Week 2

Question 1

What is inappropriate polycythemia?

Answer 1

Inappropriate polycythemia: RBC count increase without hypoxic stimulus.

No hypoxic stimuli → normal O2 saturation.

Ectopic EPO production (e.g. from RCC) → ↑ RBC production → ↑ RBC mass and RBCcount

The normal O2 saturation distinguishes inappropriate from appropriate polycythemia.

Plasma volume (PV) can be normal or increased.

Inappropriate absolute polycythemia from ectopic EPO production → normal PV.

Inappropriate absolute polycythemia from polycythemia vera → increased PV.

Question 2

In what two conditions are spherocytes seen?

Answer 2

Spherocytes are seen in hereditary spherocytosis and autoimmune hemolysis.

Question 3

Name 2 factors that inhibit secondary hemostasis. What compound disrupts pre-existing clots?

Answer 3

Inhibition of the clotting cascade occurs via activated Protein C (APC) and Antithrombin III. tPA (tissue plasminogen activator) disrupts existing clots.

Because Protein C has the shortest half life, its levels are quickly diminished when warfarin therapy is initiated. This leads to a transient hypercoagulable state characterized by skin necrosis. Heparin or Enoxaparin therapy must be initiated simultaneously. This is known as the “heparin bridge” and is always done when initiating warfarin therapy.

• The skin necrosis generally begins 3-8 days after warfarin initiation. Commonly occurs on the breasts or abdomen.

Factor V Leiden: mutated factor V can’t be inactivated by APC → hypercoagulable state. Heparin potentiates antithrombin III → inactivates: IIa (thrombin), VIIa, IXa, Xa, XIa, XIIa (“ 7+2 = 9, 10, 11, and 12”) ATIII is a serine protease inhibitor

tPA activates plasminogen which is cleaved to plasmin, which is a potent fibrinolytic agent and lyses clots that are already formed.

Question 4

What is relative polycythemia?

Answer 4

Relative polycythemia: Decreased plasma volume → increased Hct, Hb, and RBC count relative to total plasma volume.

Due to volume depletion:

• Sweating
• Diarrhea
• Burns

Corrected by fluid replacement → add whatever was lost.

Usually due to sweating → hyposomotic fluid loss → replace with hypotonic salt solution (i.e. Gatorade or Powerade).

Question 5

EBV is associated with which type of Non-Hodgkin Lymphoma?

Answer 5

EBV is associated with Burkitt’s lymphoma (also known as small noncleaved non-Hodgkin’s lymphoma):

African form commonly presents as a mass on the maxilla or mandible; American form more commonly presents as an abdominal mass

Lymphoid tissues have a “starry sky” appearance:

• dark sky = sheets of high-grade lymphocytes
• stars = macrophages eating apoptotic high grade tumor

Most common translocation = t(8;14): c-myc proto-oncogene ends up next to highly expressed Ig heavy-chain gene → c-myc overexpression

Next most common translocation = t(2;8): c-myc proto-oncogene ends up next to highly expressed Ig light-chain gene → c-myc overexpression

Question 6

Are type II hypersensitivity reactions usually tissue-specific or systemic? Why?

Answer 6

Type 2 HSRs (type II (antibody-mediated) hypersensitivity reactions): IgM and/or IgG autoantibodies bind fixed antigens in specific tissues—ie, there are no circulating immune complexes ∴ type 2 HSRs are usually tissue-specific instead of systemic (vs. type 3 HSRs which involve circulating immune complexes and are ∴ usually systemic)

2 categories of pathogenesis in type 2 HSRs:

1) Cytotoxic: antibodies can bind and initiate cytotoxicity via a variety of mechanisms, including:
- Opsonization and phagocytosis
- Complement-mediated inflammation and tissue damage
- Fc receptor-mediated inflammation and tissue damage (also known as ADCC(antibody-dependent cell-mediated cytotoxicity))

2) Non-cytotoxic: antibodies can bind and interfere with normal function—for example:
- Myasthenia gravis: anti-ACh (acetylcholine) receptor antibodies bind postsynaptic ACh receptors → prevents ACh from binding postsynaptic ACh receptors + induces downregulation of postsynaptic ACh receptors
- Graves disease: anti-TSH receptor antibodies bind and thereby stimulate TSHreceptors
- Pernicious anemia: anti-IF (intrinsic factor) antibodies bind and thereby prevent IF from binding with vitamin B12 → ↓ absorption of vitamin B12 in the ileum

Question 7

What is the clinical significance of heterozygosity for HbS?

Answer 7

Sickle cell trait: heterozygous HbS, largely asymptomatic

Question 8

Describe the pathogenesis of DIC

Answer 8

DIC is a consumptive coagulopathy characterized by generation of fibrin clots → consumption of clotting factors and platelets → hemorrhage and often death.

Note: DIC is NOT a primary disorder, rather It is a complication of several different disease processes. You must always look for an underlying cause.

Question 9

What cancer of the head and neck is associated with EBV infection?

Answer 9

EBV infection of nasopharyngeal epithelial cells may predispose to malignant transformation in certain patient populations → nasopharyngeal carcinoma (most common in China, Asia)

Question 10

Describe the mutation responsible for HbS.

Answer 10

HbS: β-globin gene point mutation substitutes valine for glutamic acid at codon 6

At low O2 tension, HbS polymerizes (the substituted Val residue allows for hydrophobic interactions to occur between Hb chains) → RBCs sickle and cell membranes stiffen, becoming more likely to hemolyze

Transportation of RBCs through inflamed tissue can also lead to occlusion of microvasculature.

Inflammatory cells release mediators → ↑ adhesion molecules → slowing of RBC passage through capillary beds → sickling and occlusion.

Sickled RBCs also obstruct microvasculature → splenic autoinfarction, painful crises

Confers malarial resistance → in parts of Africa, 1/3 of population carries HbS gene

Question 11

What is absolute polycythemia?

Answer 11

Absolute polycythemia: ↑ total RBC mass.

Question 12

During antenatal testing, it is discovered that an unborn male child has pyruvate kinase deficiency. Neither parent has a history of hematologic disorders. Which of the following is accurate?

A) Sickling of the child’s erythrocytes will cause autosplenectomy

B) Oxidative stressors will cause episodic hemolysis

C) The child will have a chronic anemia

D) The maternal allele accounts for this disease

E) The child will have spherocytosis

Answer 12

PK deficiency is an autosomal recessive disease that causes chronic hemolytic anemia.

Chronic lack of ATP leads to membrane damage → extravascular hemolysis.

Pyruvate kinase is an ATP-producing enzyme in the glycolytic pathway. Since RBCs can only produce ATP via glycolysis, this deficiency severely effects the ability of RBCs to produce energy. Decreased ATP production in the RBC → altered membrane integrity → hemolysis

Question 13

What is the most common cause of hereditary thrombophilia?

Answer 13

The most common cause or hereditary thrombophilia is the Factor V Leiden mutation.

The Leiden mutation is a single NT mutation in the Factor V gene which causes Arg → Gln substitution.

The mutant form of Factor V is resistant to cleavage by protein C.

Heterozygotes have a 5x higher risk of venous thrombosis compared to 50x higher risk seen in homozygotes.

Question 14

Which two serologic tests are used to diagnose HIV infection?

Answer 14

Dx: first test is ELISA. Confirm positives with Western blot.

ELISA is very sensitive → higher false-positive rate, so need confirmation

Both ELISA and Western blot detects antibodies to gp41 & p24 – falsely negative 1-2 months post-infection

Question 15

What cell types does parvovirus B19 infect? How is parvovirus B19 transmitted?

Answer 15

Respiratory transmission, vertical (mother to fetus), transfusions/transplants; infects/lyses erythroblasts.

Question 16

There are several causes of acquired thrombophilia. Name as many as you can.

Answer 16

Immobilization (bed rest, long plane flights)

Major surgery (especially orthopedic)

Oral contraceptive pills and pregnancy → ↑ estrogen driven synthesis of coagulation factors

Malignancy → tumor release of procoagulant mediators

Smoking (possibly endothelial damage, but true etiology is unknown)

Obesity

Prosthetic valves

Question 17

In contrast to HSV and VZV which remain latent in sensory ganglia, where does CMV remain latent? What is typically the cause of reactivation?

Answer 17

Pathogenesis: CMV infects epithelial cells in salivary glands → establishes a persistent infection in epithelial cells (e.g., renal tubule cells) and macrophages and a latent infection in white blood cells → reactivation during immunosuppression (e.g., organ transplant) or immunocompromise (e.g., AIDS).

MHC I-viral peptide complex is unstable in CMV-infected cells ∴ CMV effectively thwarts cytotoxic T-cell mediated killing by blocking MHC I expression of viral antigens on the surface of CMV-infected white blood cells.

Question 18

What are echinocytes? What diseases are they associated with?

Answer 18

Echinocytes (“burr cells”) are red blood cells with small, thorny projections of uniform size. They are seen in pyruvate kinase deficiency and uremia.

Question 19

Describe the platelet count and bleeding time findings in qualitative deficiencies of platelets.

Answer 19

Qualitative defects: Platelet count, PT and PTT are normal. ↑ BT.

Bleeding is not due to lack of platelets, instead there is a problem with platelet function. This can be caused by several different defective surface proteins or COX inhibition, clopidogrel

Question 20

What is the diagnostic test of choice when Thalassemia is suspected?

Answer 20

Hb electrophoresis is the diagnostic test of choice for thalassemias.

Question 21

Describe the pathogenesis of thrombocytopenia in ITP: where are the platelets destroyed?

Answer 21

ITP (Idiopathic thrombocytopenic purpura): autoimmune condition

Caused by auto-antibody against receptor GpIIbIIIa on the platelet surface

In children, usually follows a viral infection and is self-limited (vs. chronic course in adults)

Antiplatelet antibodies coat platelets → which are then removed by splenic macrophages

Look for thrombocytopenia with ↑ megakaryocytes in the absence of splenomegaly (to rule out splenic sequestration)

Clinical features: petechiae, menorrhagia

Dx: ↓ platelet count, ↑ bleeding time, ↑ megakaryocytes in the bone marrow.

Question 22

Name the 6 common causes of DIC. Use a mnemonic device if you find it helpful.

Answer 22

Common precipitating conditions include: Mnemonic: “ATTOMS”

• Acute pancreatitis
• Trauma
• Transfusion reaction
• Obstetric causes such as abruptio placentae and amniotic fluid embolism
• Malignancy
• Sepsis

Question 23

What happens to PT & PTT in thrombocytopenia?

Answer 23

Laboratory investigation should take place when a bleeding disorder is suspected.

Platelet count are decreased (< 150,000/mm3) in cases of platelet destruction. ↑ bleeding time, while PT & PTT are unchanged.

Question 24

What is polycythemia?

Answer 24

Polycythemia: ↑ Hct, Hb, and RBC count.

Question 25

Can you name some of the diseases seen in immunocompromised CMV-infected patients that are not typically seen in immunocompetent CMV-infected patients? Try to name at least 3.

Answer 25

Immunosuppressed (e.g., organ transplant) and immunocompromised (especially AIDS with CD4<75) patients experience a much more severe clinical course, which may include:

Eye:
- CMV retinitis (especially in AIDS patients) → progressive blindness with bilateral retinal hemorrhage and cotton wool exudates (white opaque patches at retinal periphery)

GI:
- CMV esophagitis (especially in AIDS patients) with linear ulceration (vs. “punched out” ulceration characteristic of HSV-1 esophagitis) → painful swallowing

Lung:

• Interstitial (atypical) pneumonia

Kidney:
- Progressive renal failure → ↑ BUN, ↑ Cr, urinalysis demonstrating renal tubule cells with intranuclear inclusions

Adrenal glands:
- Addison’s disease (primary adrenal insufficiency)

Question 26

What are codocytes? What do they look like?

Answer 26

Codocytes (“target cells”) are red blood cells with a “bullseye” target appearance.

Target cells are associated with:

HbC disease

Asplenia

Liver disease

Thalassemia

Mnemonic: “HALT!” said the hunter to his target.

Question 27

What is the etiology of tissue damage in serum sickness?

Answer 27

2) Serum sickness: formed immune complexes deposit in membranes where they fix complement → tissue damage

Caused by injection of foreign serum or drugs (e.g. sulfonamides, penicillin, cephalosporins, phenytoin, and thiourea)

Patients present with fever, pruritic rash, proteinuria, lymphadenopathy, and joint pain

Following the first exposure to an antigen, it takes 7-14 days for IgM antibodies to be produced in serum sickness (production of IgG follows IgM).
If a previously immunized patient is later re-exposed to the same antigen, memory B cells formed by the previous antigenic exposure can produce an IgG response within 12-36 hours, producing a much more acute and severe serum sickness reaction.

Question 28

Which factor is deficient in hemophilia A?

Answer 28

Hemophilia A (Factor 8 deficiency)

X-linked recessive with variable severity

↑ PTT but all other labs are normal: normal bleeding time, normal PT

Question 29

Describe the process by which HIV inserts itself into the host genome.

Answer 29

Viral reverse transcriptase: viral RNA → dsDNA → inserted into the host cell genome byintegrase, another viral enzyme.

Following insertion of proviral DNA into the host genome, the host cell transcription and translation machinery can be exploited to generate viral polyproteins (Gag, Pol, Env).

HIV infects:

• CD4 T lymphocytes: CD4 and CXCR4 (α-chemokine receptor)
• Macrophages: CD4 and CCR5 (β-chemokine receptor 5)

Question 30

What are some substances that can cause aplastic anemia?

Answer 30

Specific toxins that can produce aplastic anemia include: benzene, chloramphenicol, gold salts (old Tx for RA), sulfonamides, phenytoin. It can also result from radiation and chemotherapy.

Question 31

Name the factors and pathway evaluated by PT

Answer 31

Prothrombin Time (PT) evaluates the extrinsic system: Factors VII, X, V, II and I

The normal PT is between 10-12 seconds.

INR (International Normalized Ratio) is a standardized value for PT that is often quoted when following warfarin therapy. The normal value is set at 1. An elevated INR indicates relative increase in anti-coagulation (i.e. INR = 2-3) ↑ PT can be seen with warfarin therapy, or any process affecting the synthesis or consumption of coagulation factors (i.e. liver disease and DIC (Disseminated Intravascular Coagulation); respectively).

Question 32

How is CMV transmitted? Try to name 6 ways.

Answer 32

Congenital — transplacental; within birth canal during birth

Sexual — semen, cervical secretions

Breast milk

Saliva

Blood transfusion

Organ transplantation

Question 33

What co-factors in the coagulation cascade are activated by thrombin?

Answer 33

Thrombin (IIa) functions in a positive feedback loop. The actions of Thrombin can be summarized:

Activates V

Activates VIII

Activates XI

Activates XIII, which cross-links soluble fibrin monomers

Converts fibrinogen to fibrin monomers

Question 34

A 7 year old boy is brought to the emergency department by his mother after she noticed that the child had not urinated for 24 hours. The boy and his mother got in an argument last night and she is concerned that he might be “acting out” by purposefully witholding urination. A careful review of systems reveals that the child has been healthy and received all of his vaccinations on time. He has been well except for a recent bout of diarrhea which lasted for about 3 days and resolved 2 weeks ago.

Notable physical exam findings include pale conjunctiva and pallor.

Examination of a blood smear from this child is likely to reveal which of the following?

A Target Cells

B Acanthocytes

C Schistocytes

D Nothing, this is a behavioral issue

E Spherocytes

Answer 34

This is a classic history for a case of HUS (Hemolytic Uremic Syndrome). This child, who is otherwise healthy has a recent history of AGE (acute gastroenteritis) which has since resolved. These cases of AGE are usually caused by O157:H7 E. Coli (EHEC) and subsequent to this infection the patient will develop HUS.

The triad of HUS is: Microangiopathic hemolytic anemia (hence the presence of schistocytes aka helmet cells, fragmented RBCs), Thrombocytopenia and Acute renal failure. The renal failure generally presents with oliguria or azotemia. They may also have RBCs, proteins or casts present in their urine.

The description of the behavioral findings are meant to serve as a distractor, don’t be led astray!

HUS (Hemolytic Uremic Syndrome)

Most common cause of renal failure in children

Presents with classic triad of:

1) Thrombocytopenia
2) Microangiopathic hemolytic anemia
3) Acute renal failure

Usually preceded by O157:H7 (Shiga-like toxin producing) E. coli infection

Endothelial cells are damaged, predominantly in the kidney → platelets aggregate, forming microthrombi → renal injury → uremia

Clot formation consumes platelets → thrombocytopenia

Thrombi shear RBCs → schistocytes, anemia

Spherocytes are small, round RBCs which are seen in Hereditary Spherocytosis, which is an autosomal dominant disease caused by a membrane defect in either ankyrin or spectrin proteins, leading to small RBCs which frequently get caught in the spleen and hemolyzed. Suspect HS when the patient is presented with a history of frequent gallstones or a strong family history of splenectomy.

Acanthocytes are RBCs with small spiculations on the surface, also known as spur cells. These are seen in patients with liver disease and abetalipoproteinemia.

Target cells are large RBCs with extra membrane. They are classically described in patients with Thalassemia, but can also be seen in HbC/S, patients who have had splenectomy, or patients with liver disease.

Description of these characteristic RBC findings is extremely high yield for the USMLE Step 1!

Question 35

What are 2 potential viral causes of mononucleosis? What laboratory technique is used to differentiate them?

Answer 35

EBV causes heterophil-positive mononucleosis, most commonly in adolescents (“kissing disease”). This means that the patient’s serum will agglutinate non-human (i.e. sheep) RBCs. Contrast this with the heterophil-negative mononucleosis caused by CMV.

S/Sx include:

• Fatigue, fever, pharyngitis, anorexia
• Generalized tender lymphadenopathy
• Splenomegaly — danger of splenic rupture ∴ patients should avoid contact sports.

Question 36

Viral infection of cells in the oropharynx may predispose immunocompromised (e.g., AIDS) patients to the development of a nontender, adherent (i.e., non-scrapable) whitish lesion on the tongue and/or oral mucosa.

• Can you name the virus?
• What is the name of this lesion?

Answer 36

EBV infection of cells in the oropharynx may predispose to oral hairy leukoplakia in susceptible patients:

Nontender, adherent (i.e., non-scrapable) whitish lesion on tongue or oral mucosa due to hyperproliferation of lingual epithelial cells

Most commonly seen in AIDs patients

Question 37

HHV-8:

• what is another name for HHV-8?
• transmission?

Answer 37

HHV-8 (KSHV — Kaposi sarcoma-associated herpesvirus) — sexually transmitted

HHV-8 viral gene induces VEGF (vascular endothelial growth factor) → Kaposi’s sarcoma:

• malignancy of vascular endothelial cells — dark purple lesions on skin, oral mucosa, GI tract, lungs
• most common cancer in AIDS patients
• most common location: hard palate
• lymphocytic infiltrate in Kaposi sarcoma — vs. neutrophilic infiltrate in bacillary angiomatosis, which is caused by infection with Bartonella henselae and mimics the gross appearance of Kaposi sarcoma

Nuclear antigen (HHV-8-encoded protein) inactivates the RB tumor suppressor protein (rb gene is on chromosome 13) → ↑ uncontrolled cell proliferation, which contributes to malignant transformation

HHV-8 also infects B-cells → primary effusion lymphoma

Question 38

What treatment options are available for CMV infection?

Answer 38

Tx: Ganciclovir; Foscarnet if ganciclovir-resistant

CMV does not have thymidine kinase (vs. HSV and VZV, which do) ∴ acyclovir is ineffective against CMV.

CMV does have a viral kinase which creates a guanosine analog ∴ ganciclovir can be effective in preventing replication of the DNA genome of CMV

However, ganciclovir-resistant CMV may occur via the UL97 gene → use Foscarnet

Question 39

What are the three basic causes of thrombocytopenia?

Answer 39

1. ↓ platelet production: characterized by decreased megakaryocytes in the bone marrow.

For example:

• Aplastic anemia
• Alcohol
• Antineoplastic drugs
• Malignancy (e.g., myelofibrosis; metastatic spread of cancer to bone marrow)

2. ↑ platelet destruction: peripheral destruction associated with increased megakaryocytes in bone marrow.

For example:

• Bernard-Soulier syndrome
• DIC (disseminated intravascular coagulation)
• Drug-induced thrombocytopenia (i.e., heparin, penicillin, quinidine, methyldopa)
• HUS (hemolytic uremic syndrome) / TTP (thrombotic thrombocytopenic purpura)
• ITP (idiopathic / immunologic thrombocytopenic purpura)

3. ↑ platelet sequestration: platelets are retained in the spleen.

For example: portal HTN → hypersplenism

Question 40

What is the common treatment for von Willebrand Disease? Describe the mechanism.

Answer 40

Treatment of vWD generally consists of ddAVP (Desmopressin, a Vasopressin analog) which causes release of vWF from endothelial cells. Note this would not work in the subtype of vWD which completely lacks vWF.

Question 41

Exanthem subitum:

• what are two other names which are synonymous with exanthem subitum?
• what is the causative agent?
• how old are the patients which are typically affected?

Answer 41

HHV6 → exanthem subitum (sixth disease; roseola): primarily seen in infants 6 – 24 months of age

High-grade fever for 3-4 days → lacy body rash that spares the face and appears after the fever has resolved

Compare with fifth disease (erythema infectiosum), which is caused by parvovirus B19:low-grade fever for 7-10 days → classic erythematous macular rash starts on the the face (“slapped cheeks”) that appears after resolution of the fever → 2-3 days after the slapped cheeks first appear, the rash may spread to the extremities where it takes on a lacy, reticular pattern.

Most common cause of infant febrile seizures

Question 42

During secondary hemostasis, which of the following is part of the intrinsic pathway?

A Factor IX

B Factor VII

C Factor II

D Protein C

E Antithrombin III

Answer 42

The intrinsic pathway cascade is: XII → XI → IX. Factor IXa, together with Factor VIIIa, activates the first factor in the common pathway (Factor X). Factor VII is the main factor in the extrinsic pathway. ATIII and Protein C inhibit coagulation. Factor II (thrombin) is activated by Factor Xa.

Goal: generate fibrin for the clot

Question 43

Describe the mechanism of type I hypersensitivity from the initial antigen exposure to induction of inflammation.

Answer 43

Initial antigenic exposure induces synthesis of IgE, which binds to the surface of mast cells and basophils via its Fc portion.

Note: IL-4 from Th-2 cells induces the class switching from IgG → IgE.

Re-exposure to same antigen → crosslinking of surface bound IgE molecules →degranulation of basophils and mast cells. This initiates the immediate phase of the reaction.

Immediate Phase: Release of histamine, tryptase, kininogenase, prostaglandins, platelet aggregating factor, and ECF-A. Since no products need to be synthesized by the cell, this process is rapid.

Note: These mediators are responsible for the immediate edema, erythema and pruritis that result after exposure.

While the initial phase is in progress, the cell also begins synthesizing leukotrienes and their derivatives as a part of the late phase of the reaction.

The products of the late phase reaction are inflammatory and attract neutrophils and eosinophils.

Late Phase: Leukotrienes are synthesized via the lipoxygenase pathway and are released up to 6 hours after exposure. These mediators are also called slow reacting substances of anaphylaxis (SRS-A).

Question 44

What is appropriate polycythemia?

Answer 44

Appropriate polycythemia: RBC count increase in response to chronic hypoxia.

Hypoxic stimuli → ↓ O2 saturation due to:

• High altitude
• Primary lung disease
• Cyanosis (due to heart disease or CO exposure)

↑ RBC count, RBC mass, and EPO.

Plasma volume (PV)= normal.

Question 45

What are the elements in the history that will differentiate between coagulation defects and platelet defects?

Answer 45

Keys to differentiating bleeding disorders:

Coagulation cascade defects will have a history of hematoma, hemarthrosis and bleeding at circumcision

Labs: ↑ PTT, normal BT. Normal PT is often found in hemophilia but PT prolongation can occur with factor II, V or VII deficiency.

Platelet defects: patients will have history of mucosal bleeding with recurrent epistaxis, petechiae and small ecchymoses and purpura

Labs: ↑ ↑ BT, ↑ PTT (in vWD because of VIII deficiency), normal PT.

Also look at the platelet count as it will tell you if the problem is due to platelet number or platelet function.

Bleeding caused by Vit K dependent factor deficiency, liver disease, coumadin therapy

PT, ↑ PTT, normal BT

Question 46

Homozygous mutations of which cellular receptor confers immunity to HIV infection? What effect does heterozygous mutations of the same effector have on HIV infection?

Answer 46

CCR5 mutations: homozygous mutations → immunity
heterozygous mutations → slower course

Question 47

Name 3 antigens which are targeted by systemic lupus erythematous autoantibodies.

Answer 47

SLE: formation of autoantibodies to endogenous antigens such as double stranded RNA, nuclear antigens (ANA-antinuclear antibodies, anti-dsDNA), as well as RBCs, WBCs, and platelets,

Question 48

What factors and pathway are evaluated by PTT?

Answer 48

PTT (Partial Thromboplastin Time) evaluates the intrinsic system: Factors XII, XI, IX, VIII, X, V, II and I.

The normal PTT is between 25-40 seconds.

PTT is used to follow heparin but not LMWH (i.e. enoxaparin) therapy.

↑ PTT is seen with factor deficiencies, DIC, vWD and anti-phospholipid syndrome (associated with SLE).

Question 49

Describe how HIT (Heparin induced thrombocytopenia) takes place.

Answer 49

Heparin binds to platelet antigen (Platelet Factor 4)

Autoantibody formed against the Heparin/PF4 complex.

This is an example of Type II Hypersensitivity

These immune complexes induce activation of platelets → patients become procoagulant and are at risk for thromboembolic events

Note: the presence of heparin is required to trigger platelet activation. Thus, all heparin administration should be immediately stopped in patients suspected of having HIT

Question 50

What class of enzymes do many coagulation factors belong to?

Answer 50

Many coagulation factors are secreted as zymogens. Upon activation, they become serine proteases that can activate downstream factors

Question 51

What is type III hypersensitivity?

Answer 51

Circulating antigen-antibody complexes deposit on the surface of blood vessels activating complement that eventually leads to tissue destruction. (If the complexes are formed extravascularly, they are called in situ immune complexes).

Examples include: SLE (systemic lupus erythematosus), PAN (polyarteritis nodosum),PSGN (poststreptococcal glomerulonephritis), serum sickness, Arthus reaction, and hypersensitivity pneumonitis

Question 52

Name the vitamin K-dependent coagulation factors.

Answer 52

Factors X, IX, VII, II (mnemonic “1972”) are vitamin K-dependent

Their synthesis is inhibited by warfarin, a vitamin K antagonist which inhibits the γ-carboxylation step in the synthesis of the factors II, VII, IX, X (as well as Proteins C and S).

Question 53

Deficiency of what 5 factors will cause an increased PT?

Answer 53

↑ PT is caused by deficiency of fibrinogen (factor I) or II, V, VII, X (“1752”)

Question 54

Describe the platelet count, bleeding time, PT, and PTT findings in DIC.

Answer 54

Consumption of all hemostatic components leads to:

• Microangiopathic hemolytic anemia
• Thrombocytopenia
• ↑ Bleeding time
• ↑ PT and ↑ PTT
• Because it is a consumptive coagulopathy, ↓↓ coagulation factors (Factor V, Factor VIII)

↑ Fibrin split products (D-dimers) as the excessive clotting activates fibrinolysis(plasmin)

Question 55

A 19-year-old tennis player begins wheezing and complains of shortness of breath. His muscles also start cramping. The medical officer at the sporting event injects him with epinephrine and diagnoses him with a Type I hypersensitivity. Which of the following is not considered a major mediator of this type of hypersensitivity reaction?

A C5a

B Interleukin 6

C Interleukin 1

D C1a

E Tumor necrosis alpha

Answer 55

The major mediators of anaphylaxis are tumor necrosis factor alpha, Interleukin-1, Interleukin-6, leukotrienes, prostaglandins, histamine and the complement mediators C3a and C5a (commonly referred to as ‘anaphylotoxins’). C1a does not contribute to the pathogenesis of anaphylaxis and is thus not involved in Type I hypersensitivity reactions.

Complement activation is commonly seen in Type II and III hypersensitivities.

Major Mediators of Type I Hypersensitivity

Histamine: Preformed in granules of mast cells and basophils. Acts on the post-capillary venules to cause vasodilation and increased capillary permeability.

Serotonin: Preformed in granules of platelets and mast cells. Released during acute phase, and acts similarly to histamine → vasodilation and increased vascular permeability.

Leukotrienes: Synthesized on demand (i.e. not preformed). Increase vascular permeability and are best known for their role in bronchoconstriction.

ECF-A (Eosinophil Chemotactic Factor of Anaphylaxis): Preformed in granules of mast cells. Attracts eosinophils to the site of inflammation.

Eosinophils are recruited to the site of inflammation as a part of the late-phase reaction. Once present, they release several mediators, among them arylsulfatase and histaminase which can act to decrease the severity of inflammation. However, LTC4 and PAF are also released which overall activate mast cells to further release cytokines.

Thus, eosinophils are now believed to amplify and sustain the inflammatory response, thus necessitating treatment with corticosteroids.

Note: Eosinophils contain a variety of preformed cytoplasmic granule mediators (e.g. major basic protein and eosinophilic cationic protein) that can cause epithelial damage

Question 56

Describe the morphology of RBCs in DIC

Answer 56

Microthrombi can cause mechanical trauma to circulating RBCs → schistocytes aka “helmet cells”

Question 57

Where is folate absorbed? Where is B12 absorbed? Describe the important steps in each.

Answer 57

*Folate is absorbed in the jejunum. The enzyme intestinal conjugase (which is inhibited by phenytoin) is required for absorption.

*Vitamin B12 is absorbed in the terminal ileum. B12 absorption is slightly more complicated:

• B12 is bound by R-factor which protects it from gastric acidity
• In the duodenum, pancreatic enzymes hydrolyze the R-factor bond and B12 is bound by IF (which is synthesized by gastric parietal cells).
• The B12-IF complex is absorbed in the terminal ileum.

*Folate and B12 are required for the synthesis of dTMP.

Question 58

Epstein-Barr virus is associated with which subtype of Hodgkin’s lymphoma?

Answer 58

EBV is strongly associated with the mixed cellularity subtype of Hodgkin’s lymphoma:

Presents as mediastinal mass or nontender lymphadenopathy

Constitutional “B” Sxs can mimic the presentation of mono (e.g., swollen lymph nodes, recurrent fevers)—a monospot should be ordered to rule out infectious mononucleosis prior to carrying out more extensive work-up for Hodgkin’s

Malignant cell = Reed-Sternberg cell: B-cell origin, CD15+, CD30+, binucleate with prominent nucleoli (“owl eyes”)

Mixed cellularity type (25%) has the most Reed-Sternberg cells

Question 59

What are the typical clinical features of thrombocytopenia?

Answer 59

Clinical features are much different than coagulation defects!

Petechiae (small pinpoint hemorrhages) and purpura (small ecchymoses) are common. Bleeding typically occurs from mucosal surfaces (i.e. epistaxis, menorrhagia, bleeding gums), GI bleeds.

Question 60

What are the symptoms of B12 deficiency? What happens if you give someone folate if they are B12 deficient?

Answer 60

B12 deficiency causes neurological symptoms:

• Loss of dorsal column function (↓ vibration and position sense)
• Loss spinocerebellar tracts → ↓ proprioception
• Demyelination of the lateral corticospinal tract → spasticity, weakness

Neurological symptoms are due to failure of Methylmalonyl CoA → Succinyl CoA.
↑ Methylmalonyl CoA causes an ↑ Propionyl CoA (the precursor) → replacement of acetyl CoA with Propionyl CoA → demyelination.

Note: Megaloblastic anemia caused by B12 deficiency can be corrected by folate administration, but the neurological symptoms can not!

Question 61

Patients with severe thalassemias can experience abdominal pain as a result of what process?

Answer 61

Hypersplenism, from extramedullary hematopoiesis and increased extravascular hemolysis, can result in splenic infarction and abdominal pain. Note, the increased hemolysis can also lead to bilirubin gallstones leading to RUQ pain.

Question 62

Describe the molecular pathogenesis of paroxysmal nocturnal hemoglobinuria.

Answer 62

Paroxysmal nocturnal hemoglobinuria: a spontaneous (de novo) somatic mutation of the GPIanchor necessary for CD55 and CD59 attachment. The corresponding gene is PIGA(phosphatidylinositol glycan class A), on the X chromosome.

CD55 and CD59 inactivate complement. The GPI anchor deficiency leads to complement mediated hemolysis.

Patients occasionally (paroxysmally) wake up with hemoglobinuria (nocturnal)

Sxs: anemia, thrombosis, pancytopenia, hypercoagulable state