Plasma Cell Pathology

A. Multiple myeloma

1. Plasma cell neoplasm that results in the proliferation of monoclonal plasma cells. These tumor cells produce nonfunctional immunoglobulins.

2. Laboratory findings include:

a. Monoclonal IgG spike.

b. Bence-Jones proteins found in urine.

3. Radiographic findings: characteristic “punched-out” radiolucencies in bones.

Blood-Lymphatic Pathology

Disorders of primary hemostasis

1. General characteristics of disorders of primary hemostasis (due to problems of blood vessels or platelets):

a. Occur early in life.

b. Unlike secondary hemostasis, bleeding occurs in more superficial areas such as skin and mucous membranes rather than in secondary hemostasis.

c. Signs include petechiae.

d. Can be caused by vascular and platelet abnormalities or alterations in the plasma proteins required for adhesion of platelets to vascular subendothelium.

e. Laboratory findings include prolonged bleeding time, as seen in platelet disorders.

2. Vascular abnormalities

Scurvy

(1) Caused by a vitamin C deficiency leading to decreased synthesis of collagen. Note: vitamin C is necessary for the formation of collagen via hydroxylation of lysine and proline.

(2) Symptoms include:

- Delayed wound healing.

- Petechiae and ecchymosis.

- Gingival bleeding, swelling, and ulcerations.

3. Platelet abnormalities

a. Thrombocytopenia

(1) Characterized by a decreased number of platelets.

(2) The most common type of bleeding disorder.

(3) Can be caused by a number of diseases, such as irradiation, acute leukemia, disseminated intravascular coagulation (DIC), or idiopathic thrombocytopenic purpura (ITP).

b. Thrombocytopenic purpura

(1) Idiopathic: An autoimmune disease characterized by the presence of autoantibodies against platelets, resulting in the removal of platelets by splenic macrophages.

(2) May also be drug-induced.

Disorders of secondary hemostasis

1. General characteristics of disorders of secondary hemostasis (due to problems with clotting factors):

a. Symptoms occur later in life.

b. As compared to disorders of primary hemostasis, bleeding occurs in deeper areas and larger vessels (i.e., joint spaces).

c. Laboratory findings include abnormal:

- Partial thromboplastin time (PTT)—measures the intrinsic and common clotting pathway (i.e., tests all coagulation factors except factor 7).

- Prothrombin time (PT)—measures the extrinsic pathway.

- Does not affect the bleeding time.

Hemophilia

a. Caused by a deficiency of particular clotting factor(s).

b. All types of hemophilia affect the intrinsic pathway of the clotting cascade.

c. Signs and symptoms include:

- Prolonged PTT.

- Continuous bleeding from cuts or trauma, which can lead to excessive blood loss.

- Bleeding into joint cavities (hemarthroses) and muscle.

Two types:

(1) Hemophilia A (classic hemophilia)

- Caused by a deficiency of factor 8 (antihemophilic factor).

- Transmission: sex-linked recessive—only occurs in males; however, females can be carriers.

(2) Hemophilia B (Christmas disease)

- Caused by a deficiency of factor 9 (plasma thromboplastin).

- Transmission: sex-linked recessive—only occurs in males; however, females can be carriers.

- Lower incidence rate than hemophilia A.

(3). Vitamin K deficiency

- Causes include malnutrition and malabsorption of fats.

- A decrease in clotting factors 2, 7, 9, and 10 and prothrombin is observed.

- Prolonged PT.

Disorders of both primary and secondary hemostasis

1. von Willebrand’s disease

a. Characterized by a defective von Willebrand’s factor (vWF). Defective vWF affects both primary hemostasis by affecting platelet adhesion to

endothelium, and secondary hemostasis, by a defective factor 8.

b. Genetic transmission: autosomal dominant.

It is the most common hereditary bleeding disorder.

2. Liver disease—disease of the liver results in a decreased production of coagulation factors and therefore can lead to problems with hemostasis.

3. Disseminated intravascular coagulation a condition in which clots form throughout the vasculature. This uses up all available clotting factors and platelets, resulting in problems with bleeding.

Abnormalities in chromosome number
Trisomy 21 (Down syndrome)
(1) The most common chromosomal disorder.
(2) A disorder affecting autosomes. It is generally caused by meiotic nondisjunction in the mother, which results in an extra copy of chromosome 21 or trisomy 21.
(3) Risk increases with maternal age.
(4) Clinical findings include mental retardation and congenital heart defects. There is also an increased risk of developing acute leukemia
and an increased susceptibility to severe infections.
(5) Oral findings include macroglossia, delayed eruption of teeth, and hypodontia.

Trisomies 18 and 13
(1) Trisomy 18 (Edwards syndrome):
characterized by an extra copy of chromosome 18. Oral findings include micrognathia.
(2) Trisomy 13 (Patau’s syndrome): characterized by an extra copy of chromosome 13. Oral findings include cleft lip and palate.
(3) Meiotic nondisjunction is usually the cause of an extra chromosome in both of these trisomies.
(4) Clinical findings for both of these trisomies are usually more severe than trisomy 21. Most children with these diseases die within months after being born due to manifestations such as congenital heart disease.

Klinefelter’s syndrome
(1) One of the most common causes of male hypogonadism.
(2) Characterized by two or more X chromosomes and one or more Y chromosomes. Typically, there are 47  chromosomes with the karyotype of XXY.
(3) The cause is usually from meiotic nondisjunction.
(4) Clinical findings include atrophic and underdeveloped testes, gynecomastia, tall stature, and a lower IQ.

Turner’s syndrome
(1) One of the most important causes of amenorrhea.
(2) Characterized by having only one X chromosome, with a total of 45 chromosomes and a karyotype of XO.
(3) Clinical findings include underdeveloped female genitalia, short stature, webbed neck, and amenorrhea. Affected females are usually
sterile. Unlike other chromosomal disorders, this one is usually not complicated by mental retardation.

Treacher Collins syndrome (mandibulofacial dysostosis)
(1) Genetic transmission: autosomal dominant.
(2) A relatively rare disease that results from abnormal development of derivatives from the first and second branchial arches.
(3) Clinical findings include underdeveloped zygomas and mandible and deformed ears. Oral findings include cleft palate and small or absent parotid glands.

Lymphangitis 
is the acute inflammation due to bacterial  infections spread into the lymphatics most common are group A β-hemolytic streptococci. 
lymphatics are dilated and filled with an exudate of neutrophils and monocytes.  
red, painful subcutaneous streaks (the inflamed lymphatics), with painful enlargement of the draining lymph nodes (acute lymphadenitis).  
subsequent passage into the venous circulation can result in bacteremia or sepsis. 

HAEMORRHAGIC DISORDERS

Normal homeostasis depends on

 -Capillary integrity and tissue support.

- Platelets; number and function

(a) For integrity of capillary endothelium and platelet plug by adhesion and aggregation

(b) Vasoactive substances for vasoconstriction

(c) Platelet factor for coagulation.

(d) clot retraction.

- Fibrinolytic system(mainly Plasmin) : which keeps the coagulation system in check.

Coagulation disorders

These may be factors :

Deficiency .of factors

• Genetic.
• Vitamin K deficiency.
• Liver disease.
• Secondary to disseminated intravascular coagulation.or defibrinatian

Overactive fibrinolytic system.

Inhibitors of  the factors (immune, acquired).

Anticoagulant therapy as in myocardial infarction.

Haemophilia. Genetic disease transmitted as X linked recessive trait. Common in Europe. Defect in fcatorVII   Haemophilia A .or in fact .or IX-Haemaphilia B (rarer).

Features:

• May manifest in infancy or later.
• Severity depends  on degree of deficiency.
• Persistant wound bleeding.
• Easy Bruising with Hematoma formation

Nose bleed , arthrosis, abdominal pain with fever and leukocytosis

Prognosis is good with prevention of trauma and-transfusion of Fresh blood or fTesh plasma except for danger of developing immune inhibitors.

Von Willebrand's disease. Capillary fragility and decreased factor VIII (due to deficient stimulatory factor). It is transmitted in an autosomal dominant manner both. Sexes affected equally

Vitamin K  Deficiency. Vitamin K is needed for synthesis of factor II,VII,IX and X.

Deficiency maybe due to:

Obstructive jaundice.

Steatorrhoea.

Gut sterilisation by antibiotics.

Liver disease results in :

Deficient synthesis of factor I II, V, Vll, IX and X  Incseased fibrinolysis (as liver is the site of detoxification of activators ).

Defibrination syndrome. occurs when factors are depleted due to disseminated .intravascular coagulation (DIC). It is initiated by endothelial damage or tissue factor entering the circulation.

Causes

Obstetric accidents, especially amniotic fluid embolism. Septicaemia. .

Hypersensitivity reactions.

Disseminated malignancy.

Snake bite.

Vascular defects : (Non thrombocytopenic purpura).

Acquired :

Simple purpura a seen in women. It is probably endocrinal

Senile parpura in old people due to reduced tissue support to vessels

Allergic or toxic damage to endothelium due to  Infections like Typhoid Septicemia

Col!agen diseases.

Scurvy

Uraemia damage to  endothelium (platelet defects).

Drugs like aspirin. tranquillisers, Streptomvcin pencillin etc.

Henoc schonlien purpura Widespeard vasculitis due to hypersensitivity to bacteria or foodstuff

It manifests as :

Pulrpurric rashes.

Arthralgia.

Abdominal pain.

Nephritis and haematuria.

Hereditary :

(a) Haemhoragic telangieclasia. Spider like tortous vessels which bleed easily. There are disseminated lesions in skin, mucosa and viscera.

(b) Hereditary capillary fragilily similar to the vascular component of von Willbrand’s disease

.(c) Ehler Danlos Syndrome which is a connective tissue defect with skin, vascular and joint manifestations.

Platelet defects

These may be :

(I) Qualitative thromboasthenia and thrombocytopathy.

(2) Thrombocytopenia :Reduction in number.

(a) Primary or idiopathic thrombocytopenic purpura.

(b) Secondary to :

(i) Drugs especially sedormid

(ii) Leukaemias

(iii) Aplastic-anaemia.

Idiopathic thrombocytopenic purpura (ITP). Commoner in young females.

Manifests as :

Acute self limiting type.

Chronic recurring type.

Features:

(i) Spontaneous bleeding and easy bruisability

(ii)Skin (petechiae), mucus membrane (epistaxis) lesions and sometimes visceral lesions involving any organ.

Thrombocytopenia with abnormal forms of platelets.

Marrow shows increased megakaryocytes with immature forms, vacuolation, and lack of platelet budding.

Pathogenesis:

hypersensitivity to infective agent in acute type.

Plasma thrombocytopenic factor ( Antibody in nature) in chronic type

Iron deficiency anaemia.

Absorption of iron is affected by :
- Iron stores.
- Rate of erythropoiesis
- Acid pH aids absorption.
- Phosphates and phytates in diet impair absorption.

Causes  of deficiency:

- Increased demand:
o    Growth (in children)
o    Menstruation, Pregnancy, lactation.
- Inadequate intake and absorption.
o    Dietary deficiency.
o    Achlorhydria or gastrectomy.
o    Malabsorption states.

- Chronic blood loss
o    Peptic ulcer, bleeding piles
o    Menorrhagia.
o    Hook worm infestation

Features:
- Anaemia.
- Koilonychia.
- Atrophic glossitis and angular stomatitis.
- Dysphagia-Plummer Vinson syndrome.

Blood findings:

- Microcytjc_hypochromic cells, ring cells and pessary cells.
- Anisocytosis and poikilocytosis.
- Low MCV. MCH and MCHC.
- Serum iron is low but iron binding capacity is increased

Bone marrow

Erythroid hyperplasia with imcronormoblasts. Iron stains reveal depleted stores

Differential  diagnosis .-

- Sideroblastic anaemia which is also microcytic hypochromic  but there is excess iron in the erythroid cells .Some are pyridoxine responsive.
- (ii) Thalassaemia