Heme- Platelets

What is involved in primary hemostatsis?

What is involved in primary hemostatsis?

Adhere: to injured blood vessels
Activate: internally undergo conformational changes, release mediator molecules to recruit more platelets, and express receptors needed for aggregation
Aggregate: through fibrinogen to form a platelet plug

What is involved in secondary hemostasis?

Coagulation cascade
Thrombin localized to site of injury

What is involved in tertiary hemostasis?

Cross linking of fibrin strands
Clot maturation and wound healing

What is the normal platelet count?

150,000- 450,000

At what value of platelet count is there an increased risk of spontaneous bleeding?

<10,000

What are pinpoint sized hemorrhages of small capillaries?

Petechiae

What are small demarcated hemorrhages/ bruising?

Purpura

What is large/ diffuse bruising?

Ecchymosis

What are the clinical manifestations of thrombocytopenia?

Petechiae, purpura, ecchymosis, mucosal bleeding, menorrhagia, intracranial hemorrhage

Aplastic anemia, myelodysplastic syndromes are examples of what?

Primary bone marrow disorder

Leukemia, myeloma, metastatic cancer, infection (tb) are examples of what?

Bone marrow infiltration

What drugs can cause bone marrow injury?

Chemo, chloramphenicol, thiazides, alcohol

Which nutritional deficiencies can be cause decreased platelet production?

Vitamin B12, Folate, Copper

What can result when someone inappropriately develops antibodies against one’s platelets?

Immune thrombocytopenia (ITP)

Immune thrombocytopenia (ITP) is commonly directed against surface glycoproteins complexes which are involved in?

Platelet adhesion and aggregation during primary hemostasis

What lab values and symptoms can you see in someone with ITP?

-Severe: (platelets <30,000) petechial bruising, bleeding from mucous membranes (conjunctival hemorrhages, gingival bleeding and epistaxis)
-Mild: (platelets >50,000)

For ITP, in an otherwise healthy asymptomatic patient, is there a cause?

No readily apparent cause

Which type of ITP is most often seen in children, often preceded by a viral illness, thrombocytopenia may results in bleeding, self-limiting?

Acute

Which type of ITP is usually seen in adults, often idiopathic, more often in women age 20-40, not self-limitng?

Chronic

How can ITP be diagnosed?

Diagnosis of exclusion
*Bone marrow should be assessed if: >60 yrs old, other cytopenia, failure to respond to trial of steroids, planning to have patient undergo splenectomy

For treatment of ITP, are transfusions used to treat the patient?

No, it is commonly avoided unless there is significant bleeding

What are treatment options of ITP?

-Watchful waiting
-Corticosteroids: slow response w/ high relapse rate w/ taper (prednisone 1-2 mgkg and dexamethasone 40mg daily x4)
-IVIG: Faster response, watch for nephrotoxicity (saturation of Fc receptors on macrophages blocking disposal, compete with Fc on idiopathic ab (IgG)

What are secondary treatments of ITP?

-Splenectomy (pt needs pneumococcal morbidity)
-Rituximab (anti CD20 ab, watch for infusion reactions)
-Romiplostim (thrombopoietin analogue)
-Eltrombopag (signaling cascades that induce proliferation and differentiation of megakaryocytes from bone marrow progenitor cells)

What occurs when heparin bound to surface protein on platelets triggers formation of auto-antibodies that cross-react with platelets in the presence of heparin?

Heparin induced thrombocytopenia (HIT)

How could a patient present with HIT?

-Hospitalized patient who develops thrombocytopenia w/in 5-10 days of receiving heparin
-Platelets do not decrease below 30,000
-Bleeding not common
-Activated platelets render patient hypercoagulable- both venous or arterial thrombosis frequently occurs

How do you diagnose HIT?

-50% decline in plt count
-4T scoring system
-Demonstration of HIT ab
-Doppler lower extremity to rude out sub clinical DVT

Should you treat HIT with a platelet transfusion?

NO

How should HIT be treated?

-Discontinue all forms of heparin
-Avoid platelet transfusion (may worsen inc thrombotic risk by providing substrate for HIT ab)
- Anticoagulate for concomitant thrombosis (use direct thrombin inhibitors; Argatroban-IV)

What occurs in Thrombotic thrombocytopenic purpura (TTP)?

Platelets function in primary hemostasis by adhering to injured blood vessels via von Willebrand factor thus forming link and making a platelet plug formation

What is a natural processing enzyme that cleaves large vWF multimers that form in these platelet plugs- acts as checks and balance- preventing vaso-occlusion?

ADAMTS13

What can falsely trigger platelet plug formation in the absence of an injured blood vessel?

Toxins, cytokines, drugs, infection, HIV, Immune complexes, pregnancy

A deficiency in ADAMTS 13 can be caused by….

Inherited deficiency (rare)
Upshaw-Schulman syndrome
Inhibitory antibody that blocks ADAMTS13

What two events need to occur for TTP?

Inappropriate platelet plugs form and a lack of ADAMTS 13

A lack of ADAMTS13 can result in what?

Blood flow impeded, Ischemia leading to multi organ failure and death

What is included in the Pentad for TTP?

-Microangiopathic hemolytic anemia (MAHA): Schistocytes
-Thrombocytopenia (consumption)
-Fever
-Renal insufficiency (microthrombi)
-Neurologic system abnormalities (microthrombi)

How do you diagnose TTP?

-MAHA: anemia, elevated LDH/ indirect bilirubin/ reticulocytes
-Thrombocytopenia
-PT and PTT are normal
- >3 schistocytes
-ADAMTS 13 test

For treatment of TTP, how is plasma exchange used?

Removes the offending factor or trigger blocking ADAMTS 13
-exchange 60ml plasma/kg with FFP daily until platelets >150k and neurologically stable
-Then every other day for short period of time

What meds are used for treatment of TTP?

Glucocorticoids (prednisone), Rituxan, Caplacizumab (more for high risk score)

What can cause splenic enlargement leading to thrombocytopenia secondary to sequestration?

Portal hypertension, liver cirrhosis, congestive heart failure, infectious mononucleosis, myelo/ lymphoproliferative disorders and certain malignancies

What can prompt an abnormal agglutination type reaction resulting in platelet crumbling, is a harmless phenomenon?

Pseudo-thrombocytopenia

What can prevent clumping and render normal platelet count assesment?

Citrate agent

Thrombocytopenia is defined as a platelet count less than?

100,000

Thrombocytosis is defined as a platelet count greater than?

450,000

What results from growth factor independent (autonomous) overproduction of platelets by clonal/ neoplastic megakaryocytes, as in one of the myeloproliferative or myelodysplastic disorders?

Primary thrombocytosis

In primary thrombocytosis, what can high counts be associated with?

Vasomotor symptoms (HA/ Visual symptoms/ lightheadedness/ atypical chest pain/ acral dysesthesia)
Thrombotic or bleeding complications

What mechanism is used for secondary thrombocytosis?

Cytokine-driven (reactive) mechanism

What mechanism accounts for majority of platelet counts, rarely symptomatic, rarely thrombotic or bleeding complications?

cytokine- driven (reatctive)
Ex: iron def (most common), malignancy, post- splenectomy, inflammatory disorders

What are the congenital platelet disorders?

Von Willebrand disease, Bernard- Soulier syndrome

What are the acquired platelet disorders?

Myeloproliferative, myelodysplastic, acute leukemias

What can indicate a referral to a hematologist should be made?

Unexpected surgical bleeding, mucosal bleeding, unexplained menorrhagia, ITP, HIT, TTP, pre-surgical for patient with known or suspected platelet disorder

What can indicate patient should receive antiplatelet therapy?

Prevention and treatment of arterial thrombosis, vascular disease/ atherosclerosis, acute corornary syndrome (MI, angina), stroke, atrial fibrillation, vascular stents, percutaneous coronary intervention (angioplasty)

What is a heterogenous group of disorders characterized by cellular proliferation of one or more hematologic cell lines in the peripheral blood?

Myeloproliferative neoplasms W

What are examples of myeloproliferative neoplasms?

Polycythemia vera, essential thrombocythemia, CML

What is polycythemia vera and what is the hemoglobin value in men and women?

Clonal disorder with proliferation and maturation of erythroid, megakaryocytic and granulocytic elements
-Men: >18.5
-Women: >16.5

*has 3-10 % chance of progressing to myelofibrosis or AML

What lab trends would you see in PV?

Hemoglobin and Hematocrit: INCREASED
WBC and platelet: INCREASE (potentially)
Erythropoietin: LOW
JAK2 Mutation: 95% will have it

How can a patient with PV present?

Usually asymptomatic (symptomatic due to poor oxygenation of tissues due to blood hyper viscosity)
Chronic headache, malaise, weakness, visual disturbance, pruritus after bathing, tinnitus, plethora, hypertension, thrombosis, hepatosplenomegaly

What is the treatment for PV?

-curative therapy is allogeneic stem cell transplant w/ goal to decrease blood volume to prevent thrombotic event
-ASA 81 mg
-Therapeutic phlebotomy (removal of 400-500 mL of blood 1-2 x weekly until Hct < 45%)
-Myelosuppressive therapy (hydroxyurea and interferon alpha)

What values may you see with essential thrombocythemia?

CBC with differential (platelets >450,000)
Peripheral smear
<1,000,000 platelet count can have excessive bleedings thanks to acquired von Willebrand syndrome
JAK2 mutation

How can a patient present with essential thrombocythemia?

Asymptomatic at time of diagnosis but will develop vasomotor, thrombotic, or hemorrhagic manifestations
-Splenomegaly (early satiety, abdominal bloating)

ASA 81mg, myelosuppressive therapy (hydroxyurea), and anagrelide is the treatment for what?

Essential thrombocythemia
*If reactive/ secondary in nature, treat underlying cause

What are examples of hematopoietic iron overload states?

Thalassemia, Sideroblastic anemia, dysplastic/ megaloblastic anemias/ G6PD deficiency

What are examples of secondary iron overload?

Transfusion hemosiderosis, porphyria cutanea tarda, alcoholic cirrhosis

What are examples of inherited iron overload states?

Classic (HFE) hemochromatosis (Type I), Juvenile hemochromatosis (Type II)

What is the abnormal accumulation of iron in parenchymal organs, leading to organ toxicity also the most common inherited liver disease?

Hemochromatosis
*most common cause of SEVERE iron overload

Most who are diagnosed with Hemochromatosis are of _______ origin

Northern European origin; highest prevalence in people of celtic origin

Why is onset of hereditary hemochromatosis later in women?

Menstruation causes physiologic blood loss, increasing iron removal

What gene on what chromosome is affected in bronze diabetes aka hemochromatosis?

HFE1 gene on chromosome 6, associated with inc level of iron absorption

In hemochromatosis, there is an excessive accumulation of what in vital organs?

Iron

How is iron stored and how is it regulated?

Stored as ferritin and hemosiderin
-Ferritin synthesis is regulated by iron availability

What can be used as an indicator of total body stores?

Serum ferritin which is in equilibrium with tissue stores

Mucosal cells of the small intestine can regulate?

Iron absorption

When can symptoms begin for hemochromatosis?

30-50 years of age; most pts are asymptomatic and diagnosed when serum levels are elevated.
-early symptoms include severe fatigue, impotence, arthralgia

Most common: hepatomegaly, skin pigmentation, arthritis

What are signs and symptoms of hemochromatosis?

Usually asymptomatic but:
-Asthenia, loss of libido/ impotence/ gonadal failure, darkening of skin, insulin dependent diabetes, arthralgias, cardiac failure, cirrhosis (most common cause of death), RUQ abdominal pain

What causes cirrhosis in hemochromatosis?

progressive iron deposition in the liver parenchyma

Hepatomegaly, seen in more than 95% of patients, can be accompanied by what?

signs on chronic liver disease such as abdominal pain, and cutaneous signs (palmar erythema, spider angioma, jaundice)

What testing and lab values do you need to diagnose hemochromatosis?

-Transferrin sat >50% (initial test)
-Serum iron >150 ug/dl
-Serum ferritin >200 mcg in premenopausal women and 300 mcg/L in men (>1000 suggests liver damage with fibrosis or cirrhosis)
-most important: genetic testing for HFE1 gene
-Liver biopsy -NO LONGER NECESSARY

What is the treatment for hemochromatosis?

Goal: remove the iron before it can produce irreversible parenchymal damage
-Aggressive iron unloading (phlebotomy, chelation - deferasirox aka exjade, jadenu)
-Avoid all PO iron preps and excessive dietary iron
-Liver transplant if end stage liver disease or hepatocellular disease

What is the sole recommended treatment for hereditary hemochromatosis?

Phlebotomy aka to rid the body of excess iron and to maintain normal iron stores

How often is phlebotomy performed?

Once a week until serum ferritin is <50 mcg/L
-Maintenance of one unit is performed once every 2-4 months based on ferritin level

How is Chelation therapy done?

Deferoxamine administered iv or subcutaneously at doses from 25-40 mg/kg. Intravenous infusion usually 8-10 hrs in duration and repeated 5 nights per week

Which is the oral iron chelator taken once daily as an adjunct to phlebotomies or instead of phlebotomy?

Deferasirox (exjade or jadenu)

What are complications of hemochromatosis?

liver cirrhosis, hepatocellular carcinoma, congestive heart failure, cardiac arrhythmias, DM, hypogonadism, impotence, arthropathy, thyroid dusfunction, sepsis

Skin pigmentation changes due to inc melanin formation and iron deposition in the skin should cause you to consider?

Hemochromatosis

What should you advise patients that have hemochromatosis?

Avoid any extra PO iron
Avoid cooking in iron skillets
Be aware of inc susceptibility to infection -avoid raw seafood
Avoid alcohol
Avoid excess vitamin C

What is the most important prognostic factor at the time of diagnosing hemochromatosis?

Presence or absence of hepatic fibrosis or cirrhosis

Is blood a drug?

YERRRRRR

What should you always do with blood transfusions?

Obtain written patient consent

What blood components are included in whole blood?

PRBCs, Leukodepleted RBCs, Washed RBCs, frozen (deglycerolized RBCs), Irradiated red cells, CMV-negative red cells

What are examples of platelet use?

Pooled random donor, single donor pharesis, HLA matched single donor

What are the coagulation factors?

FFP, Cryoprecipitate

Use of whole blood has been replaced by what?

PRBC infusion

What is used for large volume blood loss, sustains coagulation factors, and platelets must be replaced separately?

Whole blood

What are packed RBCs or PRBCs used for?

To treat anemias, contains RBCs, WBCs, platelets

What is the role of leukodepleted RBCs?

Reduces HLA alloimmunization & CMV transmission

What is the role of washed RBCs?

RBCs are repeatedly washed and suspended in saline (removes 99% of plasma)

What is the role of frozen (deglycerolized RBCs)?

long term storage of those with rare blood types

What is the role of irradiated red cells?

for immunocompromised patients

What is the role of cmv negative cells?

For cmv negative recipients having bone marrow transplants

What is the main purpose of RBC transfusion?

Improve O2 delivery to tissues, NOT treat hypovolemia

Each unit of PRBCs will increase Hbg by what?

1g/dl