Hemorrhagic Disorders

Slide 1 · Hemorrhagic Disorders

Clinical patterns, hemostatic mechanisms, and consequences

Vessel wall

Platelets / vWF

Coagulation factors

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Recognize the bleeding phenotype before narrowing the mechanism.

Classify hemorrhage by vessel-wall, primary-hemostatic, or secondary-hemostatic dysfunction.

Discriminate petechiae, purpura, ecchymoses, hematomas, and hemarthroses.

Explain why volume, rate, site, and iron loss govern clinical consequences.

Slide 3 · What constitutes a hemorrhagic disorder?

Bleeding results when vascular integrity or hemostatic containment fails.

Vessel integrity

Platelet plug

Fibrin reinforcement

Vessel walls must remain intact to keep circulating blood intravascular.

Platelets and von Willebrand factor rapidly seal minute vascular defects.

Coagulation factors strengthen that initial seal with fibrin.

Slide 4 · Hemorrhage is a final common manifestation

Different causes converge on escape of blood from the circulation.

Structural rupture

Hemostatic failure

A ruptured large vessel can overwhelm otherwise normal hemostasis.

A subtle hemostatic defect can produce bleeding only under challenge.

Similar blood loss can therefore reflect very different pathophysiology.

Slide 5 · Normal hemostasis: Four linked steps

Stopping hemorrhage requires an ordered, localized response.

Vasoconstriction

Platelet plug

Fibrin deposition

Clot resolution

Immediate vasoconstriction transiently limits flow.

Platelet adhesion and aggregation build a primary plug.

Thrombin-derived fibrin stabilizes that plug; Repair and resorption follow.

Slide 6 · Vasoconstriction buys time

A temporary decrease in blood flow cannot substitute for a durable clot.

Injury

Reduced flow

Need for plug

Arteriolar contraction occurs promptly after vascular injury.

Reflex mechanisms and endothelin participate in constriction.

Hemorrhage would resume without platelet and coagulation responses.

Slide 7 · The primary plug seals microvascular defects

Platelets act at the disrupted endothelial surface within minutes.

Exposed matrix

Adherent platelets

Intact endothelium

Schematic

Exposed subendothelial collagen and vWF promote platelet adhesion.

Adherent platelets activate, change shape, and release granules.

Recruitment and aggregation form a rapid provisional barrier.

Slide 8 · Fibrin converts a provisional seal to a durable one

Secondary hemostasis reinforces the platelet plug against continued bleeding.

Platelet aggregate

Fibrin mesh around the plug

Schematic

Injury exposes tissue factor in the vessel wall.

Thrombin generation converts fibrinogen into insoluble fibrin.

The fibrin meshwork consolidates the plug.

Slide 9 · Platelet and coagulation systems cooperate

The two hemostatic phases are sequential but not independent.

Platelets

Thrombin

Fibrin

Activated platelets furnish surfaces for coagulation reactions.

Thrombin also amplifies platelet activation and aggregation.

Deficiency in either arm can jeopardize final clot stability.

Slide 10 · Endothelium regulates localization

Hemostasis must occur at injury, not throughout the circulation.

Intact surface

Disrupted surface

Intact endothelium shields underlying vWF, collagen, and tissue factor.

Normal endothelial mediators inhibit platelets and clotting.

Injury shifts the balance toward focal thrombus formation.

Slide 11 · Use the bleeding pattern as a mechanistic clue

Anatomic distribution often separates platelet, factor, and vessel disorders.

Mucocutaneous

Deep / joint

Palpable purpura

Skin and mucosal puncta suggest a primary-hemostatic problem.

Deep muscle or joint bleeding suggests a coagulation-factor defect.

Palpable purpura and bruising raise concern for small-vessel pathology.

Slide 12 · The severity spectrum is broad

Hemorrhagic disorders range from silent tendencies to lethal catastrophes.

Minute bleeds

Challenge-related

Catastrophic

Small-vessel microbleeds may appear after minor daily trauma.

Mild defects may first emerge with dental work, surgery, or childbirth.

Large-vessel rupture may rapidly exceed any hemostatic reserve.

Slide 13 · Major vessel rupture is a distinct emergency

Mechanical disruption can overwhelm an intact coagulation system.

Large-vessel defect

Massive blood loss

Physiologic collapse

Aortic dissection and abdominal aortic aneurysm are textbook examples.

Rupture complicating myocardial infarction may involve the cardiac wall.

Rapid large-volume hemorrhage may be fatal despite normal platelets and factors.

Slide 14 · Hemostatic stress exposes occult defects

The timing of first bleeding can be clinically informative.

Latent defect

Hemostatic challenge

Overt bleeding

Operative or dental injury creates a larger hemostatic challenge.

Childbirth and menstruation can expose a bleeding tendency.

Minor baseline symptoms do not exclude clinically relevant dysfunction.

Slide 15 · Primary hemostasis: The characteristic phenotype

Defective platelet plug formation typically produces mucocutaneous bleeding.

Platelet plug inadequate

Superficial leakage

Small hemorrhages arise in skin and mucous membranes.

Petechiae and purpura are especially characteristic.

Epistaxis, gastrointestinal bleeding, and heavy menstrual bleeding may occur.

Slide 16 · Why the mucosa bleeds readily

Tiny capillary defects normally depend on rapid platelet sealing.

Minor capillary injury

Delayed seal

Mucosal bleeding

Minor trauma can rupture small vessels in skin or mucosa.

Platelets normally occlude these openings almost immediately.

An impaired early plug allows visible punctate or mucosal bleeding.

Slide 17 · Von Willebrand factor bridges adhesion

The platelet–subendothelial interface is central to primary hemostasis.

Exposed collagen

VWF bridge

Platelet

GpIb

Exposed subendothelial vWF supports platelet attachment.

Platelet GpIb engages vWF, especially under high shear.

Deficiency of vWF disrupts early adhesion and promotes bleeding.

Slide 18 · Inherited vWF defects can be clinically subtle

A mild bleeding tendency may be recognized only after hemostatic challenge.

Inherited adhesion defect

Challenge-related bleed

Inherited vWF defects as common mild causes.

Typical symptoms fit a mucocutaneous bleeding pattern.

A procedure-related history can be more informative than appearance at rest.

Slide 19 · Aspirin can impair primary hemostasis

An acquired platelet-related exposure belongs in the bleeding history.

Aspirin exposure

Platelet dysfunction

Bleeding tendency

Aspirin consumption is a textbook example of a mild bleeding tendency.

Manifestations may be revealed during mucosal injury or procedures.

The same bleeding pattern may arise without an inherited disorder.

Slide 20 · Uremia causes acquired platelet dysfunction

Renal failure may impair platelet adhesion and aggregation.

Uremia

Adhesion / aggregation↓

Bleeding

The defect concerns platelet performance, not only platelet number.

Adhesion and aggregation are the functions explicitly affected.

Bleeding in a patient with renal failure merits this mechanism in the differential.

Slide 21 · Platelet function and platelet count are different

Mucocutaneous hemorrhage can reflect qualitative or quantitative platelet abnormalities.

Functional impairment

Reduced platelet count

Aspirin and uremia are examples of impaired platelet activity.

Thrombocytopenia denotes decreased circulating platelet count.

Severely low counts carry risk of intracranial bleeding.

Slide 22 · Petechiae: Pinpoint extravasation

The textbook defines petechiae as minute hemorrhages of 1–2 mm.

Petechiae

They are typically seen on skin or mucosal surfaces.

Their size and multiplicity reflect small-vessel leakage.

They are a classic clue to a primary-hemostatic defect.

Slide 23 · Petechiae connect morphology to mechanism

Failure to seal numerous minute capillary defects yields scattered puncta.

Microinjury

Insufficient platelet seal

Petechiae

Minor vessel trauma occurs routinely in superficial tissues.

Rapid platelet plugs ordinarily prevent sustained red-cell escape.

A primary-hemostatic defect makes these sites clinically conspicuous.

Slide 24 · Purpura: Larger superficial hemorrhages

Purpura are slightly larger than petechiae, approximately ≥3 mm in the source.

Petechiae versus purpura

Both terms describe extravasated blood rather than a cause.

The classification is morphologic: Size alone is not etiologic diagnosis.

Palpability adds a separate clue toward vascular pathology.

Slide 25 · Bleeding vocabulary is not interchangeable

Record both lesion size and its physical character.

1–2 mm • petechiae

≥3 mm • purpura

1–2 cm • ecchymoses

Petechiae: 1–2 mm pinpoint hemorrhages.

Purpura: Larger hemorrhagic macules, around 3 mm or greater.

Ecchymoses: Typically 1–2 cm bruises description.

Slide 26 · Epistaxis reflects a mucosal bleeding phenotype

Recurrent nosebleeds can point toward defective primary hemostasis.

Nasal capillary injury

Plug defect

Epistaxis

Nasal mucosa contains fragile superficial capillary networks.

Platelet plug defects impair rapid sealing after minor disruption.

Epistaxis should be interpreted alongside skin and menstrual symptoms.

Slide 27 · Gastrointestinal bleeding is not mechanism-specific

The bleeding site must be interpreted together with other findings.

Systemic hemostasis defect

Local bleeding lesion

Primary-hemostatic disorders can present with gastrointestinal bleeding.

A structural gastrointestinal lesion can also be the source of blood loss.

Chronic gastrointestinal blood loss may deplete body iron.

Slide 28 · Menstrual blood loss is a useful clinical signal

Heavy menstrual bleeding may expose a mild bleeding tendency.

Hemostatic stress

Excess blood loss

Iron depletion

Menstruation imposes recurrent hemostatic demand.

Bleeding can reflect platelet or vWF-related dysfunction.

If recurrent, iron loss may culminate in deficiency anemia.

Slide 29 · Severe thrombocytopenia changes the risk profile

The consequence of platelet deficiency is not always superficial.

Visible skin bleeding

Occult critical-site bleeding

Petechiae may coexist with clinically dangerous hemorrhage.

Intracerebral bleeding is a feared complication of very low platelet counts.

Therefore, small cutaneous lesions cannot alone establish low severity.

Slide 30 · Primary hemostasis: Integrate the clues

A constellation is more useful than any single symptom.

Morphology

Distribution

Etiologic context

Petechiae or nonpalpable purpura point to superficial microvascular leakage.

Epistaxis and excessive menstruation strengthen a mucosal pattern.

Medication exposure, renal disease, and inherited vWF defects suggest mechanisms.

Slide 31 · Secondary hemostasis defects compromise fibrin

A weakly reinforced clot is associated with deep bleeding.

Coagulation defect

Insufficient fibrin

Deep bleeding

Coagulation factors generate thrombin and fibrin following injury.

A factor defect limits consolidation of the platelet plug.

Bleeding may involve muscles, soft tissues, and joints.

Slide 32 · Tissue factor initiates physiologic coagulation

The source emphasizes injury-associated coagulation initiation in vivo.

Tissue factor

Factor activation

Thrombin

Fibrin

Disrupted tissues expose membrane-associated tissue factor.

The tissue factor–factor VII pathway drives thrombin generation.

Thrombin cleaves fibrinogen to insoluble fibrin.

Slide 33 · Factor deficiencies explain inherited deep bleeding

Hemophilias are examples of coagulation-factor disorders.

Inherited factor defect

Reduced stable fibrin

Severe bleeding

Factor deficiencies are usually inherited.

Without treatment, severe factor deficiencies can cause major hemorrhage.

A deep-tissue phenotype is particularly informative.

Slide 34 · Why platelet plugs alone may be insufficient

A provisional capillary seal cannot always maintain durable hemostasis.

Primary plug

Fibrin reinforcement

Durable seal

Platelets arrest bleeding rapidly after injury.

Fibrin polymerization reinforces and stabilizes the plug.

When clotting factors fail, ongoing or recurrent tissue bleeding can follow.

Slide 35 · Soft-tissue hemorrhage indicates a different pattern

Bleeding within deep tissues suggests a factor-mediated deficit.

Superficial petechiae

Deep soft tissue

The source specifically names soft tissues and muscle.

Deep bleeding contrasts with the usual superficial petechial phenotype.

Location is suggestive, not a definitive biochemical assay.

Slide 36 · Muscle hemorrhage can be substantial

Deep muscle compartments can contain blood not visible at the skin.

Deep tissue bleeding

Blood accumulation

Clinical effect

Coagulation-factor defects are associated with muscular bleeding.

A localized collection may become a hematoma.

Clinical significance depends on the volume, rate, and location.

Slide 37 · Hemarthrosis: A characteristic hemophilia clue

Bleeding into a joint following minor trauma is especially characteristic.

Blood in joint space

Schematic

The clinical name is hemarthrosis.

Hemophilia exemplifies a secondary-hemostatic factor deficiency.

A joint-centered symptom pattern prompts a factor-defect hypothesis.

Slide 38 · Why do factor defects favor joints?

A characteristic pattern need not imply a settled mechanistic explanation.

Observed phenotype

Mechanism uncertain

Hemarthrosis as distinctive in hemophilia.

The precise reason for this distribution is stated to be unknown.

Do not teach a speculative explanation as an established causal pathway.

Slide 39 · Intracranial hemorrhage crosses categories

Severe platelet and factor disorders can both cause fatal intracranial bleeding.

Platelet disorder

Factor disorder

Platelet defects usually present superficially but can become critical.

Coagulation-factor defects often bleed deeply but can also involve the brain.

Site and severity must be considered separately from typical phenotype.

Slide 40 · Primary versus secondary: Phenotype comparison

The most useful distinction is mucocutaneous versus deep bleeding.

Primary hemostasis

Secondary hemostasis

Primary: Petechiae, purpura, epistaxis, heavy menstruation.

Secondary: Hemarthrosis, muscular and other soft-tissue hemorrhage.

Both: Potentially life-threatening intracranial hemorrhage.

Slide 41 · Clinical patterns guide rather than prove

Phenotypic overlap limits any one-feature diagnostic conclusion.

Pattern

Context

Mechanism

Purpura may accompany platelet defects or vessel-wall disease.

Intracranial bleeding can complicate either primary or secondary defects.

Clinical history and underlying cause are required for classification.

Slide 42 · Small-vessel disease forms a third pathway

Abnormal vascular structure can permit extravasation even with platelets present.

Vasculitis

Amyloidosis

Scurvy

Generalized small-vessel abnormalities produce palpable purpura.

Ecchymoses are also characteristic.

Examples include vasculitis, amyloidosis, and scurvy.

Slide 43 · Palpable purpura implicates vessel pathology

Texture provides diagnostic information beyond hemorrhagic diameter.

Palpable purpura

The source connects palpable purpura with generalized small-vessel defects.

Palpability distinguishes it from flat hemorrhagic macules.

It supports investigation of vessel damage or fragility.

Slide 44 · Ecchymoses: Visible bruising

The textbook uses approximately 1–2 cm for ecchymotic lesions.

Ecchymosis

Blood has escaped into soft tissues, producing a patch of discoloration.

Ecchymoses may accompany vessel-wall pathology.

The appearance itself does not identify the specific underlying disease.

Slide 45 · A hematoma is a localized collection of blood

The quantity of extravasation can produce a palpable mass.

Extravasation

Local accumulation

Hematoma

Blood accumulating in tissue may create a discrete collection.

The term describes a physical consequence, not a specific etiology.

Hematomas can accompany hemorrhages of several mechanisms.

Slide 46 · Vasculitis injures small-vessel walls

Inflammatory vascular injury is a mechanism of hemorrhagic lesions.

Vascular inflammation

Wall disruption

Palpable purpura

Vasculitis among small-vessel disorders.

Damaged vessels can permit red-cell escape into tissues.

Palpable purpura is a characteristic clinical clue.

Slide 47 · Amyloidosis is an example of vessel fragility

Fragile vessels may bleed with otherwise modest mechanical challenge.

Amyloidosis

Vessel fragility

Cutaneous hemorrhage

Amyloidosis as a cause of vessel-wall fragility.

The resulting phenotype may include purpura or ecchymoses.

Vascular structural pathology must remain in the differential.

Slide 48 · Scurvy illustrates noncoagulation bleeding

Tissue fragility is another mechanism of spontaneous bruising.

Scurvy

Vessel fragility

Purpura / bruising

Scurvy is specifically listed among vessel-fragility disorders.

Purpura and ecchymoses may occur from small-vessel weakness.

An abnormal skin phenotype does not always signal a platelet defect.

Slide 49 · Interpret three superficial lesion forms

Morphology combines scale, distribution, and palpability.

Petechiae

Purpura

Ecchymoses

Petechiae are pinpoint; Purpura are larger.

Ecchymoses are broader areas of extravasation.

Palpable purpura particularly raises suspicion of vessel-wall disease.

Slide 50 · Mechanism-oriented bedside classification

Combine lesion type with the compartment in which bleeding occurs.

Mucocutaneous

Deep compartments

Small vessel

Punctate mucocutaneous hemorrhage: Start with primary hemostasis.

Deep joint or muscle hemorrhage: Start with factor-mediated hemostasis.

Palpable purpura / ecchymoses: Consider small-vessel abnormalities.

Slide 51 · Three variables govern the harm of bleeding

Clinical impact depends on volume, rate, and anatomical site.

Volume

Rate

Location

Large total blood loss can threaten circulating volume.

Rapid hemorrhage may outpace physiologic compensation.

Small bleeds in confined vital sites may be catastrophic.

Slide 52 · Volume and rate must be considered together

The same volume is more dangerous when lost abruptly.

Limited loss

Greater rapid loss

Hypovolemic shock

Rapid loss up to 20% may have little impact in healthy adults.

Greater losses can cause hemorrhagic (hypovolemic) shock.

The statement is contextual, not an individual resuscitation threshold.

Slide 53 · Hemorrhagic shock is a perfusion failure

A sufficiently large rapid loss compromises blood circulation.

Major blood loss

Reduced circulation

Tissue hypoperfusion

Shock

Circulating blood volume falls with major hemorrhage.

Systemic tissue perfusion may then be inadequate.

This is the pathway to hypovolemic shock described in the source.

Slide 54 · Location can dominate over visible volume

The skull transforms a local hemorrhage into a neurologic emergency.

Subcutaneous site

Intracranial site

A small subcutaneous collection may have limited consequences.

An intracranial bleed can be fatal despite a smaller volume.

The rigid skull constrains expansion.

Slide 55 · Intracranial hemorrhage raises pressure

An unyielding compartment magnifies the effect of added blood.

Rigid skull + bleeding

Rising pressure

Reduced perfusion

Schematic

Extravasated blood occupies space within the cranial vault.

Intracranial pressure may rise as volume accumulates.

Pressure elevation can impair the brain’s circulation.

Slide 56 · Reduced cerebral blood supply compounds injury

Hemorrhage can harm tissue beyond the local collection.

Intracranial bleed

↑ Pressure

↓ Perfusion

Brain injury

Rising intracranial pressure threatens cerebral perfusion.

Compromised blood supply adds an ischemic mechanism.

Thus the clinical danger extends beyond the bleeding focus.

Slide 57 · Brainstem herniation is a fatal pathway

Critical mass effect can displace brain tissue across intracranial partitions.

Hemorrhage

Mass effect

Brainstem herniation

Brainstem herniation as a possible consequence.

The initiating event is intracranial pressure from accumulating blood.

This explains the danger of bleeding into a constrained compartment.

Slide 58 · External blood loss depletes iron

Loss of red cells from the body removes their iron from recycling.

External blood loss

Net iron loss

Iron deficiency

Anemia

Chronic or recurrent external hemorrhage can produce iron deficiency.

Peptic ulcer bleeding and excessive menstrual bleeding are examples.

Over time, iron loss can culminate in iron deficiency anemia.

Slide 59 · Peptic ulcer bleeding can act cumulatively

Repeated gastrointestinal loss may be more important than a single dramatic bleed.

Recurrent ulcer bleeding

Ongoing iron loss

Deficiency anemia

The source identifies peptic ulcer hemorrhage as a chronic external loss.

Repeated loss removes hemoglobin-bound iron from the body.

A chronic anemia phenotype can therefore accompany a bleeding disorder.

Slide 60 · Menstrual hemorrhage can impair iron balance

Repetition of a moderate loss may produce a systemic consequence.

Recurrent menses

Iron loss

Iron deficiency anemia

Excessive menstrual bleeding is a hemostatic stress presentation.

Repeated external red-cell loss creates cumulative iron depletion.

This explains a pathway to iron deficiency anemia.

Slide 61 · Internal hemorrhage has a different iron fate

Retained extravasated red cells can be broken down and recycled.

External: Iron exits

Internal: Iron retained

Bleeding into tissues or body cavities retains red cells within the body.

Their iron is ordinarily recovered for later hemoglobin synthesis.

This contrasts with chronic blood escaping to the exterior.

Slide 62 · Blood loss and iron loss are not synonyms

Different bleeding locations can have different hematologic consequences.

Immediate consequence

Long-term consequence

Major internal bleeding may be immediately life-threatening by volume.

Chronic external bleeding removes iron from physiologic circulation.

Assessment must distinguish acute hemodynamic injury from iron depletion.

Slide 63 · Clinical vignette: Pinpoint lesions and epistaxis

Hypothetical presentation: Recurrent nosebleeds with scattered petechiae.

Clinical reasoning — hypothetical vignette

Petechiae

Epistaxis

The cutaneous lesions are small and superficial.

The associated bleeding is mucosal.

Which arm of hemostasis is most strongly suggested?

Slide 64 · Vignette reasoning: Early plug failure

The combined distribution favors a primary-hemostatic mechanism.

Pattern

Primary hemostasis

Etiologic context

Petechiae suggest small-vessel leakage not immediately sealed.

Mucosal bleeding strengthens the platelet/vWF pattern.

Consider inherited vWF defects, drugs, uremia, or low platelet count.

Slide 65 · Clinical vignette: Bleeding into a knee

Hypothetical presentation: Joint swelling after minor trauma.

Clinical reasoning — hypothetical vignette

Minor trauma

Hemarthrosis

The primary abnormality is blood accumulation in a joint.

No petechial eruption is described.

Which hemostatic mechanism does this pattern prioritize?

Slide 66 · Vignette reasoning: Suspect factor deficiency

Hemarthrosis is characteristically associated with hemophilia.

Coagulation defect

Deep joint bleeding

Hemarthrosis

Joint bleeding is a deep-compartment phenotype.

A defect in secondary hemostasis weakens fibrin reinforcement.

The textbook cautions that its distinctive joint predilection is unexplained.

Slide 67 · Clinical vignette: Raised hemorrhagic lesions

Hypothetical presentation: Palpable purpura with ecchymoses.

Clinical reasoning — hypothetical vignette

Palpable purpura

Ecchymoses

The rash is hemorrhagic and palpably elevated.

The lesions coexist with broader bruises.

Which pathology compartment becomes particularly important?

Slide 68 · Vignette reasoning: Investigate vessel walls

The morphology points toward small-vessel injury or fragility.

Vessel wall

Injury

Fragility

Palpability is a useful clue to vascular-wall disease.

Vasculitis is one textbook example of vessel injury.

Amyloidosis and scurvy are examples of vessel fragility.

Slide 69 · Clinical vignette: Recurrent silent blood loss

Hypothetical presentation: Repeated gastrointestinal bleeding and anemia.

Clinical reasoning — hypothetical vignette

GI bleeding

Repetition

Anemia

The source of blood loss is external to the body's iron economy.

Repeated episodes may be less dramatic than a single large hemorrhage.

What accounts for the progressive anemia?

Slide 70 · Vignette reasoning: Progressive iron depletion

Recurrent external hemorrhage removes iron as well as blood.

Recurrent bleeding

Iron depletion

Deficient hemoglobin synthesis

Anemia

Red-cell iron is not recoverable after blood exits the body.

Continued depletion limits hemoglobin production.

Iron deficiency anemia is the textbook consequence.

Slide 71 · Integrative decision map

Begin with distribution, then test the most plausible mechanism.

Skin + mucosa

Joint + muscle

Palpable purpura

Mucocutaneous puncta → platelet/vWF pathway.

Joint/muscle bleeding → coagulation-factor pathway.

Palpable purpura/ecchymoses → vessel-wall pathway.

Slide 72 · Risk assessment uses a separate axis

Cause of bleeding and consequence of bleeding are different questions.

Etiology

Immediate hazard

Cumulative effect

Mechanism: Vessel wall, platelet plug, or coagulation factors.

Immediate hazard: Rate, magnitude, and location.

Long-term consequence: External iron loss and deficiency anemia.

Slide 73 · Five clinicopathologic principles

The most consequential distinctions connect mechanism to anatomy.

Mucocutaneous puncta suggest impaired primary hemostasis.

Muscle and joint bleeding suggest impaired secondary hemostasis.

Palpable purpura suggests small-vessel pathology.

Intracranial bleeding may be fatal even when total volume is modest.

Chronic external blood loss can lead to iron deficiency anemia.