillary walls

• Acquired Vascular disorder

Senile Purpura

- found in elderly population due to aging

- loss of collagen & subcutaneous fat/elastic fibers to support small blood vessels

- causes rupture & leakage of blood

- classified as an Acquired Vascular Disorder

Bernard-Soulier Syndrome

- defect = lack of Glycoprotein 1b (GP 1b) on platelets

- results in no von Willebrand's Factor connection to platelet for adhesion step

• Disorder of platelet Adhesion

• No Response to Ristocetin because the increased vWF has nothing to interface with on the platelet

• WILL NOT respond to treatment with Normal plasma because there are no GP1b receptors on the platelet. Cannot interface with vWF in the normal plasma

Lab tests used in diagnosing Bernard-Soulier

- Bleeding Time or PFA - increased (no agglutination step which effects function)

- Platelet Count - decreased (not necessarily diagnostic/characteristic)

- Large Platelets

- Platelet Aggregation Study - normal with all agents except Ristocetin

Type 1 von Willebrand's Disease

- most common type

- decreased amount of all multimers

- possibly due to abnormal release

- structure is normal, just not enough quantity released

- F8:C Level = low or normal

- APTT Value = prolonged or normal

- PT Value = normal

Will RESPOND to treatment with normal plasma because the patient lacks vWF and normal plasma will contain vWF.

-Disorder of platelet Adhesion

Type 2 von Willebrand's Disease

- decrease in high molecular weight multimers

- possibly due to inability to stabilize large multimers

- F8:C Level = low or normal

- APTT Value = prolonged or normal

- PT Value = normal

Type 3 von Willebrand's Disease

- most severe

- all multimers absent

- possibly due to reduced synthesis or rapid breakdown at sites of synthesis

- F8:C Level = very low

- APTT Value = prolonged

- PT Value = normal

Platelet Type (Platelet Defect) von Willebrand's Disease

- GP 1b has increased affinity for vWF

- platelets agglutinate & are removed

- decreased platelet count

- F8:C Level = low or normal

- APTT Value = prolonged or normal

- PT Value = normal

DDVAP

D-Desamino Vasopressin = DDAVP

- treatment of von Willebrand's disease

- induces body to release stored vWF

- best for Type 1 cases

• It's effective in Type 1 von Willebrand Disease and some cases of Type 2A and 2M.

• Not effective (and may worsen) in Type 2B or Type 3.

Aspirin

- inhibits cyclooxygenase (needed for TXA2 production)

- inhibits platelet aggregation because platelets need TXA2 to aggregate

Glanzmann's Thrombasthenia

- defect = platelets that lack Glycoprotein IIb & IIIa

- classified as a Disorder of Aggregation

Uremia

Toxins Interfere with Platelet aggretation

Plt Aggregation Disorder

Hereditary afibrinogenemia

Little to no fibrin

Disorder of plt aggregation

Lab tests used in diagnosing Glanzmann's

- PFA - increased (cannot close hole in membrane

- PT - normal

- APTT - normal

- Platelet Count - normal

- Platelet Aggregation - normal only with Ristocetin, abnormal with every other aggregate

Hermansky-Pudlak Syndrome

- platelet dense granule deficiency

- dilation of canicular system on platelet surface (dilation of channels)

- Swiss cheese platelets (seen with electron microscope only)

- results in deficient release reaction (abnormal aggregation)

- storage pool disease/Disorder of Release

Gray Platelet Syndrome

- marked decrease in platelet Alpha Granules

- hypo or agranular platelets

- lack normal release reaction because they lack granules

- storage pool disease/Disorder of release

Wiskott-Aldrich Syndrome

- immune deficiency

- micro platelets

- decreased alpha & dense granules in platelets

- platelet sequestration - decreased platelet number

- recurrent infection - B & T cell dysfunction (serum IgM decreased)

- storage pool disease/Release disorder

-Also a platelet production disorder (probably primarily)

Chediak-Higashi

- storage pool disease/Release disorder

- platelets lack normal dense granules

- effects granulocytes

Thrombocytopenia

Decrease in platelets due to either a decrease in production or an increase in destruction

May Hegglin

- ineffective thrombopoiesis with large, bizarre platelets

- dohle-like bodies

- most asymptomatic (some have bleeding infections)

-Platelet Production Disorder

Fanconi Syndrome

Congenital Aplasia

Platelet Production Disorder

Neonatal Hypoplasia

1. Congenital Viral Infection newborns with rubella (lack megakaryocytes = no platelets)

2. Maternal Drug Exposure (e.g., thiazides, alcohol, chemo, anticonvulsants) drugs ingested by mom (toxic to fetal megakaryocytes; recover few weeks postpartum; may need platelet transfusion if too low)

-Disorder of platelet Production

2 general categories of causes of decreased platelet production

Congenital & Acquired

Causes of congenital platelet hypoplasia (4)

- Fanconi Syndrome

- Wiskott-Aldrich

- May Hegglin

- Neonatal Hypoplasia

Causes of Acquired Platelet Hypoplasia (9)

- irradiation

- drugs

- ethanol

- early Aplastic Anemia

- Pernicious Anemia & Folate Deficiency

- viruses

- bacterial infections

- malignancies

- Myelodysplastic Syndromes (MDS)

Idiopathic Thrombocytopenia Purpura (ITP)

- platelet aggregates and/or microparticles occlude microvasculature

- HIT Ab binds to heparan on the endothelial cell surface & stimulates expression of tissue factor (initiates coag cascade)

- it is unknown why some patients become only Thrombocytopenic and others develop thrombosis also

-Increased Platelet Destruction

Most Common Lab Findings of ITP

- Platelet Count often <20,000 (at risk of spontaneous bleeding)

- Large platelets (variable size & shape; not diagnostic)

- Bone Marrow - megakaryocyte hyperplasia (BM trying to respond)

- Bleeding Time or PFA - increased

- Deficient clot retraction

Chronic ITP

- most common in ages 20 - 50 years old

- fluctuating

- bleeding episodes days or weeks

- spontaneous remission uncommon

- may be seen as early manifestation of AIDS

Platelet Destruction (immune mediated)

Acute ITP

- mostly in kids

- most have history of infection 2 - 21 days prior (typically viral)

- sometimes occurs after immunizations

- usually self-limiting (80% spontaneous remission)

Mechanisms of Drug Induced Immune Thrombocytopenia

1. A true autoantibody develops that is not dependent on the presence of the drug (antibody still present even with discontinuation of drug)

2. Hapten - linkage of drug to platelet, then antibody forms

3. Drug - antibody complex attaches to platelet (drug present to induce antibody)

Common Drugs Implicated in Drug-Induced Immune Thrombocytopenia

Heparin, Quinidine, Quinine

Heparin-Associated Thrombocytopenia (HAT)

- direct, non-immune mediated platelet activation

- not associated with risk of thrombosis

• Resolution: Spontaneous, even if heparin is continued

• Treatment: None required (continue heparin if clinically indicated)

• Contrast: Important to distinguish from Type 2 HIT, which is immune-mediated and prothrombotic

Heparin-Induced Thrombocytopenia (HIT)

Development of antibody to Platelet Factor 4-Heparin Complex

after patient is put on heparin,

resulting in subsequent fall in platelet count

Type 1 HIT

- develops 1-3 days into treatment

- benign

- platelet count rarely falls below 100 x 10^3

Heparin-Induced Thrombocytopenia.

Type 2 HITTS

A subgroup of patients experience platelet counts as low as 20 x 10^3 as well as thrombosis

Heparin Induced Platelet Aggregation (HIPA)

- test for presence of Heparin-Induced antibody in patient plasma

- use normal donor platelets + patient PPP + dilutions of heparin

- if antibody is in patient's plasma, the platelets will aggregate due to the presence of the antibody

Neonatal Alloimmune Thrombocytopenia

- appear normal at birth, then get petechiae & Purpura

- pathophysiology same as HDN (Rh antigens)

- platelet specific antigen that is absent in Mom but present in baby

- HPA-1A Antigen

Why is ITP a problem in pregnant women?

- Neonatal Autoimmune Thrombocytopenia

- mother has ITP or SLE, which effects the platelet count of the baby

- high risk delivery

- Fetal Scalp Platelet test - if fetal platelets are low after testing, C-section becomes preferred method over vaginal delivery

HELLP Syndrome

- H = Hemolysis (schistocytes, hemoglobinemia, haptoglobin increase, bilirubin & LDH increase)

- EL = Elevated Liver Enzymes

- LP = Low Platelet Count

Considered a variant of pre-eclampsia

Pre-Eclampsia

Pregnancy induced hypertension in association with either edema or proteinuria after 20 weeks gestation

Eclampsia

Severe form of pre-eclampsia in which there is also seizures or coma

Thrombotic Thrombocytopenic Purpura (TTP) Hallmark Findings

- hemolytic anemia w/ schistocytes

- thrombocytopenia

- fluctuating neurological dysfunction/confusion

- fever

- progressive renal disease

-Increased platelet Destruction

TTP

- endothelial cell injury of unknown nature

- platelet thrombus forms - microthrombi

- small platelet aggregates & unusually large von Willebrand Factor that occlude capillaries in organs

- autoantibody against ADAMTS13/ADAMTS13 deficiency

How to distinguish TTP and HUS

Severity of renal failure (more severe in HUS) &

absence of neurological symptoms in HUS

Neurologic signs in TTP reflect microvascular ischemia, not bleeding, and are often transient or fluctuating as thrombotic burden waxes and wanes.

Thrombocytosis

A disorder in which the body produces too many platelets

Reactive Thrombocytosis

Response to :

blood loss,

major surgery,

childbirth,

tissue necrosis,

inflammatory disease,

exercise,

etc.

Essential Thrombocythemia (ET) Findings & Pathophysiology

- Bone Marrow - increased megakaryocytes

- Platelet Count >600,000, often >1 million

- large masses of platelet aggregates

- giant & bizarre forms, many small forms also

- spontaneous platelet aggregation & platelet function defects that result in thrombotic & hemorrhagic complications