heme part two

neutrophils

• first responders to bacterial and fungal infection

• most abundant leukocyte

• 80%

• respond quickly to an invader

lymphocytes

• key mediators of adaptive immunity

• t cells, b cells, NK cells

• central to viral defense

• 60% when you have a virus

• lower when a bacterial infection

monocytes

• differentiate into tissue macrophages

• phagocytose pathogens and debris

• cleaning up garbage

eosinophils

• combat parasitic infection

• modulate allergic and inflammatory response

• gather with inflammation

basophils

• release histamine and mediators

• drive hypersensitivity reactions

• least number of white blood cells

• 1-3%

hemostasis

• the process by which bleeding is stopped after vessel injury

• happens in two coordinated phases

• what platelet count and function disorders primarily disrupt

platelet plug

• primary hemostasis

• vessel injury triggers endothelin release, causing local vasoconstriction

• von Willebrand factor (vWF) bridges platelets to the site of injury

• activated platelets release vWF, serotonin, ADP, fibrinogen, calcium, and thromboxane A2, recruiting and aggregating more platelets

• loose but functional within seconds to minutes

secondary hemostasis

• coagulation cascade

• stabilizes the platelet plug with a fibrin mesh, through the coagulation cascade

• two converging pathways activate the cascade

intrinsic pathway

• triggered by contact with exposed collagen

• involves factors XII, XI, IX, VIII

• aPTT screens this and common pathways

• factor VIII and IX deficiencies (hemophilia A and B) prolong the aPTT

extrinsic pathway

• triggered by tissue factor released from damaged tissue

• involves factor VII

• PT/INR screens this and common pathways

common pathway

• both converge on this

• factor X activates prothrombin (factor II) to thrombin, which converts fibrinogen to fibrin

• PT/INR/aPTT

fibrinolysis

• taking the clot back down

• once a vessel has healed, the clot must be broken down so normal blood flow resumes

• plasminogen is converted to plasmin, which degrades fibrin into D-dimer and other fragments

• an elevated D-dimer signals recent clot formation and breakdown, though it is nonspecific

• hemostasis is a balance

  • too little clotting activity, or too much breakdown, causes bleeding disorders

  • too much clotting activity, or too little breakdown, causes thrombotic disorders

disseminated intravascular coagulation (DIC)

• pathologic activation of both clotting and fibrinolysis at once, causing simultaneous clotting and bleeding

• a life-threatening complication of another underlying disease or condition, never a primary diagnosis on its own

• pathologically active coagulation and fibrinolysis occurring at the same time, so the patient can clot and bleed simultaneously

• common triggers: sepsis, severe trauma or burns, acute hemolytic transfusion reaction, obstetric complications (abruption, retained placenta, eclampsia), malignancy, severe liver disease, and complicated surgery

• multisystem: bleeding from IV sites and mucosa alongside organ dysfunction from microvascular clotting

• CBC and coagulation studies (prolonged PT/aPTT, low fibrinogen, elevated D-dimer)

• treatment addresses the underlying cause plus targeted clot prevention and bleeding management

neutrophilia

• granulocytosis

• increased neutrophil count, most often triggered by bacterial infection or acute inflammation

• a surge of immature forms in circulation is called a leukemoid reaction, and can mimic leukemia on a CBC

• serum neutrophil count plus work-up to determine the underlying cause, treatment is directed at that cause

neutropenia

• decreased number of circulating neutrophils, reducing the ability to fight infection

• multiple causes: marrow suppression (chemotherapy), autoimmune destruction, severe infection, medications

• clinical manifestations: signs and symptoms of bacterial or fungal infection, with the respiratory tracts as the most common site

• serum neutrophil count plus work-up to determine the underlying cause; treatment is directed at the cause

absolute neutrophil count

• total WBC count x (% neutrophils + % bands) / 100

• >1500 cells/mL is generally normal

• below 500 cells/mL defines severe neutropenia and typically triggers neutropenic precautions, though the exact threshold varies by institution

lymphomas

• cancers arising from malignant lymphocytes within lymphoid tissue, and they are the most common blood cancers overall

• the seventh most common cancer in adults

• fifth most common cancer in children

• two main categories: hodgkin and non-hodgkin

• shared risk factors include HIV infection and epstein-barr virus exposure

hodgkin lymphoma

• typically starts in lymph nodes of the upper body: neck, chest, and arms

• classical: about 90% of cases

• nodular lymphocyte predominant: about 10% of cases

• presence of reed-sternberg cells on biopsy

• incidence of classic has been declining

• painless, enlarged lymph node in the neck or supraclavicular area, sometimes a mediastinal mass on chest x-ray, and B symptoms (fever, night sweats, weight loss)

• lymph node biopsy with formal staging: chemotherapy and radiation, with bone marrow or stem cell transplant for refractory disease

non-hodgkin lymphoma

• accounts for about 90% of all lymphomas and roughly 5% of childhood cancers

• no reed-sternberg cells on biopsy

• inherited immune or autoimmune conditions, infection exposure, toxin exposure, obesity, and inflammatory gastrointestinal disease

• both aggressive and indolent subtypes exist, with unorganized, unpredictable patterns of metastasis

• testing and staging similar but treatment depends heavily on subtype

• overall prognosis is generally worse, underscoring why accurate subtyping matters

multiple myeloma

• cancer of plasma cells, the antibody-producing descendants of b lymphocytes

• malignant plasma cells respond abnormally to antigen stimulation and proliferate in the bone marrow

• often preceded by monoclonal gammopathy of undetermined significance (MGUS), a premalignant state that can progress

• the malignant clone produces abnormal immunoglobulins (monoclonal protein, or M protein)

• common chromosomal abnormalities drive disease behavior and prognosis

• plasma cells interact with bone marrow stromal cells, disrupting the normal balance of osteoblast and osteoclast activity, which drives the bone disease seen clinically

CRAB criteria

• calcium elevation

• renal failure

• anemia

• bone lesions

calcium elevation

• hypercalcemia from osteoclast-driven bone breakdown

renal failure

• light chain deposition and damage to renal tubules

anemia

• marrow crowding by malignant plasma cells

bone lesions

• lytic lesions visible on skeletal survey from osteoclast activation

myelodysplastic syndrome

• a group of hematopoietic neoplasms characterized by abnormal growth, differentiation, and maturation of blood cells

• arises from mutations in the multipotent myeloid progenitor cell

• can be asymptomatic, or present with symptoms related to whichever cytopenia dominates (fatigue from anemia, infection from neutropenia, bleeding from thrombocytopenia)

• complete history and physical, CBC, and bone marrow biopsy

• formal prognosis-estimating systems guide risk stratification

• ranges from observation and supportive care in low-risk disease to more aggressive therapy, since it can progress to acute myeloid leukemia

leukemia

• reflects abnormal leukocyte production that can infiltrate and affect multiple organs

• categorized along two axes:

  • cell line: lymphoid versus myeloid

  • maturity: acute (immature cells) versus chronic (more mature cells)

• four types

acute lymphoblastic leukemia (ALL)

• most common in children

acute myeloid leukemia (AML)

• more common in adults, often rapidly progressive

chronic lymphoid leukemia (CLL)

• most common leukemia in older adults, often indolent

• proliferation of mostly mature, malignant B cells

• driven by an interplay of genetic, epigenetic, and microenvironmental factors

• generally asymptomatic at presentation, often found incidentally on routine CBC

• routine blood count showing marked leukocytes

• management ranges from watchful observation to aggressive therapy, depending on stage and symptom burden

chronic myeloid leukemia (CML)

• defined by the philadelphia chromosome, driver of targeted therapy

• proliferation of mostly mature and maturing granulocytes

• defined by the philadelphia chromosome, a genetic fusion that drives disease and enables targeted therapy

• manifestations increase as the patient progresses through chronic, accelerated, and blast phases

• targeted tyrosine kinase inhibitor therapy has transformed this into a largely manageable chronic condition

acute leukemias

• abnormalities in immature precursor leukocytes with uncontrolled proliferation, blocked differentiation and maturation, and resistance to apoptosis

• genetically and phenotypically heterogeneous; risk factors include prior chemotherapy or radiation, certain genetic syndromes, and some environmental exposures

• largely a result of cytopenias: fatigue and pallor from anemia, infection from neutropenia, bleeding or bruising from thrombocytopenia

• bone and joint pain from marrow expansion, plus other physical findings such as lymphadenopathy or hepatosplenomegaly

• history, physical exam, peripheral blood smear, CBC, and bone marrow biopsy confirm the diagnosis and subtype

• goal is complete remission, achieved through chemotherapy, and bone marrow transplant for eligible patients

thrombocytopenia

• too few platelets

• platelet count below the normal range, carrying a real risk of life-threatening bleeding as it worsens

• a count below roughly 15,000 cells/mL3 carries a risk of spontaneous bleeding without any trauma

• decreased production: marrow failure, infiltration, or nutrient deficiency

• increased destruction: immune-mediated, mechanical, or consumptive processes

• always take a careful medication history

• many drugs (including heparin) can trigger immune-mediated platelet destruction

immune thrombocytopenic purpura

• a hypocoagulable state where the immune system destroys its own platelets

• primary is the most common cause and can be acute or chronic

• secondary can follow autoimmune disease, live vaccination, infection, or malignancy

• often asymptomatic and found incidentally

• when symptomatic, presents as abnormal bruising or bleeding

• treatment is individualized, aimed at preventing or managing severe bleeding rather than normalizing the count in every patient

thrombotic thrombocytopenic purpura

• a true coagulation emergency: a deficiency of ADAMTS13, the enzyme that cleaves von Willebrand factor

• uncleaved vWF causes excessive platelet clumping, so microthrombi form in the microvasculature while circulating platelets are consumed

• presents with the classic combination of microthrombi, thrombocytopenia, and bleeding, plus neurologic, cardiovascular, and GI involvement

• elevated LDH and reticulocyte count, schistocytes on smear, low haptoglobin

• plasmapheresis is first line and urgent, since untreated is often fatal

thrombocythemia

• too many platelets

• an elevated platelet count, which raises thrombotic risk

• two types

secondary (reactive) thrombocytosis

• pooling and release of platelets after splenectomy

• a reactive response to infection or inflammation, typically resolves once the trigger is treated

primary thrombocytosis

• a myeloproliferative neoplasm with autonomous platelet overproduction, carrying higher thrombotic and bleeding risk than the secondary form

hemophilia

• two types

• both are x-linked

• clinical manifestations include deep bleeding, petechiae, bruising, gastrointestinal bleeding, and hematuria

• prolonged aPTT with specific factor assays confirming the deficient factor

• factor replacement therapy and bleeding precautions

• women carry, men affected

• deep joint and muscle bleeding

hemophilia a

• deficiency or abnormality of clotting factor VIII

hemophilia b

• deficiency of clotting factor IX

von Willebrand disease

• the most common hereditary bleeding disorder

• types range from 1 through 3, plus acquired and spontaneous forms

• manifests as abnormal, often mucocutaneous bleeding (easy bruising, epistaxis, heavy menstrual bleeding)

• evaluation of hemostasis including vWF antigen and activity

• DDAVP to release stores in mild disease, cryoprecipitate or factor concentrate for more severe bleeding

• affects primary hemostasis, the platelet vessel wall interaction

thrombophilia

• hypercoagulable state

• a state of increased coagulation tendency, raising the risk of venous thromboembolism

• acquired causes: antiphospholipid syndrome, the most common

• inherited causes:

  • factor V leiden mutation and prothrombin gene mutation are the most common

  • congenital deficiencies of antithrombin, protein C, or protein S are less common but often more severe

• clot formation requires both a prothrombotic state and an inciting trigger (surgery, immobility, pregnancy)

• many patients are asymptomatic until they present with a DVT or PE

• treatment depends on individualized thrombosis risk, balanced against bleeding risk from anticoagulation